Sustainable metal catalysis in CH activation

Accepted Manuscript Review Sustainable Metal Catalysis in C-H Activation Nikolaos V. Tzouras, Ioannis K. Stamatopoulos, Argyro T. Papastavrou, Aggeliki Liori, Georgios C. Vougioukalakis PII: DOI: Reference:

S0010-8545(17)30021-8 http://dx.doi.org/10.1016/j.ccr.2017.04.012 CCR 112447

To appear in:

Coordination Chemistry Reviews

Received Date: Accepted Date:

17 January 2017 14 April 2017

Please cite this article as: N.V. Tzouras, I.K. Stamatopoulos, A.T. Papastavrou, A. Liori, G.C. Vougioukalakis, Sustainable Metal Catalysis in C-H Activation, Coordination Chemistry Reviews (2017), doi: http://dx.doi.org/ 10.1016/j.ccr.2017.04.012

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Sustainable Metal Catalysis in C-H Activation Nikolaos V. Tzouras, Ioannis K. Stamatopoulos, Argyro T. Papastavrou, Aggeliki Liori, Georgios C. Vougioukalakis* Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece Corresponding Author *

phone, +30 210 7274230; fax, +30 210 7274761; email, [email protected]

CONTENTS 1. INTRODUCTION 2. MAGNESIUM 3. CALCIUM 4. MANGANESE 4.1. Introduction 4.2. Directing group assisted C(sp2)-H activation 4.3. Activation of C(sp)-H bonds in terminal alkynes 4.4. Carbene insertion into C(sp2)-H bonds 5. IRON 5.1. Introduction 5.2. C(sp3)-H activation 5.3. C(sp2)-H activation 5.3.1. Arylation of C(sp2)-H bonds 5.3.2. Cyanation of C(sp 2)-H bonds 5.3.3. Borylation of C(sp2)-H bonds 5.3.4. Amination of C(sp2)-H bonds 5.3.5. Thiolation of C(sp2)-H bonds 5.3.6. Allylation of C(sp2)-H bonds

1

5.3.7. Alkylation of C(sp2)-H bonds 5.3.8. Alkynylation of C(sp2)-H bonds and cyclization reactions 5.4. C(sp)-H activation 6. COPPER 6.1. Introduction 6.2. C-X bonds formation through C-H activation 6.2.1. C-C bond formation reactions 6.2.2. C-N bond formation reactions 6.2.3. C-O bond formation reactions 6.2.4. C-P bond formation reactions 6.2.5. C-S bond formation reactions 6.2.6. C-Se bond formation reactions 6.3. Cross-dehydrogenative coupling reactions 6.4. Sonogashira coupling 6.5. Homocoupling of terminal alkynes 6.6. Carboxylation of terminal alkynes 6.7. Miscellaneous transformations of terminal alkynes 6.8. Multicomponent reactions 6.9. Arylation reactions 6.10. Alkynylation reactions 6.11. Alkenylation-synthesis of allenes 6.12. Alkylation reactions 6.13. Allylation reactions 6.14. C-H amination 6.15. Triazoles in copper-catalyzed C-H activation 7. ZINC 7.1. Introduction 2

7.2. Addition of terminal alkynes to C=N, C=O or C=C bonds 7.3. Installation of C(sp)-X bonds (X = Si, Sn) 8. CONCLUSIONS AND OUTLOOK 9. ACKNOWLEDGEMENTS 10. REFERENCES

ABSTRACT The omnipresence of C-H bonds in organic compounds renders them highly attractive targets for the installation of functional groups towards the construction of valuable molecular scaffolds. Consequently, C-H activation has extended beyond scientific curiosity and has evolved from being a concept of fundamental interest to constituting an important, modern tool of organic synthesis. The intensity of research efforts and accompanying discussion surrounding this topic has given rise to a plethora of innovative, cutting-edge advancements. These advancements demonstrate the vast potential of the C-H activation approach regarding the design of highly efficient and selective catalytic methodologies for the synthesis of fine chemicals, natural products, and advanced materials. However, the overall sustainable nature of this approach, emanating from some of its main attributes such as atom- and stepeconomy, is compromised by the frequent need of homogeneous catalysts based on rare, expensive, and even toxic noble transition metals. In order to address this issue and achieve truly sustainable catalytic C-H activation, significant research efforts have focused on the development of homogeneous catalytic systems based on more abundant, first row transition metals. In this respect, various catalytic protocols involving the use of highly abundant, inexpensive, readily available, and also biorelevant metals such as Mg, Ca, Mn, Fe, Cu, and Zn have been elegantly developed in recent years. Catalysts based on the aforementioned sustainable metals exhibit unique behavior in terms of reactivity/selectivity and their use does not only provide an alternative to noble metal catalysis, but also expands the scope of C-H 3

activation. The present review provides a comprehensive examination of selected works that highlight the evolution and growing importance of this merge of two vibrant concepts in modern organic synthesis: sustainable metal catalysis and C-H activation. Keywords Homogeneous catalysis; Organometallic catalysis; Sustainable metal catalysis; C-H activation; Functionalization; Organic synthesis, Metal complexes; Magnesium; Calcium; Manganese; Iron; Copper; Zinc 1. INTRODUCTION Sustainability, efficiency and selectivity are among the most paramount foundations upon which modern organic synthesis has been built. The activation of inert and ubiquitous C-H bonds, apart from being a fundamentally interesting concept, has emerged as a powerful strategy for the design and development of sustainable synthetic procedures [1-3]. The ability of homogeneous catalysts to circumvent the need for extreme reaction conditions and obviate the employment of highly reactive reagents in order to selectively functionalize stable C-H bonds has sparked a cascade of innovative advancements in recent years [4-16]. In conjunction with the increasing mechanistic understanding with regards to the modes of action of transition metal catalysts in such transformations [17-23], which enables the rational design of improved catalytic systems, C-H activation has extended beyond scientific curiosity. Valuable synthetic aspects of this approach are not limited to high efficiency, stepand atom-economy, and selectivity, allowing for its utilization in late-stage diversification procedures [24], natural product synthesis [25], and towards the construction of advanced materials [26-28]. However, the field of catalytic C-H activation has been undisputedly dominated by homogeneous catalysts based on rare, expensive, and often toxic noble

4

transition metals such as ruthenium, rhodium, palladium, rhenium, iridium, and platinum [18, 29-39], a fact that compromises its sustainable nature. Even though sustainability is to a certain extent achieved by carrying out C-H activation processes under mild conditions [40, 41], efforts towards the development of catalysts based on inexpensive and abundant first row transition metals have lately increased significantly [42-47]. More importantly, the vibrant and highly promising concept of sustainable catalysis [48] has been integrated with C-H activation as well, with metals such as Mg, Ca, Mn, Fe, Cu and Zn, which are not only inexpensive and readily available, but also exhibit low toxicity and are omnipresent in biological systems, having found ample use. It should be noted, however, that the subject of toxicity is rather complicated and does not solely depend on the nature of the metal. Thus, even though the aforementioned metals are in general less toxic than their noble metal counterparts, factors such as their concentration, the ligand(s) used and the other characteristics of the catalytic systems should be considered when examining toxicity. A considerably large number of homogeneous catalytic protocols involving catalysts based on these metals have been elegantly developed through the years and this area has traversed a phase of evolution, so as to currently constitute a vital subfield of C-H activation. Magnesium and calcium are both among the most abundant metals in earth’s upper continental crust, being absolutely indispensable for the function of biological systems [48]. As anticipated, the inexpensive and sustainable nature of these metals has led to their widespread use in chemical processes, although new aspects of their chemistry have recently begun to surface [48, 49]. As both are alkaline earth metals, they often exhibit similar chemical behavior and catalytic activity. Their coordination compounds are redox-inactive d0 complexes and can act as Lewis acids, while mostly calcium has often been compared to the trivalent lanthanides on account of its ability to participate in σ-bond metathesis and insertion reactions [49, 50]. The use of magnesium-based compounds as stoichiometric reagents is well 5

known, even for C-H functionalization reactions [51, 52]. Within the past decade, exciting new findings regarding the action of magnesium-based catalysts in catalytic 1,5-hydride transfer/ring closure processes through C(sp3)-H activation have arisen, and have been thoroughly discussed [8, 53-55]. Organometallic reagents based on calcium have been used for C-H activation procedures as well, albeit more rarely [56, 57]. To date, a number of catalytic protocols employing magnesium- and calcium-based catalysts for the construction of valuable molecular scaffolds through C-H activation have been described and will be presented herein. Manganese and iron are both highly abundant transition metals with rich coordination chemistry. Moreover they are well known for their imperative function in biological processes of fundamental importance for life on earth [48]. Naturally, the remarkable ability of heme-containing cytochrome P450 enzymes to efficiently facilitate the selective activation and oxygenation of inactive C(sp3)-H bonds of various hydrophobic compounds has served as inspiration for the design of biomimetic complexes based on iron and also manganese, as well as their use as catalysts for C-H oxidation reactions [58-61]. These non-heme, metalloporphyrin or salen-type complexes operate via an outer sphere, hydrogen abstraction and heteroatom recombination mechanism involving high-valent oxo-metal species and have been a topic of intense research and discussion. Manganese carbonyl complexes have also been known to participate in C-H activation reactions for decades [62]. Catalytic protocols in which the manganese catalyst displays an organometallic mode of action have recently begun to emerge at an impressive rate and have received increasing interest [61-64]. Iron, on the other hand, is the most abundant and environmentally benign transition metal and aside from its historic use in the general field of catalysis, it has been proven to be of immense importance for catalytic, organic transformations [65]. Apart from the use of iron in bioinspired catalysts for C-H activation, significant advancements have been recently made with 6

regards to the integration of iron-catalysis into the C-H activation platform [66-68]. A plethora of useful C-H transformation reactions facilitated by iron-based complexes have been reported in which iron exhibits diverse behavior and will be discussed in the present work. Copper and zinc are also known for their relatively low toxicity and wide availability, while their action in biological systems is essential for most life forms and is well understood [48]. The efficacy and versatility of copper-based catalysts in the field of C-H activation thus far render copper the most important among the sustainable metals that will be discussed in this review [69-76]. Unambiguously, the vast number of diverse C-H functionalization transformations that can be achieved through copper-catalysis, often under mild and environmentally benign conditions, showcase this metal’s potential as a sustainable and efficient alternative to noble metal-catalysis. Due to the large amount of review articles in this field, only selected representative examples that have not been extensively or previously reviewed will be discussed herein. The field of zinc catalysis has also become increasingly important as a modern tool for organic synthesis [77]. Among their numerous applications, zinc-based catalysts have found notable use in the transformation of alkynes [78]. Importantly, the field of zinc-catalyzed reactions involving the in situ generation of zincacetylides from terminal alkynes has progressed steadily through the years, resulting in the development of interesting C(sp)-H functionalization protocols. Our research group is deeply interested in sustainable catalytic methodologies for useful organic transformations [79]. In this context, the purpose of the present review is the compilation, accurate presentation and thorough discussion of the vast majority of research works that have contributed to the field of catalytic C-H activation with the use of catalysts based on the aforementioned sustainable metals. Catalytic C-H activation has thus far had tremendous impact on contemporary organic synthesis, with the use of sustainable metals 7

having witnessed exponential growth in recent years and thus being expected to advance even further in the future. To the best of our knowledge, a comprehensive review article gathering past and present advancements regarding the applications of these six sustainable metals in catalytic C-H activation processes is currently missing from the literature and could potentially trigger novel research through provision of added insight and combinatory analysis. The main focus of our present work is on homogeneous catalytic C-H activation/functionalization reactions, in which the metal catalysts operate via an organometallic mode of action, with the metal center actively participating in the C-H activation step of the corresponding mechanisms, which are discussed when appropriate. Nonetheless, selected examples that do not fit this description perfectly may also be found herein, as they were deemed important for our discussion regarding the chemical behavior of these metals and accurate portrayal of the field under examination. On this basis, the works presented and discussed herein are those contributing to the field of sustainable metal catalysis towards C-H activation until February 2017. 2. MAGNESIUM Besides the use of Knochel-Hauser bases for directed C-H metalation reactions [51], as well as the use of magnesium carbenoids for C-H insertion reactions [52], examples of magnesium-based compounds participating in C-H activation were scarce until 2012. Recently, interesting protocols have emerged, involving magnesium-based coordination and organometallic compounds in challenging and useful catalytic C-H activation reactions. As expected, the nature of the ligands on the magnesium-based catalyst is of utmost importance and the development of these novel catalysts sets the stage for interesting future advancements.

8

Until recently, the development of methods leading to C-H activation by magnesiumbased catalysts remained an unmet challenge. In 2012, Kanai, Matsunaga and co-workers reported the development of a magnesium-catalyzed enantioselective benzylic C-H bond functionalization of isoindolinones, which represent an important structural motif in various natural products and biologically active compounds [80]. Specifically, after ligand and metal-source screening, it was found that the catalytic system with Schiff base 1e (Figure 1) facilitates the enantioselective addition of N-Bocisoindolinones to aryl, heteroaryl, alkenyl and enolizable alkyl imines, affording 3-substituted isoindolinones (4, Scheme 1) in 64-95% yield, 84-99% ee and 50:50-91:9 d.r. Ligand screening revealed that ortho- and para-MeO substitution in Schiff base 1 is crucial for both reactivity and selectivity. Schiff base 1e proved to be superior with regards to reactivity and enantioselectity than 1a and the authors suggested that this is possibly due to a difference in the Brønsted basicity of the Mg-aryloxide species.

Figure 1. Structures of Schiff bases 1a-1e, N–Boc-isoindolinones 2a-2d and 2thiophenesulfonyl imines 3 [80]. In general, 10 mol% catalyst loading yielded the best results, although in the case of isoindolinone 2a and cyclohexylmethanimine 3i it was successfully reduced to 5 mol% without compromising yield and stereoselectivity. In all cases, high enantioselectity was 9

observed, while diastereoselectivity depended mainly on the imine structure, with imines 3e3h giving poor to moderate diastereoselectivity.

Scheme 1. Mg-catalyzed enantioselective addition of isoindolinones 2 to imines 3 [80]. It is important to note that the reaction between 2a and 3i gave excellent results, highlighting the fact that the catalyst displays chemoselectivity towards the activation of the benzylic C-H bond of the isoindolinone, while suppressing the isomerization of the imine to the corresponding enamide. Also, for imines that gave poor diastereoselectivity, each diastereomer was produced in high enantioselectity. More

recently,

Tsurugi,

Mashima,

and

co-workers

discovered

that

dimeric

organomagnesium complex 5 (Scheme 2) can be utilized as an efficient precatalyst for the organomagnesium catalyzed isomerization of terminal alkynes to allenes and subsequently to internal alkynes. C-H activation plays a vital role in both processes and the reactions described fall into the category of temporally separated autotandem catalysis, because of their subsequent occurrence on a macroscopic level [81]. Terminating the reaction after the first cycle results in the formation of the corresponding allene (7), while the corresponding internal alkyne (9) can be obtained after the second cycle is completed, without any external intervention. Initially, it was observed that use of complex 5 (2 mol%) resulted in the almost complete transformation of 6a to 7a (>95% yield) in 9.5 hours at 60 oC and that maintaining the 10

reaction mixture at the same temperature afforded the corresponding internal alkyne (9a) after 5 days. Optimization studies revealed that complex 5 was the most efficient precatalyst among all magnesium complexes that were screened for this reaction. This was due to the critical effect of the bidentate secondary amine-based ligand regarding the generation of the catalytically active species (I, Scheme 3), via deprotonation of the terminal alkyne and tautomerization of the alkynyl-magnesium species, by increasing the polarity of the Mg-C bond. An increase in catalyst loading and reaction temperature led to significant decrease in reaction time (t1= 4 hours and t2= 30 hours for 6a) without severely compromising product yield (Scheme 2).

Scheme 2. Organomagnesium catalyzed isomerization of terminal alkynes to allenes and internal alkynes [81]. With the optimal conditions in hand, a range of substrates were successfully transformed into the corresponding allenes and internal alkynes as shown in Scheme 2. Nonbenzylic 11

alkynes showed low to no reactivity, while the rate of isomerization of electron-poor benzylic alkynes to allenes was much faster than in the case of electron-rich benzylic alkynes. The rates of isomerization of the allenes to internal alkenes were similar for all substrates (t2= 1137 hours). Ph

6a (2 eq)

Me2N

N

R Ph

6a (>2 eq)

Mg

Mg

5

Ph

R

N

Me2N Mg

NMe2

7a

I

Ph

10

N R H R'

Ph H

R= CH(Ph)CH2Ph R'= alkynyl, allenyl, propargyl

1,3-H

First Cycle

Ph Me2N

9a

II

Ph

N R Mg H R'

[Mg] Ph

Ph Ph

Second Cycle

H

6a

1,3-H

[Mg] Me2N

Ph

Me2N

N R Mg H R'

[Mg]=

N R Mg H R'

III Ph Ph 7a

Scheme 3. Proposed mechanism for the temporally separated autotandem isomerization of phenylpropyne (6a) to phenylallene and 1-phenyl-1-propyne, with the use of magnesiumbased precatalyst 5 [81]. The mechanism shown in Scheme 3 was proposed for this transformation. The key intermediates (I, II and III) are in equilibrium through 1,3-hydride shifts and are formed by the treatment of 5 with an excess of 6a through the initial formation of complex 10. Both products are formed through four-membered transition states (σ-bond metathesis) and the

12

temporal separation of the two isomerization steps is caused by 6a, which acts as an acid releasing 7a without any further isomerization [81]. 3. CALCIUM Although stoichiometric examples of C-H activation involving calcium have been disclosed decades ago, the development of catalytic protocols of high practical potential took place much more recently. Herein, interesting works that highlight the evolution of calciumbased C-H activation systems will be presented and discussed. Even though currently there are a limited number of studies in this field, the use of inexpensive and environmentally benign calcium complexes as catalysts for useful transformations is an attractive strategy that is expected to find ample future use. The activation and subsequent functionalization of typically inert C-H bonds by the use of calcium was reported in two separate publications by Mochida and coworkers [82, 83]. In the context of metal-vapor reaction studies, it was found that calcium atoms insert into C-H bonds of aromatic, heterocyclic, and alicyclic compounds to afford the corresponding organocalcium

hydrides.

The

organometallic

reagents

thus

produced

reacted

with

trimethylchlorosilane to give trimethylsilyl-sustituted products and trimethylsilane (Scheme 4). Arylcalcium hydrides also reacted with various organic substances to afford arylsubstituted substrates and reduced substrates [83].

Scheme 4. Insertion of calcium atoms into C(sp2)-H and C(sp3)-H bonds and reaction of the corresponding organometallic hydrides with trimethylchlorosilane [82, 83].

13

According to the authors, in the cases of aromatic and heterocyclic substrates, selective CH activation by calcium atoms may depend on the spin densities of the corresponding anion radicals, which were detected by ESR (electron spin resonance). Although the previously described process is neither catalytic nor sustainable as extreme conditions are required to generate calcium atoms in the vapor state, it constitutes an early, interesting example of C-H activation by calcium and its utilization in useful organic transformations. The catalytic carboxylation of methane with CO to afford acetic acid almost quantitatively (Scheme 5) was reported by Fujiwara and coworkers [84]. The catalyst used in this system was CaCl2 and after mechanistic studies the authors proposed that the active metal species involved in the rate determining step, which is hydrogen abstraction from methane, is a CaO˙ radical. Therefore, the metal center is not directly involved in the C-H activation step but this catalytic system clearly underlines the growing importance of alkaline earth based homogenous catalysts in C-H activation.

Scheme 5. Optimized conditions for the CaCl2 catalyzed carboxylation of methane with CO [84]. In another work, intramolecular C-H activation in a benzyl-calcium complex (13, Scheme 6) was reported by Harder in 2003 [85]. Upon heating the reaction mixture of homoleptic complexes 11 and 12, the heteroleptic calcium complex 13 was formed first. After one day, the deprotonation of a methyl group in the backbone of the anionic dipp-nacnac ligand (N,N’bis(2,6-diisopropylphenyl)-β-diketiminate) by the benzyl anion led to the formation of the dimeric calcium complex 14 with bridging dipp-nacnac dianions.

14

Scheme 6. Ligand exchange between 11 and 12 to give heteroleptic complex 13 and subsequent formation of 14 [85]. Harder suggests that the previously mentioned deprotonation reaction can be classified as intramolecular C-H activation, cyclometalation, or even as a directed metalation reaction. It is important to note that the twofold deprotonation of the dipp-nacnac ligand is an unusual reaction, which takes place to a limited extent even when a strong base such as nBuLi/KOtBu in THF is used. Also, the reaction between (ortho-Me2N-C6H4)CHSiMe3-K+ and dipp-nacnacK+ does not result in the aforementioned deprotonation. These results suggest that the reaction shown in Scheme 6 can be safely described as C-H activation and that Ca2+ is essential in order for the reaction to take place [85]. More recently, interesting examples of intramolecular C-H bond activation by calcium have emerged, establishing pathways for the synthesis of valuable molecular structures [86], [87] and adding new mechanistic insight [88]. An efficient catalytic system based on Ca(II) was developed by Yaragorla et al. for the C(sp3)-H functionalization of methyl azaarenes (15) [89]. This approach for the synthesis of the biologically significant (E)-2-styryl azaarenes (17), 2-aryl-1,3-bisazaarenes (18), and 3,3-bisazaarenyl indolinones is characterized from solvent-free conditions, substrate diversity, and good to high yields in relatively short reaction times. By changing the reaction conditions, either (E)-2-styryl azaarenes (17) or 2aryl-1,3-bisazaarenes (18) can be obtained selectively, using the same starting materials. 15

When isatin (19) is used as the electrophile, 3,3-bisazaarenyl indolinones are produced (20, Scheme 7). Ca(OTf)2 5 mol% Bu4NPF6 2 mol%

R

130 oC, 4-5 h R

N

R'

R' 17 (62-98%) H H

N

R' CHO

H 15

Ca(OTf)2 5 mol% Bu4NPF6 5 mol%

16

R

CH3CN 100 oC, 10-12 h

15a: R=H (2-methylquinoline) 15b: 16a: R'= H 16b: R'= 4-CH3 16c: R'= 4-NO2 16d: R'= 4-Br N 16e: R'= 4-Cl 15c: 16f: R'= 4-F 16g: R'= 3-CHO N 16h: O CHO 15d: R= Cl (7-chloro-2methylquinoline)

R N

N

18 (78-86%)

16i: 4-hydroxy-3-methoxybenzaldehyde 16j: CHO N O

O

R 2

O

H H

N

N H

H 15a, 15d

19

Ca(OTf)2 5 mol% Bu4NPF6 5 mol%

R

H N

N

CH3CN 100 oC, 24 h

N R

20 (73%, 70%)

Scheme 7. Ca(II)-catalyzed C(sp3)-H activation of methyl azaarenes [89]. The catalyst used in this system is Ca(OTf)2. Optimization studies for the synthesis of (E)2-styryl quinoline revealed that 5 mol% catalyst loading is needed in order to minimize reaction time and maximize product yield. In the absence of Ca(II) catalyst, the reaction resulted in low product yield and proceeded at a significantly lower rate (up to 40% after 24 hours). Although the catalyst alone proved sufficient in promoting this transformation, use of 2 mol% Bu4NPF6 as an additive led to a noticeable decrease in reaction time. Moreover, higher temperature and neat conditions favor the formation of (E)-2-styryl azaarenes. For the synthesis of 2-aryl-1,3-bisazaarenes 5 mol% catalyst loading in acetonitrile at a lower temperature gave the best results. Under the optimized conditions, a wide array of substrate

16

combinations led to various products for both reactions. When lutidine (15c) was used as a substrate, C-H functionalization of both methyl groups was achieved [89]. From a mechanistic perspective, calcium seems to be indirectly involved in the C-H cleavage step, providing the ideal environment for the formation of the active nucleophile I (Scheme 8), through its interaction with the nitrogen atom of quinaldine (15a). According to the proposed mechanism, the catalyst facilitates the formation of intermediate III by activating the electrophile (II, Scheme 8). Intermediate III can either undergo E2 elimination, affording the desired styryl azaarene 17aa, or lead to the formation of a benzylic carbocation (V, Scheme 6). In the next step, intermediate V may again lead to the production of the desired styryl azaarene via E1 elimination, or it may react with nucleophile I to produce the bisazaarene 18aa (SN1 type reaction). The possibility of carbocation formation was what prompted the authors to optimize the reaction conditions towards obtaining bisazaarenes as the main products [89].

17

Scheme 8. Proposed mechanism for the Ca(II) catalyzed C-H functionalization of azaarenes [89]. The same research group also reported the one pot synthesis of azaarenyl benzylpyrazolones (25, Scheme 9) by utilizing the previously described Ca(OTf)2 catalyzed C(sp3)-H functionalization of methyl azaarenes [90]. In this protocol, Ca(OTf)2 is used as the catalyst in 10 mol% catalyst loading, water is used as the solvent and no additive is needed. Therefore, sustainability and step economy in the synthesis of biologically relevant compounds are its main advantages. A variety of azaarenyl benzylpyrazolones (25a-25f) were synthesized under the optimal reaction conditions, while different substitution patterns of the substrates seem to have little to no effect on product yield.

18

Scheme 9. C-H functionalization of methyl azaarenes catalyzed by Ca(OTf)2 as a part of a four component, one pot synthesis of azaarenyl benzylpyrazolones [90]. Aliphatic aldehydes were also amenable to this protocol, leading to the corresponding products in moderate yields. Furthermore, a plausible mechanism was described, in which Ca(OTf)2 displays the same mode of action discussed above (Scheme 6) in facilitating the CH cleavage step. 4. MANGANESE 4.1. Introduction The first example of C-H activation by manganese was reported as early as 1970 by Stone and co-workers [91]. During their studies, on ortho-metalation reactions between azobenzene (26) and transition metal carbonyl complexes, it was found that the reactions between 26 and manganese complexes Mn2(CO)10 (27), MnMe(CO)5 (29), and [MnPPh3(CO)4]2 (30) yielded the corresponding five-membered manganacycles 28 and 31 (Scheme 10). MnMe(CO)5 (29) displayed remarkably higher reactivity than the other two manganese complexes in this 19

reaction. The manganacycle complexes were isolated by column chromatography and characterized by means of IR and NMR spectroscopies.

Scheme 10. Synthesis of manganacycles 28 and 31 from azobenzene (26) and manganese carbonyl complexes: The first example of C-H activation by manganese [91]. This pioneering publication set the stage for the development of several stoichiometric protocols, involving the use of various manganacycle complexes as reagents in C-H functionalization processes. In general, the regioselectivity of the manganacycle formation reaction is determined by coordination of directing groups present in the substrates to the metal center. These protocols have been mainly used for the activation of C(sp 2)-H bonds in properly substituted arenes [62]; however examples of C(sp3)-H (vide infra) and olefinic C(sp2)-H bond activation also exist [92-94]. These examples of manganese mediated C-H activation reactions are reviewed recently [62] and only few selected examples are discussed herein. The activation of more challenging C(sp3)-H bonds by their coordination to manganese in organometallic complexes was observed and studied by Brookhart and Lamanna [95]. In this work, direct activation of C-H bonds through interaction with manganese in cyclohexenyl species 33 (Scheme 11), derived from protonation of the (cyclohexadiene) manganese tricarbonyl anion 32 was reported. In species 33 an endo hydrogen is bridged between carbon

20

and manganese, constituting a part of a two electron three center bonding arrangement as depicted in Scheme 11. The result of this type of coordination is that the bridged hydrogen is rendered acidic and the C-H bond is activated. Deprotonation of species 33 with strong bases such as KH, NaH or n-BuLi leads to the regeneration of complex 32.

Scheme 11. Direct C-H activation in (cyclohexenyl) manganese species [95]. Reaction of 32 with methyl iodide or methyl fluorosulfonate ultimately leads to endo ring methylation and coordination of a second C-H bond to manganese. Moreover, formation of intermediate I followed by methyl migration to the endo side of the ring gives a mixture of the monomethylated complexes 34a and 34b. Presumably, 34a is formed first and 34b arises by isomerization of 34a through a diene hydride intermediate. Thus, conversion of 33 to 34 leads to the activation of a second C-H bond through coordination to manganese. Quantitative deprotonation of 34 by KH leads to the formation of monomethylated cyclohexadiene anion 35. The overall conversion of 32 to 35 can be formally described as electrophilic substitution of an endo hydrogen of cyclohexadiene facilitated by manganese C-H activation. This work illustrated the potential of manganese in the functionalization of C(sp 3)-H bonds.

21

In a later work, intramolecular C(sp3)-H activation by manganese was observed as the result of the thermal reaction between CH3Mn(CO)5 (29) and (C6H5)2PCH2SiCH2P(C6H5)2 (36). The product of this reaction was the stable manganacycle complex 37, bearing a methylene bridge between silicon and manganese [96]. This constitutes a rare example of manganacycle formation via C(sp3)-H activation.

Scheme 12. Intramolecular C-H activation by manganese [96]. The potential for catalytic C-H activation was observed and investigated by Jones and coworkers in 1992 [97]. It was determined, by catalytic H/D exchange with C6D6 or D2, that under thermal or photochemical conditions complex MnH3(dmpe)2 (38) can activate aromatic and benzylic C-H bonds. Complex 38 was described as having an η2-H2 ligand and loses molecular hydrogen readily to afford active intermediate [MnH(dmpe)2], which can activate C-H bonds of substrates or ligands leading to catalytic H/D exchange. The mechanism was proposed to involve oxidative addition, hydride/deuteride positional interchange, and reductive elimination. Heteroatom coordination, in the case of THF or anisole, to manganese strongly influenced the selectivity in C-H bond activation by the catalyst. The results of this study suggested that high electron density on the metal center has substantial impact on the reactivity of the active intermediate in the activation of C-H bonds. Years later, Hartwig and Chen reported the first C-H activation reaction catalyzed by a manganese complex [98]. In this study, stoichiometric amounts of manganese and rhenium complexes were used initially in order to establish whether catalytic borylation of n-pentane with B2pin2 under UV irradiation was possible. It was found that manganese complex 39

22

(Scheme 13) successfully promoted the regiospecific borylation of n-pentane in the terminal position, affording 40 in 35% yield. When benzene was used as the substrate, catalytic borylation was effectively carried out under 2 atm of CO using 10 mol% of manganese complex 39, to afford phenylboronate ester 41 in good yield. Regarding the rhenium based catalyst, it was proposed that the regiospecific C-H functionalization most likely occurred by σ-bond metathesis involving Re(III) and that terminal boronate esters were the kinetic products of this reaction. [Cp'Mn(CO)3] (39) stoichiometric reaction

Bpin

hv, CO, 25 oC O

40 (35%)

O B B

O

O

B2pin2

[Cp'Mn(CO)3] 10 mol% hv, CO (2 atm), 25 oC, 36 h

Bpin 41 (76%)

Scheme 13. Photochemical borylation of pentane and benzene with Cp'Mn(CO)3 (39: Cp΄= C5H4Me). The first report of catalytic C-H activation by a manganese complex [98]. Many manganese-based homogeneous catalytic systems for C-H functionalization operate via hydrogen abstraction by high valent manganese species. These radical based C-H activation processes are catalyzed by complexes with bio-inspired design that can homolytically cleave C-H bonds. This chemistry is particularly interesting [99-108], well reviewed in the literature [58], [109], [60], [61] and will not be discussed in the present work. 4.2. Directing group assisted C(sp2)-H activation The development of catalytic systems for the functionalization of C-H bonds in which the manganese-based catalysts display an organometallic mode of action has received significant interest only during the past decade [62], [63]. The majority of these systems involve substrates that possess directing groups dictating the regioselectivity of the C-H 23

functionalization reactions, by coordinating the metal center of the catalyst. During the preparation of the present work an excellent perspective article in the field of manganesecatalyzed C-H activation was published [64]. As a result, only the most important developments in this field are discussed herein in detail, with emphasis on those not reviewed in the past. The first contribution to this chemistry was made by Kuninobu, Takai and co-workers in 2007 [110]. They reported the imidazole-directed, manganese-catalyzed insertion of aldehydes into Caryl(sp2)-H bonds. Initially, stoichiometric C-H activation and aldehyde insertion was successfully carried out using manganese complex MnBr(CO)5 (43) to afford alcohol 44 (Scheme 14) in moderate yield. However, when complex 43 was used substoichiometrically, only traces of the product (44) could be obtained. In order to regenerate complex 43 and render the process catalytic in manganese, triethylsilane (HSiEt3) was used as an additive (2.0 equivalents) and a range of the corresponding silylethers (46) were produced in moderate to high yields. Notably, using complex 43 in 5 mol% catalyst loading, the reaction between 42 and benzaldehyde (16a) afforded the corresponding silylether in 93% yield. Aldehydes bearing an electron-donating (45a) or an electron withdrawing (45b) group at the para-position also resulted in high yields, while the use of aldehyde 45c with a methyl group at the ortho-position led to a decrease in product yield, possibly due to steric hindrance. Interestingly, screening of other complexes as possible catalysts revealed that only Mn2(CO)10 (27) and MnMe(CO)5 (29) showed adequate catalytic activity, while the rheniumbased analog [ReBr(CO)5], as well as ruthenium, rhodium, and iridium complexes did not catalyze this reaction.

24

Scheme 14. Imidazole-directed, manganese-catalyzed insertion of aldehydes into Caryl(sp2)-H bonds [110]. The applicability of this protocol was further demonstrated with the use of chiral imidazolidines as substrates. The imidazolidine moiety proved to be an efficient directing group and this asymmetric transformation was carried out with exceptional results in the case of silylether 48c, which was obtained in 80% yield and 95% diastereomeric excess. With regards to the mechanism, the authors proposed that the C-H activation step occurs via oxidative addition of the ortho-C-H bond of the phenyl group in 42 to the catalytically active Mn(I) species, thus producing intermediate Mn(III) complex I (Scheme 15). Subsequently, insertion of the aldehyde into the polar Caryl-Mn(III) bond gives intermediate 25

complex II. The authors stressed that the polarity of the Caryl-Mn(III) bond significantly affects this step. Silylation of the alkoxy moiety in II by the action of HSiEt3 and release of molecular hydrogen result in product formation and regeneration of the active catalyst.

Scheme 15. Proposed mechanism for the formation of silyl ethers (46) [110], [63]. It was noted that this transformation could be possibly carried out entirely by a Mn(I) species [110]. The fact that complex MnMe(CO)5 (29) was also an efficient catalyst for this reaction strongly supports this possibility, although the catalytically active species in this case would be different than the one derived from 43. A different mechanism was proposed by Valyaev et al., on the basis of more recently developed similar systems that have been extensively investigated from a mechanistic scope [63]. In this proposed mechanism, the 26

catalytic cycle begins with the formation of manganacycle complex Ι΄ (Scheme 15) and in the following steps only Mn(I) intermediates are involved. The formation of Ι΄ from 42 could possibly be the result of a base-assisted deprotonation step, in which manganese and another molecule of 42, acting as a base, activate the Caryl(sp2)-H bond in a synergistic mode of action. Reactions involving similar steps will be presented in the following sections (for example, see Scheme 24). In a later work, Kuninobu/Takai and co-workers reported that manganese complex MnBr(CO)5 (43) could also be utilized as a catalyst for olefinic C-H bond activation [111]. While this publication was primarily focused on rhenium catalyzed insertion of polar and nonpolar unsaturated bonds into olefinic C(sp2)-H bonds of substrates bearing a directing group, it was noted that the reaction between olefin 49, benzaldehyde (16a) and triethylsilane (HSiEt3) leads to the formation of silylether 50 in 46% yield in the presence of a catalytic amount of complex MnBr(CO)5 (43) (Scheme 16). The mechanism proposed by the authors was essentially the same as the one described in Scheme 15, with the C-H activation step occurring again via an oxidative addition mode.

Scheme 16. Directing group assisted, manganese catalyzed insertion of benzaldehyde (16a) into the C(sp2)-H bond of olefin 49 [111]. Years after the above discussed works, directing group assisted manganese catalyzed C(sp2)-H functionalization by addition to C-Het. multiple bonds was further investigated. Specifically, Ackermann and co-workers reported the first manganese catalyzed aminocarbonylation of heteroaryl C-H bonds in substrates bearing pyridine moieties as 27

directing groups (51, Scheme 17) [112]. A variety of aryl amides (53) were synthesized in moderate to excellent yields with the use of MnBr(CO)5 (43) in 10 mol% catalyst loading. This protocol proved applicable for substrates with varying substitution patterns and also included the late-stage diversification of the C-H functionalization products by removal of the pyridyl directing group and their transformation to quinoxalinones. Detailed mechanistic studies pointed towards a catalytic cycle in which the C-H activation step is a pyridinedirected C-H metalation leading to a Mn(I) catalytically active intermediate. The proposed rate determining step is the insertion of the isocyanate (52) into the Mn(I)-C bond. In the same year, Wang and co-workers made an important contribution to this field by developing a directing group assisted, manganese catalyzed C(sp2)-H functionalization by direct addition to aldehydes and nitriles [113]. In this work, a wide variety of alcohols (56) and aldehydes (59) were prepared in moderate to high yields from the corresponding aldehydes (55) and more challenging nitriles (58) respectively, by directed activation of both aryl and alkenyl C-H bonds. Complex MnBr(CO)5 (43) was again used as the precatalyst, along with Me2Zn and ZnBr2 in stoichiometric amounts for the dual activation of C-H bonds and electrophiles. Moreover, a variety of directing groups were successfully used in these reactions (Scheme 17). Mechanistic studies revealed that the catalytic cycle commences with the generation of complex MnMe(CO)5 (29) by the action of Me2Zn. The key mechanistic steps that follow are the fast directed cyclomanganation of the substrate with the simultaneous release of methane and the subsequent insertion of the aldehyde, which is also activated by the Lewis acid ZnBr2, into the Mn(I)-C bond.

28

Scheme 17. Directing group assisted manganese catalyzed C(sp2)-H functionalization by addition to C-Het. multiple bonds reported by the research groups of Ackermann and Wang [112], [113]. An important advancement in this field was made very recently by Ackermann and coworkers, who developed an operationally simple, multifaceted catalytic protocol for the selective functionalization of indoles via hydroarylation of compounds bearing C-Het. double bonds. The development of this protocol highlighted the unique behavior of Mn(I)-based catalytic systems regarding the C-2 selectivity in indole functionalization, circumvented the use of additives, and provided valuable mechanistic insight [114]. Screening of diverse transition metal complexes as potential catalysts revealed that use of Pd(PPh3)4, Re2(CO)10, Rh2(CO)4Cl2 and Co2(CO)8 among others resulted in the exclusive formation of C-3 functionalized molecules, conforming to the inherent reactivity of the substrate. Only

29

Mn2(CO)10 (27) could efficiently catalyze the C-2 functionalization in the absence of additives, while MnBr(CO)5 (43) gave the same result in the presence of NaOAc. Various ketones and aldehydes (61) were amenable to this protocol, along with diversely substituted heterocycles bearing pyridine directing groups, leading to the chemoselective formation of functionalized molecules (62) in high to excellent yields (Scheme 18, a). Of note, imines (63) were also used as substrates for the first time with satisfying results, further proving the applicability of Mn(I) catalysis (Scheme 18, b).

30

Scheme 18. a) Manganese catalyzed hydroarylation of aldehydes and ketones. b) Manganese catalyzed hydroarylation of imines [114]. Mechanistic investigation led to the proposal of a plausible catalytic cycle which commences by a C-H metalation step affording intermediate I (Scheme 19). This intermediate was isolated and proved to be catalytically competent. Coordination of substrate 61 and subsequent insertion into the Mn(I)-C bond lead to intermediate III, which was also identified. Protonative demetalation ensues, releasing the product (66) and regenerating the catalytically active intermediate. The origin of this system’s selectivity was suggested to be the C-H activation step, that is, a σ-bond metathesis involving a ligand to ligand H-transfer. OH R R'

N

O

N

N

Mn(CO)4 N

66

R

R' 61

I C-H activation H N N

CO

65 R R N N

R'

R' O

O Mn(CO)4

N

Mn(CO)3 N

III

II

CO

Scheme 19. The proposed catalytic cycle for the manganese catalyzed hydroarylation of C=O bonds [114]. Wang, Chen, and Zhou uncovered yet another aspect of the rapidly growing field of catalytic C-H activation, by elegantly developing a novel catalytic system based on MnBr(CO)5 (43) for the directing group assisted alkenylation of aromatic substrates (67, Scheme 20) with terminal alkynes (68) [115]. This protocol is characterized by high chemo-, 31

regio-, and stereoselectivity, as it gives rise only to mono-substituted, anti-Markovnikov, Econfigured C-H alkenylation products (69). Moreover, it is worth mentioning that terminal alkynes are reasonably thought to be risky substrates for such systems, due to the acidic nature of their terminal C-H bonds and their capacity for self-trimerization. A variety of substituted olefins (69) were synthesized in moderate to high yields with the cooperative action of MnBr(CO)5 (10 mol%), the bulky weak base Cy2NH (20 mol%), and a pyridine directing group. Various substrates with a plethora of substitution patterns were amenable to this protocol, always leading to synthetically useful yields (Scheme 20, selected examples), further demonstrating its potential for incorporation into more elaborate synthetic procedures. Mn2(CO)10 (27) was also used as a catalyst for this transformation with moderate success and the use of internal alkynes as substrates was unfruitful. After conducting exhaustive mechanistic studies complemented by DFT calculations, the authors made a proposal for the reaction mechanism in which the C-H activation step is a deprotonative, directed metalation, brought about by the synergistic action of the catalyst and the weak base (Scheme 20). Many key intermediates, such as alkynylmanganese and manganacycle species were also described, thus offering useful insight for similar systems [116].

32

Scheme 20. Mn-catalyzed C-H alkenylation of aromatic compounds bearing a directing group, with terminal alkynes [115]. In the following years, the substrate scope of manganese-based catalytic systems for the addition of Caryl(sp2)-H bonds to unsaturated C-C bonds was broadened considerably. By applying the same principles as in the previously described work, Chen, Wang and coworkers established a strategy for the directing group assisted, manganese catalyzed conjugate addition of aromatic C-H bonds to α,β-unsaturated carbonyls (71, Scheme 21) [117]. Once again, MnBr(CO)5 (43) (10 mol%), Cy2 NH (20 mol%), and a pyridine directing group proved to be a simple and efficient catalytic system, characterized by high levels of chemoselectivity, regioselectivity and functional group tolerance. A variety of functionalized molecules (72) were synthesized in generally moderate to high yields, using a multitude of substituted arenes, heteroarenes, vinylketones, and acrylic esters as substrates. Mn2(CO)10 (27) and ReBr(CO)5 were also used as catalysts for this transformation, albeit with less promising results. Detailed experimental and DFT studies led to the proposal of a reaction mechanism in which the C-H activation step was the same as the one described in the previously discussed work and the step associated with the highest energy barrier is the olefin insertion into the Mn-C(sp2) bond of intermediate complex I. Coordination of the carbonyl moiety proved to be vital for the stabilization of species involved in the aforementioned step. An operationally simple catalytic system with tunable chemoselectivity, providing access to both bis/trisubstituted indolylalkenes (76, Scheme 21) and substituted carbazoles (77) was designed by the research groups of Lei and Li [118]. By employing MnBr(CO)5 (43) (10 mol%) as the catalyst and DIPEA (20 mol%) and benzoic acid (20 mol%) as additives, a range of substituted indoles (74) could be functionalized by their alkenylation with diverse aromatic, aliphatic, terminal, or even internal alkynes (73), leading to mostly high yields. In the case of internal alkynes, good regioselectivity was also observed, but product yields were 33

generally low compared to those obtained with terminal alkynes. Both Mn2(CO)10 (27) and Re2(CO)10 promoted this transformation as well, but with less promising results. By tuning the reaction (Scheme 21), it was found that MnBr(CO)5 (43) can also catalyze the [2+2+2] cyclization involving suitably substituted indoles and terminal alkynes (75). The substituted carbazoles thus produced (77) could be obtained in low, albeit synthetically useful yields. It was noted that this is probably due to the decomposition of the catalyst under these conditions. Furthermore, a directing group removal strategy for both types of products also proved possible, demonstrating the synthetic potential of these systems. Mechanistic studies revealed that benzoic acid was responsible for controlling chemoselectivity, being a key participant in an H-transfer process.

34

Scheme 21. Directing group assisted, manganese-catalyzed conjugate addition of aromatic CH bonds to α,β-unsaturated carbonyls and C-H functionalization of indoles by addition to alkynes reported by the research groups of Wang and Li respectively [117], [118]. One of the most recent advancements in the field of catalytic C-H activation was made by Wang and co-workers, when they reported a protocol for the synthesis of mono-alkenylated aromatic nitriles (80, Scheme 22) through the manganese-catalyzed ortho-C-H alkenylation of the corresponding imidates (78) with alkynes (79) [119]. The linear structure of the cyano moiety prevents it from acting as a directing group for C-H activation, so its conversion to an imidate, using an alcohol and acetyl chloride, is essential for accessing the ortho35

functionalized nitriles. Optimization studies for the reaction between ethyl benzimidate (78a) and phenylacetylene (79a) revealed that both MnBr(CO)5 (43) and Mn2(CO)10 (27) in 10 mol% catalyst loading could promote the reaction, while no product formation was observed in the absence of a catalyst or when Re2(CO)10 and Mn(OAc)2 were used. Also, it was found that use of a sub-stoichiometric amount of the mild base NaOPiv•H2O gave the best yield and that this protocol was excellent in terms of mono-/dialkenylation selectivity and E/Z stereoselectivity. NH

R2

OEt

R

Mn2(CO)10 (10 mol%) NaOPiv H2O (15 mol%)

CN R

o

DME, 120 C, 4 h

H

R2

R1

78

R1 80 (26 compounds, up to 95% yield)

79

Selected examples: CN

CN

80a (80%)

80b (60%)

CN

80c (72%)

O

CN

CN

CN

Cl

O 80d (75%)

Ph

S

80f (75%)

80e (40%)

Cl

H F3C

CN

CN

CN

OTs

O O 80g (76%)

80i (58%)a

Cl

Cl 80h (85%, 80h/80h' = 40/1)

S

CN

CN

CN

Cl Me 80j (75%)a

Cl

80k (24%, single regioisomer)a

80l (95%)

Cl

Scheme 22. Manganese-catalyzed ortho-C-H alkenylation of aromatic imidates (78) with alkynes (79) provides access to ortho-functionalized aromatic nitriles (80) [119]. Under the optimized conditions shown in Scheme 22, the substrate scope was explored and a variety of ortho-functionalized nitriles were synthesized in moderate to high yields and in relatively short reaction times. For aromatic alkynes, both electron withdrawing and 36

electron donating substituents on the benzene moiety were tolerated by this catalytic system. Moreover, substrates bearing halogen substituents reacted successfully. Aliphatic alkynes and internal alkynes were also used with success, leading to moderate yields when Mn(OAc)2 was added to the reaction mixture (Scheme 22) [119]. A variety of substituted nitrile-derived imidates also proved to be useful substrates, affording the corresponding products in good to excellent yields. Substitution on the benzene ring of the imidates could influence the reaction outcome through a secondary directing effect (80h) or sterically, as was expected. 2cyanothiophene was also amenable to this reaction, leading to product 80d in good yield. Based on mechanistic studies, as well as on findings from previous works, a plausible mechanism for this reaction was proposed (Scheme 23) [119]. The catalytic cycle commences with the base assisted cyclomanganation of imidate 78a affording manganacycle I. Alkyne insertion into the manganese-carbon bond leads to seven-membered manganacycle III via the intermediate complex II. Two possible paths may be followed from intermediate III, depending on whether an internal or a terminal alkyne is involved. In path A, coordination of an alkyne, intramolecular H-shift and ligand exchange with 78a ultimately lead to the formation of the desired product (80) via intermediates IV and V. Alkynyl assisted C-H activation in intermediate VI closes the cycle, affording intermediate complex II. In path B, direct protonation of manganacycle III, complexation of substrates, and C-H activation in the presence of NaOPiv ultimately leads to the product, simultaneously releasing intermediate II.

37

EtO NH Mn(CO)3 R2 IV

R2

R2

Path A R1 = H EtO

EtO

80 NH Mn(CO)3

NH

EtO

III

R1

H , 79

R2

Path B

H

V

EtO

R2

NH H

78a NaOPiv

78a

NH H Mn(CO)3

-EtOH

+

R1

NaOPiv Mn2(CO)10

R2

R2

78a EtO EtO

NH Mn(CO)4

NH

79

Mn(CO)3 R2

CO

EtO

NH Mn(CO)4

R1 I

II

R2 VI

Scheme 23. Proposed mechanism for the manganese-catalyzed ortho-C-H alkenylation of aromatic imidates with alkynes affording ortho-functionalized nitriles [119]. Annulations are an important class of transformations for which manganese catalyzed C-H activation has begun to emerge as a useful tool. The first report of such a system was made by Wang and co-workers in 2014, concerning the synthesis of isoquinolines (83, Scheme 24) via the dehydrogenative [4+2] annulation of imines (81) and alkynes (82) [120]. This catalytic reaction proceeds efficiently without need for any additive, resulting in the formation of molecular hydrogen as the main byproduct. With MnBr(CO)5 (43) in 10 mol% catalyst loading, a broad range of substituted isoquinolines (83) were synthesized in moderate to excellent yields. A wide array of diaryl and aryl alkyl ketimines (81), as well as aromatic, aliphatic internal, and terminal alkynes were amenable to this protocol, which also features high functional group tolerance. After conducting mechanistic studies, the authors proposed a plausible catalytic cycle that commences with the formation of manganacycle I, shown in Scheme 23, which was isolated and identified as the catalytically active species. Beyond the 38

initial C-H activation step, other key steps involve a seven membered manganacycle and, interestingly, manganese hydride species HMn(CO)4. A similar system, in terms of operational simplicity and synthetic viability, was developed by Ackerman’s research group for the manganese catalyzed annulation of N-substituted ketimines (84) and α,β-unsaturated esters (85) to gain access to cis-β-amino acid esters (86) [121]. This protocol features relatively mild reaction conditions, thus making possible the construction of sensitive β-amino acid structures with remarkable cis-stereoselectivity. By employing Mn2(CO)10 (27) in just 5.0 mol% catalyst loading, a variety of β-amino acid derivatives were synthesized in good to excellent yields, with exemplary regio- and diastereoselectivity owing to the properties of the Mn(I) catalyst (vide infra). Functional group tolerance is also a key characteristic of this protocol, as variously substituted imines (84) proved to be suitable substrates. Studies with regards to the reaction mechanism revealed that the C-H activation step is kinetically relevant and possibly takes place via base assistance (Scheme 24).

39

Scheme 24. Imine directed, Mn(I)-catalyzed annulation reactions affording substituted isoquinolines (83) and cis-β-amino acid esters (86), reported by the research groups of Wang and Ackermann respectively [120], [121]. Inspired by Ackermann’s previously described protocol, Hu and Wang further optimized and enhanced this concept by incorporating elements from their former related work [122], [113]. They reported the bicyclic annulation of imines (87, Scheme 25) with α,β-unsaturated esters (88), catalyzed by MnBr(CO)5 (43) in the presence of ZnMe2, affording the corresponding fused β-lactams (89). According to Ackermann’s work, the same compounds can be accessed from β-amino acid esters (86, Scheme 24), but the currently described protocol provides step-economy under milder conditions, while exhibiting excellent chemoand stereoselectivity. Furthermore, aldimines proved to be suitable substrates for this transformation, thus expanding the substrate scope. 40

Scheme 25. Mn(I)-catalyzed bicyclic annulation of imines (87) with α,β-unsaturated esters (90) providing the corresponding fused cis-β-lactams (89) [122]. Catalyst screening revealed that complex MnBr(CO)5 (43) was considerably more efficient than other metal carbonyl complexes such as Mn2(CO)10 (27), ReBr(CO)5, and Ru3(CO)12. In the presence of ZnMe2, a range of cis-β-lactams (89) were synthesized from ketimines bearing various functionalities in moderate to high yields (89a, 89b, 89c). Aldimines, though more challenging, also proved amenable to this protocol, affording the corresponding products in low to moderate yields (89d-89f). Various acrylate esters (88) were tested as well, leading to the observation that increased steric hindrance in the vicinity of the carbonyl moiety heavily influenced the reaction outcome (89g-89i). A plausible mechanism for this transformation was proposed, based on mechanistic studies and insight

41

gained by studies on similar systems (Scheme 25) [113], [121]. The proposed catalytic cycle commences by a transmetalation step leading to the formation of MnMe(CO)5 (29), the manganese species that participates in the C-H metalation of 87 affording manganacycle intermediate I. Insertion of 88 into the Mn(I)-C bond leads to intermediate II and subsequent intramolecular nucleophilic attack ensues affording intermediate III. During this step, the chelating coordination of the ester/enolate and imine groups on the metal center of the catalyst is thought to be the cause of the exclusively observed cis-diastereoselectivity. Another transmetalation step, accompanied by complexation of the catalyst with 87, afford intermediates IV and V. Intermediate V undergoes intramolecular cyclization, resulting in product formation, and C-H metalation/release of methane regenerates the catalytically active species. 87 MnBr(CO)5 + ZnMe2

MnMe(CO)5 CH4 R2 N

R1

Ar

R2

CH4

H MnMe(CO)4

N

R1

IV

Ar

Mn(CO)4 I Ar ZnMe R2 N O R1 R3 OR4

O

V

OR4 R3

ZnMe2, 87

88 Ar R2 N

Mn(CO)4

89

R2

O

N

R1

R1

Mn(CO)3

R3 OR4 III

Ar

R3 II

O OR4

CO

Scheme 26. Proposed mechanism for the Mn(I)-catalyzed bicyclic annulation of imines (87) with α,β-unsaturated esters (88) [122].

42

Another leading contribution to this research area was made by Kuninobu and co-workers who developed a catalytic system based on Mn2(CO)10 (27) and triphenylborane, which provides access to substituted isobenzofuranones (92, Scheme 27) from mainly aromatic esters (90) and oxiranes (91) via directed C-H activation [123]. The importance of this work lies primarily in the fact that it constitutes the first example of a manganese catalyzed C-H activation procedure, assisted by an oxygen-based directing group. Also, the reaction studied could potentially be of use as a fundamental step in natural product synthesis, as isobenzofuranones are a frequently observed structural part in naturally occurring compounds. Screening of potential catalysts for the synthesis of isobenzofuranone 92a showed that Mn2(CO)10 (27) in 5.0 mol% catalyst loading and a stoichiometric amount of triphenylborane could cooperatively furnish the desired product in high yield. Interestingly, use of MnBr(CO)5 (43) as well as ReBr(CO)5, Re2(CO)10, and other transition metal catalysts failed to produce useful results. Moreover, triphenylborane proved to be of critical importance in this protocol. Investigation of the substrate scope led to the successful synthesis of a wide variety of compounds in mostly moderate to high yields via functionalization of aryl, heteroaryl (92e), as well as alkenyl (92f) C-H bonds. Aromatic esters (90) bearing electron donating groups in the para- position resulted in the highest product yields (92b, 92c), while this protocol exhibited remarkable tolerance for diverse functional groups (92g, 92h). The use of divergently substituted oxiranes (91) led to mostly good to high yields, except for the case of isobenzofuranone 92j. In demonstration of this system’s applicability and vast synthetic potential, biologically relevant estrone derivative 92k was successfully synthesized, albeit in low yield.

43

Scheme 27. Oxygen-directing group assisted, manganese catalyzed C(sp 2)-H bond activation to access substituted isobenzofuranones (92) [123]. Mechanistic studies pointed towards a plausible mechanism for this transformation: The catalytic cycle commences with a directed oxidative addition step, leading to the formation of manganacycle intermediate I (Scheme 28). This is the rate-determining step of the reaction and can be possibly promoted by triphenylborane. Triphenylborane also promotes the isomerization of oxiranes (91) to aldehydes (91΄), which undergo insertion into the manganese-carbon bond of intermediate I affording intermediate II. Manganese facilitates the cyclization step, leading to intermediate III, and subsequent reductive elimination and

44

extrusion of methanol result in product formation and regeneration of the catalyst. The action of triphenylborane is not fully understood and further insight into this mechanism is needed, as was also noted by the authors [123].

Scheme 28. Proposed mechanism for the annulation of aromatic esters with oxiranes via C-H bond activation, catalyzed by manganese and triphenylborane [123]. Ackerman and co-workers also developed the first catalytic system for the substitutive allylation of aryl and heteroaryl C-H bonds [124]. The main features of their system include a wide substrate scope, high efficiency and compatibility with functional groups, as well as notable regio- and stereo-selectivity and vast potential from a synthetic viewpoint. Both MnBr(CO)5 (43) and Mn2(CO)10 (27) proved to be catalytically competent for this transformation, when aided by sub-stoichiometric amounts of carboxylate salts. The use of Mn2(CO)10 (27) and NaOAc as the optimal co-catalytic dyad enabled the allylation of a broad range of arenes and heteroarenes bearing imine and pyridine directing groups respectively (Scheme 29, a, b). All substitution patterns were tolerated (95a-95d, 97a-97c) and reaction yields were mostly high, underlining this protocol’s potential for incorporation in elaborate 45

synthetic procedures (97c). Moreover, positional selectivity seems to be dictated by either steric hindrance or secondary directing effects (95e). Mechanistic investigations led to the identification of the catalytically active species and shed light on the catalytic cycle, which was proposed to commence with the formation of complex [MnO2CR(CO)5], followed by the facile, carboxylate assisted C-H metalation step. The insertion of an allyl carbonate into the Mn(I)-C bond and a β-hydride elimination that leads to product formation also constitute key mechanistic steps.

Scheme 29. Manganese catalyzed substitutive allylation of aryl and heteroaryl C-H bonds [124].

46

In a recent work, Glorious and co-workers studied the aforementioned methodology further, by introducing a solvent-free protocol for the allylation of aryl and heteroaryl C-H bonds through manganese catalysis [125]. This sustainable catalytic system allows for the use of various, new coupling partners for the functionalization of directing group-bearing arenes and substituted indoles, thus broadening the synthetic scope of the field. More specifically, with the use of MnBr(CO)5 (43) in 10 mol% loading and NaOAc in 20 mol% loading, a range of arenes/heteroarenes (98, Scheme 30) were efficiently converted to the corresponding allylic alcohols (100) by reacting with vinyl-1,3-dioxolan-2-one (99). The reaction takes place either in diethyl ether or under neat conditions, leading to high yields in short reaction times and with notable scalability. High functional group tolerance was observed. Moreover, the obtained E:Z ratios were higher when the reaction was carried out in diethyl ether, while related studies showed that the choice of solvent had a great impact on E:Z selectivity. Using Mn2(CO)10 (27) as the precatalyst and 2-vinylcyclopropane-1,1-dicarboxylate (101, Scheme 30) as the coupling partner, successive C-H/C-C activation was realized, resulting in the formation of functionalized arenes/heteroarenes (102) in moderate to high yields. Again, this transformation can take place under neat conditions and with high levels of functional group tolerance.

47

Scheme 30. Manganese-catalyzed allylation through sequential activation of C-H/C-O and CH/C-C bonds [125]. In the same work, the catalytic system used for the synthesis of allylic alcohols also proved efficient for the introduction of potentially important cyclopentenylamine units [125]. This was achieved by utilizing diazabicycle 104 (Scheme 31, a) as the coupling partner. The corresponding products were obtained in good to excellent yields. Under neat conditions, higher catalytic loading was required (105c-105e). Importantly, the same catalytic system was used for olefinic C-H functionalization (Scheme 31, b). Mechanistic studies suggested

48

that the C-H activation step is reversible and that the β-carbon and β-nitrogen elimination steps, which were observed for the first time in manganese catalysis, are facile. The authors concluded that olefin coordination and insertion is the rate-limiting step.

Scheme 31. Manganese-catalyzed synthesis of functionalized cyclopentenes (105) and skipped dienes (107, 108) [125]. A groundbreaking advancement, which showcased the potential of manganese-catalyzed C-H activation in organic synthesis, was made very recently by Ackermann’s research group, when they disclosed the development of a new protocol for the efficient alkynylation of indoles and pyroles with haloalkynes (Scheme 32) [126]. By using MnBr(CO)5 (43) as the

49

precatalyst in 5.0 mol% loading and Cy2NH as the required base, various indoles and pyroles (109) were alkynylated with silyl-substituted alkynyl bromides. Apart from the excellent yields, positional selectivity, and functional group tolerance, this protocol also benefits from the use of a readily removable pyrimidine directing group (111a-111g). In the case of the more challenging alkynyl halides without silyl-substitution, triphenylborane was used as the co-catalyst in 0.05 mol% loading, giving excellent results (111h, 111i). The versatility of this catalytic system was demonstrated with the synthesis of molecules bearing a fluorescent tag and complex peptide motifs (111j, 111k), as well as with the assembly of a cyclic peptide.

H

R1

Br

MnBr(CO)5 (5.0 mol%) [BPh3 (0.05 mol%)]* Cy2NH, DCE 80 oC, 16 h

R2

N N

N

R1

R2 N N

110

109

N

111

R1

R1 TIPS N N

N

N

111a (R1= OMe, 78%) 111b (R1= Br, 91%)

N

N

TIPS 111c (R1= Me, 82%) 111d (R1= CN, 70%)

O TIPS 111e (96%)

N N

N

TIPS 111f (92%)

N N

N

TIPS

Br

N

N 111h (99%)*

N

N

Ph

N N

TIPS 111g (89%)

N

O N

N

111i (80%)*

H N

HN O

NH

O

O O O

BocHN N N

N 111j (40%)*

TIPS N N

N

111k (70%)

Scheme 32. Manganese-catalyzed C-H alkynylation [126].

50

Mechanistic investigation led to the proposal of a plausible catalytic cycle (Scheme 33), which adds new and interesting insight into Mn(I)-based catalytic systems for C-H activation. The cycle begins with an organometallic C-H activation step, which is followed by the insertion of a haloalkyne (110) into the Mn(I)-C(sp2) bond, leading to seven-membered manganacycle II. The product is delivered through a β-elimination step, which leads to the formation of intermediate III. The authors suggested that triphenylborane, acting as a cocatalyst, is responsible for the acceleration of this step in the case of alkynes that do not feature the β-silicon effect. An oxidative addition/reductive elimination sequence could not be excluded [126].

R , Cy2NH2Br

N N

R

N

N

N

111

Mn(CO)4 Br

N

110

I C-H activation

N N

H, Cy2NH N

109 Br R

N N

N

MnBr(CO)4 III

R N N

N

Mn(CO)4 II

Scheme 33. Proposed catalytic cycle for the manganese-catalyzed C-H alkynylation of indoles [126]. Yet another new reaction for C(sp 2)-H functionalization by means of Mn(I) catalysis was introduced by Ackermann and co-workers in a recent report describing the design of a heterobimetallic catalytic system for the cyanation of heteroarenes [127]. This protocol involves the use of NCTS (N-cyano-N-phenyl-para-toluenesulfonamide) (113, Scheme 34) as the cyanating reagent and ZnCl2 as the key co-catalytic additive. MnBr(CO)5 (43) as the 51

precatalyst in 10 mol% loading in combination with Cy2NH as the base in 20 mol% loading catalyzed the cyanation of variously substituted indoles. High functional group tolerance was observed in all cases and the products could be obtained in good to excellent yields (Scheme 34). Amongst others, sterically-hindered substrates were amenable to this reaction (114c). It is also worth noting that pyroles and thiophenes with a pyridine directing group could be functionalized with remarkable positional selectivity. Mechanistic investigations in conjunction with computational studies revealed that the catalytic cycle involves a C-H activation step and a rate-determining C-C bond formation step. It was determined that zinc stabilizes the transition state shown in Scheme 34 through coordinative interactions. The seven-membered manganacycle intermediate formed through the aforementioned transition state (I) is also stabilized by the co-catalytic additive in the same fashion [127].

52

Scheme 34. Cyanation of heteroarenes through synergistic, heterobimetallic Mn(I)/ZnCl2 catalysis [127]. 4.3. Activation of C(sp)-H bonds in terminal alkynes Even though the vast majority of manganese-catalyzed C-H activation procedures involve the use of substrates bearing directing groups, manganese is not limited to this mode of action. Kuninobu et al. have reported a manganese-catalyzed process for accessing biologically relevant hydantoin derivatives (1117, Scheme 35) from terminal alkynes (115) and isocyanates (116) [128]. This reaction was proposed to involve an integral C-H activation step, namely an oxidative addition of a terminal alkyne to the metal center. Interestingly, among the transition metal complexes screened, only MnBr(CO)5 (43) proved to be an efficient catalyst for this transformation, while ReBr(CO)5 failed to promote the reaction and Re2(CO)10 and Fe(CO)5 exhibited relatively lower catalytic competency. With MnBr(CO)5 (43) in 5.0 mol% catalyst loading variously substituted aromatic alkynes were successfully used as substrates, with those bearing electron withdrawing substituents leading to the highest product yields in a chemo- and stereo-selective fashion. Primary aliphatic alkynes led to low yields, while internal alkynes did not react under the reaction conditions. Use of aryl and secondary alkyl isocyanates also led to satisfactory results; however, primary and tertiary alkyl isocyanates were prone to self-trimerization. With regards to the reaction mechanism, the authors proposed that the catalytic cycle begins with the coordination and oxidative addition of a terminal alkyne to the Mn(I) center, leading to Mn(III) intermediate II shown in Scheme 35. Insertion of two isocyanate molecules affords intermediate III and subsequent reductive elimination, coordination of the alkyne moiety, and intramolecular cyclization lead to product formation and regeneration of the catalyst [128]. It was also noted that an alternative path, involving the formation of a manganese-alkylidene 53

intermediate, may also be possible. Despite its obvious advantages, this protocol suffers from a limited substrate scope and the need for relatively high reaction temperature.

Scheme 35. Manganese-catalyzed C(sp)-H activation of terminal alkynes (115) and their reaction with isocyanates (116) to access substituted hydantoines (117) [128]. The unprecedented use of MnCl2 (118) as an effective catalyst for the three component coupling reaction (Scheme 36, a) between aldehydes (119), amines (120) and terminal alkynes (121) to afford substituted propargylamines (122) was reported by Chen and coworkers in 2014 [129]. This catalytic protocol also contains the one pot diastereoselective synthesis of substituted fused triazoles (125) via the aforementioned three component 54

coupling and the subsequent Huisgen 1,3-dipolar intramolecular cycloaddition reaction (Scheme 31, b). Optimization studies revealed that the simple, inexpensive and easy to handle manganese salt MnCl2 (118) in 10 mol% catalyst loading could efficiently promote the A3 coupling reaction (coupling between an aldehyde, an amine and an alkyne) between benzaldehyde (16a), piperidine (120a) and phenylacetylene (79a) under solvent-free conditions, affording the corresponding propargylamine (122a) in remarkably high yield (98%).

55

a)

O R1

H

H N

R2

R4

R3

H

R3 N

R2

neat, 90 oC, 12 h

R4 R1

122 (32 compounds, up to 98% yield)

121

120

119

MnCl2 (10 mol%)

Selected examples O

O

N

N

N

N

122d (65%)

122c (96%)

122b (90%)

122a (98%)

O

S

N

N

N

N

122h (91%)

122g (94%)

122f (97%)

122e (93%)

O

F

O Si

N

N

N

N

122l (97%)

122k (96%)

122j (89%)

122i (98%)

Cl O

b) R1

H

N H

R2

o

N

neat, 90 C, 12-14 h

N3

N

R2 R1 125 (20 compounds, up to 84% yield, dr: 94 to 99%)

124

123

119

N N

MnCl2 (10 mol%)

H

Selected examples 125a (84%) N N N

125b (75%) N N

N

N

N

125c (79%) N N N

125d (76%) N N

N

N

N

Cl NC F 125e (78%) N N N

N

125f (76%) N N N

N

125g (83%) N N N

125h (74%) N N N

N

N

S O

O

Scheme 36. a) Three component coupling reaction between aldehydes, amines and terminal alkynes catalyzed by MnCl2, affording the corresponding propargylamines (122). b) One pot diastereoselective synthesis of fused triazoles (125) [129]. Under the optimized conditions, a wide variety of substituted propargylamines were synthesized in generally excellent yields. Use of piperidine and morpholine gave the best 56

results, while use of the bulky, acyclic diisopropylamine afforded the corresponding product (122d) in relatively lower yield. Aromatic, heterocyclic and aliphatic aldehydes were all amenable to this protocol, leading to the corresponding products (e.g: 122f, 122e and 122i respectively) in excellent yields. Electron donating and electron withdrawing groups on the substrates seem to have no significant effect on the reaction outcome. When (S)-2(azidomethyl)pyrrolidine (123) was employed, the manganese catalyzed A3 coupling was succeeded by the intramolecular cycloaddition of the azide and alkyne moieties, leading to the formation of the corresponding tricyclic products (125) in high yields, under solvent-free conditions and in just 12 to 14 hours in a diastereoselective manner. Again, the diverse substitution patterns of the substrates do not seem to affect the result of this one-pot procedure in terms of product yield or diastereoselectivity. The proposed mechanism for this A3 coupling reaction is shown in Scheme 37 [129]. According to this mechanism, the C-H activation step is a base-assisted metalation of the terminal alkyne, which leads to the formation of intermediate manganese-alkynilide (I) and iminium cation II. Nucleophilic addition of species I to the iminium cation ultimately leads to product formation and regeneration of the catalyst.

57

Scheme 37. Proposed mechanism for the Mn(II) catalyzed three component coupling reaction between aldehydes, secondary amines, and alkynes [129]. 4.4. Carbene insertion into aryl C(sp2)-H bonds. A quite different mode of action of manganese in catalytic C-H activation was observed and studied by Pèrez and co-workers in 2016 [130]. They reported the direct functionalization of inactive aryl C(sp2)-H bonds via carbene insertion, catalyzed by manganese and iron complexes. The selectivity of these systems is noteworthy, as the desired carbene insertion into aryl C(sp 2)-H bonds appears to be remarkably more favored than the competitive Buchner reaction (ring expansion into cycloheptatriene), the homocoupling of two carbene units, or even the carbene insertion into C(sp3)-H bonds in alkylbenzenes. Initially, chloride or triflate salts of Fe(II) and Mn(II) were employed as catalysts in the reaction between ethyl diazoacetate (EDA) and benzene at 80 oC with the use of additive NaBAr4F (BAr4F = tetrakis(bis-3,5-trifluoromethyl-phenyl)borate) as a Cl-, or OTf- scavenger (Scheme 38). While the iron salts promoted the consumption of EDA, both the insertion product (126) and the Buchner reaction product (127) were formed in moderate, comparable total yields (based on EDA). The manganese salt failed to completely promote the consumption of EDA, but its use resulted in the chemoselective formation of the insertion product (126:127 > 99:1). A screening of iron and manganese complexes, bearing polydentate amino-based ligands (LMX2: X = Cl or OTf, Scheme 33), gave more insight and promising results. It was found that the additive (at least 2 equivalents) was essential for the complete consumption of EDA and the yield increased in all cases. Remarkable selectivity towards the insertion reaction was observed in all systems where the iron or manganese complex precatalyst employed contained a tridentate or tetradentate amino-based ligand (126:127 > 99:1). In general, moderate to high yields were obtained for all catalytic systems 58

in which the aforementioned ligands were involved, with precatalysts (L1)FeCl2 (128) and (L1)Fe(OTf)2 (129) giving the best results (86% and 83% yield respectively). The manganese-based precatalyst (L1)Mn(OTf)2 (131) also promoted the selective formation of the insertion product, but with slightly decreased yield (76%). Steric or electronic modification of the pyridine ring did not significantly affect the outcome in any case. When the pentadentate amino-based ligand coordinated iron complex was used as the precatalyst, no product formation was observed. The substrate scope was also explored using (L1)Fe(OTf)2 (129) as the precatalyst. A variety of substituted benzenes were amenable to this protocol, resulting in generally moderate to good yields (up to 75%). The use of substrates bearing electron withdrawing groups (Cl, CF3) resulted in very low yields (<10%) [130].

59

Scheme 38. a) Direct functionalization of inactive aryl C(sp2)-H bonds via carbene insertion, catalyzed by manganese and iron complexes. b) Iron and manganese complexes screened as precatalysts for this reaction [130]. After conducting detailed mechanistic studies, the authors made a proposal describing the catalytic cycle (Scheme 39). The cycle commences with the formation of dicationic intermediate I, to which EDA coordinates in a dihapto mode affording intermediate complex II. Extrusion of a nitrogen molecule leads to the formation of metallocarbene species III, which in turn reacts with the arene via an outer sphere mechanism, affording intermediate IV. Finally, the release of the electrophilic aromatic substitution product regenerates the catalytically active intermediate (I), thus closing the catalytic cycle.

Scheme 39. Proposed mechanism for the (L1)MX2 (M =Fe, Mn, X = Cl, OTf) catalyzed reaction between substituted arenes and EDA [130]. 5. IRON 5.1. Introduction

60

The Earth’s atmosphere during the Archean era (3800-2500 million years ago) is thought to have been anoxic, with the partial pressure of atmospheric oxygen being about 10-12 times the present value [131]. Life on earth existed under anaerobic conditions long before the blue-green algae started to produce oxygen. The reducing atmosphere was full of hydrocarbons, especially methane, the oxidation of which contributed to the maintenance of a low oxygen concentration 1evel. At that time, iron was abundant in earth’s crust, in the form of metallic iron. A form of life oxidized the iron to Fe(III) and deposited it as pure ferric oxide in the vast mountain ranges of Australia and Brazil. Ferric oxide contributed to hydrocarbon oxidation and to the generation of carbon dioxide. This was the point of origin for a new chapter in selective hydrocarbon activation chemistry [132]. Barton, along with many other researchers, studied the oxidation of saturated hydrocarbons catalyzed by iron in the presence of oxygen [133]. The identity of the active oxidant in this transformation has been a matter of serious debate [134-139]. Nevertheless, this constitutes an early approach for the functionalization of inert C-H bonds and has paved the way for catalytic C-H activation by iron species. The C-H bond of methane is one of the strongest aliphatic bonds and its dissociation energy is 439 kJ/mol at 298 K. A slightly weaker C-H bond is that of ethane, with dissociation energy of 423 kJ/mol at the same temperature. The phenyl C-H bond has 473 kJ/mol dissociation energy, also at the same temperature [140]. The inertia of these C-H bonds and their analogues, along with the need for their functionalization, was the major motivation for the research efforts in the field of catalytic carbon-hydrogen bond activation [25]. 5.2. C(sp3)-H activation

61

As mentioned above, the C-H bonds of methane are notably inert. Through experimental and theoretical studies it has been found that FeIVO can serve as an active species for the activation of these bonds [141-146]. The C-H bond of methane is also weakened through electron transfer from methane to the ferryl active site of monooxygenase enzymes, cytochrome P450 enzymes, and functionalized porphyrines [147-152]. On this basis, significant research efforts have focused on the development of non-heme iron catalysts. These catalysts bear iron centers that are not attached to heme-containing proteins, but their structure and characteristics resemble those of heme [153], [154]. Also, methane can be successfully oxidized to methanol by Fe-O species immobilized on graphene surfaces [155], [156]. In 2013, Li and co-workers prepared nanosized solid Ce0.9Fe0.1O2, with which they oxidize methane at 500 oC. Oxygen molecules were adsorbed on the prepared catalyst’s surface. The adsorbed oxygen in the solid Ce-Fe-O could lead to the complete oxidation of methane, while the bulk of lattice oxygen was found responsible for the selective oxidation of methane [157]. In any case, iron activates an oxygen molecule that is present in the environment, where the transformation of methane takes place. Subsequently, the oxygen molecule generates a radical that initiates the reaction of C(sp3)-H activation. Since our main objective is to discuss reactions in which iron is directly involved in the C-H activation step, this field will not be examined in depth. Methane is the most structurally simple molecule that bears a C(sp 3)-H bond. However, in organic synthesis, C(sp 3)-H bonds that are present in highly complex molecules are frequently the target for installation of functionalities. Considerable advancements have been made with regards to the development of iron-based catalytic systems for the oxidation of C(sp3)-H bonds [158-162]. Herein, we summarize the work that has been carried out until now by the scientific community in order to overcome the inert nature of C(sp3)-H bonds.

62

In 2007, Nakanishi and Bolm introduced the reaction of catalytic benzylic oxidation under mild conditions [163]. In this non-organometallic C-H activation reaction, tert-butyl hydroperoxide acts as the oxidant and iron(III) chloride as the catalyst providing the corresponding oxidation product 153 of the benzylic saturated carbon of substrate 152. According to the experimental procedure, the catalyst is used in small quantities, while additional acid or ligand was not necessary for the reaction to proceed. These reaction conditions were tested on numerous substrates, as shown in Scheme 40. Less activated reductants, having one annelated aryl group in their cyclic system, led to benzylic oxidation products in moderate yields similarly to acyclic compounds bearing one (hetero)-aryl group [163, 164].

Scheme 40. Catalytic benzylic oxidation under mild conditions [163].

63

In 2008, Li and co-workers developed a C-C bond formation protocol including the direct, selective, non-organometallic activation of C-H bonds adjacent to a heteroatom [165]. The coupling of tetrahydrofuran (154a, Scheme 41) with ethyl benzoylacetate (155a) was chosen as the model reaction to reach the desired product 156 under optimized reaction conditions. The best results were achieved when 3 equivalents of tert-butyl peroxide and 10 mol% of diiron nonacarbonyl [Fe2(CO)9] (157) were employed under reflux. Both cyclic and linear ether derivatives 154a-154e, 154f-154h gave the corresponding products, reacting with various dicarbonyl substrates 155. These experiments showed that not only β-ketone esters, but also 1,3-diketones and β-ketone amides reacted with ether derivatives to give the desired products in good yields under the standard reaction conditions. Also, substrates containing sulfide (154i) and amine (154j) groups could be used in this iron-catalyzed C-H transformation. Experiments using deuterated tetrahydrofuran were also carried out to prove that iron-carbene species is not formed during the course of the reaction. Finally, Li and coworkers conducted kinetic isotopic effect (KIE) experiments and proved that the C-H bond cleavage is the rate-determining step of this transformation [165].

64

Scheme 41. C-C bond formation by C-H bond activation adjacent to a heteroatom [165]. A year later, Gan, Shi and co-workers reported the direct C-H olefination of benzylic C(sp3)-H bonds under mild conditions, using di-tert-butyl peroxide (DTBP) as the oxidant and iron(II) chloride (158) as the catalyst, to access their coupling products with substituted vinyl acetates (Scheme 42) [166]. In this study, diverse benzylic derivatives were used and it was found that electron-withdrawing groups lead to an increase in reaction yield, while electron-donating groups decrease its efficiency. Steric hindrance in ortho-substituted substrates, such as in the case of substrate 159g, was tolerated, although leading to lower yields. Cyclic diphenyl methane derivatives, such as 159e, 159h, 159i, were also suitable substrates for the reaction and resulted in good yields, varying from 69% to 77%. Similar results were obtained when toluene was used as a substrate (159k) with the moderate yield of 48%, while the benzylic methyl group of 159l showed excellent reactivity and the corresponding product was obtained in 94% yield. With regards to the aryl vinyl acetates that were used, such as in the ortho-, meta- and para-substituted derivatives 159b-d, it was found that steric effects have substantial impact on this protocol’s efficiency. Also, the reaction is favored when substrate 160 bears electron withdrawing groups such as in the case of substrates 160f and 160g [166].

65

Scheme 42. Catalytic benzylic olefination under mild conditions [166]. The benzylic olefination was proposed to proceed through a radical or a cationic process. Thus, this is another example of a non-organometallic C-H activation mode. Byproducts, such as those formed by the reaction of dimerization of diphenyl methane (163) and tert-butyl ether (164), shown in Scheme 43, were the major ones observed. An intermolecular isotopic competitive study was conducted, showing that a proton abstraction process is possibly involved in the rate-determining step. This transformation proceeds through either the radical process, or the cationic one. According to the proposed catalytic cycle, radical species I, generated in the first step from the action of oxidant, undergo further oxidation to the cation, which is subjected to electrophilic attack to yield the desired product.

66

Scheme 43. Proposed mechanism for the catalytic benzylic olefination [166]. In the same year, Palaniandavar and co-workers reported the synthesis and characterization of three iron complexes that catalyze the oxidation of saturated hydrocarbons using meta-chloroperoxybenzoic acid as co-oxidant [167]. These complexes are of the structural formula [Fe2(µ-O)(L11)2] (166), [Fe2(µ-O)(L12)2]·2H2O (167), and [Fe2(µ-O)(L13)2] (168), as shown in Scheme 44. Cyclohexane, ethylbenzene, cumene, and adamantane were used as substrates and were oxidized under a nitrogen atmosphere at room temperature. Oxidation of cyclohexane by utilizing 167 in the presence of meta-chloroperoxybenzoic acid (m-CPBA) leads to the formation of both cyclohexanol and cyclohexanone after 12 hours, while after 4 hours only cyclohexanol is formed. This fact suggests that the initially formed cyclohexanol is oxidized to cyclohexanone under catalytic conditions with an increase in reaction time. Also, a trace amount of 1-chlorocyclohexane was observed and its formation was attributed to the chloride ion in the coordination sphere of iron that was transferred to the substrate by an oxidative ligand transfer (OLT) pathway. Under the same reaction conditions, 67

ethylbenzene was oxidized to 1-phenylethanol and α-methylstyrene in small amounts, while cumene provided the corresponding alcohol product, 2-phenyl-2-propanol, along with styrene. In both cases, acetophenone was the major product. Oxidation of adamantane by the diiron(III) complex 167 exclusively afforded the hydroxylation products 1-adamantanol and 2-adamantanol. In contrast, the mononuclear analogue of 167 also provided adamantanone, as well as 1-chloroadamantane. In the case of adamantane, oxidation occurred both on secondary and tertiary carbons [167]. Note that this also a non-organometallic C-H activation mode of iron.

Scheme 44. The catalytic cycle for the oxidation of alkanes using m-CPBA as co-oxidant and the ligands used for the iron complexes [167]. 68

In 2009, Tu and co-workers reported the direct C-C cross-coupling of alcohols with olefins through the direct functionalization of C-H bonds at the α-position (Scheme 45) [168]. The coupling of 3-phenylpropanol (173a) with 1,1-diphenylethylene (174a) was selected for the optimization studies. Several iron sources, ligands, and solvents such as toluene, tetrahydrofuran, n-butylbromide, dimethylformamide, and dichloroethane were studied in this regard. FeCl2 (142) and Fe(acac)3 (160) proved to be less effective catalysts than FeCl3 (161), while dichloroethane was the solvent of choice. N,N,N’,N’-Tetramethylethylenediamine (TMEDA), NEt3, trans-1,2-diaminocyclohexane (DACH) and some additives such as lithium or copper salts were also tested as ligands, but no significant yield improvement was observed. Subsequently, a series of primary alcohols (173a-i) were treated with alkenes (174a-e) or tertiary alcohols (176a-d) leading to the corresponding secondary alcohols (175) in moderate to good yields. The coupling reactions using β-aryl alcohol 173g or 173h did not proceed to completion.

Scheme 45. Cross-coupling of alcohols with alkenes [168]. In the same work, Tu and co-workers conducted a series of experiments in order to propose a plausible mechanism for the cross-coupling reaction of alcohols with alkenes. 369

Phenylpropanal instead of the starting alcohol 173a was treated with the alkene 174a under the standard reaction conditions, but the formation of the targeted product was not observed. This proved that “oxidation/hydroacylation/reduction” or “transfer-hydrogenative coupling” processes are not involved in this transformation. In addition, several deuterium-labeling experiments were carried out in order to investigate the hydrogen transfer from alcohols (173) to alkenes (174). Also, D2O was used as an alternative source of hydrogen. The deuterium of D2O was partially installed at the C2 position of the product 175 (Scheme 46). Furthermore, the cross-coupling reaction was carried out using PhSH as radical scavenger and the observed inhibiting effect suggested the intervention of free radical species resulting from homolysis. According to the proposed mechanism, the reaction starts with iron-initiated activation of the C(sp3)-H bond adjacent to oxygen of the alcohol (173) leading to the transition state (I) shown in Scheme 46. Then, radical pair II is formed, followed by simultaneous free-radical addition and disassociation to afford [Fe]IV-H and free-radical species III. Finally, the metal hydride ([Fe]IV-H) undergoes an outer sphere-type hydrogen transfer to give the coupling product 175, regenerating the iron-catalyst [Fe]III. R1 OH H H R3

[Fe]

H +

R2

R1 174

R3

OH 173

R2 I [Fe]IV [Fe]III

R3

H + R 1

OH H

R2 II

R2 R3 OH H

3 2

175

1

R1

R3 [Fe]IV

H

OH

R2

R1 III

Scheme 46. Proposed mechanism of cross-coupling reaction of alcohols with alkenes [168].

70

A year later, Mancheño and Richter reported the activation of benzylic C(sp 3)-H bonds adjacent to an oxygen or nitrogen atom [169]. Substrate 177 (Scheme 47) undergoes oxidation by 2,2,6,6-tetramethyl-1-oxopiperidin-1-ium tetrafluoroborate (178) to form intermediate I, which interacts with 179 to provide carbon-carbon coupling product 180. In this reaction, iron serves as the catalyst, activating the nucleophile, in cooperation with the oxidant, which activates the benzyl ether (non-organometallic mode of action). This protocol leads to moderate to good yields. Isochromane derivatives 177c and 177d were found to be more reactive than noncyclic benzyl ethers 177e and 177f, while nitrogenated substrates 177g-j showed higher reactivity compared to the oxygenated analogues. Intramolecular reaction of substrates 177k and 177l yielded the expected annulated products. N,N-diBocprotected benzylamine (177m) yielded the mono N-Boc-protected derivative as major product, along with mono-N-Boc benzylamine which does not re-enter the catalytic cycle. Malonates and β-keto esters 179a-i were used as activated carbon nucleophiles to provide the desired products, besides the case of substrate 179g that showed no reactivity due to the fact that it coordinates strongly with the catalyst. Trace amounts of water led to the formation of oxidized product 182, while in the absence of both malonate and iron catalyst the oxygenated product of isochromane dimerization 183 was formed [169].

71

Scheme 47. Possible ionic mechanistic pathways for the reaction of Fe-catalyzed dehydrogenative coupling with the use of T+BF4– [169]. In the same year, Nakamura and co-workers reported the C(sp 3)-H bond activation of aliphatic amines bearing an N-(2-iodophenyl)methyl group, such as 184 and its derivatives, to prepare α-substituted product 185 (Scheme 48) [170]. The reaction commences with the formation of a radical on the iodo-substituted carbon of the molecule. The formation of a radical was confirmed by the phenylation of the asymmetric N-methyl-N-butylamine 184e, that took place preferentially at the more substituted chain. The formed radical is subsequently localized on the α-carbon of the amine, through 1,5-hydrogen transfer.

72

Deuterium-labeling

experiments

showed

that

1,5-hydrogen

transfer

takes

place

intramolecularly and, therefore, does not constitute the rate determining step of the reaction. 1,5-Hydrogen transfer is followed by C(sp3)-C(sp2) bond formation on the coordination sphere of the formed organoiron intermediate to yield product 185 through reductive elimination, as shown in Scheme 48. The reaction was found to be dependent on the solvent used, while many aliphatic amines were amenable to this protocol [170].

Scheme 48. Iron-catalyzed C-C bond formation at the α-position of aliphatic amines with Grignard or organozinc reagents [170].

73

A year later, Chen, Qiu and co-workers reported the iron-catalyzed coupling of imidazoles with benzylic compounds via the oxidative activation of C-H bonds [171]. The coupling of benzimidazole (186a) and diphenylmethane (159a) was chosen as the model reaction in order to find the optimal reaction conditions (Scheme 49). Although copper salts are often used as catalysts in oxidative coupling reactions, their application in this particular coupling resulted in the desired product with less than 5% yield. Iron trichloride was also tested; however, iron dichloride showed the best reactivity. PhI(OAc)2, 2,3-dichloro-5,6-dicyanobenzoquinone, 1,4-benzoquinone, and di-tert-butyl peroxide (DTBP) were tested as oxidants, with the latter being the most efficient. The choice of solvent had a substantial influence on the outcome of the reaction. When the reaction took place in dimethyl sulfoxide and methanol no product was obtained, but when the reaction was carried out in chlorobenzene at 120 oC, utilizing iron dichloride as iron source, the yield was increased to 72%. These were the optimal conditions for the coupling reaction. The coupling of a variety of benzylic hydrocarbons (187a-187m, 159a, 159c, 159d, 159k) with benzimidazole was investigated. Some diarylmethanes bearing either electron-withdrawing or electron-donating groups (159a, 159c, 159d, 187a-187c, 187e, 187f) react efficiently and the corresponding products are obtained in moderate to good yields. Yet, strong electron-withdrawing groups disfavor the reaction and lead to considerably low yields. Less activated benzylic hydrocarbons, such as 187g and 187h also lead to α-aminated products. Benzimidazole can also react with primary benzylic C-H bonds (187i-187m, 159k). As expected, 4-chlorotoluene (187m), bearing an electron-withdrawing group, shows lower activity towards oxidative C-H activation. To further investigate the scope of the reaction, the authors examined the dehydrogenative coupling of various imidazoles (186b-186k) with a benzylic C(sp3)-H bond under the optimal reaction conditions. Benzimidazole (186b) having two methyl groups at its 5- and 6-position showed relatively lower activity compared to 186a. 186c-186g, having either electron-withdrawing or electron-

74

donating groups, displayed higher activities than benzimidazole. 4,5-Diphenyl-1H-imidazole reacted with diphenylmethane to afford the corresponding product in relatively lower yield. The lower reactivity of 4,5-diphenyl-1H-imidazole was attributed to the fact that it is a relatively large molecule with increased steric hindrance. 5-Dicyano-1H-imidazole (186j) reacted quantitatively with diphenylmethane, while imidazole (186k) was totally unreactive [171].

Scheme 49. Coupling of imidazoles with benzylic compounds [171]. Chen, Qiu and co-workers proposed that the coupling reaction between imidazoles and benzylic compounds starts with the abstraction of a hydrogen atom from diphenylmethane (159a) by a di-tert-butyl peroxide molecule in the presence of FeCl2 to form a diphenylmethane radical (non-organometallic mode of action). The radical thus formed, gets oxidized to a benzylic cation through a single-electron transfer process assisted by a Fe(III) ion. Eventually, nucleophilic reaction of benzimidazole (186a) with the benzyl cation affords product 188a (Scheme 50). 75

Ph t

BuOH +

N N

162

Ph

t

BuOOtBu + Ph Ph 159a

FeIICl2

188a

t

BuOH

162 NH N 186a

t

BuO-FeIICl2 + II Ph Ph

t

BuO-FeIIICl2 + I Ph Ph

Scheme 50. Proposed mechanism for the coupling reaction between imidazoles and benzylic compounds [171]. In the same year, Huang and co-workers developed a method for the alkenylation of 2substituted azaarenes through C(sp 3)-H bond activation catalyzed by iron acetate (Scheme 51) [172]. The reaction between 8-methoxy-2-methylquinoline (189a) and tosylimine (190a) was chosen in order to probe the optimal reaction conditions. The reaction was carried out in various solvents such as DMF, DMA, dioxane, CH2ClCH2Cl, 2-PrOH, toluene and mesitylene, using iron acetate as the catalyst. In all cases, the desired product was formed with more than 90% isolated yield. The effect of temperature on the reaction outcome was examined and it was found that reactions conducted at 120 oC gave the best results. Finally, the effect of catalyst loading was investigated and it was shown that when the catalyst loading was decreased from 10 to 1 mol% the reaction still yielded the desired product almost quantitatively. Afterwards, the scope of the reaction was examined using various N-sulfonyl aldimines (190a-190s). The reaction was not significantly influenced by the substituents on the aromatic ring of the aldimines, as the reactions of 190a-190q with 8-methoxy-2methylquinoline (189a) revealed. Both electron-poor and electron-rich aryl-substituted aldimines yielded the desired products efficiently. Naphthyl aldimine (190l) and aldimines bearing either a heteroaromatic (190m) or an alkenyl substituent (190q) led to the desired

76

product with excellent yields. para-Nitrobenzenesulfonyl protected aldimines 190n-190q gave the corresponding olefins in more than 90% yield, while use of Boc and Cbz protected aldimines resulted the desired products with less than 20% yield. Subsequently, a series of 2substituted azaarenes (189a-189o, 15a, 15c, 15d) were examined to further explore the scope of the reaction. Diversely substituted 2-methylquinolines led to the formation of 2alkenylated quinolines in good to excellent yields with high regioselectivity. Finally, apart from quinolines and quioxalines a series of 2-substituted pyridines (15c, 15b, 189n, 189o) afforded the corresponding 2-alkenylated pyridines in good yields [172]. R1

R1 N

R2

+

Ar

N

189

Fe(OAc)2 (5 mol%) toluene, 120 oC, 24h

R3

O

N

189a

Br

N O

189c

N 189f

O

N 189g

O

N 189h

N

N 189i

O

N

N 15c

189m

189d

Br

Cl

O

N

N

189b Cl

189e

Cl

N

15a

Ar

191

190 O

N

N

N 189j

O

N

N 189k

189l

N

N

N

189n

189o

15b

190a: Ar= C6H5, R3= Ts 190b: Ar= 4-ClC6H4, R3= Ts 190c: Ar= 2-ClC6H4, R3= Ts 190d: Ar= 3-ClC6H4, R3= Ts 190e: Ar= 4-BrC6H4, R3= Ts 190f: Ar= 2-BrC6H4, R3= Ts 190g: Ar= 3-BrC6H4, R3= Ts 190h: Ar= 2,4-Cl2C6H3, R3= Ts 190i: Ar= 2,6-Cl2C6H3, R3= Ts 190j: Ar= 4-CH3C6H4, R3= Ts 190k: Ar= 4-CH3OC6H4, R3= Ts 190l: Ar= 1-naphthyl, R3= Ts 190m: Ar= 2-furyl, R3= Ts 190n: Ar= 4-CH3C6H4, R3= Ns 190o: Ar= 2-BrC6H4, R3= Ns 190p: Ar= 4-CH3OC6H4, R3= Ns 2ak 190q: Ar= (E)-C6H5CH=CH, R3= Ns 190r: Ar= C6H5, R3= Boc 190s: Ar= C6H5, R3= Cbz

Scheme 51. Alkenylation of 2-substituted azaarenes with N-sulfonyl aldimines [172]. Huang and co-workers also conducted experiments towards exploring the mechanism of the alkenylation reaction of 2-substituted azaarenes with N-sulfonyl aldimines. For that purpose, radical scavengers such as TEMPO and 1,1-diphenylethylene were employed in the standard reaction. The desired product 191 was still obtained with high yield, suggesting that 77

a free radical process was not involved in the alkenylation reaction. Kinetic isotope effect (KIE) experiments were carried out and revealed that the C-H bond cleavage is the ratedetermining step of this transformation and a concerted E2-elimination is most likely to be involved in the C-H and C-N cleavage step. Finally, using deuterium labeled substrates, it was found that intermediate I (Scheme 52) was responsible for the final olefin product [172].

Scheme 52. Proposed alkenylation reaction mechanism of 2-substituted azaarenes with Nsulfonyl aldimines [172]. In 2013, the catalytic coupling of an aryl Grignard reagent with an alkene under mild conditions was reported by Nakamura and co-workers [173]. It was found that the reaction proceeds through abstraction of an allylic hydrogen atom from the C(sp 3) of substrate 192, generating allylbenzene derivative 193. Deuterium labeling experiments showed that the abstraction of the allylic hydrogen atom is the rate determining step of this reaction, which is carried out at 0 oC in tetrahydrofuran using 5 mol% of the catalyst. It was also shown via deuterium labeling experiments, that both the aryl Grignard reagent and mesityl iodide participate in the hydrogen abstraction step to form complex II shown in Scheme 53, which presumably forms two π-allylic complexes of iron (III and IV). The mesityl substituted derivative of 193 was not observed, proving that steric effects hinder reductive elimination. In this study, various Grignard reagents were used, leading to moderate yields. Linear alkenes yielded only a trace amount of the desired products and the benzylic C-H bonds in toluene or

78

diphenylmethane were entirely unreactive, while halogen substituted derivatives led to the desired product with low yields [173].

Scheme 53. Catalytic allylic arylation of olefins [173]. In 2015, Varma and co-workers reported the iron catalyzed α-cyanation of secondary and tertiary amines towards 196a-196h with excellent yields (Scheme 54) [174]. The cyanation reaction is catalyzed by iron oxide nanoparticles supported via non-covalent interaction on graphitic carbon nitride (g-C3N4), in the presence of hydrogen peroxide and sodium cyanide. The cyanation mechanism possibly involves the formation of an oxo-iron(IV) species by the action of hydrogen peroxide, which upon its reaction with tertiary amine 195 results in the formation of an iminium ion through an outer sphere mechanism. The reaction of π-complex

79

II with in situ generated HCN provides the desired α-aminonitrile (196) shown in Scheme 54 [174].

Scheme 54. Iron catalyzed α-cyanation of secondary and tertiary amines [174]. Also in 2015, Liu, Li, and co-workers developed an iron-based catalytic protocol for the cross-dehydrogenative arylation of 3-substituted oxindoles (197) with activated arenes (198) to synthesize 3,3’-disubstituted oxindoles (199) in good yields (Scheme 55) [175]. The reaction between oxindole 197a and anisole 198a was chosen for optimization studies. The cross-coupling product of the model reaction was obtained in 90% yield in the absence of any oxidant, under a nitrogen atmosphere, but 200 mol% FeCl3 loading was required. Following a series of optimization experiments, FeCl3 was replaced by FeBr3 that gave the desired product with exclusive para-regioselectivity in 89% yield, using 20 mol% catalyst loading under air at 120 oC in three hours. The scope of the reaction was also investigated: 2oxindoles with different N-substituents (197a-197c) reacted with anisole, with N-substituents showing little effect on product yield. Subsequently, 3-substituted N-methyl oxindoles (197d197m) reacted with anisole. N-Methyl-3-methyl-oxindole (197d) gave the desired product with moderate yield. Replacement of a methyl with a phenyl group significantly increased the 80

substrate’s reactivity. Electron-donating substituents at the para-position of the 3-phenyl ring led to higher yields compared with the electron-withdrawing ones. Cyclic ketone 197n gave no cross-dehydrogenative arylation product. In addition, various aromatic compounds were used in order to draw conclusions on their efficiency in the reaction with 197a or 197e. Arene 198f showed excellent ortho-regioselectivity, as the para-position of the phenyl ring is blocked by a methyl group. Toluene was coupled with 49% yield and electron-rich heteroaromatic compounds 198g-198j gave the cross-dehydrogenative arylation products in good yields. When benzene or chlorobenzene was used as the arene substrate, the coupling product was not obtained, showing that increased electron density on the aromatic ring is necessary for the reaction [175].

Scheme 55. Cross-dehydrogenative arylation of 3-substituted oxindoles with activated arenes [175]. With regards to this cross-dehydrogenative arylation mechanism, the reaction is proposed to start with tautomerization of oxindole substrate 197a to its enol form I in the presence of 81

Fe(III)X3, which is readily oxidized to the corresponding radical via a single-electron-transfer (SET) process, forming Fe(II) (Scheme 56). Next, radical II and Fe(II) are oxidized by oxygen, forming cation species III and Fe(III) respectively. Anisole attacks cation III to provide cationic intermediate ΙV, which, after the loss of a proton, affords the desired crossdehydrogenative arylation product 199a [175]. Note that this is another non-organometallic mode of action of iron.

Scheme 56. Proposed mechanism for the cross-dehydrogenative arylation of 3-substituted oxindoles [175]. In 2013 Nakamura and co-workers reported the first iron-catalyzed, directed C(sp3)-H bond activation reaction [176]. Using Fe(acac)3 as the iron source and a biphosphine ligand (dppbz), they achieved the β-arylation of carboxamides under mild conditions (Scheme 57). The substrates, 2,2΄-disubstituted propionamides bearing a 8-quinolinyl moiety as directing group, provide the corresponding arylated products in moderate to high yields, with the reaction outcome being sensitive to the structure of the substrate. The reaction was proposed to proceed through organometallic C-H activation, which would be consistent with the

82

sensitivity displayed towards the choice of the ligand type, with bipyridines and (mono)phosphines being ineffective.

Scheme 57. Iron-catalyzed arylation of 2,2’ disubstituted propionamides [176]. Two years later, Ackermann and co-workers reported the directing group assisted activation of inert C-H bonds using FeCl3 and 1,2-bis(diphenylphosphino)ethane (dppe) thus obtaining the corresponding methylated derivatives (183a-183c, Scheme 58) [177]. Interestingly, they chemoselectively functionalized the less active methyl C-H bond at the αposition over the more activated benzylic C-H bond of substrate 182. The methylated derivatives (183a-183c) were obtained in moderate yields. Kinetic isotope effect experiments were carried out showing that this methylation is an organometallic C-H activation reaction.

Scheme 58. C(sp3)-H directing group assisted methylation [177]. In 2017, Ilies, Nakamura and co-workers reported the iron-catalyzed reaction of α-αdisubstituted propionamides with organoboron reagents [178]. The substrates are modified with 8-aminoquinoline, which serves as the directing group. These arylation and alkenylation 83

reactions are facilitated by a catalytic system based on the combination of Fe(acac)3, a diphosphine ligand, an organoboron reagent and a zinc co-catalyst (Scheme 59). The use of organoboron instead of organozinc reagents enables the successful installation of heteroaryl and alkenyl groups. Moreover, the mild organoboron reagents prevent the reduction of the organoiron (III) active species formed during the reaction. The catalytic efficiency of this alkenylation reaction is improved with the use of the electron rich ligand (Z)-1,2-bis[bis(4methoxyphenyl)phosphine]ethene (MeO-dppen).

Scheme 59. Iron-catalyzed arylation and alkenylation of α-α-disubstituted propionamides with organoboron reagents [178]. 5.3. C(sp2)-H activation Stoichiometric cyclometalation reactions with well-defined iron complexes that proceed through C(sp 2)-H activation [179-182], as well as C(sp 3)-H activation [183], have been known in the literature since 1979. During the last decade, many research groups have focused on the development of iron-based catalytic systems that promote C(sp 2)-H bond activation [184]. This growing interest led to some significant progress in this area. A brief description of the progress in the field of direct C-H bond functionalization with the use of ligand assisted iron-based catalytic systems until 2014 has been given by Mihovilovic and Schnürch [68]. 84

5.3.1. Arylation of C(sp2)-H bonds The direct formation of C-C bonds from C-H bonds is a powerful tool for synthetic chemistry, as it circumvents the prefunctionalization of substrates with more reactive functionalities such as triflates, organoboron moieties, etc. In this regard, Nakamura and coworkers reported an iron-catalyzed C-C bond formation reaction involving C-H bond activation in 2008 [185]. They developed an iron-based catalytic system and tested it in the phenylation of α-benzoquinoline (Scheme 60). The combination of phenylmagnesium bromide, ZnCl2, TMEDA, Fe(acac)3 and 1,10 phenanthroline with 1,2-chloro-2methylpropane in THF proved to be the most effective conditions. This catalytic system led to yields up to 99% after 16 hours at 0 oC. The authors studied the effects of other factors on catalytic activity as well. For example, ligand screening revealed that 1,10-phenanthroline afforded the best results. Lower yields were obtained using bpy, while more bulky ligands such as terpyridine or neocuproine deactivated the catalytic system.

Scheme 60. Iron catalyzed phenylation of α-benzoquinoline [185]. After testing a series of dihalides, 1,2-dichloro-2-methylpropane provided the best results. Another compound that enhances the catalytic activity is TMEDA, with low substrate conversions obtained when TMEDA was not added to the reaction mixture. Lower yields were also obtained for reactions that took place at higher temperatures (80 oC). 2Phenylpyridine substrates bearing electron withdrawing or electron donating groups at the 4position of the phenyl ring, provided excellent yields. However, substrates with electrondonating groups provided better results, significantly reducing the reaction time. In all reactions, the di-phenylated product was formed with the ratio of mono/diphenylated product 85

ranging from 3:1 to 8:1. Finally, the electronic characteristics of the arylzinc reagent did not seem to affect the activity of the system. In contrast, the steric characteristics of the arylzinc reagent had a great influence on catalytic activity, as use of 2-tolylzinc provided extremely low substrate conversion [185]. In the same year, Yu and co-workers reported the direct arylation of unactivated arenes catalyzed by iron [186]. As a model reaction they studied the coupling of 4bromobenzeneboronic acid with benzene (Scheme 61). In this reaction, they tested aminobased ligands 1,4,7,10-tetraazacyclododecane (cyclen), 1,2-ethylenediamine (en), N,N,N’,N’tetramethylethylenediamine (TMEDA), proline, and terpyridine, combined with iron salts in the presence of an inorganic base (K3PO4, K2CO3, Cs2CO3). Experiments showed that the coupling product is formed only in the presence of pyrazole; however, its role in the catalytic reaction remains unclear.

Scheme 61. Iron catalyzed coupling of benzene with 4-bromobenzeneboronic acid [186]. When reactions were performed without the addition of pyrazole, the coupling product was formed only in traces. Reactions performed under oxygen or air provided higher yields, suggesting the important role of O2 as the oxidant. Reactions performed under a nitrogen atmosphere provided the coupling product in traces [186]. Under the optimized conditions for this catalytic system, the authors investigated the impact of the arylboronic acid’s structure on the reaction outcome. They performed a series of experiments, using ortho-, meta- and parasubstituted arylboronic acids and benzene as substrates (Scheme 62).

86

Scheme 62. Catalytic coupling reactions between various substituted arylboronic acids and benzene (selected results) [186]. Steric hindrance significantly affects the reaction regardless of the functional group, with the ortho-substituted arylboronic acids providing much lower yields of the corresponding coupling product [186]. Additionally, substrates with increased acidity deactivate the catalytic system, as in these cases the coupling product is obtained in traces. Experiments with mono-substituted benzenes and phenylboronic acid showed that benzenes bearing electron withdrawing groups lead to higher yields (Scheme 63). However, in all cases, selectivity was moderate, resulting in a mixture of ortho/meta/para-coupling products. Interestingly, the ortho-coupling product is produced in higher yields in comparison with meta or para coupling products. Reactions carried out in the presence of a radical trap suggested the absence of radical species in the reaction mechanism. More specifically, addition of 20 mol% 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) in the reaction mixture did not decrease the yield of the coupling product [186].

87

R B(OH)2 +

212a

R

[Fe]/cyclen K3PO4/pyrazole 48 h, 110 oC 213

214

Product

Arene CH3 159k

Yield CH3

o/ m/p

213a (38%)

50:19:31

213b (82%)

57:24:19

213c (56%)

55:26:19

Cl Cl

214a

Br

214b

Br

Scheme 63. Iron catalyzed arylation of substituted arenes with phenylboronic acid (selected results) [186]. One year later, Nakamura and co-workers reported a method for the synthesis of orthosubstituted aromatic ketones by utilizing an iron-based catalytic system [187]. The combination of [Fe(acac)3] (10 mol%), 4,4’-di-tert-butyl-2,2’-bipyridine (dtbpy), a mild oxidant (1,2-dichloroisobutane - DCIB), and Ph2 Zn effectively converts an acetophenonederived imine (e.g., 4-methoxy-N-(1-phenylethylidene)aniline) into the corresponding orthophenylated product (Scheme 64). Τhis transformation is an imine-directed conversion of an ortho C-H bond into a C-C bond and it was carried out under mild conditions (20 hours, 0 oC in THF). The activity of the catalytic system decreases significantly at higher temperatures. Moreover, the catalytic system displays good tolerance when substrates bearing functional groups such as chlorides, bromides, and sulfonates are used. Also, substrates bearing CF3 substituents are more active, while those having halogen or -CN groups provided lower yields [187].

Scheme 64. The iron-catalayzed imine-directed activation of ortho C-H bonds [187].

88

A direct, iron-catalyzed coupling reaction between aryl halides and benzene was reported in 2010 by Lei and co-workers [188]. Using the coupling of para-bromoanisole with benzene as model reaction (Scheme 65), they tested various iron salts with amine-based ligands. The presence of a base is necessary, with the base’s nature affecting the catalytic activity of the system. For example, inorganic bases deactivate the catalytic system, while NaOtBu affords only traces of the coupling product.

Scheme 65. Direct, iron-catalyzed coupling of aryl halides with benzene. Reaction conditions: aryl halide (0.5 mmol), base (3.0 equiv) in benzene (3 mL, 34 mmol, 4 mL, 45 mmol, 5 mL, 56 mmol) [188]. The best yields (up to 79%) were achieved using FeCl3 as the iron source (20 mol%), DMEDA as the ligand (30 mol%), and LiHMDS or KOtBu as the base (3 equiv.). Substrates bearing electron-donating substituents provided higher yields (72-81%) than those having electron-withdrawing moieties (Scheme 66). The fact that ortho-substituted substrates provide much lower yields suggests that steric hindrance is an important factor dictating catalytic activity [188]. Moreover, the reaction works well with aryl iodides too. An interesting difference is the improvement on the activity of the catalytic system with the use of KOtBu instead of LiHDMS (Scheme 67).

89

Scheme 66. Iron catalyzed coupling of aryl bromides with benzene (selected results). Reactions conditions: aryl bromide (0.5 mmol) and LiHMDS (2.0 equiv) in benzene (4.0 mL, 45 mmol) [188].

Scheme 67. Direct coupling reaction between aryl iodides and benzene. Reactions conditions: aryl iodide (0.5 mmol), KOtBu (3.0 equiv), benzene (4.0 mL, 45 mmol). Yields in parentheses refer to reactions carried out with LiHMDS (2.0 equiv) in benzene (4.0 mL, 45 mmol) [188]. Experiments with 1-bromo-2-chlorobenzene and 1-bromo-4-chlorobenzene revealed the selectivity of the catalytic system towards aryl bromides, affording the products derived from C-Br activation with good yields (71% and 72% respectively) (Scheme 68) [188]. 90

Additionally, reactions between substituted aryl bromides and functionalized arenes led to the formation of isomers (Scheme 69). Interestingly, the ortho-substituted products were obtained in higher yield compared to the meta- or para-substituted ones, despite the increased steric hindrance.

Scheme 68. Arylation of ortho- and para-bromo-chlorobenzene [188].

Scheme 69. Coupling reaction of aryl bromides with functionalized arenes. Reaction conditions: i) 4-bromoanisole (0.5 mmol) intoluene (4.0 mL), ii) PhBr (0.5 mmol) in anisole (40 mmol) [188]. Nakamura and co-workers published another work, reporting the nitrogen-directed arylation of aryl pyridines and imines [189]. They amongst others focused on the role of the oxidant in the catalytic reaction. More specifically, they replaced the dihalide oxidant with air or molecular oxygen, using the phenylation of phenylpyridine as a model reaction (Scheme 70).

91

Scheme 70. Iron-catalyzed nitrogen-directed phenylation of phenylpyridine [189]. Excess of oxygen as the oxidant led to poor yields, as it deactivates the catalytic system. On the other hand, a slow diffusion of oxygen or air improves product yields. The main product is the mono-phenylated phenylpyridine with di-phenylated phenylpyridine forming in smaller amounts. Yields up to 80% of the mono-phenylated adduct were obtained, using 15 mol% catalyst loading and 5 equivalents of the diphenylzinc reagent. The large excess of the organozinc compound is necessary because a considerable amount is consumed in homocoupling and oxidation reactions affording the di-phenylated adduct and phenol products, respectively [189]. The catalytic cycle involves the ortho-metalation of the arylpyridine (or imine) with the in situ generated organoiron species, oxidation of the metallacycle intermediate thus formed by molecular oxygen, and transmetalation with the diarylzinc reagent. Reductive elimination eventually leads to the arylation product [189]. A major drawback of this catalytic system was the use of a large excess of zinc salts. To address this issue, the same research group later on published a work on the ortho-arylation of aryl pyridines and imines with Grignard reagents [190]. In this more recent work, the authors described an alternative procedure that circumvents the use of large excess of reagents. Basically, the aryl zinc reagent was replaced by an aryl Grignard reagent, which

92

was slowly added to the reaction mixture (Scheme 71). The use of chlorobenzene as cosolvent had a positive impact, decreasing the required stoichiometry of the organometalic reagent closer to the theoretical minimum and providing high reaction rates under mild conditions. This is a consequence of the fact that the key iron-based intermediate formed during the reaction was more stable when chlorobenzene was added to the reaction mixture.

Scheme 71. Iron-catalyzed arylation of aryl pyridine or imine derivatives with Grignard reagents [190]. The phenylation of 2-phenylpyridine with PhMgBr was used as the benchmark reaction to optimize the reaction conditions (Scheme 72). Different bidentate amine ligands and solvent mixtures were probed. The most promising results were obtained with 4,4΄-di-tert-butyl-2,2΄bipyridine (dtbpy) as the ligand and a benzene/THF mixture as the solvent. Addition of benzene significantly increased yields, simultaneously decreasing the formation of biphenyl deriving from the oxidative homocoupling of the Grignard reagent [190]. With these conditions in hand, the authors examined the effect of other aromatic co-solvents. The phenylation of benzo[h]quinoline was selected for this purpose, as it normally affords low yields (Scheme 73).

Scheme 72. Nitrogen-directed phenylation of 2-phenylpyridine with Grignard reagents. Reaction conditions: 2-phenylpyridine (0.4 mmol), Fe(acac)3 (0.04 mmol), ligand (0.04 93

mmol), PhMgBr (1.25 M in THF, 1.2 mmol), 1,2-dichloro-2-methylpropane (0.8 mmol), solvent (3 mL). PhMgBr was added over about 30 s [190].

Scheme

73.

Iron-catalyzed

ortho-arylation

of

benzo[h]quinoline

with

4-

methoxyphenylmegnesium bromide and arene/THF as solvent. Reaction conditions: benzo[h]quinoline (0.4 mmol), Fe(acac)3 (0.04 mmol), ligand (0.04 mmol), 4MeOC6H4MgBr (1.19M in THF, 1.28 mmol), 1,2-dichloro-2-methylpropane (0.8 mmol), solvent (2.9 mL) [190]. The improved arylation procedure of using chlorobenzene as the co-solvent and by slowly adding the Grignard reagent was employed on the arylation of various arylpyridine derivatives (Figure 2). Substrates bearing electron-donating groups (233a, 233b) provided higher yields compared with substrates functionalized with electron-withdrawing groups (233d, 233e). Lower yields were obtained for ortho-substituted substrates bearing groups with unfavorable steric characteristics (235a, 235b). Heteroaryl substrates (237, 239) could be phenylated, albeit leading to relatively low yields.

94

Figure 2. Nitrogen-directed iron-catalyzed arylation of arylpyridine derivatives with arylmagnesium bromide [190]. This more simple experimental procedure allowed, amongst others, for the study of the reaction mechanism. Experimental results provided significant insight, supporting the formation of an ortho-metallated intermediate. On this basis, the proposed catalytic cycle is shown in Scheme 74. Initially, the ligand coordinates to the metal center and reaction with the Grignard reagent forms the catalytically active aryliron species I. The iron center of these species (I) is coordinated in a reversible way, leading to the formation of aryliron species II. In the next step, irreversible metalation at the ortho position of the intermediate aryliron species (II) with simultaneous elimination of an arene molecule leads to the formation of ortho-ferrated intermediate III. Reductive elimination of this ortho-ferrated intermediate 95

upon interaction with 1,2-dichloro-2-methylpropane (241) affords the ortho-arylation product, isobutene and dichloroiron species IV. Finally, the catalytically active species I is regenerated through a transmetalation step involving intermediate IV and the Grignard reagent. Direct reaction of active species I with the dichloroalkane leads to the formation of the undesirable homocoupling product of the Grignard reagent. The authors speculated that the aromatic solvent acts as a ligand, stabilizing a low valent iron species and that the slow diffusion of the Grignard reagent is an effective way to control the formation of the catalytically active iron species [190].

N N

226

H II

H Fe(acac)3 + dtbpy

ArMgBr

ArH

FeAr2Ln

N

LnFeAr2 I

III

FeArLn

2MgBrCl Cl

Cl 2ArMgBr

241

LnFeCl2 IV 230

N + Ar

242

Scheme 74. Proposed reaction mechanism for the nitrogen-directed iron-catalyzed arylation of arylpyridine derivatives [190]. Along the same lines, Nakamura and co-workers have also reported the iron-catalyzed stereospecific activation of olefinic C-H bonds with Grignard reagents [191]. Initially, following the procedure with the slow addition of the Grignard reagent, they studied the phenylation of vinylpyridines achieving high product yields. Use of different solvent mixtures was shown to affect the stereochemistry of the final product (Scheme 75).

96

Scheme 75. Stereoselectivity control of the final product in the iron-catalyzed phenylation of 1-substitued vinylpyridines [191]. The double bond geometry of the substrate is another factor that influences the outcome of the reaction. As shown in Scheme 76, substrates with E or Z stereochemistry on the double bond exert different reactivity, with substrates having E double bond configuration affording higher yields. As anticipated, the nature of the Grignard reagent affects the reaction yields as well. Reagents with electron-withdrawing or donating groups react well, meta-substituted reagents lead to high yields, while ortho-substituted reagents show no reactivity at all (Figure 3).

Scheme 76. Comparison of E or Z isomers’ reactivity in the iron-catalyzed phenylation of 1substitued vinylpyridines [191].

97

Figure 3. Reactions with Grignard reagents bearing different functional groups in the ironcatalyzed phenylation of 1-substitued vinylpyridines (selected results). Reaction conditions: olefin (0.4 mmol), Fe(acac)3 (10 mol %), dtbpy (15 mol %), and 1,2-dichloro-2methylpropane (2 equiv) in PhCl, slow addition of PhMgBr in THF (3.2 equiv) at 0 oC over 5 min [191]. A five-membered metallacycle intermediate, which undergoes reductive elimination affording the final product (Scheme 77, reaction a), was postulated. The absence of products that can be attributed to the carbometalation pathway (reaction b) and the fact that only the Eisomer is active in the phenylation reaction, suggest that the reaction does not proceed through a Heck-type mechanism involving β-hydride elimination [191].

Scheme 77. Possible reaction pathways for the iron-catalyzed phenylation of 1-substitued vinylpyridines: (a) C-H activation, (b) carbometalation [191]. Another protocol employing aryl halides and metallic magnesium instead of preformed Grignard reagents in the same nitrogen-directed iron-catalyzed phenylation reaction was reported by Nakamura and co-workers in 2012 [192]. An important modification in this approach is the use of THF/1,4-dioxane as the solvent mixture (Scheme 78). 98

Scheme 78. Iron-catalyzed nitrogen-directed coupling of arenes with arylbromides [192]. Although the reaction may be initiated by the in situ generation of a Grignard reagent, the formation of such a compound is not certain considering the reaction conditions and participating reagents [192]. This protocol was applied in the coupling of benzo[h]quinolone with various arylhalides in the presence of metallic magnesium (Figure 4). Bromo arenes provided high yields, iodo arenes were less reactive, and chloro arenes were non-reactive. Steric factors affected the reactivity of the halide, as ortho-substituted arenes led to much lower yields. Heterocyclic halides containing sulfur or oxygen are also amenable to this protocol, albeit providing the corresponding coupling products in low yields.

99

Figure 4. Iron-catalyzed nitrogen-directed ortho-arylation of benzo[h]quinolone with arylhalides in the presence of metallic magnesium (selected results). Reaction conditions: benzo[h]quinoline (0.40 mmol), organic halide (3.0 equiv.), Fe(acac)3 (2.5 mol%), dtbpy (2.5 mol%), metallic magnesium (3.3 equiv.), DCIB (2.0 equiv.) in THF/1,4-dioxane (1:1) at 0 °C, vigorous stirring [192]. A disadvantage of this iron-catalyzed nitrogen-directed phenylation is the formation of both mono- and di-phenylated products. In this regard, Nakamura and co-workers have also reported the arylation of benzamide derivatives leading to the exclusive formation of the corresponding monoarylated products (Scheme 79) [193].

100

Scheme 79. Nitrogen-directed iron-catalyzed ortho-monoarylation of N-methylbenzamide [193]. Use of N-methylbenzamide (264) leads to the formation of coupling product 265 in good yield, while the coupling of primary benzamine 266 or substrates with bulkier groups (267, 268) is unsuccessful. A possible explanation is the strong coordination of 266 to the metal center and the stereoelectronic features of 267 and 268 that do not allow the effective coordination of the ligand to the metal center. The reactivity of various substrates with different characteristics (bulky substituents, electronic features) was evaluated in screening experiments (Figure 5). Substrates bearing electron withdrawing or electron donating groups provided the coupling product in good yields. Grignard reagents with steric constraints proved unreactive under the experimental conditions.

Figure 5. Iron-catalyzed ortho-arylation of N-methylarenecarboxamides (selected results). Reaction conditions: N-methylarenecarboxamide (0.50 mmol), ZnCl2·TMEDA (1.50 mmol), dtbpy (0.10 mmol), ArMgBr (ca. 3.5 mmol), Fe(acac)3 (0.10 mmol), DCIB (1.00 mmol), THF, 0 oC [193].

101

The proposed mechanism for this coupling reaction (Scheme 80) is similar to the mechanism of the iron-catalyzed ortho arylation of arylpyridines, which is shown above in Scheme 74. ZnAr O ZnAr

O

N

277

N H

H

ArH

FeAr2Ln

II ZnAr

ZnAr Fe(acac)3 + dtbpy

2Ar2Zn (Mg2+/TMEDA)

O

O LnFeAr2 I

N

N

III

FeArLn

2ArZnCl IV 2Ar2Zn

Cl

LnFeCl2

Cl 241

FeArLn ferracycle formation is not favored in case of ortho substituted substrates

ZnAr

O

N Ar

+ 242

278

Scheme 80. Proposed catalytic cycle for the iron-catalyzed nitrogen-directed ortho-arylation of N-methylarenecarboxamides [193]. In a related work, Ackermann and co-workers reported the use of triazole as directing group in iron-catalyzed C-H activation/arylation reactions (Scheme 81) [194]. For this reason, various benazamide substrates modified with 1,2,3-triazole groups were prepared. Based on the protocol developed by the Nakamura group, Ackermann and co-workers used FeCl3 as the iron source and 1,2-bis(diphenyphosphanyl)ethane as the ligand (dppe). Under mild reaction conditions, the triazolyldimethylmethyl (TAM) amide substrate led to the coupling product in excellent yield.

102

Scheme 81. Iron-catalyzed C-H activation/arylation of TAM-bearing amides as substrates [194]. The nature of the triazole N-substituent significantly affects the reactivity of the substrate (Scheme 82). Amides bearing N-alkyl or N-aryl triazoles (282a-282d) lead to the corresponding coupling product in moderate to excellent yields. Changing the proton of the amide for a methyl group dramatically decreases substrate’s reactivity, as the use of a tertiary amide does not provide the corresponding coupling product. Ester 281f is also inactive, as well as secondary amides (282g, 282h) and pyridyl-substituted amide 281i.

Scheme 82. Reactivity of various 1,2,3-triazole-bearing amides in the iron-catalyzed C-H activation/arylation reaction [194]. Substrates bearing a TAM group provided the highest yields (Scheme 76). Benzamides having electron withdrawing or electron donating groups provide the coupling product in high yields. As shown in Scheme 83, a variety of Grignard reagents were also examined. Both the meta- and the para-substituted Grignard reagents that were employed participated successfully in the arylation reaction, affording the coupling products in high yields [194]. 103

Scheme 83. Iron-catalyzed arylation of benzamides modified with a TAM moiety [194]. The application of the same catalytic system in the functionalization of olefinic C-H bonds led to interesting results (Scheme 84). Phenylated alkene 271 is obtained with excellent diastereoselectivity as the sole product in the Z-configured olefin in relatively good yield. Finally, the TAM group can be easily removed affording the desirable products in high yields, as is shown in Scheme 85.

Scheme 84. Iron-catalyzed TAM-directed arylation of alkenes [194].

Scheme 85. Removal/hydrolysis of the TAM directing group [194].

104

In the same year, DeBoef and co-workers reported a related, nitrogen-directed ironcatalyzed arylation of heterocycles [195]. The catalytic reaction proceeds via C-H bond activation in the presence of an imine directing group. Initial experiments, using a pyridinebased substrate, showed that Fe(acac)3 (10 mol%) with 4,4′-di-tert-butyl bipyridine (dtbpy) as the ligand (Fe/ligand ratio 1:2) give the best results, while addition of KF decreases the formation of the biphenyl side-product. The structural and electronic characteristics of the moieties bonded to the nitrogen-directing atom affect the substrate’s activity (Scheme 86). Screening experiments showed that, in general, aniline derivatives provide the best yields, with para-methoxyphenyl (PMP) affording lower yields. Oximes ethers and alkyl imines proved to be inactive substrates.

Scheme 86. Impact of the directing group in the iron-catalyzed imine-directed arylation of heterocycles [195]. Various heterocyclic substrates were studied under the optimized reaction conditions (Figure 6). In many cases, the conversion was quantitative, but the isolated yields of the final products appeared much lower due to the difficult chromatographic separation. Ketone products were easily formed in most cases by acidic hydrolysis of the corresponding imines (Figure 6). The stereochemical features of the substrate have a substantial effect on the outcome of the reaction. Substrates with a quinoline or a 3-methyl thiophene core were

105

unreactive. A thiophene containing substrate was more reactive compared to one containing a benzothiophene ring. It is also notable that substrates containing an oxygen-based heterocyclic ring with higher steric hindrance appear more active [195].

Figure 6. Products derived from the iron-catalyzed imine-directed arylation of heterocycles bearing variable heterocyclic rings [195]. The nature of the Grignard reagent is another factor that affects the efficiency of the catalytic system. By studying the arylation of thiophene, the authors tested several Grignard reagents with diverse functional groups (Scheme 87). Grignard reagents with halogenated aryl substituents provide low to high yields, while reagents bearing electron donating groups on the aromatic ring provide slightly decreased yields, in comparison with 308a. The coupling product was not formed in reactions with methyl or cyclohexyl Grignard reagents [195].

106

Scheme 87. The iron-catalyzed imine-directed arylation of thiophene with Grignard reagents [195]. In 2014, Ilies, Nakamura, and co-workers reported a new method for the direct functionalization of C(sp2)-H bonds [196]. By introducing the use of organoboron compounds, they managed to replace the Grignard or organozinc reagents used in previously reported procedures. This approach begins with the preparation of borate 311 by the reaction of BuLi with boron compound 41 at low temperature (-78 oC), followed by the addition of the other reagents (solution of iron salt with the ligand and zinc reagent) at room temperature. 1,2-Dichloroisobutane (DCIB) is then added and the mixture is heated up to 70 oC (Scheme 88).

Scheme 88. Iron-catalyzed nitrogen-directed arylation with organoboron compounds [196]. This protocol is efficient with slight modifications for alkenyl, aryl, and heteroaryl compounds bearing quinolylamide or pyridine directing groups. Both alkenyl and aryl boron compounds are amenable to the reaction. Under the optimized conditions, a large number of substrates (44 examples) afforded the coupling product in good yields with excellent regioselectivity (E or Z isomers were obtained with over 99% selectivity in most cases). Some selected results are shown in Figure 7. The key step in this transformation was proposed to be the zinc-mediated transmetalation from boron to iron. This step leads to the formation of an organoiron(III) intermediate that undergoes C−H cleavage and C−C bond formation [196]. 107

Figure 7. Products obtained from the iron-catalyzed nitrogen-directed coupling of various substrates with alkenyl and aryl boronates (selected results) [196]. Another iron-catalyzed arylation methodology has been reported by Ghosh and coworkers [197]. Iron(III) complex 309, derived from the reaction of anhydrous FeCl3 with N2,N6-bis(2,6-diisopropylphenyl)pyridine-2,6-dicarboxamide

(L16)

[198]

upon

its

deprotonation with BuLi, catalyzes the arylation of furan with Grignard reagents (Scheme 89).

+

309 (0.02 mol %)

RMgCl

25 oC, Ar, 1h DBE (6 equiv)

O 328

327

MgCl

MgCl

329 MgCl

MgCl

3

328a (42 %)

R

O

5

328b (33 %)

328c (32 %)

328d (27 %) 2Li+

O i-Pr

O

O

O

O

i-Pr i-Pr

i-Pr i-Pr

N Fe N Cl i-Pr i-Pr

L16

I

330

N NH

HN

i-Pr

i-Pr n-BuLi

N N

N

i-Pr

i-Pr FeCl3

N

O iPr

Scheme 89. Iron-catalyzed arylation of furan with Grignard reagents [197].

108

The first iron-catalyzed tandem C-H activation was reported by Desage-El Murr, Fensterbank, and co-workers in 2014 [199]. Using low valent iron complexes with noninnocent bisiminopyridine ligands, they achieved the arylation of aryl halides with benzene. Based on mechanistic investigations complemented by DFT studies, the authors proposed that the reaction proceeds through an inner sphere C-H activation mechanism, which is a rare phenomenon for iron complexes. 5.3.2. Cyanation of C(sp2)-H bonds The direct cyanation of arenes through C-H bond activation is an attractive method for the preparation of benzonitriles, a valuable class of compounds that can undergo a number of transformations. In 2011, Chen and co-workers reported the iron-catalyzed cyanation of trimethoxybenzene, indole, and 2-arylpyridine (Scheme 90) [200]. FeI2 proved to be the most efficient iron source in this regard, at 30% loading, while air proved to be competent as the oxidant. PhI(OAc)2 as the oxidant afforded higher yields, in shorter reaction time compared to air. The cyanation of indoles proceeds only with PhI(OAc)2 as the oxidant, while the cyanation product is obtained in moderate to high yields using various indole substrates. In general, substrates bearing electron donating groups provided higher yields (Scheme 91). With regards to the cyanation of substituted 2-arylpyridines, use of PhI(OAc)2 as the oxidant led to moderate to high yields (Scheme 92). Concerning the regioselectivity of the reaction, meta-substituted substrates lead to the exclusive formation of the ortho-cyanated product [200].

109

Scheme 90. Iron-catalyzed cyanation of methoxybenzenes (n= 2, 3) [200].

Scheme 91. Iron-catalyzed cyanation of indoles [200].

+ R

CuCN

N

FeI2 (30 mol%) PhI(OAc)2, 130 oC

N

N

N

336a (71%)

N 336c (63%)

N

336b (80%)

232a (64%)

F

Cl

MeO

N CN 337

332

336

226 (63%)

R

234b (60%)

NC N

N 336d (68%)

N

336e (57%)

N 336f (56%)

N N 336g (59%)

208 (50%)

Scheme 92. Iron catalyzed cyanation of 2-arylpyridines [200]. A method for the iron-catalyzed oxidative cyanation of arenes was furthermore reported by Wang co-workers in 2014 [201]. This protocol works well towards the cyanation various aromatic substrates, including heterocyclic compounds. The catalytic reaction proceeds through a radical mechanism, in which the iron atom participates in the activation of the C-H bond through the formation of a metallated intermediate. 110

5.3.3. Borylation of C(sp2)-H bonds In 2010, Ohki, Tatsumi, and co-workers reported the synthesis of iron complex Cp*Fe(LMe)Me (Cp*= η5-C5Me5, LMe= 1,3,4,5-tetramethyl-imidazol-2-ylidene), prepared via the reaction of Cp*Fe-(TMEDA)Cl (TMEDA= N,N,N’,N’-tetramethylethylenediamine) with methyllithium and LMe (Scheme 93) [202]. This iron complex is sensitive against air and moisture, but thermally stable in solution. The reaction of complex 339 with furan or thiophene proceeds stoichiometrically at room temperature, affording the corresponding complexes via C-H activation (340, Scheme 94). When benzene is used as the substrate, the same reaction requires prolonged reaction time and more intense conditions (7 days at 80 oC).

Scheme 93. Synthesis of complex [Cp*Fe-(LMe)Me] [202].

Scheme 94. Stoichiometric reaction of 339 with furan, thiophene, or benzene [202]. The catalytic activity of complex 339 was evaluated in the borylation of furan, thiophene, and their substituted analogues (Scheme 95), showing remarkable selectivity and activity. Furan and thiophene lead to the exclusive formation of the 2-Bpin ester product, while 2substituted furans and thiophenes lead to the 5-Bpin ester derivatives. In the case of 3substituted furans or thiophenes the reaction leads to the formation of a mixture of regioisomers with the major product being substituted in the 5-position [202]. 111

Fe Me

N N

318 (10 mol% to Bpin)

O

E +

H B

+ O

341

tBu

342 (HBpin) portionwise addition

343 (TBE)

O E

o

60 - 70 C

B O

+ tBu

344

345

E = O or S

Scheme 95. Iron-catalyzed borylation of furan and thiophene [202]. The best results in terms of product yield and selectivity in the borylation reaction were achieved with a 1:6:2 molar ratio of HBpin/furan/TBE, respectively. The reaction proceeds in the presence of TBE and requires a small concentration of HBpin, as larger amounts of HBpin can lead to the formation of a stable complex with 340 (Scheme 96). For this reason, HBpin was added to the reaction mixture in small portions.

Fe Ar

N N 340

342 O H B O 2.2 equiv. C6D6, RT

Fe

H H

N N

O B O O

+

Ar B O

346

344

O Ar =

340a

346a (> 99%)

344a (> 99%)

340b

346b (86%)

344b (72%)

340c

346c (78%)

344c (68%)

S

Scheme 96. Reaction of complex 319 with an excess of HBpin [202]. The proposed mechanism for the catalytic borylation reaction is shown in Scheme 97. The complex is initially activated by reacting with the substrate. The next step, leading to the formation of the coupling product, is the borylation of the iron-furyl group of complex I with HBpin and the formation of iron-hydride intermediate II. This intermediate reacts with tertbutylethylene, which inserts into the Fe-H bond of the iron hydride, leading to the formation

112

of iron alkyl complex III. The final step is the regeneration of the catalyst by the reaction of complex III with furan (327).

Scheme 97. Proposed mechanism for the iron-catalyzed borylation of furan [202]. Τhe first iron-catalyzed dehydrogenative borylation of heteroarenes with pinacolborane was reported in 2015 [203]. This catalytic system is based on a well-defined iron bis(diphosphine) complex (350). The catalytic reactions were performed using 5 mol% catalyst loading under UV irradiation (350 nm) at room temperature (Scheme 98). The borylated products were received in moderate to high yields without the need of additives. Substituted arenes led to the corresponding products as a mixture of meta and para borylated derivatives. This protocol is efficient for substrates having a heterocyclic ring.

113

Scheme 98. Iron-catalyzed borylation of heteroarenes with pinacolborane [203]. 5.3.4. Amination of C(sp2)-H bonds The catalytic amination of C-H bonds represents an efficient approach for the synthesis of nitrogen-based heterocyclic compounds. The field of iron-catalyzed C-H amination is extensively discussed in recent review articles [66, 204, 205]. Working in the field of ironcatalyzed C-H activation, Ilies and Nakamura reported the amination of aromatic carboxamides with N-chloramines and N-benzoyloxyamines [206]. The corresponding anthranilic acid derivatives are obtained in high yields, in the presence of an iron/diphosphine (dppbz) catalyst (Scheme 99). The nature of both the directing group and the ligand are important factors that strongly affect the reaction outcome. Substrates bearing the 8aminoquinoline directing group provide the best yields. Less electron rich ligands favor the formation of the desired aminated product, in contrast to more electron rich ligands which favor the formation of the phenylated product.

Scheme 99. Iron-catalyzed amination of carboxamides [206]. 5.3.5. Thiolation of C(sp2)-H bonds In 2012, Zhang et al. reported the iron-catalyzed direct thiolation of trimethoxybenzene with disulfides (Scheme 100) [207]. In brief, they found that FeBr3 in 20 mol% loading afforded the most effective catalyst for this transformation. The solvent and the oxidant utilized significantly affect the reaction outcome, with the higher yields obtained using DMF

114

as the solvent at 145 oC under air. Higher yields were obtained with the use of disulfides bearing electron-withdrawing groups on the phenyl ring as substrates. A variety of substituted disulfides can be used as substrates, as steric parameters do not affect the reaction [207]. OMe

OMe R S S

+ MeO

OMe

FeBr3 (20 mol %)

R 355

OMe

OMe S

S OMe

354

353

MeO

MeO

DMF, air, 145 oC

R

MeO

S

OMe

MeO

OMe

OMe 355a (72%)

Cl

OMe S OMe

355b (59%)

355c (78%) NO2

OMe MeO

S OMe 355d (75%)

OMe MeO

S

MeO

OMe

S

O

OMe

OMe 355e (87%)

OMe

355f (53%)

Scheme 100. Iron-catalyzed thiolation of trimethoxybenzene [207]. 5.3.6. Allylation of C(sp2)-H bonds In 2013, Ilies and Nakamura reported the iron-catalyzed allylation of N-(quinolin-8yl)carboxamides with allyl ethers (Scheme 101) [208]. Due to the directing effect of the carboxamide-quinoline group, the ortho-allylated product is exclusively formed in all cases. Substrates bearing electron donating groups provide excellent yields and require shorter reaction times. On the other hand, substrates with electron withdrawing groups lead to high yields, but after prolonged reaction time. Finally, substrates with naphthalene, pyrene, and heterocyclic rings are also amenable to this protocol [208].

115

O R

N H

+

O R N H

THF, 70 oC, 4 h

N 357 (1.2 equiv)

356

dppen :

OPh

Fe(acac)3 (5 mol%) dppen (5 mol%) ZnCl2TMEDA (1.2 equiv) t BuCH2MgBr (3.4 equiv)

Ph2P

N

358 (96%) O

PPh2

N H

L19 t

N

Bu

359 (1%)

O N H

X

X 356a X = H 356b X = Me 356c X = OMe 356d X = F 356e X = Cl 356f X = Br 356g X = CF3 356h X = CO2Me

(96%) (97%) (96%) (93%) (93%) (92%) (90%) (74%)

4h 4h 4h 24h 15h 24h 36h 6h

O

O

Qn

N H

Qn

356i X = Me (95%) 4h 356j X = OMe (98%) 4h

O N H

Qn N H 356l (98%) 4h

356k (74%) 160h O

O N H 356m (68%) 135h

Qn

N

N H

360 (91%) 18h

Qn

Qn

O S

N H

Qn

361 (61%) 40h

Scheme 101. Iron-catalyzed allylation of N-(quinolin-8-yl)benzamides with allyl ethers [208]. A year later, Ilies and Nakamura published another work on the allylation of 1phenylpyrazoles with allyl phenyl ethers [209]. Pyrazole, as a directing group, is less efficient compared to the carboxamide-quinoline. This was ascribed to the more difficult formation of the metallacycle intermediate in the case of pyrazole-bearing substrates. Compared to the reaction conditions used with the carboxamide-quinoline [208], bidentate bipyridine ligand L15 (dtbpy) combined with a diphenylzinc reagent provided better results (Scheme 102) [209].

116

Scheme 102. Iron-catalyzed allylation of pyrazole-bearing substrates [209]. To study the effect of the allylating reagent, the authors tested various such compounds with different leaving groups (Figure 8). This study showed that reagents with less active leaving group show poor reactivity, while electrophilic reagents with better leaving groups react with diphenyl zinc, providing compound 365 (Scheme 102). The allylation products are obtained in moderate to high yields in most cases (Figure 9), but the results were generally less promising when compared with the use of N-(quinolin-8-yl)benzamides as substrates. The latter were also functionalized in shorter reaction times.

Figure 8. Electrophilic allylating regents with different leaving groups and the effect of their use on the reaction outcome [209].

117

N

N

N

N

N

N

N

N

X 366a X = H (80%) 48h 366b X = Me (67%) 36h 366c X = OMe (60%) 18h 366d X = NMe2 (64%) 48h 366e X = F (23%) 15h

366g (9%) 48h

366f (65%) 48h

366h (54%) 24h

X N

N

366i X = Me (71%) 24h 366j X = CO2Et (32%) 48h

N

N

366k (72%) 36h

Figure 9. Iron-catalyzed allylation of various pyrazole-containing aromatic substrates [209]. 5.3.7. Alkylation of C(sp2)-H bonds Working on the field of iron-catalyzed C(sp 2)-H bonds alkylation, Cook and co-workers reported a study on the directed, ortho alkylation of 8-aminoquinoline-bearing amides [210]. Initially, the authors studied the catalytic alkylation of carboxamides, using Fe(acac)3 as the iron source in 10 mol% loading, combined with dppe as the ligand in 15 mol% loading and a primary bromide (3 equiv) in 2-Me-THF. The slow addition of the Grignard reagent, during a period of 9 minutes, is an important parameter for the success of the reaction. The activity of the catalytic system was satisfactory in the cases of various substrates, including those bearing heterocyclic rings, leading to the coupling product in moderate to high yields (Scheme 103).

118

Scheme 103. Iron-catalyzed alkylation of carboxamide-quinolines with n-butyl bromide (selected results) [210]. Meta-substituted substrates provide the coupling product exclusively alkylated in the less hindered ortho position (368a-368g). The impact of the alkyl bromides’ characteristics on the efficiency of the reaction were also studied. By using meta-tolylbenzamide with various alkyl bromides as substrates, the corresponding coupling products were obtained in moderate to high yields (Scheme 104). Primary alkyl iodides lead to low yields, while, under the standard reaction conditions, no coupling product was formed with the use of primary alkyl chlorides, tosylates, and phosphinates [210]. O Me

N H

alkyl halide (3.0 equiv) PhMgBr (3.45 equiv)

Q

[Fe(acac)3] (10 mol%) dppe (15 mol%) 2-MeTHF (1M), 65 oC, 9 min

H 369

Me

Br

R'

Br

OR'

Me

Me

MeO2C

Br 370h (62%)

TMS

Br

370i (31%)

tBu

Br

370d R' = Me (68%) 370e R' = Ph (70%)

370b R' = Me (82%) 370c R' = Bn (58%)

370a (82%)

O Me

Br

370j (47%)

EtBr 370k (90%)

N H

370

Me O

O

Me

Me

Q

R

Br

370f (74%)

Ar

I

370g Ar = 4-(MeO)C6H4 (47%)

Br Ar 370l Ar = Ph (72%) 370m Ar = 4-(MeO)C6H4 (47%)

Br 370n (76%)

Scheme 104. Iron-catalyzed alkylation of meta-tolylbenzamide with various alkyl halides [210]. Later on, in the same year, Cook and co-workers also reported the analogous alkylation of carboxamides utilizing secondary alkyl groups, which is in general more difficult than by utilizing primary alkyls [211]. The directed ortho-alkylation of 8-aminoquinoline-based aryl carboxamides with primary benzylic or secondary alkyl groups was achieved by using the same iron source [Fe(acac)3] and a bidentate phosphine ligand (dppe). Some interesting features of this protocol are the high yields, combined with exceptional regioselectivity on a 119

gram scale, the short reaction time (less than 10 minutes), and the use of reagent-grade solvent in benzylations, which can be performed in open air. Back-to-back with the last work of Cook and co-workers, Nakamura’s research group reported the use of alkyl tosylates and mesylates for C–H alkylation, highlighting the unique features of iron catalysis [212]. More specifically, they reported the alkylation of aromatic and alkyl carboxamides bearing the 8-aminoquinoline directing group with primary and secondary alkyl tosylates, mesylates and halides, using Fe(acac)3, a diphosphine ligand, and ArZnBr. The protocol is effective with diphosphine ligands possessing a π-bridge, such as dppen or dppz, but not with 1,2-ehtylenediphosphine (dppe). Monophosphine and bipyridine ligands were also ineffective. Finally, an interesting characteristic of this protocol is the stereospecificity of the reaction for alkene substrates, with the starting secondary tosylate retaining its regiochemical integrity, but not the stereochemistry of the chiral center. One year later, Yoshikai and co-workers reported the imine-directed catalytic alkylation and alkenylation of substituted indoles using an in situ formed iron-based N-heterocyclic carbene (NHC) complex as the catalyst (Scheme 105, PMP: para-methoxyphenyl) [213]. This reaction is the first example of an iron-catalyzed hydroarylation combined with a chelation-assisted C−H activation. In their attempt to optimize the catalytic system, Yoshikai and co-workers utilized a variety of ligands. The use of SIXylHCl (L21) leads to the highest product yields. Other factors affecting the catalytic activity are the solvent, the presence of TMEDA, and the Grignard reagent used. More specifically, higher yields are obtained with Et2O as solvent, while the catalytic system is inactive in the absence of TMEDA, and replacement of CyMgCl with t-BuCH2MgBr deactivates the catalytic system. Substituted styrene derivatives as substrates provide the corresponding products in moderate to high yields (Scheme 106).

120

Scheme 105. Optimization of the iron-catalyzed imine-directed alkylation of substituted indoles (PMP: para-methoxyphenyl) [213].

NPMP R

Fe(acac)3 (10 mol %) SIXyl HCl (10 mol %) CyMgCl (100 mol %) TMEDA (2 equiv)

+ N Me

Ar

371

O R

H+

o

N Ar Me 375 Ar = Ph, o-Tol

Et2O, 60 C, 6 h

374 (1.5 equiv)

CHO

CHO

CHO Me

N Me

N Me

Ph

N Me R

375a (93%)

375b (77%)

CHO

CHO

CHO

N Me 375e (83%)

375c R = F (91%) 375d R = OMe (88%)

N Me

N Me

O O

375g (58%)

375f (91%)

CHO

Ph

CHO

CHO R

N Me

N Bn

N Me

R 375h R = F (77%) 375i R = OMe (39%)

375m (89%)

375j R = Bu (39%) 375k R = Ph (34%) 375l R = SiMe3 (67%) PMP N

PMP N

Ph

Ph

376 (8%)

Ph

377 (15%)

121

Scheme 106. Imine-directed iron-catalyzed C2-alkylation of substituted indoles with vinylarenes (PMP: para-methoxyphenyl) [213]. The same catalytic system with minor modifications is efficient in the alkenylation of substituted indoles with internal alkynes (Scheme 107) [213]. This reaction also proceeds through chelation assistance for the selective activation of the C2 indole C-H bond. The modified catalytic system, consisting of Fe(acac)3 (10 mol%), SIXyl· HCl (20 mol%), and PhMgBr (110 mol%) in THF, provides high yields with high syn-stereoselectivity. Yields and stereoselectivity are also dependent on the nature of the alkyne, with terminal alkynes being inactive substrates under the given reaction conditions. Based on NMR labeling experiments, a possible mechanism was proposed for these two reactions, in which metallacycles II and III shown in Scheme 108 are the key intermediates.

Scheme 107. Iron-catalyzed imine-directed alkenylation of substituted indoles with internal alkynes (PMP: para-methoxyphenyl) [213].

122

Scheme 108. Proposed catalytic cycle for the iron-catalyzed imine-directed alkylation and alkenylation reactions of substituted indoles [213]. In the same year, Nakamura and Ilies reported the iron-catalyzed alkylation of alkenes and arenes

with

alkylzinc

halides

(Scheme

109)

[214].

Initial

experiments

with

benzo[h]quinolone afforded the starting material, while the reaction between a quinolylamide and 2-phenethylzinc chloride in the presence of an iron/diphosphine in situ generated catalyst afforded the desired coupling product. The addition of a mild oxidant (DCIB) is necessary for the catalytic reaction. The coupling products are formed in high yields with Z stereochemistry. Styrene is also formed in a very small percentage and 1,4-diphenylboutane is formed in traces. Furthermore, the same protocol is efficient for the alkylation of quinolylamide-substituted aryl substrates. As shown in Figure 10, reactions with several substituted arenes provided the coupling product in high yields. Finally, various alkyl Grignard reagents and 3-methyl-N-(quinol-8-yl)benzamide as the substrate successfully yielded the corresponding coupling products (Figure 11).

123

Scheme 109. Iron-catalyzed alkylation of quinolylamides [214].

Figure 10. Iron-catalyzed alkylation of quinolylamide-substituted arenes [214].

Figure 11. Grignard reagents utilized in the iron-catalyzed alkylation of 3-methyl-N-(quinol8-yl)benzamide [214].

124

5.3.8. Alkynylation of C(sp2)-H bonds and cyclization reactions In 2016, Shao and co-workers reported the cyclization of nitrones (393, Scheme 110) with gem-substituted vinyl acetates (394) [215]. Screening of possible iron sources revealed that Fe(acac)3 provides the best results. Among the solvents screened, dichloromethane provided the desired product with the optimal yield, while the addition of NaSbF6 also proved beneficial. Investigation of the substrate scope with regards to the arylnitrones showed that both electron-donating and electron-withdrawing groups were well-tolerated under the reaction conditions. Substrates bearing 4-methyl,

methoxy, methylthio,

halogens,

trifluoromethyl and cyano groups on the phenylimino moieties provided the corresponding quinoline products in moderate to good yields. Moreover, meta- or para-substituted substrates provided the desired products in high yields. On the contrary, 1-naphthyl nitrone failed to provide any products. Ortho-substituted substrates on either phenyl ring provided trace amounts of the corresponding products, suggesting that the reaction is sensitive to steric hindrance. Vinyl acetates substituted with aryl groups led to excellent yields, while in the absence of an aryl group the reaction is not favored and provides the corresponding product with moderate to low yields. The authors attribute this tendency to the ability of the aryl group to stabilize the carbocation intermediate in the proposed catalytic cycle. Based on preliminary mechanistic experiments, the authors suggested that this reaction is unlikely to follow a Lewis acid-catalyzed pathway. Also, a [3+2] cycloaddition pathway followed by an iron-catalyzed ring-opening reaction was excluded, given that the corresponding cyclization intermediate was not detected. Since this transformation does not match the characteristics of a Lewis acid-catalyzed reaction, it was proposed that an iron-catalyzed C-H activation pathway may be followed. The authors proposed that iron cleaves the C-H bond at the orthoposition of the phenyl ring, while the N-oxide serves as directing group in order to form the intermediate that initiates the reaction, as shown in Scheme 110. 125

Scheme 110. Proposed catalytic cycle for the cyclization of nitrones with gem-substituted vinyl acetates [215]. In the same year, Ilies and Nakamura reported an oxidative, iron-catalyzed regioselective annulation [216]. The reaction takes place between α,β-unsaturated amides or benzamides and alkynes, and provides the corresponding pyridones or isoquinolones respectively, using Fe(acac)3 and a diphosphine ligand (dppen) (Scheme 111). The C-H activation in reactions with benzamide substrates occurs at the ortho position of the aromatic ring.

126

Scheme 111. Iron-catalyzed annulation of α,β-unsaturated amides or benzamides with alkynes [216]. In a recent article, Ackerman and co-workers reported the iron-catalyzed alkynylation of carboxamides (400, Scheme 112) bearing a triazolyldimethylamine (TAM) directing group [217]. The combination of Fe(acac)3 with a biphosphine ligand (dppen) provides the desirable product in high yields, with the presence of a zinc salt being essential. The reaction provides an elegant pathway for the synthesis of heterocyclic compounds such as pyridines, pyrrolones and isoquinolones.

Scheme 112. Iron-catalyzed alkynylation of carboxamides bearing a triazolyldimethylamine [217]. 5.4. C(sp)-H activation Even though the field of C(sp)-H bond activation is dominated by copper catalysis, some interesting examples of iron-based catalytic systems can be found. For example, Li and coworkers have utilized FeCl3 in the three component coupling reaction shown in Scheme 113 [218]. This reaction is basically the coupling of an aldehyde (403), an alkyne (405), and an amine (404) affording product 406 under neat conditions in air. Both aromatic and aliphatic aldehydes undergo this transformation, affording the corresponding propargylic amines. Aliphatic aldehydes display higher reactivity and “cleaner” reactions. On the other hand, aromatic aldehydes afford lower conversions and lower yields. The structure of the amine has a significant effect on the reaction yield as well. Acyclic dialkylamines and diallylamines were less efficient, while cyclic dialkylamines, such as piperidine, pyrrolidine, azepane, and

127

morpholine, reacted effectively to provide the propargylamines in moderate to good yields. Various alkynes were examined: Both aromatic and aliphatic alkynes are amenable to this protocol, leading to good yields [218].

Scheme 113. The iron-catalyzed three component coupling of an aldehyde, an alkyne, and an amine [218]. Another catalytic application of iron salts with substrates containing C(sp)-H was reported in 2009 by Volla and Vogel, who developed a method for the preparation of propargylamines [219]. This method is based on the formation of a C-C bond between a terminal alkyne (phenylacetylene) and a tertiary amine, through an iron catalyzed cross-coupling reaction (Scheme 114). Among the iron salts and oxidants tested, FeCl2 and (tBuO)2, respectively, afforded the best results. Under the optimized conditions, the reaction tolerates various substituted terminal alkynes and amines, providing the coupling product in moderate to high yields (Scheme 115). Products that derive from the oxidation of benzylic C-H bonds were not detected, suggesting the high chemoselectivity of the catalytic system and the C-C coupling reaction towards the less sterically hindered R-C-H bonds of the amines [219].

Scheme 114. The iron-catalyzed coupling of tertiary amines with terminal alkynes [219].

128

Scheme 115. Iron-catalyzed coupling of various terminal alkynes and tertiary amines (selected results) [219]. In 2011, Narsaiah and co-workers reported a method for the preparation of aryl(iminomethyl)propargyl ethers by a three component reaction co-catalyzed by CuBr and FeCl3 (Scheme 116) [220]. Various substituted amines and aldehydes were used, affording the targeted coupling product in good yields. The catalytic reaction can be divided into two stages: an imine is first formed, at low temperatures, followed by its reaction with the activated alkyne [220].

Scheme

116.

Cu

and

Fe

co-catalyzed

three

component

reaction

leading

to

aryl(iminomethyl)propargyl ethers (selected results, R1:H) [220].

129

Another application of an iron-based catalytic system in a multicomponent reaction was reported by He and co-workers in 2012 [221]. In this case, iron salts promote the coupling reaction of a terminal alkyne, a secondary amine, and dichloromethane, affording the corresponding propargylamine (Scheme 117). Initial experiments, for the optimization of the reaction conditions, showed that the combination of FeCl3 with 1,1,3,3-tetramethylguanidine (TMG) afford the best results. This catalytic system was applied in experiments with terminal alkynes bearing various functional groups. Aromatic alkynes with either electron-donating or electron-withdrawing groups were reactive, providing the desired propargylamine in good yields. On the contrary, aliphatic terminal alkynes were inactive. Substrate scope investigations with regards to the amine showed that acyclic and heterocyclic secondary aliphatic amines lead to moderate to excellent yields, while the propargylamine was not formed with use of aromatic or aliphatic primary amines (Scheme 118).

Scheme 117. Three component, iron-catalyzed synthesis of propargylamines [221].

130

Scheme 118. Substrate scope for the three component, iron-catalyzed synthesis of propargylamines, with regards to the terminal alkynes (i) and secondary amines (ii) utilized [221]. The proposed catalytic cycle is shown in Scheme 119. The reduction of iron(III) to iron(II) is obviously a necessary step. Iron(II) interacts with the alkyne, forming a Fe-acetylide intermediate (I), which is considered to be the active nucleophilic species. In the next step, interaction of intermediate I with CH2Cl2 leads to the formation of iron(III) species II. Finally, reductive elimination affords propargylchloride III, regenerating the catalyst. Propargylchloride III can further react with a secondary amine in the presence of TMG affording the desired propargylamine.

131

Scheme 119. Proposed catalytic cycle for the three component iron-catalyzed synthesis of propargylamines [221]. In the same year, Yao and co-workers reported another iron-catalyzed, three component reaction for the synthesis of quinolines [222]. In the presence of Fe(OTf)3 under solvent-free conditions, a terminal alkyne, an aldehyde, and an amine undergo a coupling reaction forming the quinoline product shown in Scheme 120. Other iron sources provide lower yields of the targeted product. Various substituted anilines are amenable to this protocol, affording the corresponding quinolines in high yields (Scheme 121). Substituted aldehydes, even those bearing a heterocyclic ring, also lead to high yields (Scheme 122). This protocol tolerates diverse functional groups, as shown from experiments employing substituted anilines, aldehydes, and terminal alkynes, in which the final quinoline products were obtained in good yields. An advantage of Fe(OTf)3 as iron source is that it remains active and it can be reused: Experiments with recycled Fe(OTf)3 showed only a slight decrease in the yields of the obtained quinoline [222].

132

Scheme 120. The iron-catalyzed three component reaction for the synthesis of substituted quinolones [222].

Scheme 121. Iron-catalyzed three component reaction for the synthesis of substituted quinolones: the effect of the amine utilized [222].

133

Scheme 122. Iron-catalyzed three component reaction for the synthesis of substituted quinolones: the effect of the aldehyde utilized [222]. 6. COPPER 6.1. Introduction Copper is present in Earth’s crust in a relatively high concentration (0.0068%). This first row transition metal has been widely used in organic synthesis over the last one hundred years, while its salts are inexpensive and environmentally benign. Furthermore, copper-based complexes have been extensively employed as catalysts in C-H activation reactions concurrently activating CO2. Progress has been also realized in copper-mediated regioselective and chemoselective C(sp 2 or sp 3)-H bond functionalization reactions with the aid of directing groups. All aforementioned approaches comprise powerful and usually atomeconomical strategies for the transformation of various C-H bonds into useful functional groups and have been used in the synthesis of complex organic molecules and natural products. The first section of this chapter is general in character and focuses on the types of bonds that can be constructed through copper-catalyzed C-H activation. The sections that follow focus on either the type of reaction that is catalyzed by copper, the transformation that takes place, or the substrates that are functionalized. 6.2. C-X bonds formation through C-H activation As discussed above, cross-coupling reactions combine two molecular fragments leading to the formation of new C-C, C-N, C-O, C-P, C-S or C-Se bonds. A lot of effort has been invested in improving the cross-coupling reaction conditions, as well as, towards expanding substrate scope and functional group tolerance. 6.2.1. C-C bond formation reactions Copper-catalyzed C-H activation with simultaneous C-C bond formation has emerged as a promising synthetic approach. In 2011, a general method for the copper-catalyzed arenes 134

cross dimerization using iodine as terminal oxidant was published by Do and Daugulis (Scheme 123) [223].

Scheme 123. Copper-catalyzed cross-coupling of two aromatic compounds using iodine as the oxidant [223]. This methodology involved two in situ reactions: the oxidation of one of the substrates and the direct arylation of the most acidic C-H bond of the other cross-coupling partner. Oxidation involves an iodination step. Several experiments aiming at the optimization of the iodination step have been performed by altering the base and the additives, using dioxane or 1,2-dichlorobenzene as solvent. The use of dioxane promotes the regioselective iodination of the most acidic arene C-H bond. Coupling can be achieved between electron-rich and electron-poor arenes, as well as between five- and six-membered ring heterocycles. Moreover, five- or six-membered ring heterocycles and electron poor arenes can be efficiently coupled. Electron-neutral arenes, like benzene, cannot be used as either of the coupling components, because of the requirement of a relatively acidic C-H bond with a pKa of 35-37 or below for the copper-catalyzed arylation reaction (in DMSO) and also due to lack of reactivity in the iodination step. According to Do and Daugulis, homocoupling products are also frequently formed [223]. They observed that the optimum ratio of the coupling components is between 1/1.5 and 1/3, in contrast to the previously reported methodology, in which one of the substrates is used as solvent. Good functional group tolerance with ester, aldehyde, ether, nitrile, ketone, and amine substituents was observed. Selective crosscoupling of two electron-deficient arenes was observed in the existence of a sufficient C-H 135

bond acidity difference between the coupling partners. Poly-functionalization was also observed in the case of arenes containing multiple active C-H bonds [223]. In 2012, Das and co-workers reported, fοr the first time, the direct C-H alkenylation of 1,3,4-oxadiazoles with trans-β-iodostyrenes in the presence of CuI as metal source, DMEDA (N,N’-dimethylethylene diamine) as ligand, and LiOtBu as base (Scheme 124) [224]. Moderate yields were obtained with trans-β-bromostyrene or by changing the ligand or the base. The coupling of oxadiazoles containing either electron donating or electron withdrawing groups (426, Scheme 124) proceeded smoothly. Although not extensively studied, the mechanism was proposed to involve three sequential steps: base assisted transmetalation (complex II, Scheme 125), oxidative addition of trans-β-iodostyrene to form Cu(III) complex III and reductive elimination to form the alkenylated product.

Scheme 124. Copper-catalyzed C-C cross coupling of 1,3,4-oxadiazoles [224].

Scheme 125. Proposed mechanism for the Cu-catalyzed alkenylation of 1,3,4-oxadiazoles [224].

136

Trifluoromethylated compounds are valuable organic substrates with many applications [225-229]. In 2012, Chu and Qing developed a method to efficiently functionalize heteroarenes and electron-deficient polyfluoroarenes, using trifluoromethyltrimethylsilane as nucleophile, towards the corresponding trifluoromethyl derivatives [230]. 2-Phenyl-1,3,4oxadiazole was used as model substrate to optimize the reaction conditions. Treatment of 2phenyl-1,3,4-oxadiazole (1.0 equiv) with CF3SiMe3 (4.0 equiv), Cu(OAc)2 (40 mol %) and 1,10-phenanthroline (phen) (40 mol %) in the presence of tBuONa (1.1 equiv) and NaOAc (3.0 equiv) as co-base under air in 1,2-dichloromethane (DCE) at 80 °C afforded the desired derivative in 92% yield. The scope of this C-H oxidative trifluoromethylation reaction was also explored. The reaction tolerates both electron-donating (430b-430d) and electronwithdrawing groups (430e-430h) at the para position on the aryl rings (Scheme 126).

Scheme 126. Oxidative trifluoromethylation of 1,3,4-oxadiazole derivatives [230]. In the same work, Chu and Qing reported the trifluoromethylation of 1,3-azoles and perfluoroarenes (Scheme 127). The optimum reaction conditions for the trifluoromethylation of 1,3,4-oxadiazole derivatives lead to slow reaction rates in the case of 1,3-azoles and perfluoroarenes. For these substrates, di-tert-butyl peroxide was used as the oxidant instead of air. Trifluoromethylation of benzo[d]oxazoles bearing various substituents provided products 432a-432d in good yields. Both chloro- and bromo-substituted 431 reacted 137

efficiently. Benzo[d]imidazole and benzo[d]thiazole were also applicable in the reaction, providing 432e, 432g in moderate to good yields. A substrate bearing a terminal alkene also yielded the desired product 432f. Pentafluorobenzene provided 432h in excellent yield, while 2,3,5,6-tetrafluoro-4′-methoxybiphenyl showed lower efficiency.

X N

R

Cu(OAc)2 (40 mol%) phen (40 mol%) CF3Si(CH3)3, tBuONa, NaOAc (CH3)3CO2C(CH3)3 DCE, N2, 80 oC

H

Y 431 O

O N 432a (72%)

F S CF3 N 432g (74%)

N 432b (88%)

Ph

F

F

N 432c (58%) F

CF3 F F 432h (93%)

432 N CF3

CF3 Br

CF3

Y

O

O CF3

CF3

X N

R

Cl

N CF3

N

CF3 N 432f (32%)

N 432e (57%)

432d (75%)

F

O

CF3 F F 432i (63%)

N N

N N

N N

CF3 O 432d (83%)

CF3

O 432a (81%) O

CF3 O 432e (69%)

F3C

Scheme 127. Oxidative trifluoromethylation of 1,3-azoles, perfluoroarenes, and 1,3,4oxadiazoles [230]. Substituted indoles have been also subjected to Cu-catalyzed trifluoromethylation by Chu and Qing (Scheme 116) [230]. The conditions shown in Scheme 126 were applied to electron-rich indoles, affording the corresponding products in less than 20% yield. Thus, a series of optimization studies were carried out to improve the efficiency of the reaction. Potassium fluoride was chosen as the ideal base, Ag2CO3 was the best oxidant, and Cu(OH)2 was found to be the ideal copper source with 10 mol% loading. The reaction under these optimal conditions delivered 434a in 93% yield. Subsequently, a series of 3-subsituted indoles were successfully converted to the corresponding 2-trifluoromethyl indoles (434b434k). Methyl, ethyl, phenyl, or benzyl N-protected indoles afforded the desired products 434a-434d. A series of substrates bearing functional groups on C5 of the indole, such as Cl, Br, and CO2Me, yielded products 434e-434g when subjected to trifluoromethylation. In the case of N-tosyl indole, only traces of 434k were observed due to the electron-withdrawing

138

protecting group, while an indole bearing the CO2 CH3 group on C3 was totally unreactive and therefore product 434l was not formed (Scheme 128). R2 H 433

N R1 CH3

CH3

R2

Cu(OAc)2 (40 mol%) phen (40 mol%) CF3Si(CH3)3 (3 eq.), KF (3 eq.) AgCO3 (2 eq.) DCE, N2, 80 oC

R3

R3 CF3 N R1 434

CH3

CH3 Cl

CF3

CF3

N CH2CH3 434b (80%)

N CH3 434a (93%)

CF3 N Ph 434c (89%)

CF3

CF3

N Bn 434d (71%)

H3C

CH3

N CH3 434e (68%)

H3C

CH3

H3CO2C

Br CF3 N CH3 434f (72%)

CF3 N CH3 434g (83%)

CF3 N CH3 434h (64%)

CF3 N CH3 434i (82%)

CF3 N Ts 434k (trace)

CO2CH3 CF3 N CH3 434l N.R.

Scheme 128. Copper-atalyzed oxidative trifluoromethylation of substituted indoles [230]. In the same work, Chu and Qing proposed two pathways for the plausible mechanism of copper-catalyzed oxidative trifluoromethylation of heteroarenes and polyfluoroarenes (Scheme 129). According to the first pathway, the catalytic cycle begins with the reduction or disproportionation of the Cu(II) catalyst into a Cu(I) species, followed by reaction with trifluoromethylsilicate, which is generated in situ, to form I. Subsequently, transmetalation and activation of an Ar-H bond generates species III, which might be oxidized to the corresponding intermediate IV. Finally, reductive elimination of the (aryl)-Cu III(CF3) intermediate IV affords the expected product and regenerates the Cu(I) catalyst. According to the second suggested pathway, the key intermediate in the Cu-mediated C-H functionalization of heteroaromatic compounds under basic conditions is II. Transmetalation of arylcopper complex II with trifluoromethylsilicate, which is also generated in situ, affords species III and then, as in the other proposed pathway, the desired coupling product [230].

139

Scheme 129. Plausible mechanism for the copper-catalyzed oxidative trifluoromethylation reaction [230]. In 2014, Yu and co-workers developed the first example of ortho C-H trifluoromethylation of oxazoline-substituted amide bearing arenes (Scheme 130) using the Ruppert–Prakash reagent (TMSCF3) [231]. With regards to the fluoride source, it was found that KF efficiently promotes the trifuoromethylation. Metal source screening revealed that Cu(OAc)2 with Ag2CO3 is the most convenient combination for the reaction, while, in some cases, Ag2CO3 can be omitted. The optimized conditions (Cu(OAc)2/Ag2CO3 as metal source in ratio 0.10 mmol/ 0.15mmol, KF as fluoride source, DMSO as solvent, 100 oC, air) were used for the synthesis of a series of products shown in Scheme 131.

Scheme 130. Ortho C-H trifluoromethylation of arenes using TMSCF3 [231].

140

Scheme 131. Substrate scope for the ortho C-H trifluoromethylation of arenes using TMSCF3 [231]. The mechanism proposed involves a copper-catalyzed C-H activation key step, rather than an electrophilic aromatic substitution or a radical pathway. The oxazoline group directs the C-H activation in 437, followed by a disproportionation step yielding a chelated organocopper(III) complex II. Transmetalation of this organocopper species with TMSCF3

141

yields the Cu III-CF3 intermediate III. Reductive elimination then leads to the desired orthotrifluoromethylated arene 438 (Scheme 132). O

O N H H

Oxa Cu(OAc)2 -2HOAc

O N

CuII N

Cu(OAc)2 O

-CuOAc

I

437a

N CuIII N F3C III

O

O

O TMSCF3 -TMSOAc

N CuIII N AcO II

HOAc O

-CuOAc

N H CF3

Oxa

438a

Scheme 132. Proposed mechanism for the ortho-C-H trifluoromethylation of arenes using TMSCF3 [231]. In 2015, Xu and co-workers developed a copper-catalyzed protocol leading to trifluoromethylated phenanthrolines [232]. 1,10-Phenanthroline, in the presence of Cu(OAc)2 and trifluoromethyltrimethylsilane (TMSCF3), under the reaction conditions shown in Scheme 133, was exclusively converted to its ortho-trifluoromethylated derivative. No bistrifluoromethylation products were isolated, even when a large excess of TMSCF3 (>5.0 equiv) was utilized. Also, a series of symmetrically and unsymmetrically substituted phenanthrolines (439) were subjected to the reaction leading to the corresponding orthotrifluoromethylated derivatives (440). 4,7-Diphenyl phenanthroline provided the desired product 440b with excellent yield. Other phenanthrolines provided the targeted compounds 440c-440e with lower yields, while 5-nitrophenanthroline yielded two readily separable products 440f and 440g. Moreover, control experiments were carried out to probe the reaction mechanism. A free radical pathway was excluded. It was proposed that N,Nbidentate phenanthroline initially coordinates to copper, generating tetrahedral complex I. The acetate ligand of this complex may then activate the CF3 group of TMSCF3 through a hypervalent silicon species generating intermediate II. Given that the C=N bond of 142

phenanthroline is prone to nucleophilic addition, coordination to copper further activates the C=N bond to nucleophilic addition. At the same time, the coordination of the Lewis basic substrate may cooperatively enhance the nucleophilicity of the CF3 group to generate III from II. Finally, the desired product 440 is formed after aerobic oxidation of III [232].

Scheme 133. Trifluoromethylation of phenanthrolines and proposed reaction mechanism [232]. In 2014, Besset, Poisson, and co-workers reported the direct, selective functionalization of unsaturated C-C bonds with ethyl bromo(difluoro)acetate (441) [233]. The reaction was

143

applied to a variety of substituted 3,4-dihydro-2H-pyran substrates and the desired products 443a-443h (Scheme 134) were obtained with moderate to good yields. Copper(II) triflate was utilized as the metal source. Yet, both copper(II) and copper(I) catalysts provided the desired fluorinated dihydropyran products. The base played a crucial role in the outcome of the reaction, with potassium carbonate providing the optimum conditions. Treatment of 2(benzyloxy)-3,4-dihydro-2H-pyran with either 2-bromo-N,N-diethyl-2,2-difluoroacetamide or an N-morpholino derivative resulted, in both cases, modest yield of products 443d, 443e. Finally, the same transformation was successfully applied to glycal derivatives, with which products 443f-443h were obtained (Scheme 134). In order to exclude or verify the existence of radicals in the reaction mechanism, free radical inhibitors or radical scavengers were applied to the reaction. The proposed reaction mechanism starts with the oxidative addition of the copper(I) catalyst to the C-Br bond of ethyl bromo(difluoro)acetate providing the copper(III) intermediate I. Subsequent nucleophilic attack of the dihydropyran derivative 442a generates the oxonium species II, which is then transfrormed to enol ether III. At the final step of the catalytic cycle, reductive elimination regenerates the catalyst and delivers the desired product 443a.

144

Scheme 134. Cu-catalyzed functionalization of substituted 3,4-dihydro-2H-pyrans [233]. Terminal and internal alkynes were subjected to the same reaction conditions [233]. This led to the formation of the corresponding alkenes in E/Z mixtures. Surprisingly, trace amounts of the substituted terminal alkynes were moreover obtained. The reaction was then optimized so as to selectively afford the difluoromethylated terminal alkyne. The highest obtained yield was 29% for the formation of product 408a (Scheme 135). A brief investigation of the scope of the reaction revealed that it is also compatible with electronwithdrawing substituents with products 408b and 408c isolated as well.

145

Scheme 135. Cu-catalyzed formation of difluoromethylated terminal alkynes [233]. In 2015, Xu, Mao, and co-workers reported a copper-mediated direct cyanation of terminal alkynes utilizing AMBN (azobisisoamylonitrile) or AIBN (azobisisobutyronitrile) as cyanide source [234]. Based on the fact that the preparation of alkynyl cyanides (446, Scheme 136) was simple and easy to achieve with direct acetylenic C(sp)-H cyanation, Xu and co-workers tested this transformation on a number of alkynes.

Scheme 136. Approaches to the cyanation of terminal alkynes [234]. In the search for the most efficient conditions for this reaction, several parameters were investigated. Copper nitrate was found to be the copper source of choice, acetonitrile the best solvent, and AIBN the optimum cyanide reagent. The cyanation of terminal alkynes under an atmosphere of argon led to the corresponding addition products (447, Scheme 136). Amongst others, this finding showed the vital role of oxygen in the cyanation reaction. A series of tests in arylacetylenes showed that substrates with electron donating groups on the benzene ring do not participate as effectively as those bearing electron-withdrawing groups, which provide lower yields. This transformation showed good functional group tolerance with alkyl and silyl alkynes, as well as, with their ether, ester, and amide derivatives, comprising a quite general approach to a diverse set of alkynes.

146

Scheme 137. Proposed reaction pathways for the cyanation of terminal alkynes [234]. The reaction mechanism proposed justifies the formation of both 446 and 447 (Scheme 137). Initially, an isobutyronitrile radical generated from AIBN under innert conditions reacts with the arylacetylene to give I. Intermediate I then reacts with Cu(II) species to form vinyl copper(III) complexes II. Protonation of II, either by the abstraction of a proton from arylacetylene, or from the H2O existing in the system, yields the desired product 411. The initially generated isobutyronitrile radical is oxidized to radical III by O2, when the reaction is conducted in air. After releasing one equivalent of acetone, radical III is converted to the cyano radical. Finally, reductive elimination of intermediate IV forms product 446 and Cu(I). Cu(I) is then oxidized to Cu(II) by O2, closing the catalytic cycle [234]. In the same year, Georg and co-workers developed a copper-catalyzed approach for the synthesis of highly functionalized macrocycles [235] This method selectively generates an endocyclic (Z)-double bond through an intramolecular coupling of the vinyl iodide and the terminal alkyne fragments, followed by an in situ alkyne reduction (Scheme 138).

147

Scheme 138. Ene-yne coupling/reduction approach in the total synthesis of oximidine II [235]. Georg and co-workers found that sodium formate acts as reducing reagent, leading to the in situ reduction of the dienyne and affording the desired triene macrocycle in one step [235]. Vinyl iodide 451 was chosen as the model substrate for the optimization of the reaction conditions (Scheme 127). Substrate screening showed that the reaction is ring-strain dependent, being efficient only for 11 to 13-membered rings.

Scheme 139. The coupling/reduction tandem transformation developed by Georg and coworkers [235]. 6.2.2. C-N bond formation reactions C-H activation towards the construction of C-N bonds is of utmost importance in Organic Synthesis. Despite significant advancements in this field, this transformation is still a major challenge, due to the fact that the required reaction conditions are often harsh. In 2006, a Cucatalyzed cross-cycloaddition between arylisocyanides (454, Scheme 140) and isocyanides (455) was reported by Yamamoto and co-workers [236]. Cu 2O, combined with 1,10phenathroline, efficiently catalyzes this kind of cross-cycloaddition affording the corresponding 1,4-disubstituted imidazoles in high yields (Scheme 140). 148

R R NC + CN

EWG

Cu2O 1,10-phenathroline THF, 80 oC

N

EWG N

454

455

456

Scheme 140. Synthesis of imidazoles through the copper-catalyzed cross-cycloaddition of two different isocyanides [236]. According to the mechanism proposed for this transformation (Scheme 141), the reaction begins with the C-H bond activation of isocyanide by Cu2O. Nucleophilic addition of I, or its tautomer I΄, originating from the reaction of 455 with Cu 2O, to arylisocyanide 454 provides intermediate ΙΙ. An intramolecular [3+2] cycloaddition in ΙΙ generates intermediate ΙΙΙ, which, upon its protonation from 455, affords the final substituted imidazole product 456.

Scheme 141. The proposed mechanism for the copper-catalyzed cross-cycloaddition between isocyanides 454 and 455 [236]. Prompted by the scarcity of methods for the synthesis of N-alkynylated sulfoximes, Bolm and co-workers developed a highly efficient oxidative cross-coupling methodology for their preparation (459, Scheme 142) [237]. More specifically, based on the advances in the coppercatalyzed syntheses of N-alkynylheterocycles and N-alkynylamides, they developed a related strategy using dioxygen as oxidant and a copper(II) salt for the copper-catalyzed oxidative 149

cross-coupling of sulfoximes with alkynes. Interestingly, through a simple alteration in the purification procedure, they could selectively obtain the corresponding N-acyl sulfoximes in good yields.

Scheme 142. Copper-catalyzed oxidative cross-coupling of sulfoximes with alkynes [237]. The reaction conditions were similar to those for the oxidative amidation of terminal alkynes [238], as well as, to those for the oxidative alkynylation of diaryl imines [239]. Copper(II) chloride as metal source and sodium carbonate as base in 1,4-dioxane provide the optimal reaction conditions. A range of products, obtained under these conditions, are shown in Scheme 143 [237]. The products were found to be sensitive to hydrolysis, especially on acidic silica gel. Therefore, they were all purified by column chromatography on triethylamine-deactivated SiO2.

Scheme 143. Substrate scope of the oxidative N-alkynylation of sulfoximes [237]. In the same year, Wu and co-workers reported the coupling of 2-alkynylbromobenzene (424, Scheme 144) with pyrazole 425 via the copper-catalyzed hydroamination and C-H activation of pyrazole [240]. The authors proposed a mechanism in which the copper(I)catalyzed hydroamination of 2-alkynylbromobenzene with pyrazole is the first step, followed 150

by an oxidative addition of copper to aryl bromide I to form intermediate II. Intramolecular attack and then reductive elimination generates the desired product.

Scheme 144. The proposed mechanism to pyrazolo [5,1-a] isoquinolines (462) via the copper-catalyzed reaction of 2-alkynylbromobenzene with pyrazole [240]. Among the ligands tested, N-heterocyclic carbene L29 (Scheme 145) resulted in good product yields, in combination with copper iodide as metal source and potassium hydroxide as base in DMSO at 110 oC.

151

Scheme 145. Ligands utilized in the copper-catalyzed reaction of 2-alkynylbromobenzene with pyrazole [240]. An operationally simple, copper-based catalytic system was developed by Adimurthy and co-workers, providing facile access to substituted imidazo[1,2-α]pyridines, a frequently observed structural motif in pharmaceutical compounds [241]. This atom- and stepeconomical approach relies on the use of oxygen for the oxidative formation of two C-N bonds via catalytic C-H activation, with the loss of an H2O molecule as the formal reaction byproduct. With the use of CuI in 5 mol% catalyst loading and a catalytic amount of BF3/Et2O, various substituted imidazo[1,2-a]pyridines were synthesized in moderate to high yields (for some selected examples, see Scheme 146) from the dehydrogenative annulation of 2-aminopyridines (464) and methyl ketones (465). This protocol exhibits remarkable functional group tolerance. A broad range of both 2-aminopyridines (464) and methyl ketones (465) bearing diverse substitution patterns were successfully used as substrates, leading to products with functionalities that enable further modification (466b, 466c). To demonstrate this system’s potential in useful organic transformations, the anti-ulcer drug zolimidine (466e) was successfully synthesized in a single step and in satisfactory yield. With regards to the proposed mechanism, the reaction between 464 and 465 initially affords intermediate imine I, which is in equilibrium with intermediate II (Scheme 146, b). Oxidative addition takes place in the presence of oxygen, leading to intermediate Cu(III) complex III with loss of a water molecule. Finally, reductive elimination leads to product release and regeneration of the catalyst.

152

a) NH2 R

CuI (5 mol%) BF3/Et2O (10 mol%)

O

N

R'

464

465 2.0 equiv

N R

DMF, 60 oC, 24 h, O2 1 atm

N

R'

466

Selected examples N

N

N

N

466a (93%)

466b (59%)

N

N

N Br

N

S

N

466c (80%)

466d (68%) O

N S

N

O

zolimidine 466e (64%) b) N

R

R

464 + 465

H N

R'

R'

N

N II

I

H2O

N

O2 Cu(I) N R

N

R

N III

R'

R'

Cu (III)

466

Scheme 146. Cu-catalyzed oxidative annulation of 2-aminopyridines (464) and methyl ketones (465), providing access to imidazo[1,2-α]pyridines (466), along with the proposed catalytic cycle [241]. One year later, Adimurthy and co-workers reported an efficient copper(I)-catalyzed aerobic oxidative C-N bond formation reaction via C-H activation, towards functionalized imidazo

[1,2-α]pyridines

[242].

Another

copper-catalyzed

reaction,

affording

sulfenylimidazol[1,2-α]pyridines (469, Scheme 147), was also reported in the same work. Both reactions comprise green and sustainable methods, as they use oxygen as the oxidant and are catalyzed by copper. Among various copper salts tested, CuI exhibited the highest 153

efficacy, in combination with BF3/Et2O as additive. With regards to the generation of sulfenylimidazol[1,2-α]pyridines, this three-component reaction gave moderate to excellent yields under the optimized conditions shown in Scheme 148.

Scheme 147. Copper(I)-catalyzed aerobic oxidative C-N and C-S bond formation originating from C-H activation: synthesis of functionalized imidazo[1,2-a]pyridines [242].

Scheme 148. Scope of the three-component reaction towards sulfenylimidazol[1,2α]pyridines [242]. In an extension of their previous work [243], Satoh, Miura, and co-workers reported that tritylamines undergo an uncommon cyclization involving the cleavage of two C-H bonds and another C-N bond [244]. This intramolecular reaction is catalyzed by copper under 1 atmosphere of oxygen and provides access to 9-phenylacridine derivatives. Copper acetate as 154

the copper source and mesitylene as the solvent were the optimal reaction conditions. A range of products are shown in Scheme 149. It is worth mentioning that some of these products exhibit intense fluorescence in the solid state [244].

Scheme 149. Copper-catalyzed cyclization of tritylamines towards acridine derivatives [244]. A plausible mechanism was proposed (Scheme 150), in which an associative pathway is involved, through a C-N bond cleavage/formation sequence. In the first step, coordination of the amine group of 470a to copper followed by cyclometalation leads to the five-membered

155

intermediate I. Reductive elimination leads to intermediate II. After succeeding electrocyclic reactions IV is formed, which loses a hydrogen atom affording product 471a.

Scheme 150. Proposed reaction pathway from 470a to 471a and 471a’ [244]. In a recent report, Cai and Gu developed an efficient methodology for the direct oxidative C-H amination of benzoxazoles (472, Scheme 151) with primary amines (473) via coppercatalyzed C-H bond activation with good to excellent results [245]. Exploration of the amine scope revealed that benzylamines substituted with either electron-donating or electronwithdrawing groups reacted efficiently with benzoxazole. Primary amines (e.g. nbutylamine), tertiary amines, and piperidine gave equally good yields. By investigating the azole scope, it was found that alkyl- and halogen-substituted benzoxazoles lead to good yields, in contrast to azoles bearing an electron-withdrawing group. With regards to the copper source, CuCl gave the best results. The use of acid as an additive was also essential [245].

156

Scheme 151. Copper-catalyzed direct amination of benzoxazoles with primary amines [245]. In 2015, Wang, Tang, Yang, and co-workers reported the first example of a coppercatalyzed domino reaction towards functionalized indolizinones using pyridine, ketones, and terminal alkynes as starting materials [246]. This method is of high importance, as it provides access to multi-functionalized heterocycles in an one-pot reaction. With the optimal conditions in hand (Scheme 152), a range of substrates were successfully transformed into the corresponding indolizinones. Both aliphatic and aromatic phenylacetylenes can successfully be used as substrates, by simply changing the temperature and the reaction time. Phenylacetylenes substituted with electron-donating or electron-withdrawing groups display equal reactivity. Remarkably, para-substituted substrates at the benzene ring resulted in lower yields in comparison to meta- and ortho- substituted aromatic substrates. A set of experiments also showed that the structure of pyridine ketones plays a crucial role in the reaction outcome. The authors concluded that the two 2-pyridyl nitrogen atoms in substrates 439a and 439b coordinate to the copper ion, a route not possible in the case of substrate 439d, thus facilitating nucleophilic attack of the terminal alkyne. The CF3 group in substrate 439c, as a strong electron-withdrawing group, had the same effect (Scheme 140). The proposed mechanism for this reaction is shown in Scheme 141. At first, a nucleophilic attack of an alkynylcopper(I) species occurs to form a propargylic alcohol substituted with pyridine rings, with the aid of the copper ion and the base. Polarization of the Cpyridyl–Ccarbonyl bond can be effectively promoted either with coordination of the carbonyl oxygen to the copper ion (direct polarization), or with coordination of the pyridyl group (induced polarization). The copper-bonded electropositive para-N on the pyridyl group could effectively induce polarization of the Cpyridyl–Ccarbonyl σ bond, thus facilitating nucleophilic attack at the carbonyl group. Finally, cyclization/1,2-migration in the propargylic alcohol results in product formation. 157

Scheme 152. Pyridine ketones utilized in the copper-catalyzed formation of functionalized indolizinones [246].

Scheme 153. Possible mechanism for the copper-catalyzed domino synthesis of 3,8adisustituted indolizinones [246]. Recently, considerable attention has been paid to the synthesis of functionalized quinolines and their derivatives, as they can be amongst others used in medicinal chemistry and crop protection. In 2016, Bolm and co-workers reported a cross-coupling between heterocyclic N-oxides and N-H sulfoximines through a copper-catalyzed dual C-H/N-H activation, accessing functionalized quinoline derivatives [247]. Copper(I) bromide as the metal source and toluene as the solvent led to the highest yields. Note that this coupling reaction proceeds without the use of ligand or base. The reaction can also proceed in the absence of solvent; however, the aerobic atmosphere is necessary (Scheme 154) [247].

158

Scheme 154. Selected examples of the products obtained from the dehydrogenative coupling reaction of quinoline N-oxides with sulfoximine derivatives [247]. As shown in Scheme 154, the method was tested on several substrates resulting in high yields. It is evident that neither the substitution pattern nor the electronic effects had a significant impact on the yields. Product 478d shows the exclusive coupling at C2 of the heterocycle, in contrast to the neighboring methyl substituent on C8 that remains untouched. Product 478i reveals the reaction’s excellent site selectivity. The position of any kind of substituent (-Br, -OMe) on the arene unit of S-aryl-S-methyl-sulfoxime has no significant importance in the product formed (478j, 478k). The proposed mechanism for this reaction is shown in Scheme 155. The catalytic cycle begins with the coordination of copper(I) to the N-

159

oxide and then to sulfoxime. Reductive elimination from copper(III) species III affords the desired product and regenerates the catalyst.

Scheme 155. Proposed mechanism for the copper-catalyzed synthesis of sulfoximidoylfunctionalized quinolines [247]. 6.2.3. C-O bond formation reactions In this section, we discuss selected works concerning the copper-catalyzed formation of CO bonds via C-H activation. Several approaches have been developed in this field, utilizing aldehydes [248], alcohols, amines [249] and benzoic acids [250] along with substituted 2phenylpyridines to obtain the corresponding ortho‑benzoxylation products. Below, we report some of the most recent works that have been done towards ortho‑benzoxylation. In 2014, Patel and co-workers reported the selective benzoxylation of the unreactive ortho C-H bond of phenylpyridines [251]. The protocol utilized copper acetate as the catalyst, tertbutyl hydroperoxide as the oxidant, and the reaction was conducted in chlorobenzene at 120 o

C. Substituted 2-phenylpyridines (479) reacted with a series of styrenes (480) under the

optimized conditions. In all cases, the products (481a-481n) were isolated in moderate to good yields (Scheme 156). Electron-donating substituents on styrenes favor the reaction, judging from the yields obtained in the cases of 481b-481e. Moderately electron-withdrawing 160

substituents on styrenes were also tolerated and the expected products (481f, 481g) were successfully obtained, albeit in lower yields. Styrenes bearing strongly electron-withdrawing groups, such as meta-NO2, failed to provide an ortho-benzoxylated product. The orthobenzoxylation of 2-(p-tolyl)-pyridine was also studied. The reactivity trends of the substituted styrenes were found to be identical to those observed for 2-phenylpyridine, while the reaction did not lead to the desired product when the terminal aliphatic alkene 1-methyl 4-butene was used as the substrate [251].

Scheme 156. ortho‑Benzoxylation of 2‑phenylpyridine with terminal aryl alkenes catalyzed by copper [251].

161

In the same work, Patel and co-workers also used substituted aryl alkynes to obtain analogous products to those prepared from the ortho-benzoxylation reaction shown in Scheme 156. Thus, a series of terminal alkynes reacted with 2-phenylpyridine and 2-(p-tolyl)pyridine, affording ortho-benzoxylated products 481 (Scheme 157). Arylalkynes bearing electron-donating groups were found to be good substrates, providing ortho-benzoxylated products 481o-481r in moderate yields. Alkynes having electron-withdrawing substituents provided products 481f and 481g in low yields. By using 1-naphthylalkyne as substrate, 481s was formed in 60% yield. In general, the yields of the products obtained using substituted phenylacetylenes followed similar trends as those with substituted styrenes. The determination of the reaction mechanism was a challenge to overcome and several experiments were carried out in this regard. Amongst others, experiments using radical quencher TEMPO undoubtedly revealed that the reaction proceeds through a radical path. Three possible mechanistic pathways were suggested [251].

162

Scheme 157. ortho‑Benzoxylation of 2‑phenylpyridine with terminal aryl alkynes catalyzed by copper [251]. Two years later, the same research group expanded the scope of the ortho-benzoxylation reaction using benzylic ethers (483, Scheme 158) as alternative arylcarboxy sources [252]. Patel and co-workers amongst others investigated whether the benzyl ether serves as an aroyl equivalent or as an arylcarboxy source during the reaction, by subjecting 2-phenyl pyridine 226 and dibenzyl ether 483 to the reaction conditions. The dibenzyl ether was found to serve as a carboxy (ArCOO-) source in the presence of the Cu catalyst. The tendency of Cu to insert into the ArCOO- group was found to be similar to the reactivity displayed with other arylcarboxy sources such as terminal alkenes, alkynes, and benzyl amines studied by the 163

same research group [251, 253]. The optimal yields were obtained when the reaction was conducted in chlorobenzene at 120 oC with 20 mol% copper(II) acetate as the catalyst and using six equivalents of 70% aqueous solution of tert-butyl hydroperoxide with regards to the substrate. Various substituted dibenzyl ethers were subjected to the reaction in order to explore its scope. Dibenzyl ethers bearing electron-neutral, electron-donating, as well as electron-withdrawing groups provided the desired product (481) in moderate to good yields, with the electron-donating substituents affording better results. 2-Phenylpyridine derivatives (479) possessing electron-withdrawing substituents afford the desired products in lower yield than those bearing electron-donating substituents. Moreover, Patel and co-workers conducted a series of experiments to further clarify the mechanism of the ortho‑benzoxylation reaction catalyzed by copper. In order to define the possible intermediates, reactions of 2phenylpyridine with benzyl alcohol, benzaldehyde, benzoic acid, and benzylbenzoate were carried out. The reactions of benzyl alcohol and benzaldehyde with 2-phenylpyridine led to the desired products (481) confirming their intermediacy during the reaction. The radical path of the mechanism was also confirmed. According to the proposed mechanism, intermediate species I undergoes proton abstraction of an α-C(sp3)-H bond to provide oxonium species II. Nucleophilic attack of water on the oxonium species leads to the formation of an unstable hemiacetal species ((benzyloxy)(phenyl)methanol, III). Subsequently, III is cleaved to give an equimolar mixture of benzyl alcohol (IV) and benzaldehyde (V). This mixture, in the presence of excess tert-butyl hydroperoxide forms radical VI, which forms perester species VII, after proton abstraction from the benzaldehyde. Homolytic cleavage of VII forms carboxy radical VIII. Oxidative addition of carboxy radical VIII to the chelated copper complex IX produces unstable copper intermediate X, which undergoes reductive elimination delivering the desired product (Scheme 158) [252].

164

O

O CuI

CuII

483

I t

BuOOH

t

BuO + H2O

TBHP

OH H2O

O

O

III

II

O

OH

H

O

O t

t

BuOOH

O

t

BuO + tBuOOH

Bu

+ IV

t

V

BuO + H2O

t

VI

VII

BuOH

t

O

OAc t

CuII

t

BuOOH

BuO

O

BuOH + H2O

N R1

R1

VIII

IX chelated complex

H

oxidative addition

N AcO

OCOPh CuIII N

479 CuII(OAc)2

R1

X

[O]

CuIOAc

reductive elimination OCOPh N R1 481

Scheme 158. Copper-catalyzed ortho-benzoxylation reaction mechanism [252]. In the same year, Bhanage and Yedage published a work on chemoselective ortho benzoyloxylation of 2-phenylpyridine [254]. Initially, they used arylamides as benzoyloxy surrogates to the ortho-benzoxylation reaction (Scheme 159). The reaction of Nmethoxybenzamide (484a) with 2-phenylpyridine was the model reaction studied in order to define the optimal reaction conditions. Copper acetate as the catalyst and tert-butyl hydroperoxide as the oxidant in chlorobenzene at 120 oC were the reaction conditions of 165

choice. Under the optimal conditions, Bhanage and Yedage studied the substrate scope, using a series of arylamides (484a-484k) bearing different functional groups at the 2-, 3-, and 4positions. Arylamides bearing electron-donating substituents such as Me, OMe, and t-Bu (484a-484f) resulted in the corresponding products 481 in good yields. On the other hand, reactions with arylamides having weakly electron-withdrawing groups such as Cl (484i) and Br (484k) on the aromatic ring resulted in moderate to good yields. 2-Chloro-Nmethoxybenzamide (484j) afforded the product of the reaction in lower yield compared to the 4-substituted substrates 484i, 484k. Benzoyloxylation of 2-(p-tolyl)pyridine was also found to proceed smoothly with substituted N-methoxybenzamides under the optimized reaction conditions. Dibenzyl ethers were also found to be amenable to this protocol and, in those cases, the reaction followed the same trends as those of the protocol published by Patel’s research group.

Scheme 159. Copper-catalyzed

ortho-benzoxylation of 2-phenylpyridine with N-

methoxybenzamide derivatives [254].

166

More recently, Jana and Singh reported the copper-catalyzed regio- and chemo-selective hydroxylation of benzamides [255]. This reaction was performed with 8-aminoquinolinederived benzamides as substrates, considering the ability of bidentate monoanionic ligands to stabilize the higher oxidation states of metals. The substitution pattern on the benzamide had a profound effect on chemoselectivity. Intermolecular C-H insertion and reductive elimination was proposed to explain the presence of the homocoupling product instead of the hydroxylation product in some cases (Scheme 160). To justify this hypothesis, the authors added external ligands to stabilize the monomeric species and facilitate intramolecular reductive elimination, providing the acetoxylation product first. This product, upon hydrolysis, gives the corresponding phenolic compound. Pyridine as the external ligand, in a mixture of DMF/DMSO as solvent at 100 oC, afforded the optimal conditions. A broad range of substrates were investigated (Scheme 161). The catalytic system displayed tolerance towards a wide range of substituents at the para position (alkyl, phenyl, alkoxy, acyl, fluoro, bromo), as well as, at the ortho position (486f-486j, Scheme 161). The steric and electronic effects induced by the meta substituents had substantial influence on product selectivity. Electron donating groups such as methyl and methoxy, and even bromo led to the formation of both regioisomers of the hydroxylation.

Scheme 160. Copper-catalyzed C-H hydroxylation of 8-aminoquinoline-derived benzamides [255].

167

O

O N H

H

R

Cu(OAc)2 . H2O (1.0 equiv.) pyridine (10.0 equiv.) DMF:DMSO (3:1) 100 oC, 2 h

N

485

O

O

NHQ

NHQ OH 486a (99%) (91% gram scale) F

X

OH

O

Ar

O

O

OH 486p (74%)

NHQ OH 486j: 54%

OH 486i: 78% O

OH

O NHQ

Ac

OH 486n (96%)

OH

R

NHQ F3C

OH 486o (96%)

O NHQ

NHQ N

OH 486f (96%) SMe O

486l Ar= Ph (98%) 486m Ar= 2,4-difluoro O phenyl (88%)

NHQ

NHQ

O

NHQ

486k (85%)

CF3 O

NHQ

O NHQ

4

Me

OH 486h: 80%

O

N

486

NHQ

OH 486g (90%)

OH

R

486b X=F (95%) 486c X=Cl (91%) 486d X=Br (93%) 486e X=I (88%)

NO2 O NHQ

N H OH

OH

486r R=Me (97%) 486s R=tBu (87%) 486t R=Et (85%) 486u R=n-pent (91%)

486q (72%)

Scheme 161. Substrate scope for the copper-catalyzed C-H hydroxylation of 8aminoquinoline-derived benzamides [255]. These transformations, that is, the dimerization and hydroxylation of benzamides, intrigued Sun, Hu and co-workers [256]. Their approach was a copper-mediated dimerization and hydroxylation of benzamides through aerobic C-H bond functionalization. Optimization studies regarding both reactions were conducted (Scheme 162). A variety of substrates were examined under the optimal conditions shown in Scheme 162. Substrates bearing electrondonating or electron-withdrawing substituents (methoxy, fluoro, trifluoromethyl, alkyl, bromo) were both amenable to this protocol, leading to the corresponding dimerization and hydroxylation products in moderate to excellent yields. Good functional group tolerance was observed for benzamides substituted with electron-withdrawing groups and heteroarenes, such as pyridines and thiophenes.

168

NHQ O O

0,5 eq Cu(OAc)2 DMSO, 108 oC, 1h Quench with HCl Cu-mediated

QHN 487a

H O

NHQ 485a

1.0-1.2 eq Cu(OAc)2 (nBu)4NI, DMSO 90 oC, 1 h Quench with base,H2O No Ag2CO3 is needed

OH O

NHQ 486a

Scheme 162. Cu-mediated dimerization and hydroxylation of 8-aminoquinoline-derived benzamides [256]. The proposed reaction mechanism is shown in Scheme 163. The reaction begins with the complexation of 485b with copper to form Cu(II)-complex I. A C-H activation step affords Cu(III)-aryl species II. The C-H activation step could either be a one-step disproportionative C-H activation, or a two-step process, enabled from the acetate ligand: concerted metalationdeprotonation to give a Cu(II)-aryl species, followed by disproportionation or oxidation to afford Cu(III)-aryl intermediate II. The base (K2CO3) could deprotonate excess benzamide 485b and thus promote a two ligand coordination on the copper ion to give intermediate III. Reductive elimination followed by the work-up generates the dimerization product 487b. In the other case, TBAI is used as an additive and probably iodide serves as ligand for copper preventing dimerization, which leads to formation of the C-O bond, therefore to intermediate VII. The final work-up of intermediate VII generates the hydroxylation product (Scheme 163).

169

Scheme 163. Proposed reaction mechanism for the copper-mediated dimerization and hydroxylation of 8-aminoquinoline-derived benzamides [256]. 6.2.4. C-P bond formation reactions Alkynylphosphanes (or phosphinoalkynes) constitute a highly interesting class of compounds. They have unique electronic properties that arise from the interactions of phosphorus’ orbitals with the π-system of the alkyne moiety. Alkynylphosphanes are also attractive molecules for inorganic chemistry, as they are highly versatile ligands for metal

170

complexes or clusters, able to interact with metal systems through the phosphine lone pair, the alkyne π-system, or both (difunctional ligands). In 2003, Antipin and co-workers reported the preparation of alkynylphosphanes through a copper-catalyze cross-coupling reaction between terminal alkynes and chlorophosphanes (Scheme 164) [257]. The reaction proceeds at room temperature, in the presence of trimethylamine, and reaches completion within one to six hours with the desired product being formed almost quantitatively. Diarylchlorophosphanes, dialkylchlorophosphanes, aryldichlorophosphanes, and phosphorus trichloride reacted with terminal alkynes to provide the mono-, bis-, or tris(alkynyl)phosphanes, in most cases in high yields. When tBuPCl2 reacted with phenylacetylene, the reaction temperature needed to be elevated to 120 oC and the desired product was obtained in 50% yield after 24 hours. Poor electrophiles also yielded alkynyl phosphonites and phosphinites when reacted with terminal alkynes under the same reaction conditions. The dependence of the reaction outcome on the nature of the alkyne was also studied using terminal alkynes bearing alkyl and aryl substituents, sensitive functional groups, and heteroaromatic groups. In all cases, the terminal alkyne reacted with phosphanes and the corresponding condensation product was afforded in excellent yields [257].

Scheme 164. Copper-catalyzed cross-coupling of chlorophosphanes and chlorophosphites with terminal alkynes [257]. X-ray analysis revealed that Ph2PCl reacts with CuI forming tetrahedral (Ph2PCl)3CuI, suggesting that the reaction mechanism is similar to the Castro-Stephens coupling. This reaction is also closely related to the Sonogashira coupling and it is proposed to proceed through the formation of a copper-acetylide intermediate when Cu reacts with a terminal alkyne in the presence of Et3N (Scheme 165). 171

Scheme

165.

Proposed

mechanism

for

the

copper-catalyzed

cross-coupling

of

chlorophosphanes and chlorophosphites with terminal alkynes [257]. The use of organophosphorus compounds as achiral or chiral ligands for transition metal catalyzed transformations is growing rapidly in both academia and industry. Based on this fact and the necessity for gaining access to these compounds, Kumaraswamy and co-workers introduced the copper-catalyzed activation of the C-H bond in terminal alkynes followed by coupling with phosphine-borane substrates [258]. More specifically, they reported the formation of a phosphorous-carbon bond, resulting in phenacyl tertiary phosphine-boranes, catalyzed by di-µ-hydroxyl-bis (N,N,N΄,N΄-tetramethylenediamine) copper(II) chloride {[Cu(OH)·TMEDA]2Cl2} (Scheme 154). This copper complex was characterized through various techniques, including X-ray diffraction, mass spectrometry, and 1H- and

13

C-NMR.

The phenacyl tertiary phosphine boranes were obtained in good yields with satisfactory functional group tolerance (Scheme 166). The proposed mechanism is shown in Scheme 167. The monomeric Cu(II) catalyst II initially activates the phosphine-borane and then the alkyne, generating complex IV. Reductive elimination and hydrolysis afford the final phenacyl tertiary phosphine-borane 493. 172

Scheme 166. Copper-catalyzed hydrophosphination/oxygenation of aryl-substituted terminal alkynes and olefins [258].

173

Scheme 167. The mechanism proposed by Kumaraswamy and co-workers for the coppercatalyzed synthesis of phenacyl tertiary phosphine-boranes [258]. 6.2.5. C-S bond formation reactions Building blocks containing sulfur are of significant interest, considering the fact of their presence in a large number of biological molecules and compounds with pharmaceutical activity. As a result, the development of protocols leading to the facile preparation of thiolated compounds comprise an important synthetic field. Copper-based catalytic systems represent an attractive approach. Along these lines, Liu and co-workers recently reported the regioselective sulfenylation of thiazolo-triazoles [259]. By employing CuI in 20 mol% loading, they achieved the regioselective thiolation of thiazolo [3,2-b]-1,2,4-triazoles (Scheme 168). The presence of a base is necessary, while the desired products are obtained in high yields and with excellent regioselectivity.

174

Scheme 168. Copper-catalyzed thiolation of thiazolo-triazoles [259]. Moreover, the preparation of heterocyclic compounds containing sulfur is a feasible catalytic approach as demonstrated in the recently published work of Liu, Chen, and coworkers [260]. More specifically, benzylamides bearing a directing group (2-phenyl2oxazoline) can be transformed into the corresponding imidazo[2,1-b][1,3] thiazinones, through a copper-mediated tandem reaction with 2-mercaptobenzimidazoles (Scheme 169). The products are obtained in moderate to high yields (47-84%), while a variety of benzamides and 2-mercaptoimidazoles bearing different substituents are well tolerated.

Scheme 169. Copper-catalyzed annulation of benzylamides with 2-mercaptoimidazoles [260]. Another interesting work in the field of copper-catalyzed C-S bond formation was published in 2016 [261]. In this study, Messaoudi and co-workers reported the first example of a copper-catalyzed thioglycosylation of benzamides with thiosugars, using Cu(OAc)2•H2O as copper source (Scheme 170). Amenable substrates bear 8-aminoquinoline as a directing group, with the substitution taking place at the ortho position. The protocol is efficient for diversely substituted benzamides, leading to low to excellent yields (25-98%). Notably, complete regioselectivity is exhibited only with ortho-substituted benzamides, while metaand para-substituted benzamides provide mixtures of mono- and di-thioglycosylated products. Finally, the directing group can be removed, leading to the formation of the corresponding acids or esters, through acidic or basic hydrolysis, respectively.

175

Scheme 170. Copper-catalyzed thioglycosylation of benzamides [261]. 6.2.6. C-Se bond formation reactions Organic chalcogens, especially those containing selenium and tellurium, are structural motifs commonly found in a variety of molecules related to biological, pharmaceutical, and material sciences. Various procedures have been explored thus far in order to synthesize such compounds. However, the preparation of sulfur- and selenium-containing compounds are often challenging, because the required chalcogenide reagents frequently poison the catalytically active metal species. Recently, progress was made in this regard by the direct introduction of chalcogenides in organic fragments, via C-H functionalization strategies that can overcome the limitations of traditional metal-catalyzed cross-coupling methods. Dichalcogenides are used as substrates in the synthesis of diorgano monoselenides and monotellurides, given that they are stable compounds in air and are easy to handle. In 2014, Momeni, Movassagh, and co-workers investigated the copper-catalyzed C-X bond formation between terminal alkynes and dichalcogenides (X= S, Se, Te). The concept behind this transformation was the activation of the C-H bond of the terminal alkyne catalyzed by copper and then the coupling of the corresponding acetylide with a complex of copper-liganddichalcogenide to generate alkynyl chalcogenides (Scheme 171) [262].

176

Scheme 171. Copper-catalyzed synthesis of alkynyl chalcogenides: The ligand, 4′-(4methoxyphenyl)- 2,2΄:6′,2′′-terpyridine (Mtpy) is used in combination with copper [262]. This simple protocol proved rather efficient in the C-H functionalization of a wide variety of aromatic as well aliphatic alkynes using diselenides. The reaction takes place with excellent results and high tolerance was exhibited towards functional groups present in the para position of the aromatic diselenides. This approach was also efficient when aryl- and nonaryl- substituted alkynes were used. Given the excellent results obtained for the synthesis of alkynyl selenides, the same transformation was also explored in the case of disulfides. In this case, however, longer reaction times and lower yields were observed. The telluration of alkynes proceeded smoothly as well. However, lower yields were again obtained, regardless of the nature of the alkyne. A plausible mechanism, shown in Scheme 172, was also proposed [262].

Scheme 172. Proposed mechanism for the copper-catalyzed synthesis of alkynyl chalcogenides [262]. One year later, Rueping and co-workers, also focusing on organic chalcogens, developed a new oxidative trifluoromethylselenolation of boron derivatives and alkynes [263]. More specifically, they performed the coupling of tetramethylammonium trifluoromethylselenate 177

with readily available alkynes and then with boronic acids and esters, at room temperature, under aerobic and copper(II)-mediated conditions. The latter, combined with bpy (2,2’bipyridine) or dtbpy (4,4’-di-tert-butyl-2,2’-bipyridine) as ligands in THF under oxygen, proved to provide the best conditions for the trifluoromethylselenolation of a series of aliphatic and aromatic/heteroaromatic alkynes, bearing either electron-donating or electronwithdrawing functional groups (Scheme 173). This catalytic system was also efficient when other nucleophiles, such as boronic acids and ethers, instead of terminal alkynes, were used. The coupling can also be achieved when selenium and TMSCF3 are used as starting materials, instead of tetramethylammonium trifluoromethylselenate. (Scheme 174) [263]. In this case, the required tetramethylammonium trifluoromethylselenate is generated in situ.

178

Scheme 173. Substrate scope for the copper-catalyzed trifluoromethylselenolation of terminal alkynes [263].

Scheme 174. One-pot synthesis of tetramethylammonium trifluoromethylselenate and the subsequent copper-catalyzed trifluoromethylselenolation of terminal alkynes [263]. The C-H selenylation reaction reported earlier by Momeni, Movassagh, and co-workers [262], was more recently extended, focusing on the use of 1,2,3-triazoles. In particular, a study by Cera and Ackermann showed that the copper-catalyzed C-H selenylation of triazoles can be achieved via weak O-coordination that competes with the strong N,N΄-bidentate coordination frequently observed in chelation-assisted C-H activation (Scheme 175) [264]. As shown in Scheme 160, the C-H selenylation of substrate 510 exclusively proceeds at the C5 position of the triazole moiety, through the weakly coordinating O-bonding motif. This protocol is equally efficient for both selenylations and sulfonylations, yielding excellent chemo- and positional selectivities. weak O-coordination

H Bn N N N 510

O

Ph N H

Ph

+

Se Se Ph 511

strong N,N-bidentate

CuOAc (0,04 mmol) Na2CO3 (0,2 mmol) PhI(OAc)2 (0,4 mmol) DMSO, 130 oC 16 h air

PhSe Bn N N N

O N H

Ph

512

Scheme 175. Copper-catalyzed C-H selenylation assisted by weak O-coordination that overrides the strong (N,N) bidentate motif [264]. 6.3. Cross-dehydrogenative coupling reactions 179

In 2010, Li and Correia published a work on the copper-catalyzed cross-dehydrogenative coupling (CDC) of alkynes with benzylic C-H bonds [265]. DDQ (2,3-dichloro-5,6-dicyano1,4-benzoquinone) was used as the oxidizing agent, as it had previously proven to be efficient in C-C bond formations through benzylic C-H bonds activation. In this case, copper(II) triflate is the optimal copper source. Reducing the loading of copper triflate was profitable for the reaction (entry 7, Scheme 176). On the contrary, using solvents as dimethyl formamide (DMF), dichloroethane (DCE), or nitromethane (MeNO2) was disappointing in terms of product yield (entries 9-11, Scheme 161).

Scheme 176. Optimization of the copper-catalyzed alkynylation of diphenylmethane with phenylacetylene [265]. A series of alkynes were studied as substrates. Electronic modifications on the phenyl group of the alkyne is crucial for the reaction outcome. The competing oxidative dimerization is more likely to happen when electron-rich alkynes are used, considering the very low yield obtained in the case of 3- flourophenylacetylene, which can be attributed to the lower nucleophilicity of the electron-deficient alkyne. Aliphatic alkynes, for example n-hexyne, are not compatible with this system. According to the proposed mechanism, benzylic radical (I) 180

is formed through a single-electron transfer (SET) with DDQ and copper. This radical can be further oxidized to a benzylic cation (III) through a second SET. The reduced hydroquinone can abstract the acidic proton from the alkyne forming the copper acetylide (II), which is added to the benzylic carbocation (III) forming the desired product (514) (Scheme 177).

Scheme 177. Proposed mechanism for the copper-catalyzed CDC reaction [265]. A copper-catalyzed dehydrogenative cross-coupling reaction was reported in 2011 by Zhang and co-workers, involving secondary amines as one of the cross-coupling partners [266]. The reaction is catalyzed by copper triflate, while a sub-stoichiometric amount of water plays an important role for the in situ generation of the catalyst, and selectfluor was used as the oxidant. Under the reaction conditions described in Scheme 178, a series of 4H3,1-benzoxazines (516) were successfully synthesized. Substrates with either electronwithdrawing or electron-donating groups on the benzene ring were well tolerated under these reaction conditions. High regioselectivity was achieved in the case of para-methyl181

substituted annulation products (516a, 516b), which were obtained using substrates with ortho-methyl and meta-methyl groups on the benzene ring. Substrates bearing halogen substituents on the benzene ring successfully reacted, providing the corresponding products in high yields (516c, 516d, 516g). By altering the acyl directing group in 515, annulation products 516k-516n could also be obtained. On the other hand, N-para-tolylacetamide, 3methyl-N-para-tolylbutanamide, and 2-phenyl-N-para-tolylacetamide are non-unsuitable substrates for this transformation. This result was attributed to the lack of directing ability of these particular substrates. With regards to the reaction mechanism, it was proposed that the reaction starts with the successive activation of both benzylic methyl and aromatic C-H bonds, by the in situ generated Cu IIIFOH complex. Subsequent intramolecular C-O coupling leads to the formation of the final annulation products 516 [266].

Scheme 178. Copper-catalyzed dehydrogenative cross-coupling of N-para-tolylamides [266]. Later on, Gooßen and co-workers reported the Cu(II)-catalyzed, chelation-assisted dehydrogenative coupling of arenes with a considerably wide range of alcohols [267]. Cu(OAc)2 in 25 mol% catalyst loading, AgOTf (1.5 equivalents), O2 atmosphere, and relatively high temperature (Scheme 179) were all essential elements for carrying out the alkoxylation of various arenes bearing a directing heterocyclic substituent (517) with 182

aliphatic alcohols (518). A broad range of functionalities on the benzene ring of the arenes (517) were tolerated and remained intact during the course of the reaction, leading to the corresponding products (519) in moderate to high yields and in a regiospecific manner, dictated by the presence of directing groups (Scheme 179, selected examples). Notably, chiral alcohols were also successfully employed as substrates, reacting with retention of their configuration (519e). Furthermore, this methodology proved to be of use even in the case of benzylic C(sp3)-H bond activation, providing access to product 519g with remarkable selectivity.

Scheme 179. Cu(II)-catalyzed, chelation-assisted dehydrogenative alkoxylation of arenes [267]. Detailed mechanistic studies suggested that the C-H activation step leading to the formation of intermediate I is the rate-determining step of the reaction (Scheme 180). Fragmentation of the silver alkoxide species affords an alkoxy radical that is transferred to 183

the aforementioned intermediate in a redox process, leading to the formation of Cu(III) complex II and metallic silver. Reductive elimination ensues, releasing the product (519) and subsequent oxidation of the Cu(I) species by O2 regenerates the catalyst [267].

X R

N

X R

H 517

I

N

Cu(II) X

HX Ag(I)OR' R'OH

Cu(II)X2

518 1/2 H2O

Ag(I)X Ag(0)

1/4 O2 + HX Cu(I)X

X R II

X R

N

Cu(III) X OR'

N

OR' 519

Scheme 180. Proposed mechanism for the Cu(II)-catalyzed dehydrogenative coupling of arenes (517) with alcohols (518) [267]. In another work published in 2014, Wang and Wang reported a protocol for the coupling between 2-alkynylbenzaldoximes and cyclic ethers, which achieves the synthesis of C-1 alkylated isoquinoline derivatives in moderate to good yields (Scheme 181) [268]. The optimized conditions comprise of a co-catalyzed system consisting of AgOTf (10 mol %) and Cu(OAC)2 (10 mol%). The most efficient oxidant among those tested was TBHP (3.0 equivalents). K3PO4 was used as an additive (1.0 equivalent) and the reaction was carried out in 1,4-dioxane at 100 oC. A number of substrates were subjected to these optimized conditions. 2-Alkynylbenzaldoximes (520) substituted with either an electron-donating or an electron-withdrawing group on the aromatic backbone were equally reactive in this

184

transformation. Changing the R2 substituent of the 2-alkynylbenzaldoximes (520), (R2 = aryl or alkyl) led to good yields in all cases.

Scheme 181. Preparation of 1-substituted isoquinolines through a dual C-H activation: Silver triflate and copper acetate co-catalyzed tandem reaction of 2-alkynylbenzaldoximes with ethers [268]. According to the proposed mechanism (Scheme 182), silver triflate promotes the 6-endo cyclization of 2-alkynylbenzaldoxime (520) to give isoquinoline N-oxide I. A dioxane radical, generated in situ by hydrogen-atom abstraction from 1,4-dioxane, reacts with intermediate II, generated through C-H activation of isoquinoline N-oxide I, to form intermediate III. A reductive elimination step leads to a C-1 alkylation product of isoquinoline N-oxide I and Cu(I) species. The deoxygenation of intermediate IV eventually affords the desired product [268].

185

Scheme 182. Proposed mechanism for the reaction between 2-alkynylbenzaldoximes and cyclic ethers, co-catalyzed by silver(I) triflate and copper(II) acetate [268]. The intermolecular dehydrogenative amidation of arenes via C-H bond activation was reported by Li, Chen, and co-workers in 2015 [269]. This study described the orthofunctionalization of 523 towards aryl C-N moieties of the type 525 (Scheme 183). A series of 2-phenylpyridine derivatives reacted with acetanilide to explore the substrate scope of this transformation. 2-Phenylpyridines bearing methyl groups provided the desired products (525b, 525c) in good yields. Substrates bearing electron-donating or electron-withdrawing substituents on the phenyl ring of 2-phenylpyridine also provided the expected products (525d-525f) in good yields. Both 2-(1-naphthyl)pyridine and benzo[h]quinoline exhibit excellent reactivity towards the corresponding products 525g (81% yield) and 525h (91% yield). Various amides were also investigated. Acetanilides bearing a methyl group in the 2or 3-position of the phenyl ring provided products 525k and 525l in high yields, while the acetanilide bearing two methyl substituents resulted in 525m in lower yield, due to the obvious steric hindrance. Both electron-rich and electron-deficient amides provided the

186

corresponding products in good to excellent yields. The desired molecules were also obtained using alkyl amides (525t), benzamide derivatives (525s), imides (525u, 525v) and a lactam derivative (525w).

N +

H N

R3

O

R1 523

N O

N O

N

N O

CH3

H3C

N O

CH3

N

CH3

N O

N O

CH3

N

N

CH3

N

N O

CH3 CH3

N O

CH3 CH3

N

CH3

N

N O

CH3

CH3 525j (67%)

525i (66%)

N O

OCF3 525e (51%)

N

N

525h (91%)

CH3

N

OCH3 525d (63%)

N

525g (81%)

N O

CH3

N

CH3 525c (62%)

N

CF3 525f (56%)

N O

CH3

N

CH3 525b (68%)

N O

R3

R1

525

N

525a (77%)

R2

N

524

CH3

N O

N O

CuBr (10 mol%) benzene (0.1 mL), xylene (0.1 mL) air (1 atm), 140 o C, 24 h

R2

CH3

N O

CH3

N

N

H3C 525k (72%)

CH3

N O

525l (86%)

N O

CH3

N

525m (58%)

CH3

CH3

N O

N O

N

N

OCH3

525n (69%)

Ph

525o (80%)

N O

CH3 525q (76%)

N O

N O

N

525u (62%)

Cl

525r (69%)

525v (75%)

N O

O N

O

525t (61%)

525s (79%)

N

N

N O

CH3

N

N

NO2 525p (86%)

CF3

O

N

Ph

NH

N 525y (61%)

525w (77%) 525x (81%)

Scheme 183. Copper-catalyzed, nitrogen-directed intermolecular ortho-amidation of arenes [269].

187

Deuterium kinetic isotope effect studies revealed that C-H bond cleavage in 2phenylpyridine was involved in the rate-limiting step. The proposed catalytic cycle starts with the coordination of the nitrogen directing group to copper(I) bromide, affording copper species I (Scheme 184). Subsequent oxidation of I under air affords intermediate II. Coordination of the amide generates complex III. Finally, upon reductive elimination, the Naryl amide product (525) is formed and the catalytic cycle closes with the regeneration of the copper(I) bromide catalyst [269].

Scheme 184. Proposed reaction mechanism for the intermolecular, copper-catalyzed, nitrogen-directed ortho-amidation of arenes [269]. One year later, the enantioselective cross-dehydrogenative coupling of N-aryl glycine ester derivatives with terminal alkynes was reported by Liu and co-workers [270]. The formation of 528a from phenylacetylene and ethyl 2-(para-tolylamino)acetate was used as benchmark reaction to scrutinize the ideal reaction conditions. Among the chelating ligands that were examined, the best reactivity was exhibited by L32 (Scheme 185). The ideal copper salt in

188

combination with L32 was found to be copper(II) triflate, giving the best results with regards to the both the enantiomeric ratio and the yield obtained. Molecular oxygen served as the oxidant and the reaction was conducted in toluene. A series of substituted aryl acetylenes were examined in the cross-dehydrogenative coupling reaction, providing the desired products 528b-528f in good yields. The reaction of alkyl acetylenes substituted in the αposition resulted in lower yields (528g-528i). Moreover, cyclopropyl (528j), silyl ether (528k), and benzyl ether (528l) derivatives were well tolerated. The scope of the glycine derivatives (526) was also explored. Monomethyl substituted aniline provided the best results in terms of enantiomeric ratio and product yields. Replacing the methyl substituted aniline with either more electron-rich or electron-deficient groups led to a drop in the efficiency of the reaction (528m-528p). In addition, isopropyl ester provided the targeted product (528q) in higher yield than ethyl and isobutyl esters (528b, 528r, 528s). Finally, the aryl group linked to the nitrogen was shown to be necessary for the reaction to proceed, since 528t and 528u were isolated in less than 5% yield [270].

189

Scheme 185. Copper-catalyzed cross-dehydrogenative coupling of N-aryl glycine esters with terminal alkynes [270]. 6.4. Sonogashira coupling Copper catalysis is a powerful tool in C-C, C-N, and C-O(S) coupling reactions. Among the various copper-catalyzed cross-coupling reactions, the Sonogashira coupling has gained a great deal of interest. In 2011, Mao and co-workers described a high-yielding Sonogashira coupling of terminal alkynes with aryl halides [271]. More specifically, they developed a new, ligandless approach, involving Cu(acac)2•H2O as the copper source. Cu(acac)2•H2O in 10 mol% loading proved rather efficient, as did DMSO as the solvent and potassium carbonate as the base. An inert atmosphere (argon or nitrogen) is necessary for the Glacertype elimination to occur, forming the homocoupling product, and, therefore, for an overall high-yielding coupling. A range of products formed under these conditions are shown in Scheme 186. The reaction is tolerant against a variety of functional groups in a series of

190

electron-rich and electron-poor para-substituted phenylacetylenes. It also proceeds smoothly when aryl halides substituted with polar groups (nitro, ketone, amine, and ester) are used. This catalytic system was also efficient when aryl bromides were treated with phenylacetylenes in the presence of TBAB as additive and, in some cases, two equivalents of NaI (Scheme 187).

Scheme 186. Substrate scope for the ligandless, [Cu(acac)2]·H2O-catalyzed Sonogashira coupling of alkynes with aryl iodides [271].

Scheme 187. [Cu(acac)2]·H2O-catalyzed coupling of alkynes with aryl bromides in the presence of TBAB as additive [271].

191

In 2014, Thibonnet, Petrignet and co-workers described the total synthesis of two natural phthalide products, (±)-herbaric acid and (±)-(4-methoxybenzyl)-5,7-dimethoxyphthalide (Figure 12). The total syntheses of these two compounds consist of 8 steps and 5 steps, respectively, using 3,5-dimethoxyaniline as starting material [272]. The key steps in these syntheses include a copper-catalyzed tandem cross-coupling and oxacyclization reaction of terminal alkynes and 2-iodobenzoic acid derivatives via 5-exo-dig cyclizations, with high stereo-, regio-, and chemo-selectivities. This straightforward method allows for the preparation of a variety of phthalides, which belong to a group of pharmacologically important compounds (Scheme 188).

Figure 12. Examples of natural phthalides [272].

Scheme 188. Copper-catalyzed, one-pot approach for the synthesis of phthalides [272]. In 2015, Gao, Zhang and co-workers reported another copper-catalyzed Sonogashira coupling reaction, using polycyclic aromatic hydrocarbons as ligands [273]. The optimized conditions for this reaction involve the use of 4 mol% Cu(OTf)2, 10 mol% of pyrene as the ligand (L35, Figure 13), potassium carbonate as the base, and DMF as the solvent. The optimized conditions are suitable for the functionalization of a variety of terminal alkynes (539), both aliphatic and aromatic, affording the corresponding products in high yields, as shown in Scheme 174. Moreover, ortho-substitution on the aryl iodides (538) has no impact on the reaction outcome (Scheme 189). The proposed mechanism commences with the C-H 192

bond activation of the terminal alkyne by copper. Oxidative addition of the aryl halide to the copper-alkyne complex generates intermediate II. Reductive elimination generates the desired product and regenerates the catalyst (Scheme 190). The mechanism also involves the formation of a diyne by-product (541).

Figure 13. Polycyclic aromatic hydrocarbons utilized as ligands in the copper-catalyzed coupling of terminal alkynes with aryl iodides [273].

Scheme 189. CuI/pyrene-catalyzed Sonogashira cross-coupling of aryl iodides and terminal alkynes [273].

193

Scheme 190. Proposed mechanism for the CuI/pyrene-catalyzed Sonogashira cross coupling [273]. In 2015, Herres-Pawlis and co-workers reported a Sonogashira coupling catalyzed by bis(pyrazolyl)methane copper complexes [274]. The bis(pyrazolyl)methane ligands were proposed to stabilize the copper complexes, while being electronically and sterically tunable. The family of ligands shown in Scheme 191 was tested. L39 was identified as the best performing ligand in this reaction. Particular attention was paid to the donor properties of the non-pyrazolyl donor, as well as, the steric encumbrance of ligand entity as a whole.

Scheme 191. Bis(pyrazolyl)methane ligands utilized in the copper-catalyzed cross-coupling of phenylacetylene with aryl iodides [274]. A wide variety of iodoarenes and terminal alkynes can be transformed into the crosscoupling product under aerobic conditions, rather than under an inert atmosphere (Scheme 192). In the latter case, decreased yields and conversions were obtained. The change of the halide from iodide to bromide led to the formation of a large amount of homocoupling product. Given the excellent results obtained for the coupling of iodoarenes and alkynes in DMF, catalyzed by CuCl2•2H2O, the substrate scope of the reaction was then explored by performing the coupling in aqueous media. The preliminary results are shown in Scheme 193.

194

Scheme 192. Copper-catalyzed coupling of iodoarenes with acetylenes [274].

Scheme 193. Copper-catalyzed coupling of iodoarenes with phenylacetylene in water [274]. 6.5. Homocoupling of terminal alkynes 1,3-Diyne moieties are present in natural products and biologically active molecules. They are also important structural motifs found in numerous polymers and functional materials. A variety of processes have been developed for the preparation of 1,3-diynes. The oxidative coupling of terminal alkynes represents one of the most straightforward and widely used approaches to synthesize these types of compounds. In 2014, Cui and co-workers reported an economical and green protocol for the oxidative homocoupling of terminal alkynes in the absence of base and solvent [275]. This approach works efficiently in the presence of 0,5 mol% CuI and 5 mol% benzylamine as ligand. Electron-rich benzylamines were shown to be the most efficient ligands in this regard. This simple protocol proved effective in the C-H functionalization of a wide variety of alkynes, shown in Scheme 194. Interestingly, this

195

catalytic system afforded the highest TONs for a Cu-catalyzed homocoupling reaction reported until then.

Scheme 194. Substrate scope for the copper(I)-catalyzed oxidative homo-coupling of terminal alkynes [275]. More recently, Guo and co-workers reported the well known Glaser-Hay type coupling of terminal alkynes, using a copper porphyrin catalytic system [276]. High TONs (up to 950) were recorded, under very low catalyst loadings (0,1 mol%). This protocol provides a straightforward access to diverse 1,3-diynes, both symmetric and unsymmetric (Scheme 195).

Scheme 195. Copper porphyrin-catalyzed homocoupling of terminal alkynes towards 1,3diynes [276]. In the same year, Zhang and co-workers reported the synthesis of 1,3-diynes, using the dinuclear copper complex [Cu 2(ophen)2] or the tetranuclear [Cu4(ophen)4(tp)], in an environmentally benign and efficient protocol [277]. In this case, Cu4(ophen)4(tp) served as a heterogeneous catalyst, due to its poor solubility in common solvents. Interestingly, this homocoupling strategy proceeds in water, with TBAB as the phase transfer catalyst, under aerobic conditions, without a base. Arylacetylenes bearing either electron-withdrawing or

196

electron-donating substituents, as well as aliphatic alkynes are well tolerated, resulting in high yields (Scheme 196). Moderate yields were obtained for unsymmetrical 1,3-diynes with different terminal alkynes as substrates under the same conditions. The proposed mechanism for the function of this dimetallic catalytic system is shown in Scheme 197. Activation of the catalyst by molecular oxygen generates intermediate I causing a decrease of the Cu-Cu distance. Reaction of the terminal alkyne with copper(II) complex I, followed by reductive elimination affords the desired product and regenerates the catalyst.

Scheme 196. The copper-catalyzed homocoupling of various terminal alkynes [277].

197

Scheme 197. Proposed mechanism for the copper-catalyzed homocoupling of terminal alkynes [277]. 6.6. Carboxylation of terminal alkynes The concept of developing catalytic reactions in which simple organic molecules react with CO2 towards forming fine chemicals or valuable synthetic intermediates has lately attracted the intense interest of the scientific community. For example, the use of CO2 in the catalytic carboxylation of C-H bonds constitutes such a sustainable process. Various copperbased catalytic systems have been used for the carboxylation of terminal alkynes resulting in acids or the corresponding esters. Along these lines, Yu and Zhang reported the transformation of CO2 into carboxylic acids via the terminal alkynes’ C-H bond activation in 2010 (Scheme 198) [278]. They showed that an in situ formed catalytic system comprised of CuCl, a base, and TMEDA (L45, Figure 14) can catalyze this transformation for a series of aromatic alkynes, affording the corresponding alkynyl carboxylic acids in high yields. A number of other σ-donor ligands, such as N,N΄dimethylethanediamine

(L46),

1,8-diazabicyclo[5.4.0]undec-7-ene

(L47),

and

1,3-

dimesitylimidazol-2-ylidene (L50) were also shown to be efficient in the same transformation (Figure 14). Alkyl substituted terminal alkynes and terminal aromatic alkynes bearing electron withdrawing substituents on the aromatic ring showed low reactivity with this catalytic system. The combination of one equivalent of CuCl with two equivalents of a polyN-heterocyclic carbene were combined to overcome this low reactivity, affording the desired products in high yields. The best results were obtained under ambient temperature, as raising the temperature to 60 oC led to the decomposition of the active intermediate decreasing the yields. The proposed mechanism involves the formation of copper-acetylide intermediates.

198

Scheme 198. Copper-catalyzed carboxylation of terminal alkynes with CO2 [278].

Figure 14. A series of σ-donor ligands utilized in the carboxylation of aromatic alkynes [256]. Five years later, He and co-workers published a closely related work [279]. More specifically, ionic liquids (ILs) containing copper salts were shown to catalyze the carboxylation of terminal alkynes with ambient CO2, affording alkyl 2-alkynoates at room temperature. The ILs that were tested in these carboxylations are shown in Figure 15. Among them, [Cu(Im12)2][CuBr2] (557, Im12 = 1-dodecylimidazole) provided the most efficient catalytic system. It is also noteworthy that ILs containing copper(I) in both the anionic and the cationic species showed much higher activity than their counterparts incorporating copper(I) only in the form of halocuprate, that is, in the anion [279].

199

Figure 15. Copper(I)-containing ionic liquids utilized in the carboxylation of terminal alkynes [279]. The carboxylation proceeds efficiently for phenylacetylenes bearing electron-donating substituents at meta- or para-positions, as well as phenylacetylenes substituted with weakly electron-withdrawing substituents, in both cases resulting in high yields. High yields were also observed in the case of aliphatic alkynes. The presence of a strong electron-withdrawing substituent on the aromatic ring decreases the yield, because, in this case, the nucleophilicity of C-Cu bond is very low. A series of NMR experiments showed that [Cu(Im12)2][CuBr2] and terminal alkynes have a marked synergistic effect on promoting the reactions. According to the proposed mechanism (Scheme 199), the terminal alkyne is first activated by copper, followed by copper acetylide generation in the presence of cesium carbonate [279]. Then, insertion of CO2 into the Cu–C(sp) bond generates the copper propynoate intermediate. The desired ester product is obtained by using an iodoalkane, with the simultaneous regeneration of the copper catalyst.

Scheme 199. The proposed mechanism for the IL-Cu(I) promoted carboxylation of terminal alkynes with CO2 [279]. Another method for the terminal alkynes’ carboxylation that He and co-workers published in the same year [280], was a modification of a methodology developed by them in 2013

200

[281]. The initial methodology was a Cu(I)-catalyzed carboxylation with ambient CO2 using ethylene carbonate (EC) as solvent without the use of an additional ligand [281]. The improvement, published two years later, involves the use of a heterogeneous catalytic system, comprised of CuBr supported on activated carbon (CuBr@C), under mild reaction conditions (Scheme 200) [280]. The advantage of this protocol is that the catalyst is stable to air and moisture and can be easily recovered and reused without significant loss of activity. The reaction proceeds smoothly at 80 oC in only 2 hours, for a variety of electron rich and electron poor terminal alkynes.

13

C NMR and high resolution mass spectrometry (HRMS)

experiments showed that CO2 was the only carboxylative reagent.

Scheme 200. Carboxylation of terminal alkynes catalyzed by CuBr@C [280]. 6.7. Miscellaneous transformations of terminal alkynes In 2011, Thibonnet and co-workers reported a copper-mediated regioselective methodology to thieno[2,3-c]pyrane-7-ones, indolo[2,3-c]pyrane-1-ones, and indolo[3,2c]pyrane-1-ones, from the reaction of indoles and thiophenes bearing a β-iodo-α,βunsaturated carboxylic acid unit with terminal alkynes [282]. As shown in Schemes 201 and 202, this methodology tolerates different types of terminal alkynes. The reactions were mild 201

in the case of 2-iodo-thiophenecarboxylic acid, but needed high temperatures and stoichiometric amounts of copper(I) in the case that indoles were used as starting materials.

Scheme 201. Scope of the copper-catalyzed preparation of thieno[2,3-c]pyran-7-ones [282].

Scheme 202. Copper-mediated preparation of indolo[2,3-c]pyrane-1-ones and indolo[3,2c]pyrane-1-ones [282]. According to the proposed mechanism (Scheme 203), the reaction starts with the formation of copper carboxylate I, followed by the oxidative insertion of copper in the C-I bond to form copper(III) intermediate II. Subsequently, insertion of the alkyne is followed by an 6-endo-dig cyclization and reductive elimination. Regeneration of Cu(I) occurs after the hydrolysis of the C-Cu bond in intermediate V.

202

K2CO3 CO2

Y

I

O

I

Y O K,O

HO Y= S or N-Bn

Y

Y

I

CuI

O CuO

R

O

O

Y

I

H Cu I II

Y

O O R

I Cu

H

V R

O

H,I

O III Y

IV

I Cu

Y

O Cu

O

O O

R I

R

Scheme 203. Proposed mechanism for the tandem coupling oxacyclization reaction [282]. In 2014, Wang and co-workers described a copper-catalyzed method for the reaction of βketo α-diazoesters with terminal alkynes to form trisubstituted furans (568, Scheme 204) [283]. Interestingly, this required only Cu(MeCN)4PF6 (20 mol%) in toluene, in the absence of an additional ligand or a base. By utilizing this catalytic process, several terminal alkynes bearing electron-deficient or electro-rich groups reacted with a number of β-keto αdiazoesters to form the corresponding tri-substituted furans in moderate to good yields. The proposed mechanism for this reaction is shown in Scheme 204. Initially, copper activates the terminal alkyne to form copper acetylide I, which reacts with the diazoester to form coppercarbene species II. After alkynyl migratory insertion of carbene species II to the carbonic carbon generates III, protonation gives 2,3-allenoate V. Finally, cyclization of V affords the furan product. Alternatively, intramolecular nucleophilic attack of the carbonylic oxygen to the triple bond in intermediate III forms IV, followed by proton transfer to generate the desired product and the catalyst. An alternative mechanism could involve copper-catalyzed cyclopropenation, followed by ring-opening and cyclization to generate the final furan product. 203

Scheme 204. Proposed mechanism for the synthesis of trisubstituted furans from β-keto αdiazoesters and terminal alkynes [283]. Catalytic cyclization reactions represent an attractive strategy for the functionalization of terminal alkynes. Substituted thiopyranones, for example, are a class of compounds that can be synthesized through this kind of transformation. In this regard, Rao, Pal, and co-workers reported the copper catalyzed coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes under ultrasound conditions in 2014 (Scheme 205, reaction A) [284]. I

R +

S

R CuI, K2CO3 PEG, r.t., 2-3h

CO2H

O

S

(A)

O 570

569

HO I + S

OH

CO2H 569

571

CuI, Base Solvent

O

S

(B)

O 570a

Scheme 205. Catalytic synthesis of thiopyranones under ultrasound conditions [284]. Using the coupling of terminal alkyne 571 with 3-iodothiophene-2-carboxylic acid (569) as model reaction (Scheme 205, reaction B) Rao, Pal, and co-workers performed a series of experiments to optimize the reaction conditions. The best results were obtained with CuI (20% catalyst loading), 3-iodothiophene-2-carboxylic acid (1 equivalent), 2-methylbut-3-yn2-ol (1.5 equivalents) and K2CO3 (2.0 equivalents) in polyethylene glycol (PEG) as solvent, at room temperature in a sonicator under nitrogen. Under these optimized conditions, they 204

tested various substituted terminal alkynes, which provided the corresponding substituted thiopyranones in good yields (Figure 16). PEG was proposed to act as a ligand. Moreover, no coupling product is formed in the absence of ultrasounds. The proposed mechanism for the reaction is shown in Scheme 206.

Figure 16. Substituted thiopyranone derivatives formed via the coupling of 3-iodothiophene2-carboxylic acid with the corresponding substituted terminal alkyne [284].

205

Scheme 206. Reaction mechanism proposed for the formation of substituted thiopyranones [284]. The enantio- and diastereo-selective propargylation of substituted benzofuranones (572, Scheme 207) with propargyl acetates (573) catalyzed by a pybox-Cu(I) complex under mild conditions, was reported for the first time by the research groups of Zhao and Wu [285]. Various bidentate and tridendate chiral ligands were evaluated in this transformation with regards to product yield, reaction time, enantiomeric excess, and diastereomeric ratio and it was found that L58 (Scheme 207) gave the best results. Also, CuBr and Cu(acac)2 were found to be the most effective precatalysts for the system, leading to excellent results. Investigation of the substrate scope, led to the observation that the steric bulk of the C2 substituent of the benzofuranones (572) strongly affects the reaction outcome, as cyano and methyl substitution leads to decreased yields, as well as, ee and dr values. A plausible reaction mechanism, which begins with the formation of π-complex I followed by deprotonation of the activated C(sp)-H bond to afford intermediate II, was proposed. Loss of an acetate group leads to the formation of the key intermediate III, while addition of 572 to this Cu(I)-alkenylidene complex from the less hindered side leads to product formation.

206

Scheme 207. Diastereo- and enantio-selective propargylation of substituted benzofuranones with propargyl acetates, catalyzed by a pybox-Cu(I) complex [285]. One year later, Wang and co-workers reported the cross-coupling of terminal alkynes with various trifluoromethyl N-tosylhydrazones towards 1,1-difluoro-1,3-enynes (Scheme 208) [286]. By studying the reaction of phenylacetylene with trifluoromethyl N-tosylhydrazone, they found that the optimal yield was achieved by using copper iodine as metal source, tetrabutylammonium chloride (TBAC) as phase-transfer catalyst, LiOtBu as base, and LiOTf as additive, in dioxane as solvent. The scope of the reaction was then explored with these optimized conditions. A series of trifluoromethyl N-tosylhydrazones (576a-576o, Scheme 208) reacted with phenylacetylene. These experiments revealed that the reaction is not 207

significantly affected by the electronic nature of the substituents on the tosylhydrazone. Moreover, the reaction showed applicability to alkyl N-tosylhydrazones. The effect of the nature of the terminal alkynes on the reaction was also examined. Para-substituted aromatic alkynes (575a-575g) in all cases afforded the corresponding products (577) in high yields. Interestingly, the reaction was found to be tolerant to free hydroxyl groups (575o) and alkenyl moieties (575p) [286]. CuI (20mol%) LiOtBu (2eq.) LiOTf (1 eq.) TBAC (20mol%) dioxane, 60oC, 1h

NNHTs R

1

+

R2

576

575 575a: R1=

CF3

575g: R1=

575o: R1=

CH3 575b: R1=

575h: R1=

R

R1 577

OH Et

575p: R1=

OCH3

OCH3 5751: R1=

575c: R1=

Et

CO2CH3

CF2 2

N

575q: R1=

N 576a: R1= 1

575d: R =

575j: R1=

576k: R1=

576f: R1=

S

CH3

NO2

F 575k: R1= nC4H9 575l: R1=cyclopropyl 575m: R1=cyclohexyl 575n: R1=TIPS

575e: R1=

576b: R1= F

576g: R1= H3C

576l: R1=

576h: R1=

576m: R1=

CF3

Br 576c: R1= 1

S

Br

Cl

575f: R = CF3 576d: R1=

576n: R1=

576i: R1= OCH3 Br

576e: R1=

I

576j: R1=

576o: R1=

nC7H15

Scheme 208. Cross-coupling of terminal alkynes with trifluoromethyl N-tosylhydrazones [286]. According to the proposed mechanism, in the presence of base the alkyne coordinates to copper forming I (Scheme 209). Then, dediazoniation of the in situ generated diazo 208

compound 576 leads to the formation of carbene II. Subsequent carbene migratory insertion of intermediate II affords intermediate III. Intermediate III can follow two pathways to regenerate the catalyst and complete the catalytic cycle: In pathway 1, 1,1-difluoro-1,3-enyne 577 is formed upon β-fluoride elimination in III. According to pathway 2, III undergoes protonolysis to generate IV, instead of direct β-fluoride elimination, finally yielding the desired product. However, pathway 2 is questionable, given that when a synthesized derivative of IV was subjected to the standard reaction conditions, most of it was retrieved unchanged [286].

Scheme 209. Plausible mechanism for preparation of 1,1-difluoro-1,3-enynes [286]. 6.8. Multicomponent reactions Multicomponent reactions that can lead to the one-step synthesis of useful compounds are a powerful tool in synthetic organic chemistry. Today, there are various copper based catalytic systems that can promote such types of transformations. Note, that the main 209

challenge in a multicomponent reaction is to be conducted in a way that the network of preequilibrated reactions channel into the main product, without yielding side products. An interesting catalytic C(sp)-H activation methodology for gaining access to chiral propargylamines (581, Scheme 210) via the three component reaction between aldehydes (578), amines (579), and terminal alkynes (580) was developed by Knochel’s research group in 2003 [287]. This enantioselective transformation takes place in the presence of CuBr (5 mol%) and chiral ligand (R)-quinap ((R)-L59, 5.5 mol%) at room temperature leading to a variety of propargylamines in excellent yields. Furthermore, high diastereoselectivity was observed when chiral amines (579) or aldehydes (578) were used as substrates. Detailed mechanistic studies showed that the dimeric Cu(I) complex 582 is the active catalytic species in this asymmetric transformation.

Scheme 210. The three component, enantioselective synthesis of propargylamines, catalyzed by the dimeric Cu(I) complex 582 [287]. More recently, a versatile, highly efficient catalytic system based on Cu(I) was developed for the three component reaction between terminal alkynes (583, Scheme 211), dihalomethanes (584) and amines (585) (AHA coupling), providing access to propargylic amines (586) [288]. By employing CuCl in 5 mol% loading and DBU (1,8210

diazabicyclo[5.4.0]undec-7-ene) as the optimal non-nucleophilic base, a wide array of propargylic amines were synthesized in excellent yields through activation of C(sp)-H and Chalogen bonds. High product yields were obtained in most cases, using either CH3CN or water as the reaction medium, in relatively low temperature, demonstrating the sustainable and environmentally benign nature of this multicomponent reaction methodology (Scheme 211). High chemoselectivity towards the AHA coupling, as opposed to the coupling between an aldehyde, an amine and an alkyne (A3 coupling), was exhibited during the synthesis of product 586c and even when benzaldehyde (16a) was added to the reaction mixture, only traces of the A3 coupling product were obtained. Moreover, aliphatic and diversely substituted aromatic alkynes, as well as cyclic, heterocyclic, and acyclic secondary amines were amenable to this reaction, which is tolerant to a range of functionalities. Based on experimental observations, a possible mechanistic path was proposed for this transformation: It begins with the cooperative C(sp)-H activation of a terminal alkyne by Cu(I) and DBU, leading to copper acetylide formation and a sequence of oxidative addition, reductive elimination steps affording the final product.

211

Scheme 211. A copper-catalyzed, three component coupling reaction providing access to propargylic amines. The second yield (reported in the parentheses) refers to reactions taking place in water [288]. Synthetic approaches that simplify the preparation of important intermediates are always highly desired in both academia and industry. In this context, Yavari and co-workers reported a three component approach for the the synthesis of N-sulfonylamidines, utilizing a trialkylamine, a sulfonyl azide, and a terminal alkyne (Scheme 212) [289].

Scheme 212. Copper-catalyzed synthesis of N-sulfonilamides [289]. The best results were achieved with 10 mol% of CuI relative to the alkyne, along with 3 equivalents of the trialkylamine in THF at 60 oC. Many N-sulfonylamidines were obtained under these optimized conditions (Figure 17).

Figure 17. N-sulfonylamidines derived from the copper-catalyzed, three component reaction of a trialkylamine, a sulfonyl azide, and a terminal alkyne [289]. Aliphatic acetylenes provided lower yields, in comparison with phenylacetylene, while the coupling product was formed in good yields with aromatic sulfonyl azides [289]. A possible reaction mechanism was also proposed (Scheme 213). The reaction starts with the formation

212

of the copper acetylide (I) that undergoes a 1,3-dipolar cycloaddition reaction with the sulfonyl azide leading to the formation of the corresponding triazole derivative (II). Intermediate II provides the ketenimine derivative III, which, upon reacting with trialkylamine, affords zwitterion IV. Moisture leads to the conversion of intermediate IV into salt V. The final product (587) is formed by dealkylation of intermediate V by the trialkylamine.

Scheme 213. Proposed mechanism for the formation of N-sulfonylamidines [289]. In 2014, Müller and co-workers described, for the first time, a multicomponent reaction for the synthesis of 2,6-disubstituted pyrimid-4(3H)-ones and 1,5-disubstituted 2hydroxypyrazoles [290]. This approach involves a copper-catalyzed terminal alkyne C-H bond activation and C-C bond formation. More specifically, the reaction (Scheme 214) begins with the copper-catalyzed carboxylation of a terminal alkyne, followed by a Michael addition-cyclocondensation with an amidinium chloride (596). When the binucleophile utilized is a hydrazinium salt (597), the reaction results in hydroxypyrazoles 599. The optimum reaction conditions involve DMF as solvent and Cs2CO3 as base, under an ambient pressure of CO2 (supplied to the reaction mixture through a balloon). Bidentate ligands, like phenanthroline or bipyridine, are efficient in the carboxylation due to their stabilizing effect on the metal center, coming from their chelating ability. Low reactivity was observed with electron-rich and sterically hindered acetylenes. On the contrary, high yields were observed

213

with electron-neutral and electron-deficient substrates, a behavior attributed to the lower acidity of these alkynes (Scheme 215).

Scheme 214. The three component synthesis of pyrimidinones (598) and 3-hydroxy pyrazoles (599) carried out via the Cu(I)-catalyzed carboxylation of terminal alkynes [290].

Scheme 215. Reaction conditions for the one-pot synthesis of pyrimidinones 598 [290]. One year later, He and co-workers reported a similar multicomponent methodology [291]. Employing copper-catalyzed terminal alkyne activation, they developed a one-pot tandem carboxylation/annulation reaction of terminal alkynes to 3a-hydroxyisoxazolo[3,2-a]isoindol8(3aH)-ones (601, Scheme 216). They coupled the propiolic acid ester produced in situ, through the carboxylation of the terminal alkyne with CO2, with N-hydroxyphthalimide (NHPI) to obtain the cyclization product. The carboxylation step of the terminal alkyne was achieved in DMF at 80 oC, in 6 hours. Among the tested copper salts, the commerciallyavailable CuCl was identified as the copper source of choice, in combination with PPh3 as ligand. A series of terminal alkynes were studied. Substituted aromatic alkynes having electron-donating substituents, as well as, those bearing electron withdrawing moieties at the

214

meta- or the ortho-position, afforded the corresponding heterocycles in high yields (Scheme 216).

Scheme 216. The one pot, tandem carboxylation/annulation reaction of terminal alkynes to 3a-hydroxyisoxazolo[3,2-a]isoindol-8(3aH)-ones [291]. A plausible mechanism was also reported: It begins with the carboxylation of the terminal alkyne, catalyzed by CuCl/Ph3P under an ambient pressure of CO2. This generates propiolic acid ester III, through copper acetylide as the key intermediate (I) delivered from the reaction of the terminal alkyne and CuCl in the presence of a base and Ph3P as ligand. The reaction of propiolic acid ester (III) with NHPI eventually affords the targeted 3a-hydroxyisoxazolo[3,2a]isoindol- 8(3aH)-one (Scheme 217).

215

Scheme 217. Proposed mechanism for the CuCl/Ph3P-catalyzed one-pot formation of 3ahydroxyisoxazolo[3,2-a]isoindol-8(3aH)-ones [291]. Another three-component reaction involving a copper-catalyzed C-H activation was reported by Hwang and co-workers [292]. This photocatalytic protocol was successfully applied on the C-H annulation of arylamines with terminal alkynes and benzoquinone (Scheme 218).

Scheme 218. A photoinduced copper-catalyzed three component reaction [292]. After optimizing the reaction conditions (Scheme 218), Hwang and co-workers examined the impact of various functional groups, both electron donating and electron withdrawing, on all reaction components. The protocol is successful with many different functionalities, leading to the formation of the desired annulated products in good yields (Figure 18). Addition of free radical traps (TEMPO) to the reaction mixture completely deactivated the

216

catalytic system, suggesting the presence and the formation of radical intermediates in the catalytic cycle.

Figure 18. Compounds derived from the copper-catalyzed photoinduced C-H annulation of arylamines with terminal alkynes and benzoquinone (selected examples) [292]. A year later, Parrain, Commeiras, and co-workers reported a method for the preparation of 5-hydroxylactams (613, Scheme 219) through another copper catalyzed three-component reaction [293]. Initial experiments showed the formation of the desired product, along with a mixture of other byproducts. A more detailed study showed that the nature of solvent significantly affects the reaction, with the use of isopropyl alcohol decreasing the formation of the non-desired formamide. After determining the optimal reaction conditions, the authors examined this transformation for its scope (Figure 19). For this propose, reagents bearing various functional groups were used.

Scheme 219. Three component, copper-catalyzed synthesis of γ-hydroxylactams [293].

217

Figure 19. Scope of the copper-catalyzed synthesis of γ-hydroxylactams (selected examples) [293]. In all cases, this protocol provided the desired γ-hydroxylactams in moderate to good yields. A factor significantly affecting reaction’s efficiency proved to be the amine nucleophilicity. Less nucleophilic amines provide lower yields. Moreover, lower yields are obtained with deactivated amines (aniline). The reaction tolerates alkynes with electronwithdrawing or electron-donating groups, while deactivated alkynes provide lower yields [293]. In another, more recent report, Sun and co-workers described a new method for the preparation of benzoimidazo[1,2-a]imidazolones through a three-component reaction (Scheme 220) [294]. This one pot synthesis is again catalyzed by copper and involves the reaction of 2-aminobenzimidazoles, benzaldehyde, and a terminal alkyne.

Scheme 220. Copper-catalyzed synthesis of benzoimidazo[1,2-a]imidazolones [294]. 218

Molecular oxygen is essential for this reaction, given that when it is replaced with air, the yields are lower. Also, in experiments carried out under a nitrogen atmosphere, the cyclized product is not formed at all. The combination of CuI with Cs2CO3 and O2 in toluene afforded the best results. These conditions were applied to various substrates, providing the desirable products in good yields (Scheme 221). In experiments with 2-aminopyridine and 2aminopyrazines as substrates, the desirable product was successfully formed as well.

Scheme 221. Substrate scope for the synthesis of 2-aminobenzimidazoles [294]. Recently, Ma and co-workers reported a three-component strategy for the preparation of functionalized propargylic amines [295]. By following this protocol, they obtained various propargylic

amines

through

a

copper-catalyzed,

one

pot

coupling

reaction

of

phenylacetylenes, substituted acetophenones and pyrrolidine. The necessary Cu(I) catalytic species are formed in situ from CuBr2 and sodium ascorbate. By carefully studying the reaction parameters, the authors found that the combination of CuBr2 (10 mol%), sodium ascorbate (20 mol%), and Ti(OEt)4 (2 equiv) in toluene at 100 oC under argon provides the 219

best catalytic system. Having these results in hand, they studied the reaction scope, some selected results of which are shown in Scheme 222. In brief, the reaction tolerates ketones and alkynes with various functional groups, providing the target coupling product in good to excellent yields. Alkynes bearing cyano or nitro groups are an exception, as they afford moderate yields. Besides pyrolidine, other cyclic amines, such as piperidine, were also effective, affording the propargylic amines in good yields. On the other hand, secondary and primary amines proved less appropriate for this transformation.

Scheme 222. Reaction scope for the three-component, copper-catalyzed propargylic amines synthesis (selected results) [295]. 6.9. Arylation reactions In 2007, Do and Daugulis reported the copper-catalyzed arylation of C-H bonds in heterocyclic aromatic compounds, by utilizing the corresponding aryl halides [296]. This C-H arylation reaction takes place both with electron-rich five-membered heterocycles and electron-poor pyridine oxides. With regards to the aryl halide, electron-deficient aryl iodides were similarly active with electron-rich and heteroaryl iodides. A series of heterocycles were investigated. For example, oxazole can be monoarylated in 59% yield (633a, Scheme 223), with a 7% diarylated product being formed simultaneously. Diarylation occurs in the case of

220

1,3-thiazole (633b), while the electron deficient 2-phenylpyridine oxide is arylated at the 6position (633h).

Scheme 223. Copper-catalyzed heterocyclces arylation [296]. One year later, the same research group published a more general method for the catalytic arylation of arenes by C-H bond activation, again using copper catalysis (Scheme 224) [297]. This approach is effective for the arylation of either electron-rich or electron-poor heterocycles, while it can be also applied to non-heterocyclic aryl compounds with electronwithdrawing groups. Arylation of electron rich heterocycles with aryl iodides provides the corresponding coupling products in high yields. With 10 mol% CuI loading, phenanthroline is the most efficient ligand, while the optimal base depends on the acidity of the heterocyclic substrate (Scheme 224). This copper-catalyzed arylation method is effective for heterocyclic substrates with pKa lower than 35 (in DMSO).

221

Scheme 224. Copper-catalyzed arylation of electron rich heterocycles [297]. The same conditions are effective in the arylation of electron-poor heterocycles in good to excellent yields. Some selected results are shown in Scheme 225.

Scheme 225. Arylation of electron poor heterocycles [297]. Electron-poor aromatic compounds participate in this C-H arylation reaction as well, affording the targeted coupling product in good to high yields (Scheme 226).

222

Scheme 226. C-H arylation of electron poor aromatic compounds [297]. The proposed mechanism for this copper-catalyzed arylation reaction comprises of three steps: metalation, transmetalation with the copper halide, and, finally, reaction of the arylcopper intermediate with the haloarene partner (Scheme 227).

Scheme 227. The proposed mechanism for the copper-catalyzed arylation of heteroaromatic and electron poor aromatic compounds [297]. In 2014, Cazin and co-workers reported a cooperative palladium-copper system for direct C-H bond arylation (Scheme 228) [298].

Scheme 228. The cooperative, Pd-Cu catalyzed direct C-H bond arylation [298]. With regards to the proposed mechanism for this transformation (Scheme 229), copper initially performs the C-H activation of the aryl or heteroaryl compound, through an acid223

base reaction. Then, this intermediate undergoes a transmetalation reaction with the palladium intermediate, towards the final aryl or heteroaryl coupling product. Both the copper and the palladium species utilized in this cooperative catalytic system are coordinated with NHC ligands. This protocol is suitable for a series of aryl, alkenyl, and benzyl bromides and chlorides reacting with aryl and heteroaryl compounds. This suggests that the oxidative addition of the aryl halide is not the rate-limiting step in this reaction [298]. Good yields were obtained from ortho- and meta-substituted aryl halides, bearing both electron-donating and electron-withdrawing groups.

Scheme 229. Proposed mechanism for the cooperative Pd-Cu-catalyzed direct C-H bond arylation [298]. Recently, Ackermann and co-workers reported the first photoinduced copper-catalyzed CH bond activation (Scheme 230) [299]. Et2O was found to be the solvent of choice. CuI can provide the coupling product without ligand addition, but high yields require catalyst loading of 50 mol%. Addition N,N-dimethylglycine as ligand afforded the coupling product in good to high yields. Under the optimized conditions, benzothiazoles and benzoxazoles were successfully arylated to the corresponding coupling products as shown in Scheme 230.

224

N R

H

+

I Ar

Y

cat. CuI cat.Me2NCH2CO2H LiOtBu, Et2O hv, RT, 16h

R

N R

Ar Y 639 (Y=S) 640 (Y=O) Me

R

N

N

S

S

N

Me

N

R 639a 639b 639c 639d 639e 639f

R =H R = Me R = OMe R = CF3 R=F R = Cl

(70%) (73%) (70%) (60%) (79%) (80%)

639g R = OMe (63%) 639h R = CF3 (70%) 639i R = Cl (63%) 639j R = CO2tBu (46%)

O 640a R = H (64%) 640b R = Me (59%)

O 640c (72%)

Scheme 230. Photoinduced copper-catalyzed arylation of benzothiazoles and benzoxazoles [299]. The protocol is versatile, as it was also successfully applied to azoles and non aromatic oxazolines, leading to the coupling products in good yields at room temperature (Scheme 231).

Scheme 231. Photoinduced copper-catalyzed C-H arylation of azoles and oxazolines [299]. In another recent report, Tan and co-workers published a method for the copper-mediated ortho-arylation of benzamides with phenylboronic acids (Scheme 232) [300]. The selective arylation of the substrate at the ortho position is directed by the 8-aminoquinoline moiety of the benzamide. The copper salt, the amide, the base, and the phenylboronic are used in a 225

1:1:2:1 molar ratio, respectively. The best yields were achieved using Cu(OAc)2 and Na2CO3 in DMSO at 120 oC for 4 hours. Under these optimized conditions, the authors tested a variety of boronic acids and amides (Scheme 233). The coupling products are formed in good to excellent yields, while the slight decrease observed in the yields in the presence of a radical trap (TEMPO) suggests the reaction does not proceed through the formation of free radical intermediates. It should be also noted, that the directing group (8-aminoquinoline) can be removed, affording the corresponding carboxylic acid (Scheme 233).

Scheme 232. Selective copper-catalyzed ortho arylation of benzamides [300].

Scheme 233. Copper-mediated ortho-arylation of benzamides with phenylboronic acids and formation of the corresponding free carboxylic acid [300].

226

In an analogous fashion, Fruit, Besson, and co-workers recently reported a method for the selective diarylation of thiazolo[5,4-f]quinazolin-9(8H)-one (608, Scheme 234) at the C2 and C7 positions [301]. The combination of 1 equivalent of CuI with DBU leads to the selective arylation at the C2 position, while further reaction of the monoarylated product with CuI and LiOtBu affords its diarylated derivative. The presence of Pd(OAc)2 is necessary for high conversions and the reaction is performed under microwave irradiation.

Scheme 234. Sequential bis-arylation of thiazolo[5,4-f]quinazolin-9(8H)-one [301]. 6.10. Alkynylation reactions Alkyne addition is a highly useful reaction in organic synthesis. The C-H bond dissociation energy of ethyne is 133 kcal/mol [140], a fact that makes this bond relatively inert. Nevertheless, this C-H bond can be catalytically activated and then added to a variety of substrates through an alkynylation reaction. Alkynylation can be thus applied to tertiary amines [302], α-imino esters [303], β-imino esters [304] and to a variety of other saturated or unsaturated substrates. In 2011, Watson and co-workers reported the catalytic enantioselective alkynylation of isochroman acetals [305]. In other words, they developed one of the first transition-metalcatalyzed methods for enantioselective addition to prochiral oxocarbenium ions. The experiments conducted, showed that in the presence of a chiral ligand (L59-L67, Scheme 235), only Cu(I) sources provided the desired ether (658) in good yields. In addition, the copper counterion was found to have a dramatic effect on the enantioselectivity of the reaction, with the weakly coordinating counterion PF6 being the best performing one. 227

Different chiral ligands (L60-L68) were explored, with L60 providing the highest selectivity. Moreover, enantioselectivity was shown to increase by lowering the reaction temperature. Increasing the alkyne’s steric bulk did not affect the outcome of the reaction. Aryl acetylenes with both electron-donating and electron-withdrawing groups at the para position gave reactions with good enantioselectivity, besides the para-methoxy substituent that led to reduced enantiomeric excess and a para-dimethylamino substituent that afforded the corresponding racemic ether. On the other hand, both meta-methoxyphenylacetylene and meta-fluorophenyl acetylene resulted in the expected high enantioselectivity, while more electron-withdrawing groups in the meta-position led to lower enantioselectivities. Alkynes with non-aromatic substituents resulted in low reaction yields. The scope of the reaction was further probed and a series of acetal substrates were subjected to alkynylation (Scheme 235). Both electron-donating and electron-withdrawing substituents were well tolerated.

228

Scheme 235. Copper-catalyzed alkynylation of isochroman acetals [305]. The structures of the products are accompanied by values that correspond to yield (α%) and enantioselectivity (ee%). Watson and co-workers proposed that this alkynylation reaction proceeds via the formation of Cu acetylide I (Scheme 236) [305]. They also proposed that a neutral ligand dissociates from the 18-electron Cu acetylide complex I, to allow for the approach of the oxocarbenium ion and the formation of complex II. C-C bond formation may then occur, either directly from trivalent II or via π-complexation of the oxocarbenium to Cu. Copper 229

may bind either to the arene (III) or to the C=O bond (IV), or it is possible that an intermediate structure exists making it difficult to determine whether the C-C bond formation occurs via a single-electron transfer or a nucleophilic attack.

Scheme 236. Proposed mechanism for the copper-catalyzed alkynylation of isochroman acetals [305]. Two years later, Seidel and co-workers reported a direct three-component coupling for the α-alkynylation of amines [306]. 2,6-Dichlorobenzaldehyde was chosen as the model substrate, along with pyrrolidine and phenylacetylene. Optimal results for the reaction were obtained when copper(II) 2-ethylhexanoate [Cu(2-EH)2] was utilized, under microwave conditions, providing the corresponding products 664 and 665 in a 20:1 ratio and 82% yield (Scheme 237). The effect of the nature of the aldehyde on the selectivity of the reaction was also studied. When 2,6-dichlorobenzaldehyde was replaced with the electronically similar 2,4-dichlorobenzaldehyde, the reaction resulted in a dramatic reduction of the product ratio. Further experiments with other aldehydes showed that electron-poor aldehydes provide more

230

favorable product ratios, while steric factors outweigh electronics. Aromatic, alkenyl, and aliphatic substituents on the alkyne provided the desired propargylic amines with regioselectivities exceeding 25:1. Pyrrolidine is the most favorable substrate for αalkynylation; however, the reaction also proceeded with piperidine, azepane, and more challenging substrates, albeit with low regioselectivities.

Scheme 237. Copper(II)-catalyzed a-alkynylation of amines [306]. In 2015, Rajesh and Prajapati developed another three component reaction between barbituric acid, aldehydes, and terminal alkynes for the construction of pyrano[2,3d]pyrimidines [307]. On a similar note, Cao and co-workers more recently reported a threecomponent transformation affording trifluoromethylated pyrrolo[1,2-a]quinolines in a onepot reaction including a Cu(I)-catalyzed C-H alkynylation for the formation of alkynylsubstituted 1,2-dihydroquinolines, followed by a Cu(II)-assisted intramolecular cyclization [308].

231

Sawamura and co-workers reported a copper-catalyzed method for the direct allylic alkynylation of internal secondary allylic phosphates in 2013 [309]. Allylic substrates with carbonate or chloride leaving groups are not reactive under these conditions. This coppercatalyzed

allylic alkynylation proceeds with excellent γ regioselectivity and E

stereoselectivity, affording skipped enynes with an internal alkene moiety. For example, the reaction of triisopropylsilylacetylene 666 with Z-allylic phosphate 667 (Scheme 238) affords the skipped enyne 668 with exceptional regioselectivity (γ/α>99:1) and stereoselectivity (E/Z>99:1). The E-isomer of 667 reacted efficiently, suggesting that a high level of γ selectivity is possible even against unfavorable steric effects. Various derivatives of allylic phosphates, such as esters or silyl ethers, as well as six- or seven-membered ring allylic phosphates react well. Substituted aromatic alkynes and a sulfur-containing heteroaromatic alkyne underwent the reaction with 667 to afford the corresponding dienynes. Finally, aliphatic alkynes are also suitable substrates for this reaction.

Scheme 238. Allylic alkynylation of allylic phosphates-catalyzed by copper [309]. The proposed catalytic cycle for this transformation is shown in Scheme 239 [309]. The reaction begins with the oxidative addition of copper species I to the allylic phosphate to form allylcopper intermediates II or II’. These intermediates determine the γ selectivity of the reaction. Intermediates II or II’ then react with a free lithium diethyl phosphate forming intermediates IV or IV’ that upon elimination afford the desired allylated alkyne product regenerating the catalyst.

232

Scheme 239. Proposed mechanism for the copper-catalyzed γ-selective stereospecific allylic alkynylation of allylic phosphates [309]. In 2014, Sawamura’s research group published a work on the enantioselective allylic alkylation of terminal alkynes with primary allylic phosphates, using copper-based catalytic systems with N-heterocyclic carbenes as ligands [310]. In this procedure, a stereogenic center is introduced at the allylic or propargylic position, with excellent γ-branch regioselectivity and high enantioselectivity. The model reaction studied was that of (Z)-5-phenyl-2-pentenol derivatives (670, Scheme 240) with triisopropylsilylacetylene (669). (Z)-allylic phosphate [(OP(O)(OEt)2], was the only effective leaving group, among those examined. This leaving group afforded the linear, achiral product with (Z)-alkene geometry (672) as the major isomer, in a 83:17 ratio versus the branched 671. Various achiral NHC ligands were screened in the selective formation of the racemic, branched product 671. Amongst others, NHC precursor L22 was utilized, affording a 96:4 favorable selectivity, but moderate yield. In order to increase the yield, various other N-heterocyclic carbenes precursors (L22-L74) were also tested. The best results were obtained with L72. L72 displayed moderate

233

enantioselectivity (65% ee) with exceptional branch selectivity and excellent yield (96%). The nature of the base was also found to exert a strong impact on the yield, branch regioselectivity, and enantioselectivity. The scope of the reaction was explored and various allylic phosphates were used. Allylic phosphates with methyl, ethyl, octyl, cyclohexyl, silyl ether, pivalate, THP ether, p-toluenesulfonate and p-nitrobenzoate groups at the γ position in relation to the leaving group reacted effectively, providing the enyne products with high enantioselectivity. The impact of the structure of the alkyne on the reactivity, regioselectivity and enantioselectivity was explored as well, using silyl, aliphatic, and aromatic alkynes and it was found that various substrates were well tolerated. The alkene geometry of the allylic substrate (670) plays an important role in both the enantioselectivity and the efficiency of the reaction. For example, the reaction of (E)-670 resulted in the formation of the (R)-antipode of the desired product with excellent branch selectivity (>99:1), but in low product yield [310].

Scheme 240. Enantioselective allylic alkylation of terminal alkynes [310]. One year later, Watson and co-workers achieved the enantioselective addition of terminal alkynes to isochroman ketals [311]. Copper-based catalytic systems including ligands L76234

L80 (Scheme 241) were employed to mediate the addition of chiral organometallic nucleophiles to diaryl-substituted oxocarbenium ions. Ligands L79 and L80 resulted in low enantioselectivities, while L78, in combination with 7-methyl-1,5,7-triazabicyclo[4.4.0]dec5-ene (MTBD) as base, provided the optimal 87% yield with 78% ee. A number of isochroman ketals underwent alkynylation successfully, affording the corresponding products (675). A variety of functional groups were well tolerated, including ethers, thioethers, anilines, alkenes, trifluoromethyls, and acetals. 2-Naphthyl and heteroaryl substituted substrates underwent alkynylation too. On the contrary, the reaction of 1-methoxy-1methylisochromane with phenyl acetylene did not lead to the formation of the desired product. A series of acetylenes were subjected to the reaction. Alkynes bearing electron-poor or electron-rich aryl groups with both para- and meta-substituents reacted well, to provide the corresponding products. Functional groups such as ethers, trifluoromethyls, nitriles, esters, and halides underwent alkynylation. Nevertheless, aryl acetylenes with electron-rich parasubstituents, such as para-(dimethylamino) or para-methyl, led to low yields.

Scheme 241. Enantioselective alkynylation of isochroman ketals [311]. Aponick and co-workers have also reported a highly enantioselective alkynylation reaction, in this case on quinoline derivatives (Scheme 242) [312]. StackPhos, a tailor-

235

designed imidazole-based chiral biaryl P,N-ligand, was employed along with copper bromide. The reaction scope was initially explored with regards to the alkyne nucleophile. A series of alkynes, from electron-rich to electron-deficient and heteroaromatic (677a-677g), were subjected to this methodology with quinoline (676a). All alkynes reacted very well and provided the desired products (678) in high enantiomeric excess. The influence of quinoline’s nature on the reaction was also examined. Neither electron-donating, nor electronwithdrawing groups on the quinoline seem to affect the outcome of reaction significantly. The absolute stereochemistry obtained from this alkynylation reaction was attributed to the chiral biaryl axis of (S)-StackPhos that creates a chiral environment around the metal center.

Scheme 242. Enantioselective quinoline alkynylation catalyzed by copper [312]. Another, highly sustainable catalytic procedure based on Cu(I) was developed by Michalak and co-workers for the diastereoselective synthesis of propargylic Nhydroxylamines (685, Scheme 243) from terminal alkynes (683) and enantiomerically pure nitrones (684) [313]. This system utilizes the unique properties of a well-defined NHC-Cu(I) catalyst to provide access to highly functionalized molecules under mild reaction conditions 236

and using water as solvent. Various NHC-Cu(I) complexes were screened as catalysts for this transformation and all proved to be considerably competent, in contrast with Ag(I)- and Au(I)-based catalysts that gave less promising results. Among them, complex SIPrCuI (680c) was the most effective catalyst and was used in 5 mol% loading, along with trimethylamine, to facilitate the addition of diversely substituted terminal alkynes (683) to chiral nitrones (684) in a chemo- and diastereoselective manner, leading to high product yields. It is important to note that the chemoselectivity towards the addition reaction between Cu(I) acetylides and nitrones over the competing dipolar cycloaddition process was suggested to originate from the augmentation of the acetylide’s nucleophilicity by the strongly σ-donating NHC ligand, which also provides steric shielding to the Cu(I) center [313].

237

Scheme 243. Diastereoselective synthesis of propargylic N-hydroxylamines from terminal alkynes and enantiomerically pure nitrones [313]. The asymmetric alkynylation and, more generally, functionalization of isatin is an important synthetic goal [314], [315]. This is due to the fact that the chiral 3,3-disubstituted oxindole framework exists in various natural products, as well as, pharmaceutically and biologically active compounds. An asymmetric alkynylation strategy of isatin derivatives was achieved by Feng and co-workers in 2016 (Scheme 244) [316]. Copper(I) iodide as metal source displayed the best reactivity, while copper bromide and copper chloride were found to afford dramatically lower yields. The substituent on the phenylsulfonyl moiety of the guanidine ligand affects both the selectivity and the reactivity of the copper complex: Increasing the steric hindrance of the phenylsulfonyl moiety increases enantioselectivity and yield, while having an electron-donating substituent at para-position on the same moiety decreases both the yield and the enantiomeric excess. Guanidine L82, bearing a 1-naphthyl group, gave the best results in this reaction. Basic additives play an important role in forming copper(I) acetylide with terminal alkynes and, among those tested, 2,4,6-collidine was the optimal base when it was used at 20 mol%. The best solvent was toluene. A wide variety of isatins (686a-686m, Scheme 244) reacted with phenylacetylene under the optimized reaction conditions: In general, isatins having electron-withdrawing substituents (686b-686e, 686h686m) afforded good yields and enantioselectivities. Moreover, a series of substituted terminal alkynes were studied, using the 5-fluoro-substituted isatin 686c as the electrophile. Neither the electronic properties, nor the position of the substituent on the phenyl group affects the outcome of the reaction. Alkyl-substituted alkynes generated the corresponding products in good yields and enantioselectivities, as well as, alkynes bearing branched and cyclic alkyl groups or an alkene moiety. Alkynes bearing long substituted alkyl groups required higher amounts of the catalyst for the reaction to reach the expected yields [316]. 238

Scheme 244. Asymmetric alkynylation of isatin derivatives [316]. In 2016, Guo and co-workers published another work on the asymmetric alkynylation of isatin derivatives [317]. In this work, a chiral phosphine ligand (Figure 20) was used to form the catalytically active chiral complex. The reaction of 686h (Scheme 244) with phenylacetylene was used as the benchmark reaction to optimize the reaction conditions: Reaction in toluene at 60 oC for 24 hours and (R)-binap (L83, Figure 20) as ligand led to trace amounts of the desired product. Ligand L62 provided the targeted isatin derivative in 38% yield with poor enantioselectivity. Experiments with a series of chiral phosphine ligands (L84-L87) were then carried out, leading to the promising result of 48% yield and 74% ee with L87. Additionally, methyl tert-butyl ether (MTBE) served as the best solvent and 40 oC was found to be the preferable reaction temperature. The optimal catalyst loading was 5 mol%. Under these conditions, the highest yield (94%) was achieved with high enantioselectivity (92% ee) in 72 hours. The reaction was found applicable on a variety of substituted isatins. Phenylacetylenes bearing either electron-donating or electron-withdrawing

239

groups exhibited high reactivity providing isatin derivatives in high yields and high enantioselectivities.

Figure 20. Ligands utilized in the asymmetric alkynylation of isatin reaction [317]. In the same year, Poater, Michalak and co-workers transformed a number of trifluoromethyl ketones into the corresponding tertiary propargylic trifluoromethyl alcohols, in

water,

by

utilizing

well-defined

NHC-copper(I)

complexes,

with

excellent

chemoselectivity and in high yields [318]. The steric and electronic properties of the NHC ligands forming the copper(I) complexes were studied in the reaction affording 690a (Scheme 245). NHC precursors SIMes (L22, Scheme 105) and IMes (L50, Figure 14) resulted in moderate yelds. Better results were obtained with [PyIMesCuCl] (691, Scheme 245), possessing a chelating pyridine arm, and [IPrCuX]. Optimal results, in terms of yield and conversion, were obtained utilizing [SIPrCuX] complex, due to the reduced stability of the SIPr-based intermediates that result in a lower energy barrier. Additional experiments revealed that the efficiency of the reaction is not affected by the counterion of the NHC ligand precursor, as halides, acetate, and triflate counterions resulted in the formation of 690a (Scheme 230), all with approximately 90% yield. The presence of at least two fluorine atoms on the ketone was required, in order for the substrate to be active enough and the reaction to proceed with high yield (690a-690e). Sulfur- and oxygen-containing heterocyclic alkylsubstituted trifluoromethyl ketones afforded the expected products as well. Poater, Michalak, 240

and co-workers proposed that the alkynylation mechanism can be summarized in three steps: First, the entering alkyne is deprotonated; this deprotonation is assisted by triethylamine. Afterwards, a novel C-C bond is formed between the former alkyne ligand and 689. Finally, the product (690) is released from the complex, regenerating the catalyst. O R1

+

R2

R3

689 F3C OH

R3 F2ClC OH

OH

Ph

Ph

Ph

690c (50%, 100oC)

690b (90%)

F3C OH

R2

690

FH2C OH

F2HC OH

Ph 690a (94%)

HO R1

IPrCuCl (2 mol%) Et3N (20 mol%) H2O, 50 oC, 16 h

Ph 690e N.R.

690d (81%)

F3C OH

F3C OH

O

O O O

Ph O 690f (100%, 100oC)

O

Ph

Ph 690h (60%)

690g (39%)

F3C OH

F3C OH

F

O

F

Bn N

F

F3C OH O

OH Ph 690n (86%)

F3C OH Ph

Ph 690s(86%)

N

Cu Cl

PyIMesCuCl 691

690u (73%)

690t(87%)

F3C OH

N

Ph

Ph

( )5

Ph

F3C OH

F3C OH

Ph 690r (68%)

690q (98%, 100oC,28h)

690p (82%, 100oC)

690o (62%, 100 C)

F3C OH

N

O

OH o

Ph

Ph 690m (42%) OH

Ph 690l (80%, 48h)

690k (71%)

O

O

F3C OH

F3C OH

S Ph

690j (46%)

HO CF3 690i (90%)

F3C OH Ph

690v(91%) iPr

690w (65%)

iPr N

O P

N

N

iPr Cu iPr X IPrCuX 679

EtO

OEt iPr

iPr N

N

iPr Cu iPr X SIPrCuX 680

Scheme 245. Alkynylation of trifluoromethyl ketones [318]. 6.11. Alkenylation-synthesis of allenes The development of innovative catalytic methods for the synthesis of allenes or allenes’ derivatives is a field of intense research interest. In 2011, Wang and co-workers reported a new method for the direct synthesis of allenes [319]. This approach is based on a copper241

catalyzed coupling reaction of N-tosylhydrazones with terminal alkynes (Scheme 246). In this regard, the most effective catalytic system is obtained by combining Cu(MeCN)4PF6 with ligand L88, Cs2CO3 as the base, and dioxane as solvent. O

O N

R1 NNHTs

+

R

R2 692

693

_ (+) L88

N

Cu(MeCN)4PF6 (5 mol%) ligand L88 (6 mol%) Cs2CO3 (3 equiv) 1,4-dioxane, 90 oC

R1 R2

R 694

Scheme 246. Copper-catalyzed coupling of N-tosylhydrazones with terminal alkynes towards allenes [319]. Utilization of a series of terminal alkynes provided the corresponding coupling products in moderate to good yields (Figure 21). Arenes with electron-donating or electron-withdrawing moieties are appropriate substrates, while a substrate bearing a -CF3 substituent provided the coupling product in lower yield. N-tosyhydrazones bearing aryl or alkyl groups are also active under the reaction conditions, providing the corresponding substituted allenes in moderate to good yields.

Figure 21. Arenes (i) and N-tosylhydrazones (ii) utilized in the direct synthesis of allenes [319].

242

According to the proposed mechanism (Scheme 247), the reaction commences with the formation of a copper acetylide (I). Intermediate I then reacts with the diazo compound (692a) affording the copper carbene species II. Intermediate III derives from carbene II, by migratory insertion of the alkynyl moiety to the carbenic carbon. The final allene product is obtained by protonation of intermediate III, concurrently leading to the regeneration of the Cu catalyst. In this pathway, protonation occurs regioselectively at the triple bond carbon atom. Alternatively, if protonation occurs at the carbon atom attached to copper, alkyne product 694’ will be formed, which may then undergo rearrangement to afford the final allene product. It is also worth mentioning that in the copper(I)-catalyzed coupling of terminal alkynes with diazoesters or diazoamides, reported by Suárez and Fu [320], 3alkynoates, which correspond to 694’, are the main products.

Scheme 247. Proposed reaction mechanism for the direct synthesis of allenes [319]. A related study on the copper-catalyzed synthesis of allenes was published one year later [321]. In this work, Ma and co-workers initially investigated the effect of the amine in the catalytic reaction (Scheme 248). Alkylamines were more efficient, as compared to cyclic amines, with n-Bu 2NH providing the best results (yield 70%). Experiments with different 243

copper salts showed that CuI is the best copper source for the reaction, while, among the studied solvents, dioxane afforded the best yields. Having these optimized conditions in hand, the authors studied the scope of the reaction by utilizing various terminal alkynes (Scheme 249). As shown in Scheme 249, the reaction tolerates a variety of functional groups.

Scheme 248. Copper-catalyzed synthesis of substituted allenes [321].

Scheme 249. Copper-catalyzed allenes synthesis [321]. The proposed reaction mechanism is shown in Scheme 250. Interaction between Cu and the terminal alkyne leads to the formation of intermediate I, which, in the presence of a base, forms the 1-alkynyl copper compound II. Reaction of intermediate II with iminium intermediate A forms the propargylic amine III. Finally, intramolecular hydride transfer in intermediate IV affords the allene product, simultaneously regenerating the catalyst.

244

Scheme 250. Proposed reaction mechanism for the copper-catalyzed preparation of allenes [321]. More recently, Ma, Wang, and co-workers reported another method for the preparation of substituted allenes [322]. In this case, the copper-catalyzed coupling reaction between an eneyne-ketone and a terminal alkyne leads to the formation of a furan-substituted allene (Scheme 251). The combination of CuI (10 mol%) with i-Pr2NEt (0.2 equiv) as base in MeCN at 45 oC afforded the highest yields, after 10 hours reaction time. Under these optimized conditions, the effect of the nature of the terminal alkyne, as well as, of the conjugated ene-yne-ketone was thoroughly studied (Scheme 252). In brief, substituted alkynes provide the coupling product in good yields, with the reaction showing very good functional group tolerance. With regards to the ene-yne-ketones, the coupling product is also formed in good yields for compounds bearing alkyl and cycloalkyl groups.

Scheme 251. Copper-catalyzed synthesis of furan-substituted arenes [322].

245

The first step in the proposed catalytic cycle (Scheme 253) is the formation of copper acetylide II. Then, interaction of the alkyne moiety in 697 with copper intermediate II leads to the formation of copper carbene III. At the same step, the ene-yne-ketone undergoes 5exo-dig cyclization by nucleophilic attack of the carbonyl oxygen atom, affording the furan ring. Intermediate IV is formed from intermediate III through a copper carbene migratory insertion process, while traces of olefin 720 (byproduct, formed due to a 1,2-H shift from species III) can be also formed. Finally, protonation of intermediate IV affords the furansubstituted allene 698 and regenerates the catalyst.

246

Scheme 252. Furan-substituted allenes derived from various ene-yne-ketones and terminal alkynes [322].

247

Scheme 253. Proposed catalytic cycle for the copper-catalyzed coupling between ene-yneketones and terminal alkynes towards furan-substituted allenes [322]. In a related study, Wang and co-workers reported an efficient method for the preparation of phenanthrenes via the Cu(I)-catalyzed coupling of aromatic N-tosylhydrazones with terminal alkynes (Scheme 254) [323]. The ideal reaction conditions were shown to be a 2/1 ratio of N-tosylhydrazone/terminal alkyne, 10 mol % loading of CuBr2, and LiOtBu as the base (4.0 equiv) along with 20 mol% tetrabutylammonium bromide (TBAB). The best solvent was dioxane and the reactions ran at 90 °C for 4 hours and then at 120 °C for 24 hours. The scope of the reaction was then studied under these optimized conditions (Figure 22). N-tosylhydrazones bearing either electron-withdrawing or electron-donating groups react smoothly, providing the corresponding coupling products in moderate to good yields. On the other hand, aliphatic tosylhydrazones result in a mixture of allenes (major products) and phenanthrenes (smaller amounts). The studied alkynes also reacted smoothly, providing the corresponding coupling products in moderate yields with good functional group tolerance.

248

Scheme 254. The copper-catalyzed coupling of N-tosylhydrazones with terminal alkynes [323].

Figure 22. Substrate scope for the copper-catalyzed coupling of N-tosylhydrazones with terminal alkynes towards phenanthrenes [323]. 6.12. Alkylation reactions In 2013, Van der Eycken and co-workers reported the alkylation of azoles through a copper-catalyzed three component coupling reaction [324]. This transformation includes the coupling of a heteroarene (728), an amine (727), and an aldehyde molecule (726) in the presence of copper chloride. The reaction of cyclohexylcarboxaldehyde, piperidine, and 2249

phenyloxadiazole was utilized as the benchmark system in order to probe the optimal reaction conditions, which are shown in Scheme 255. Heteroarenes such as substituted oxadiazoles, thiadiazole, and oxazole were subjected to reaction yielding the desired products. The scope of the reaction was further studied by using a series of aldehyde coupling partners. The reaction tolerates both cyclic and acyclic aldehydes, with products 729b-729j and 729l-729r isolated in moderate to good yields. Moreover, cyclic and acyclic secondary amines react well under the standard reaction conditions to provide the desired coupling products. Finally, the scope of the reaction was broadened to cyclic ketones. In this manner, the direct tertiary alkylation of the azole moiety was accomplished with the reaction providing the corresponding products in moderate yields.

250

Scheme 255. The copper-catalyzed three-component coupling reaction for the alkylation of azoles [324]. Two years later, in 2015, the alkylation of electron-deficient polyfluoroarenes (730, Scheme 256) with N-tosylhydrazones (731) towards the preparation of the corresponding polyfluoro alkylated derivatives was reported by Wang and co-workers (Scheme 241) [325]. Due to their electron deficient nature, polyfluoroarenes have poor coordinating ability to and afford strong σ-bonds with transition metals, characteristics that make them difficult molecules for subsequent transformations. Moreover, this electron-deficient nature of polyfluoroarenes prevents them from alkylation reactions such as Friedel–Crafts. These issues were surpassed and an efficient catalytic protocol was developed, according to which alkyl groups can be added to polyfluoroarenes through C-H bond activation. To probe the necessary reaction conditions, the alkylation of 1,2,4,5-tetrafluorobenzene with Ntosylhydrazone was studied. A catalyst loading of 20 mol% provided the best results, when copper iodide was used as copper source and 1,10-phenanthroline as ligand for the in situ generated complex. The alkylation reaction occurred at 90 oC in a 1/1 mixture of 1,4-dioxane and acetonitrile as solvents. The scope of this transformation was studied with various Ntosylhydrazones in their reaction with 1,2,4,5-tetrafluorobenzene. N-tosylhydrazones with electron-donating groups on the aromatic ring gave slightly higher yields. Moderate yields were obtained in reactions with substrates bearing halogen substituents. Also, Ntosylhydrazones derived from cyclic ketones and 2-acetylfuran provided the desired products, while N-tosylhydrazones derived from benzaldehydes, alkyl aldehydes, and benzophenones afforded the corresponding triarylmethane derivatives. The ability of other polyfluoroarenes to participate in this reaction was also investigated. The targeted products were obtained in moderate to good yields. Diazo compounds were also subjected to the same reaction protocol. Diaryldiazomethanes were found tolerant to the reaction conditions and alkylation products 251

were isolated in good yields. On the contrary, diazoesters were not appropriate, as only trace amounts of the desired products were detected. Wang and co-workers also proposed a mechanism for these alkylation reactions (Scheme 256). The catalytic cycle begins with the deprotonation of the relatively acidic C-H bond of the polyfluoroarene substrate 730, followed by transmetalation to the copper(I) species to generate the polyfluoroaryl copper intermediate I. I then reacts with the in situ generated diazo compound to form linear species II. Migratory insertion then occurs to II leading to the formation of intermediate III. Finally, protonation of III provides the alkylation product and regenerates the catalyst.

Scheme 256. Proposed mechanism for the copper-catalyzed alkylation of polyfluoroarenes [325]. In 2016, Samanta and co-workers reported a reaction for the synthesis of heteroarenes containing conjugated π-systems [326]. This approach involves a copper-catalyzed alkylation, followed by cyclocondensation of quinoline N-oxides with diazo esters. The reaction of quinoline N-oxide with ethyl diazomalonate was chosen as the model reaction in order to find the optimal reaction conditions (Scheme 257). Cu(I) and Cu(II) salts were

252

equally efficient as copper source. Eventually, copper iodide in toluene at 100 oC and air as the oxidant were the reaction conditions of choice. Under these optimal conditions, Samanta and co-workers studied the substrate scope, using a series of quinoline N-oxides, which provided the desired products in good yields. The reaction of quinoline N-oxides substituted in the C-8 (735a-735c), C-6 (735d, 735e), C-5 (735f), or C-4 (735g) position resulted in moderate to good yields. Moreover, aryl substituted pyridine (735h-735j) and isoquinoline (735k) derivatives were well tolerated.

Scheme 257. Cu-catalyzed cascade alkylation and cyclocondensation of diazomalonate with various quinoline N-oxides [326]. Under the same optimized conditions, the authors also tested a variety of diazo esters (Scheme 258). The products are formed in good to excellent yields, while the slight decrease observed in the yields in the presence of a radical trap (TEMPO) suggests that the reaction does not proceed through the formation of free radical intermediates. Based on mechanistic

253

studies, as well as on findings from previous works, a plausible mechanism for this reaction was proposed, suggesting the dual role of the copper catalyst, as both a transition metal and a Lewis acid (Scheme 259) [326]. The catalytic cycle commences with the oxidation of Cu(I) to Cu(II) and the functionalization of the C-H bond at the C-2 position of quinoline N-oxide 733 through a deprotonation-metalation step to afford intermediate I. Reaction of diazocompound 734 with intermediate I leads to copper-carbene complex II. A migratory insertion then gives intermediate III. Next, proto-demetalation of intermediate III affords intermediate IV. Intermediate V is formed via a Lewis acid-assisted, intramolecular nucleophilic addition. Elimination of ROH from V closes the cycle, yielding the desired product and regenerating the catalyst.

Scheme 258. Cu-catalyzed cascade alkylation and cyclocondensation of quinoline N-oxide with various diazo esters [326].

254

Scheme 259. The proposed mechanism for the copper-catalyzed synthesis of conjugated πsystems using quinoline N-oxides and diazo esters [326]. 6.13. Allylation reactions In 2011, Hirano, Miura and co-workers published a work on the allylation of electrondeficient arenes with allyl phosphates [327]. The choice of the specific allylic electrophile was crucial, as the use of allyl acetate or allyl carbonate did not yield any product. With regards to the arenes substrate scope, the efficiency of the C-H cleavage process is highly dependent on the acidity of the C-H bond. The allylation products were obtained in good yields using substituted tetrafluoroarenes or tetrafluoropyridine analogues (739a-739g, Scheme 260); however, the results were poor with fluoarenes bearing less than 3 fluorine atoms. In the case of 1,2,4,5-tetrafluorobenzene, the reaction occurs at both C-H bonds, yielding a mixture of products (739h and 739h’, Scheme 260). The proposed mechanism (Scheme 261) commences with the LiOtBu-assisted direct cupration of polyfluoroarene 737i to afford pentafluorophenylcopper intermediate I. This is followed by the oxidative addition of polyphosphate E- or Z-738a. Copper species syn-III or anti-III are obtained through a

255

rapid σ-π conversion. Reductive elimination at the less hindered carbon center yields the desired allylated products E- or Z-739i (Scheme 261) [327].

Scheme 260. Copper-catalyzed direct C-H allylation of fluoroarenes with allyl phosphates. E/Z ratios are also shown where appropriate [327].

Scheme 261. Proposed mechanism for the copper-catalyzed direct C-H allylation of fluoroarenes with allyl phosphates [327].

256

In 2012, Ohmiya, Sawamura and co-workers reported a Cu-based method for the introduction of secondary alkyl groups to electron-deficient arenes. This method is characterized by high regio- and stereo-selectivity, as it gives rise only to E-configured C-H alkylated products with γ-selectivity [328]. The reaction of 4-phenyloxazole with allylic phosphate [(OP(O)(OEt)2] was utilized as the benchmark system in order to optimize the reaction conditions (Scheme 262). By comparing the reactions between 4-phennyloxazole and E- or Z-[(OP(O)(OEt)2], it was shown that γ-selectivity can be obtained even in the presence of unfavorable steric effects (Scheme 262). The scope of the reaction was explored and various allylic phosphates were used. Allylic phosphates in which the γ-substituent gradually becomes bulkier (Me < Bu < iBu) lead to the decrease of both regioselectivity and product yield. However, allylic phosphates substituted with even more demanding groups (iPr or cycloexyl) afforded the product with excellent γ-selectivity. In the case of enantioenriched allylic phosphates, a stereogenic center is introduced at the α position relative to the aromatic ring, with high 1,3-anti stereoselectivity and enantioselectivity. Allylic phosphates and arenes with ester, silyl ether, CF3, MeO, and Cl groups reacted efficiently, providing the products with high γ-selectivity. Heteroarenes such as oxazoles, oxadiazole, thiazole, or fluoroarenes were subjected to the same reaction, yielding the desired products in good yields.

257

Scheme 262. Copper-catalyzed reaction of 4-phenyloxazole with Z- or E- allylic phosphates [328]. 6.14. C-H amination In 2013, Daugulis and co-workers reported a method for the catalytic directed amination of benzamides bearing an 8-aminoquinoline moiety [329]. These compounds were successfully aminated with morpholine, using copper and silver salts. The presence of an oxidant (N-methylmorpholine oxide - NMO) and Ag2CO3 is beneficial for the reaction, as the aminated product was obtained in high yields. Cu(OAc)2 at 10 mol% loading was used as copper source. Under these conditions, the authors investigated the reaction with regards to the potential benzamide derivatives (Scheme 263) and amines (Scheme 264) employed. Substrates bearing either electron-withdrawing or electron-donating groups afforded the desired products in good yields. The same was true for substrates having heterocyclic rings. A variety of amines were also utilized. Amines bearing many different groups reacted efficiently, with primary amines affording lower yields (Scheme 264). The 8-aminoquinoline directing group can be easily removed from the aminated product under basic hydrolysis, affording the corresponding carboxylic acid (Scheme 265).

Scheme 263. Amination of benzamides bearing an 8-aminoquinoline moiety (selected results) [329]. 258

Scheme 264. Copper-catalyzed amination of benzamides bearing an 8-aminoquinoline moiety [329].

Scheme 265. Removal of the 8-aminoquinoline directing group of the aminated benzamide products [329]. In a related work, published three years later, the same research group reported an improved method for the catalytic amination of benzamides bearing the 8-aminoquinoline directing group [330]. According to this protocol, which shows a very good functional group tolerance, the presence of Ag2CO3 as co-catalyst is not essential, while oxygen from air is employed as the terminal oxidant, replacing N-methylmorpholine oxide. These changes allowed for the use of a wide variety of amines. Initially, the authors optimized the reaction conditions, studying the amination of various benzamides with morpholine (Scheme 266). The aminated products were obtained in high yields for both electron-rich and electron-poor substrates. Substrates with heterocyclic rings provided the desired products in good yields as well. The reaction was also investigated with regards to the amines utilized. Primary aliphatic amines and anilines required some modifications of the protocol: The highest yields are 259

achieved with the combination of pyridine/DMSO as solvent and higher copper loadings (1 equivalent of copper salt) (Scheme 267). The as obtained yields are moderate and lower compared to those of the reactions employing morpholine (secondary amine, Scheme 266). Both aliphatic and cyclic aliphatic secondary amines provided the corresponding products in good yields (Figure 23).

Scheme 266. 8-Aminoquinoline directed copper-catalyzed amination of benzamides with morpholine [330].

Scheme 267. 8-Aminoquinoline directed copper-catalyzed amination of benzamides with primary amines [330].

260

O

O

Q NH

O

Q NH

Q NH

O N

N

NBn O

O

O

NPr2

756c (73%)

Q NH

Q NH

O

N N

NHBoc

O O

O

NPr2 756d (67%)

NPr2

N(Me)Bn

756e (47%)

O

O

Q NH Me N PMB

S

S N

O

Q NH

O

S

O S

NPr2

756b (64%) O

O

O

S O

NPr2

756a (63%)

N

O

O S

S O

N

N

NPr2 756f (73%)

O

NPr2 756g (77%)

Figure 23. 8-Aminoquinoline directed copper-catalyzed amination of benzamides with secondary amines [330]. Substituted thiophenes can be efficiently aminated as well, using (CuOH)2CO3 as copper source at elevated temperature (Scheme 268). With a slight modification of the reaction conditions (higher copper loading and different amine equivalents), electron-poor amines afforded the corresponding aminated products too (Scheme 269). The 8-aminoquinoline directing group can be removed with basic hydrolysis, affording the corresponding carboxylic acids.

Scheme 268. 8-Aminoquinoline directed copper-catalyzed amination of thiophenes [330].

261

Scheme 269. 8-Aminoquinoline directed, copper-catalyzed amination of 754 with electron poor amines [330]. In another related recent report, Jana and co-workers published a method for the amination of benzamides using anilines [331]. The reaction is again based on benzamides bearing the 8aminoquinoline directing group. According to this approach, the copper source is added in stoichiometric ratio, while silver is also necessary as a co-catalyst. The reaction can be applied for anilines bearing various functional groups (Scheme 270).

Scheme 270. Copper mediated 8-aminoquinoline directed amination of benzamides with anilines [331]. In 2013, Xu, Zhu and co-workers reported the synthesis of acridones by a coppercatalyzed intramolecular amination reaction [332]. The combination of PPh3 and pivalic acid 262

(PivOH) with copper salts proved effective in this regard. The presence of oxygen as oxidant was essential, as in experiments carried out under argon atmosphere the aminated product was not observed. The reaction’s substrate scope was studied under the optimized reaction conditions, with substrates bearing various functional groups (Scheme 271). Substrates having electron-withdrawing or electron-donating groups in para position provided the corresponding products in good yields. Lower yields were obtained for substrates having functional groups in the ortho position, suggesting a significant impact of steric hindrance in the reaction. Substrates bearing a naphthalene moiety or a heterocyclic ring reacted efficiently as well.

Scheme 271. Intramolecular copper-catalyzed amination of various substrates towards acridones [332]. Experiments carried out in the presence of radical traps (TEMPO) proved that the reaction does not proceed through a radical mechanism. A possible mechanism is shown in Scheme 272. Initially, Cu(I) is oxidized from oxygen, affording Cu(II), that interacts with the substrate (712) leading to the formation of copper intermediate I. This intermediate can be further oxidized to Cu(III) intermediate II from another Cu(II) species. Reductive elimination from intermediate II leads to the formation of the aminated desired product (769). 263

Scheme 272. Proposed reaction mechanism for the intramolecular copper-catalyzed amination towards acridones [332]. In a more recent work, Hirano, Miura and co-workers reported the synthesis of isoindolinones by a copper-catalyzed, intramolecular benzylic C-H amination of orthomethylbenzamides [333]. Οrtho-methylbenzamides containing a directing 8-aminoquinoline moiety were successfully aminated using copper acetate as the catalyst and MnO2 as a terminal oxidant. The presence of an acidic additive, such as 1-adamantanecarboxylic acid (1AdCOOH), is beneficial for the reaction, as the aminated product is obtained in higher yields. Better yields were also obtained when microwave irradiation was applied. Τhe authors investigated the benzamide scope under these conditions. Substrates bearing either electrondonating or electron-neutral groups at the 4 position of the 2,6-dimethylbenzamide afforded the desired products in good yields (775a-775c, Scheme 273). In the presence of electronwithdrawing groups (i.e. halogens), the products were also obtained in good yields (775d775f, Scheme 273). In the case of 2-methyl-6-pentylbenzamide and 2-isopropyl6methylbenzamide, the reaction occurs exclusively at the methyl C-H bond (775g, 775h, Scheme 273). When 2,5-dimethylbenzamide and its substituted analogues (methoxy-, chloro, or bromo-) are used, higher yields are achieved with the use of Cu(OPiv)2/PivOH (775i775l, Scheme 273).

264

Scheme 274. Copper-catalyzed intramolecular benzylic C-H amination of a series of 2,5- and 2,6-disubstituted benzamides [333]. Experiments carried out in the presence of radical traps showed that the reaction does not proceed through a radical mechanism for the 8-aminoquinoline-containing substrates. A possible mechanism is shown in Scheme 274. Initially, benzamide 774 reacts with Cu(OR)2 leading to the liberation of ROH and, consequently, to the formation of N,N’-coordinated Cu species I. Copper then activates the C-H bond at the proximal benzylic position to form cyclometalated complex II. This complex is oxidized to Cu(III) complex III and, through reductive elimination, isoindolinone 11 and CuOR are formed. Reoxidation of CuOR by MnO2 closes the catalytic cycle. The proposed role of the acidic additive in the catalytic cycle is the acceleration of the C-H activation step via an acetate-assisted concerted metalationdeprotonation. In the case of benzamides bearing simpler aryl groups on the nitrogen (N-

265

naphthyl-substituted substrates) the reaction proceeds through an aminyl radical-mediated Hofmann-Loffler-Freytag (HLF)-type mechanism [333].

Scheme 274. Possible mechanism for the formation of isoindolinones through the coppercatalyzed intramolecular benzylic C-H amination of benzamides [333]. Also recently, Kaliappan and co-workers reported the first Cu-catalyzed C-H activation followed

by

a

two-fold

C-N

bond

formation

for

the

synthesis

of

N-aryl

benzimidazoquinazolinones [334]. The coupling between N-anilinoquinazolinones and aryl/heteroaryl halides to afford the desired products is achieved in the presence of Cu(OAc)2•H2O as the metal source, phenathroline as the ligand, and KI as the additive. This intramolecular C-H amination is the result of a ligand-assisted C-H activation first step. Higher yields of products are obtained in non-degassed solvents, which is in contrast to the conditions of typical Ullmann-type reactions. Exploration of the aryl halides scope revealed that bromoarenes, bromoheteroarenes and aryl bromides substituted with either electrondonating or electron-withdrawing groups reacted efficiently with N-anilinoquinazolinone (778a-778e, 778g, Scheme 275). However, no product formation was observed in the presence of a hindered aryl bromide (1-bromo-2-methyl-3-nitrobenzene, 778f, Scheme 275). It is worth mentioning that when 3-iodopyridine was used as substrate, the reaction did not proceed at all (778h, Scheme 275). It was proposed that in the case of 2-haloheteroarenes the

266

heteroatom facilitates the initial halogen exchange with KI, promoting the oxidative addition, in contrast to 3- or 4-haloheteroarenes, where such an activation does not occur. By investigating the fluorinated analogues of benzimidazoquinazolinone, it was found that good yields of the desired products are obtained with various amines (778i-778l, Scheme 275).

Scheme 275. Copper-catalyzed cascade amination of N-anilinoquinazolinones and fluoro analogues of benzimidazoquinazolinones to form N-aryl benzimidazoquinazolinones [334]. Significant progress in the field of copper-catalyzed C-H amination has been made by Warren’s research group in recent years [335]. Their work has focused on the use of welldefined copper catalysts for C-H amination reactions [336-340] and also C-H etherification [341, 342]. The systems developed and studied by Warren and co-workers operate through

267

radical-based mechanisms and thus are not the primary focus of this review, however it is important that they are mentioned. 6.15. Triazoles in copper-catalyzed C-H activation Herein, we report the methods developed for the preparation of triazole derivatives through C-H bond activation transformations catalyzed by copper. In 2013, Baltas and coworkers reported the oxidation of substituted dibenzyl triazoles into the corresponding ketones (Scheme 276) [343]. This reaction utilizes copper iodide and tert-butyl hydroperoxide (TBHP) in acetonitrile, takes place at room temperature, and generates the desired ketone chemoselectively in moderate to good yields (Scheme 276). Triazoles with remote aromatic groups at the 1-position lead to good yields (780a-780e). Both electrondonating and electron-withdrawing groups on the phenyl ring of the benzyltriazoles can be employed in the reaction, providing the desired products (780l-780n). Finally, when an αketotriazole was subjected to this oxidation reaction, the desired α,β-diketotriazole 780o was obtained with 16% yield, despite the existence of an intramolecular directing group.

268

Scheme 276. Copper-catalyzed oxidation of substituted dibenzyl triazoles [343]. Two years later, Liu and co-workers developed an efficient protocol for the synthesis of 4amino-2-aryl-1,2,3-triazole derivatives (783) by a copper-catalyzed cross-deprotonative coupling of 1,2,3-triazole N-oxides (781) with amines (782) (Scheme 277) [344]. Various copper sources, bases, and solvents were tested during the determination of the optimal reaction conditions: 20 mol% of Cu(OAc)2 with 2 equivalents of K3PO4 in dimethoxyethane at 80 °C for 12 hours. These conditions exclude the formation of the homocoupling byproduct 784 of the reaction. Alkyl- or halogen-substituted 2-aryl-1,2,3-triazole N-oxides underwent the desired transformation with excellent regioselectivity affording products 783a783h in up to 82% yield. 2-Aryl-1,2,3-triazole N-oxides were successfully subjected to the reaction with both morpholine and 3-methylmorpholine, in both cases affording the 269

corresponding products 783i-783t. It was found that 2-substituted 1,2,3-triazole N-oxides bearing both electron-donating and electron-withdrawing substituents gave the expected products in moderate to excellent yields. Acyclic secondary amines such as diethylamine, dipropylamine, and diisopropylamine successfully provided 783u-783y in good yields. The reaction was also shown to be functional with primary amines, with a slight modification of the reaction conditions: The addition of potassium tert-butoxide (tBuOK, 20 mol%) in the reaction mixture afforded the desired aminated products (783z, 783aa-783ae, Scheme 277) in good yields.

Scheme 277. Amination of 1,2,3-triazole N-oxides catalyzed by copper [344].

270

To study the mechanism of this amination reaction, Liu and co-workers performed a series of control experiments [344]. The reaction was carried out in the absence of the amine partner, or by substituting the 1,2,3-triazole N-oxide with the analogous 1,2,3-triazole. These two experiments revealed that deoxygenation of 1,2,3-triazole N-oxides occurs after the C-N bond formation step. Further experiments showed that molecular oxygen is not crucial for the reaction to proceed. Several experiments with deuterated substrates and kinetic isotope effect studies revealed a plausible mechanism for the reaction. According to this mechanism (Scheme 278), the triazole N-oxide reacts with the copper center to form organocopper intermediate I. This compound further reacts with the amine to yield intermediate II, which upon reductive elimination affords the desired coupling product (783) along with a copper species of the lower oxidation state. This copper species is then oxidized to give Cu(II) species III that reenters the catalytic cycle. H N

N 781 Ar

N O :B HBX

X CuLn

LnCuX2 III + 2 :B + H2O

CuX2 + Ln

N

N Ar

N O I

R 2R 1N N

N N Ar

HNR 1R2 + :B

783 2HBX

R 2R 1N CuLn HBX N

N Ar

N O II

Scheme 278. Proposed mechanism for the synthesis of 4-amino-2-aryl- 1,2,3-triazole derivatives catalyzed by copper [344].

271

7. ZINC 7.1. Introduction Zinc compounds are frequently employed as additives in C-H activation reactions catalyzed by other transition metals (vide supra). Also, the Lewis acidic character of zinc salts is well known and exploited in cooperative catalysis for the activation of electrophilic species. Furthermore, zinc catalysis has recently received ample attention regarding useful transformations of alkynes [78]. In the case of terminal alkynes, the catalytic C(sp)-H activation involving the use of simple zinc salts or organometallic compounds in combination with weak, non-nucleophilic bases has been established. This transformation is commonly utilized to carry out C-C bond formation reactions including addition to C=N, C=O or C=C bonds, cross-dehydrogenative couplings, as well as, three-component couplings between aldehydes, amines and terminal alkynes (A3 coupling). Τhe C-H activation step is almost identical in all the aforementioned procedures, which also often present remarkable similarities between them. In this regard, herein we shall only refer to some representative examples and only a few, selected ones, will be discussed in detail, beginning from the pioneering work of Carreira and co-workers and gradually progressing towards the more recent advancements made by the research groups of Nakamura, Baba, and Lei. 7.2. Addition of terminal alkynes to C=N, C=O or C=C bonds In a seminal publication, Carreira and co-workers reported the development of a catalytic system based on zinc for the addition of terminal alkynes (785, Scheme 279) to nitrones (786) under mild reaction conditions [345]. The combination of Zn(OTf)2 in 10 mol% loading with a sub-stoichiometric amount of iPr2NEt afforded a range of propargylic hydroxylamines (787) in high yields. The chemoselective formation of product 787a demonstrated the applicability of this protocol, which is in contrast to the traditional metal-acetylide involving 272

processes. Also, aldehydes, ketones and aldimines were amenable to this reaction, leading to promising results and foreshadowing future synthetic applications. It was postulated that this transformation involved the formation of a zinc-alkyne π-complex and the deprotonation of the terminal C-H bond by the weak base leading to zinc-acetylide formation.

Scheme 279. The first example of a zinc-catalyzed addition of terminal alkynes to C=N and C=O bonds [345]. Later on, the same research group demonstrated the synthetic potential of this protocol by applying the same principles in order to carry out the enantioselective addition of terminal alkynes (793, Scheme 280a) to aldehydes (794) using chiral ligand L89 [346]. This transformation can also take place under solvent free conditions, reducing the reaction time and leading to excellent results. Moreover, the same catalytic reaction was incorporated into the total synthesis of natural products [347]. It was later on found, that TMSOTf could accelerate the catalytic addition of zinc-acetylides to aldehydes, inducing catalytic turnover by either silylating the intermediate alkoxide or activating the aldehyde [348]. Furthermore, the diastereoselective addition of terminal alkynes to nitrones bearing a chiral auxiliary, to

273

access optically active N-hydroxylamines, was also described. This catalytic system was also based on Zn(OTf)2, while the chiral auxiliaries could be readily removed and reused for this synthetic process [349]. A different system was developed by Vallée and co-workers for the alkynylation of nitrones using a sub-stoichiometric amount of Et2Zn under mild conditions [350]. This system was later on used for the diastereoselective preparation of propargylic Nhydroxylamines (797, Scheme 280b) from terminal alkynes (793) and nitrones (796) bearing removable chiral auxiliaries [351]. More recently, Carreira’s research group used Et2Zn in a more complex autocatalytic system for the synthesis of HIV treatment drug efavirenz, involving the enantioselective addition of a terminal alkyne to a ketone [352]. a) Zn(OTf)2 (20 mol%) Et3N (50 mol%)

O R

H

H

R'

o

toluene, 60 C

794

793

Ph

Me

HO

N

OH R' R 795

L89 (22 mol%)

b) O R

N

H

R*

HO

N

R*

ZnEt2 (20 mol%) H

toluene, RT R 797

796

793

O

O

O O R* =

O

Ph OBn iPr OBn

Scheme 280. a) The enantioselective addition of terminal alkynes to aldehydes (794) using chiral ligand L89 [346]. b) The diastereoselective addition of terminal alkynes to nitrones bearing chiral auxiliaries [351]. 274

Expanding the substrate scope of the in situ generated zinc-acetylide addition reactions, Jiang et al. reported the enantioselective alkynylation of α-keto esters (799, Scheme 281a) to access chiral propargylic alcohols (800) [353]. A variety of optically active compounds were synthesized in a highly enantioselective manner, using chiral ligand L90, Zn(OTf)2 in 20 mol% loading, and triethylamine under neat conditions, with an excess of the terminal alkyne (798). Another contribution concerning C-C bond formation via the addition of zincacetylides to electrophilic centers was made by Carreira and co-workers, when they disclosed the diastereoselective conjugate addition of terminal alkynes (801) to ephedrine-derived acceptors (802, Scheme 281b) by utilizing catalytic amounts of Zn(OTf)2 [354]. The adducts formed in this way can be readily converted to valuable, chiral β-alkynyl acids (803). a) Zn(OTf)2 (20 mol%) Et3N (30 mol%)

O R

H

OR''

R'

R

OH

800

799

798

OR''

R'

70 oC, 2 d

O

O HO

OTBDMS O2N

N L90 (22 mol%)

b) N R

O

1) cat. Zn(OTf)2 Et3N

H Ph 801

O

R' O

2) KOH, PrOH, 97 oC 3) DMSO, 100 oC

802

O

R'

HO R 803

Scheme 281. a) Zinc-catalyzed enantioselective alkynylation of α-keto esters (799) to access chiral propargylic alcohols (800) [353]. b) Diastereoselective conjugate addition of terminal alkynes to ephedrine-derived acceptors (802) [354]. In another work, the three component coupling between aldehydes, amines and terminal alkynes (A3 coupling) was successfully carried out in the presence of Zn(OAc)2•2H2O in 10 mol% loading, obviating the use of a mild base or other additives. A remarkably large number of products were synthesized in mostly high yields, with this simple methodology 275

displaying notable functional group tolerance and chemoselectivity [355]. Subsequently, it was discovered that ZnI2 could promote the formation of 1,3-disubstituted allenes via a zincmediated A3 coupling reaction of terminal alkynes, aldehydes, and morpholine, followed by a key intramolecular hydride shift [356]. More recently, a diastereoselective version of these reactions was elegantly developed by Periasamy et al. [357]. More specifically, ZnCl2 in 10 mol% loading could efficiently catalyze the A3 coupling of terminal alkynes (804, Scheme 282), aldehydes and chiral piperazines (806) to afford chiral propargylamines (807) in high yields. Interestingly, the transformation of a wide range of chiral propargylamines (807) to chiral allenes (808) was easily carried out in short reaction times with the use of ZnBr2. Of note, the imine byproducts could be converted to chiral piperazines (806) with ease, thus recycling the chiral reagent. In 2016, Chandak and co-workers reported the development of a protocol for the solvent-free synthesis of propargylamines via the A3 coupling of aldehydes, amines and terminal alkynes using only Zn(OTf)2 in 5 mol% loading [358]. The same research group also reported the use of the same catalytic system for the solvent-free synthesis of 2,4-disubstituted quinolines from aldehydes, terminal alkynes and anilines [359].

Scheme 282. Zinc-catalyzed synthesis of chiral propargylamines (807) and their conversion to chiral allenes (808) [357].

276

An important contribution to this field was recently made by Baba and co-workers, when they reported the ZnCl2-catalyzed coupling of terminal alkynes and acetals (810, Scheme 283) thus gaining access to propargyl ethers (811) [360]. This reaction proceeds efficiently using ZnCl2/Et2O in just 1 mol% catalyst loading with no need for additives, while other potential metal sources such as Zn(OAc)2, Zn(OTf)2, and CuCl2 displayed moderate or no catalytic competency. A wide variety of substrates were amenable to this protocol, leading to products with synthetically useful functionalities in mostly high yields (Scheme 283). Especially designed experiments and kinetic studies pointed towards a plausible catalytic cycle, which was proposed to commence with the formation of intermediate I (Scheme 283) via activation of the acetal (810) by ZnCl2. Deprotonation and metalation of the terminal alkyne (809) by the active catalyst affords zinc-acetylide intermediate II, which interacts with an acetal leading to the formation of an oxonium cation and a zincate complex, finally leading to product formation and regeneration of the catalytically active species I. It was suggested that the aforementioned step might be rate-limiting for this transformation.

277

OR3 1

R

H

R2

OR3

ZnCl2/Et2O (1 mol%) toluene, reflux, 12 h

OR3

R2 R1 811

810

809

O

O

O O

O

O

Br

811a (98%)

811a (86%)

811a (80%)

O

O

C8H17

Cl

C8H17

811a (90%)

C8H17

O

811a (85%)

811a (90%)

OR3 R ClZn

3

R OH

OR3 810

II

R1

2

R1

H 809 OR3

OR3 R2

ZnCl2

OR3

R2

Zn(OR3)Cl I

R1

Zn(OR3)Cl

810

OR3 R2 811

R1

Scheme 283. ZnCl2-catalyzed coupling of terminal alkynes and acetals and the proposed reaction mechanism [360]. Zinc catalysis towards C-C bond formation through C-H activation has also been successfully showcased in recent works on cross-dehydrogenative coupling reactions (CDC). Muraka and Studer developed a protocol for the aerobic cross-dehydrogenative coupling of terminal alkynes with nitrones, providing access to alkynylated nitrones with use of zinc triflate as the catalyst and a quinone and oxygen as the oxidants [361]. In 2012, Nakamura

278

and Sugishi reported that in the presence of zinc the triple bond of propargylic amines could act as an internal oxidant for the cross dehydrogenative coupling of propargylic amines and terminal alkynes, leading to N-tethered 1,6-enynes [362]. This is an important finding, as it revealed a useful mode of action of zinc in C-H activation. Later on, Lei and co-workers successfully synthesized various ynones via the cross dehydrogenative coupling of terminal alkynes and ketones with zinc triflate as the catalyst and PhCOCF3 as the oxidant [363]. Again, the formation of zinc-acetylide species was the key C-H activation step as in all previously mentioned cases. In 2016, Nakamura and Li reported the zinc-catalyzed cross dehydrogenative coupling of N-propargylanilines and indoles through activation of two C(sp2)-H bonds and one C(sp 3)-H bond [364]. In this intramolecular hydroarylation-redox CDC transformation, the propargylic triple bond acts as the hydrogen atom acceptor in the presence of zinc. 7.3. Installation of C(sp)-X bonds (X = Si, Sn) The first zinc-based catalytic method for the preparation of synthetically valuable alkynylsilanes (813, Scheme 284) by silylation of terminal alkynes (812) with TMSOTf was reported by Rahaim and Shaw in 2008 [365]. This methodology results in the facile, catalytic installation of new C(sp)-Si bonds under mild reaction conditions and with notable functional group tolerance. With the use of Zn(OTf)2 in 5-15 mol% loading and triethylamine (1.5 equiv) a wide variety of challenging terminal alkynes (812) were silylated by TMSOTf (1.5 equiv), furnishing the corresponding alkynylsilanes (813) in mostly high to excellent yields. The catalyst loading could be lowered to 2.5 mol% without compromising yield in the case of 813a, while reducing the concentration of TMSOTf and triethylamine led to decreased yields. Triethylamine was chosen as the optimal base for this transformation, as use of other mild bases significantly decreased product yield. Exploration of the substrate scope led to the successful synthesis of alkynylsilanes bearing synthetically useful functionalities (813b) and 279

structural motifs (813e-813g). The nucleophilic zinc-acetylides do not show reactivity towards electrophilic centers present in the substrates, as suggested by the cases of product 813c, as well as other products in which possibly nucleophile-sensitive moieties remained intact. Use of other silylating reagents showed that more sterically hindered silyl triflates had a considerably negative effect on the reaction outcome. With regards to the mechanism, it was proposed that zinc-alkyne π-complex (I, Scheme 284) formation and subsequent deprotonation of the activated C(sp)-H bond by the mild base afford the intermediate zinc-acetylide II. Nucleophilic substitution ensues, leading to product formation and regeneration of the zinc catalyst. It is noteworthy that this protocol’s success is partially owed to the reactivity of Zn(OTf)2, which is capable of re-entering the cycle.

280

Scheme 284. Zinc-catalyzed silylation of terminal alkynes with TMSOTf [365]. In a more recent work, Baba and co-workers introduced a catalytic protocol based on ZnBr2 for the direct synthesis of alkynylstannanes (815, Scheme 285) from terminal alkynes (814) and tributyltin methoxide [366]. Alkynylstannanes (815) are highly valuable reagents for the alkynylation of organic molecules, as they are famously used in the Migita-Stille coupling for the construction of C(sp)-C(sp2) bonds [367]. By employing ZnBr2 in 5 mol% loading, a wide variety of terminal alkynes (814) could be successfully functionalized under mild conditions and with methanol as the sole reaction byproduct. Interestingly, screening of potential catalysts for this transformation revealed that only Zn(OTf)2 and the simple, inexpensive salt ZnBr2 were substantially competent, while PdCl2 and CuBr proved less promising. Under the optimized conditions, a considerably broad range of aliphatic, aromatic and heteroaryl alkynes were amenable to this protocol, affording the corresponding alkynylstannanes (e.g. 815a, 815d-815e, 815g-815h respectively) in moderate to high yields. Notably, substrates bearing nucleophile-sensitive functional groups were compatible with the reaction system and the synthetically useful product 815i having C(sp)-Si and C(sp)-Sn bonds was also efficiently obtained. In demonstration of this protocol’s synthetic potential and versatility, the one pot synthesis of aryl alkynes via the zinc-catalyzed formation of alkynylstannanes (815) and subsequent palladium-catalyzed Migita-Stille coupling was elegantly realized, resulting in moderate to high product yields. On the basis of mechanistic investigations, a plausible catalytic cycle was proposed for this transformation: The cycle commences with a transmetalation step that leads to the formation of zinc methoxide species I, which facilitates the deprotonation/metalation of a terminal alkyne (814) leading to an intermediate zinc-acetylide (II). Another key transmetalation step occurs, releasing the product and regenerating the active catalyst [366].

281

R

ZnBr2 (5 mol%) Bu3SnOMe (1.2 equiv)

H

R

THF , RT, 3 h

814

SnBu3 815

SnBu3

SnBu3

SnBu3 NC

9

O 815a (61%)

815c (39%)

815b (77%)

SnBu3

SnBu3

SnBu3

Br 815e (80%)a

O

815d (61%)a

815f (74%)

Cl

SnBu3

SnBu3

SnBu3

N

TMS

S

815i (74%)b

815h (74%)

815g (79%)

R

H

MeOH

814

ZnBr2

ZnX(OMe)

Bu3SnOMe

R

ZnX II

I (X = OMe or Br) Bu3SnBr

R

SnBu3

Bu3SnOMe

815

Scheme 285. The zinc-catalyzed synthesis of alkynylstannanes (815) [366]. a) MeCN is used as the solvent. b) 1 mmol tributyltin methoxide and 2 mmol of the terminal alkyne. 8. CONCLUSIONS AND OUTLOOK It has become evident that the use of sustainable metals in catalytic C-H activation reactions poses a powerful and highly promising alternative to more traditional noble metal catalysis. The diverse, vast number of valuable organic transformations that can be facilitated by the utilization of sustainable metal catalysts provides access to a wide array of highly

282

functionalized molecules and renders the general approach of C-H activation highly attractive as a modern tool for organic synthesis. This strategy has evolved immensely during the past two decades, resulting in the development of versatile, cutting-edge catalytic protocols, the majority of which are characterized by minimized cost, low toxicity, atom- and stepeconomy, operational simplicity, and high efficiency. However, it should be noted that sustainable metals-based catalysts are not just substitutes of the more efficient noble metal catalysts, but often display unique selectivity and catalytic competency in challenging transformations which the latter fail to promote. Magnesium- and calcium-based catalysts have only very recently entered the scene of C-H activation, giving rise to green and efficient protocols for the synthesis of synthetically useful and biologically relevant molecules. Predicting future advances in these fields is not an easy task, although the inexpensive and environmentally benign nature of the systems developed thus far is expected to attract more interest, possibly leading to new applications and to the acquisition of additional mechanistic insight regarding the modes of action of these two metals in C-H functionalization processes. Even though catalytic C-H activation reactions in which manganese operates via an organometallic mode of action have surfaced relatively recently, the directing group assisted manganese catalysis regime has evolved with a rapid manner. Manganese carbonyl complexes MnBr(CO)5 and Mn2(CO)10 have proven to be versatile and robust catalysts for an increasing number of useful transformations of great synthetic potential. It would be interesting to see these recently developed protocols being incorporated into more elaborate synthetic procedures, thus further demonstrating their applicability. Future research should, amongst others, focus on the use of more, ideally removable, directing groups containing atoms other than nitrogen or oxygen and on the catalytic functionalization of more challenging C(sp3)-H bonds, based on analogous stoichiometric systems developed in the 283

past. The development of new catalysts with more diverse ligand design or even the discovery of new catalytic reactions besides C-C bond formation could potentially lead to intriguing results. Besides the catalytic reactions that are being discussed in this review, significant progress is to be expected in metalloporphyrin-catalyzed C-H oxidation [368] and also in C(sp3)-N bond formation through manganese catalysis [369]. Mechanistic investigations, complemented by DFT studies are always necessary in order to gain more insight into already existing cooperative catalytic systems and to aid the design of novel ones. Catalytic systems for C-H activation based on iron have also received great interest, highlighting their importance in the field. In the majority of these systems, amine- and more recently phosphine-based bidentate ligands lead to excellent results, although the development of chiral ligands for enantioselective transformations or the investigation of other well-defined ligand scaffolds would also be interesting. Efforts should be focused on designing more selective catalytic systems that operate under mild, environmentally benign conditions and circumvent the need of pre-functionalized substrates. The low cost of the iron salts used, in combination with the effective, facile and step-economical nature of some protocols, makes them ideal candidates for industrial use. Also, exceptionally competent catalysts could potentially be modified, incorporated in heterogeneous catalytic systems and recycled. Among the sustainable metals discussed in the present work, copper has undoubtedly found the widest use. The inexpensive nature of the catalysts used, in combination with the fact that many catalytic C-H activation reactions take place under mild conditions and even involve the use of water as the reaction medium makes copper-catalyzed C-H activation arguably the ideal alternative to noble transition metal catalysis. Moreover, the use of oxygen or air as the sole oxidant in powerful amination, arylation, alkoxylation, and oxidative cyclization protocols further contributes to this fields’ overall sustainable nature. Expansion 284

of the substrate scope in chelation-assisted C-H activation reactions could be achieved by investigation of more diverse directing groups. More exhaustive mechanistic investigations are needed in many reaction systems and also ligand development and screening in certain systems could potentially lead to important findings and better understanding, thus enabling the rational design of catalytic systems. Finally, zinc-based catalysts have had widespread use in the functionalization of terminal alkynes

with

many highlights

being enantio-

and

diastereo-selective

syntheses,

multicomponent couplings, and CDC coupling reactions under mild conditions. Future research should focus on the development of new reaction systems for the formation of bonds other than C-C, and the potential discovery of new modes of action of zinc in C-H activation. The design of novel, state of the art catalytic C-H activation systems based on sustainable metals is a challenge of vital importance. Judging from the rapid evolution of this field, exciting new findings are to be expected in the near future. 9. ACKNOWLEDGEMENTS The authors acknowledge the contribution of COST Action CA15106 (C-H Activation in Organic Synthesis - CHAOS). IKS acknowledges the ΙΚΥ fellowships of excellence for postgraduate studies in Greece – Siemens Program, for financial support. 10. REFERENCES [1] S. Murahashi, J. Am. Chem. Soc. 77 (1955) 6403-6404. [2] J. Chatt, J.M. Davidson, J. Chem. Soc. (1965) 843. [3] A.H. Janowicz, R.G. Bergman, J. Am. Chem. Soc. 104 (1982) 352-354. [4] C.S. Yeung, V.M. Dong, Chem. Rev. 111 (2011) 1215-1292. 285

[5] S. Murai, Proc. Jpn. Acad., Ser. B. 87 (2011) 230-241. [6] N. Kuhl, M.N. Hopkinson, J. Wencel-Delord, F. Glorius, Angew. Chem., Int. Ed. 51 (2012) 10236-10254. [7] K.M. Engle, J. Yu, J. Org. Chem. 78 (2013) 8927-8955. [8] B. Peng, N. Maulide, Chem. Eur. J. 19 (2013) 13274-13287. [9] S.A. Girard, T. Knauber, C. Li, Angew. Chem., Int. Ed. 53 (2014) 74-100. [10] H. Shinokubo, Proc. Jpn. Acad., Ser. B. 90 (2014) 1-11. [11] J. Schranck, A. Tlili, M. Beller, Angew. Chem., Int. Ed. 53 (2014) 9426-9428. [12] C. Liu, J. Yuan, M. Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 115 (2015) 1213812204. [13] T.M. Shaikh, F. Hong, J. Organomet. Chem. 801 (2016) 139-156. [14] M. Gulías, J.L. Mascareñas, Angew. Chem., Int. Ed. 55 (2016) 11000-11019. [15] H.M.L. Davies, D. Morton, J. Org. Chem. 81 (2016) 343-350. [16] B. Zhao, Z. Shi, Y. Yuan, Chem. Rec. 16 (2016) 886-896. [17] J.A. Labinger, J.E. Bercaw, Nature 417 (2002) 507-514. [18] M. Lersch, M. Tilset, Chem. Rev. 105 (2005) 2471-2526. [19] D. Balcells, E. Clot, O. Eisenstein, Chem. Rev. 110 (2010) 749-823. [20] L. Ackermann, Chem. Rev. 111 (2011) 1315-1345. [21] M. Gómez-Gallego, M.A. Sierra, Chem. Rev. 111 (2011) 4857-4963.

286

[22] S.I. Gorelsky, Coord. Chem. Rev. 257 (2013) 153-164. [23] N. Kuhl, N. Schröder, F. Glorius, Adv. Synth. Catal. 356 (2014) 1443-1460. [24] J. Wencel-Delord, F. Glorius, Nat. Chem. 5 (2013) 369-375. [25] D.Y.-K. Chen, S.W. Youn, Chem. Eur. J. 18 (2012) 9452-9474. [26] K. Okamoto, J. Zhang, J.B. Housekeeper, S.R. Marder, C.K. Luscombe, Macromolecules 46 (2013) 8059-8078. [27] P. Yang, W. Yang, Chem. Rev. 113 (2013) 5547-5594. [28] Y. Segawa, T. Maekawa, K. Itami, Angew. Chem. Int. Ed. 54 (2015) 66-81. [29] T. Ishiyama, N. Miyaura, Chem. Rec. 3 (2004) 271-280. [30] I.A.I. Mkhalid, J.H. Barnard, T.B. Marder, J.M. Murphy, J.F. Hartwig, Chem. Rev. 110 (2010) 890-931. [31] T. Satoh, M. Miura, Chem. Eur. J. 16 (2010) 11212-11222. [32] T.W. Lyons, M.S. Sanford, Chem. Rev. 110 (2010) 1147-1169. [33] Y. Kuninobu, K. Takai, Chem. Rev. 111 (2011) 1938-1953. [34] J.F. Hartwig, Acc. Chem. Res. 45 (2012) 864-873. [35] P.B. Arockiam, C. Bruneau, P.H. Dixneuf, Chem. Rev. 112 (2012) 5879-5918. [36] D.A. Colby, A.S. Tsai, R.G Bergman, J.A. Ellman, Acc. Chem. Res. 45 (2012) 814-825. [37] Y. Rao, G. Shan, X. Yang, Sci. China Chem. 57 (2014) 930-944. [38] S. Motevalli, Y. Sokeirik, A. Ghanem, Eur. J. Org. Chem. 2016 (2016) 1459-1475.

287

[39] R. Zhu, M.E. Farmer, Y. Chen, J. Yu, Angew. Chem. Int. Ed. 55 (2016) 10578-10599. [40] J. Wencel-Delord, T. Dröge, F. Liu, F. Glorius, Chem. Soc. Rev. 40 (2011) 4740. [41] T. Gensch, M.N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 45 (2016) 2900-2936. [42] L.C.M. Castro, N. Chatani, Chem. Lett. 44 (2015) 410-421. [43] O. Daugulis, J. Roane, L.D. Tran, Acc. Chem. Res. 48 (2015) 1053-1064. [44] X. Cai, B. Xie, Arkivoc 2015 (2015) 184-211. [45] B. Su, Z.-C. Cao, Z.-J. Shi, Acc. Chem. Res. 48 (2015) 886-896. [46] N. Yoshikai, ChemCatChem 7 (2015) 732-734. [47] M. Moselage, J. Li, L. Ackermann, ACS Catal. 6 (2016) 498-525. [48] M.S. Holzwarth, B. Plietker, ChemCatChem 5 (2013) 1650-1679. [49] S. Harder, Chem. Rev. 110 (2010) 3852-3876. [50] M.R. Crimmin, M. Arrowsmith, A.G.M. Barrett, I.J. Casely, M.S. Hill, P.A. Procopiou, J. Am. Chem. Soc. 131 (2009) 9670-9685. [51] A. Frischmuth, A. Unsinn, K. Groll, H. Stadtmüller, P. Knochel, Chem. Eur. J. 18 (2012) 10234-10238. [52] T. Satoh, Heterocycles 85 (2012) 1-33. [53] S. Murarka, I. Deb, C. Zhang, D. Seidel, J. Am. Chem. Soc. 131 (2009) 13226-13227. [54] L. Chen, L. Zhang, J. Lv, J. Cheng, S. Luo, Chem. Eur. J. 18 (2012) 8891-8895.

288

[55] S.J. Kwon, D.Y. Kim, Chem. Rec. 16 (2016) 1191-1203. [56] P. Jochmann, T.S. Dols, T.P. Spaniol, L. Perrin, L. Maron, J. Okuda, Angew. Chem., Int. Ed. 49 (2010) 7795-7798. [57] P. Jochmann, V. Leich, T.P. Spaniol, J. Okuda, Chem. Eur. J. 17 (2011) 12115-12122. [58] A.S. Borovik, Chem. Soc. Rev. 40 (2011) 1870-1874. [59] M. Bordeaux, A. Galarneau, J. Drone, Angew. Chem. Int. Ed. 51 (2012) 10712-10723. [60] W. Liu, J.T. Groves, Acc. Chem. Res. 48 (2015) 1727-1735. [61] J.R. Carney, B.R. Dillon, S.P. Thomas, Eur. J. Org. Chem. 2016 (2016) 3912-3929. [62] C. Wang, Synlett 24 (2013) 1606-1613. [63] D.A. Valyaev, G. Lavigne, N. Lugan, Coord. Chem. Rev. 308 (2016) 191-235. [64] W. Liu, L. Ackermann, ACS Catal. 6 (2016) 3743-3752. [65] E. Bauer (Ed.), Iron Catalysis II, first ed., Springer, Switzerland, 2015. [66] C.-L. Sun, B.-J. Li, Z.-J Shi, Chem. Rev. 111 (2011) 1293-1314. [67] X. Sun, J. Li, X. Huang, C. Sun, Curr. Inorg. Chem. 2 (2012) 64-85. [68] M.D. Mihovilovic, M. Schnürch, ChemCatChem 6 (2014) 2194-2196. [69] M. Zhang, Appl. Organometal. Chem. 24 (2010) 269-284. [70] A.E. Wendlandt, A.M. Suess, S.S. Stahl, Angew. Chem., Int. Ed. 50 (2011) 1106211087. [71] K. Hirano, M. Miura, Chem. Commun. 48 (2012) 10704-10714.

289

[72] S.E. Allen, R.R. Walvoord, R. Padilla-Salinas, M.C. Kozlowski, Chem. Rev. 113 (2013) 6234-6458. [73] X.-h. Cai, B. Xie, Synthesis 47 (2015) 737-759. [74] X.-X. Guo, D.-W. Gu, Z. Wu, W. Zhang, Chem. Rev. 115 (2015) 1622-1651. [75] K. Hirano, M. Miura, Chem. Lett. 44 (2015) 868-873. [76] J. Liu, G. Chen, Z. Tan, Adv. Synth. Catal. 358 (2016) 1174-1194. [77] S. Enthaler, ACS Catal. 3 (2013) 150-158. [78] M.J. González, L.A. López, R. Vicente, Tetrahedron Lett. 56 (2015) 1600-1608. [79] A. Pinaka, G.C. Vougioukalakis, Coord. Chem. Rev. 288 (2015) 69-97. [80] Y. Suzuki, M. Kanai, S. Matsunaga, Chem. Eur. J. 18 (2012) 7654-7657. [81] R. Rochat, K. Yamamoto, M.J. Lopez, H. Nagae, H. Tsurugi, K. Mashima, Chem. Eur. J. 21 (2015) 8112-8120. [82] K. Mochida, K. Kojima, Y. Yoshida, Bull. Chem. Soc. Jpn. 60 (1987) 2255-2256. [83] K. Mochida, Y. Hiraga, H. Takeuchi, H. Ogawa, Organometallics 6 (1987) 2293-2297. [84] M. Asadullah, T. Kitamura, Y. Fujiwara, Angew. Chem. Int. Ed. 39 (2000) 2475-2478. [85] S. Harder, Angew. Chem. Int. Ed. 42 (2003) 3430-3434. [86] H. Li, X.-Y. Wang, B. Wei, L. Xu, W.-X. Zhang, J. Pei, Z. Xi, Nat. Commun. 5 (2014), doi:10.1038/ncomms5508. [87] B. Wei, H. Li, W.-X. Zhang, Z. Xi, Organometallics 35 (2016) 1458-1463.

290

[88] Y. Yang, H. Wang, H. Ma, Chem. Asian J. 12 (2016) 239-247. [89] S. Yaragorla, G. Singh, R. Dada, Tetrahedron Lett. 56 (2015) 5924-5929. [90] S. Yaragola, R. Dada, G. Singh, Synlett 27 (2015) 912-918. [91] M.I. Bruce, M.Z. Iqbal, F.G.A. Stone, J. Am. Chem. Soc. (1970) 3204-3209. [92] W. Tully, L. Main, B.K. Nicholson, J. Organomet. Chem. 503 (1995) 75-92. [93] W. Tully, L. Main, B.K. Nicholson, J. Organomet. Chem. 507 (1996) 103-115. [94] W. Tully, L. Main, B.K. Nicholson, J. Organomet. Chem. 633 (2001) 162-172. [95] W. Lamanna, M. Brookhart, J. Am. Chem. Soc. 103 (1981) 989-991. [96] J.M. Ressner, P.C. Wernett, C.S. Kraihanzel, A.L. Rheingold, Organometallics 7 (1988) 1661-1663. [97] C. Perthuisot, M. Fan, W.D. Jones, Organometallics 11 (1992) 3622-3629. [98] H. Chen, J.F. Hartwig, Angew. Chem. Int. Ed. 38 (1999) 3391-3393. [99] R.F. Moreira, P.M. Wehn, D. Sames, Angew. Chem. Int. Ed. 39 (2000) 1618-1621. [100] T.H. Bennur, S. Sabne, S.S. Deshpande, D. Srinivas, S. Sivasanker, J. Mol. Catal. A: Chem. 185 (2002) 71-80. [101] A.S. Larsen, K. Wang, M.A. Lockwood, G.L. Rice, T.-J. Won, S. Lovell, M. Sadílek, F. Tureček, J.M. Mayer, J. Am. Chem. Soc. 124 (2002) 10112-10123. [102] S.-I. Murahashi, S. Noji, N. Komiya, Adv. Synth. Catal. 346 (2004) 195-198. [103] H.R. Mardani, H. Golchoubian, J. Mol. Catal. A: Chem. 259 (2006) 197-200.

291

[104] W. Liu, J.T. Groves, J. Am. Chem. Soc. 132 (2010) 12847-12849. [105] I. Garcia-Bosch, A. Company, C.W. Cady, S. Styring, W.R. Browne, X. Ribas, M. Costas, Angew. Chem. Int. Ed. 50 (2011) 5648-5653. [106] X. Huang, T.M. Bergsten, J.T. Groves, J. Am. Chem. Soc. 137 (2015) 5300-5303. [107] H.M. Neu, J. Jung, R.A. Baglia, M.A. Siegler, K. Ohkubo, S. Fukuzumi, D.P. Goldberg, J. Am. Chem. Soc. 137 (2015) 4614-4617. [108] V.S. da Silva, S. Nakagaki, G.M. Ucoski, Y.M. Idemori, G. DeFreitas-Silva, RSC Adv. 5 (2015) 106589-106598. [109] K.P. Bryliakov, E.P. Talsi, Coord. Chem. Rev. 276 (2014) 73-96. [110] Y. Kuninobu, Y. Nishina, T. Takeuchi, K. Takai, Angew. Chem. Int. Ed. 46 (2007) 6518-6520. [111] Y. Kuninobu, Y. Fujii, T. Matsuki, Y. Nishina, K. Takai, Org. Let. 11 (2009) 27112714. [112] W. Liu, J. Bang, Y. Zhang, L. Ackermann, Angew. Chem. Int. Ed. 54 (2015) 1413714140. [113] B. Zhou, Y. Hu, C. Wang, Angew. Chem. Int. Ed. 54 (2015) 13659-13663. [114] Y. Liang, L. Massignan, W. Liu, L. Ackermann, Chem. Eur. J. 22 (2016) 14856-14859. [115] B. Zhou, H. Chen, C. Wang, J. Am. Chem. Soc. 135 (2013) 1264-1267. [116] For a recent thorough mechanistic study on Mn(I)-catalyzed C-H activation, see: N.P. Yahaya, K.M. Appleby, M. Teh, C. Wagner, E. Troschke, J.T.W. Bray, S.B. Duckett, L.

292

Anders Hammarback, J.S. Ward, J. Milani, N.E. Pridmore, A.C. Whitwood, J.M. Lynam, I.J.S. Fairlamb, Angew. Chem., Int. Ed. 55 (2016) 12455-12459. [117] B. Zhou, P. Ma, H. Chen, C. Wang, Chem. Commun. 50 (2014) 14558-14561. [118] L. Shi, X. Zhong, H. She, Z. Lei, F. Li, Chem. Commun. 51 (2015) 7136-7139. [119] X. Yang, X. Jin, C. Wang, Adv. Synth. Catal. 358 (2016) 2436-2442. [120] R. He, Z. Huang, Q. Zheng, C. Wang, Angew. Chem. Int. Ed. 53 (2014) 4950-4953. [121] W. Liu, D. Zell, M. John, L. Ackermann, Angew. Chem. Int. Ed. 54 (2015) 4092-4096. [122] Y. Hu, C. Wang, Sci. China Chem. 59 (2016) 1301-1305. [123] S. Sueki, Z. Wang, Y. Kuninobu, Org. Lett. 18 (2016) 304-307. [124] W. Liu, S.C. Richter, Y. Zhang, L. Ackermann, Angew. Chem. Int. Ed. 55 (2016) 7747-7750. [125] Q. Lu, F.J.R. Klauck, F. Glorius, Chem. Sci. (2017) DOI: 10.1039/C7SC00230K. [126] Z. Ruan, N. Sauermann, E. Manoni, L. Ackermann, Angew. Chem., Int. Ed. 56 (2017) 3172-3176. [127] W. Liu, S.C. Richter, R. Mei, M. Feldt, L. Ackermann, Chem. Eur. J. 22 (2016) 1795817961. [128] Y. Kuninobu, K. Kikuchi, K. Takai, Chem. Lett. 37 (2008) 740-741. [129] S.N. Afraj, C. Chen, G.-H. Lee, RSC Adv. 4 (2014) 26301-26308. [130] A. Conde, G. Sabenya, M. Rodríguez, V. Postils, J.M. Luis, M. Mar Díaz-Requejo, M. Costas, P.J. Pérez, Angew. Chem. Int. Ed. 55 (2016) 6530-6534.

293

[131] K.M. Towe, Nature 349 (1990) 54-56. [132] D.H.R. Barton, D. Doller, Acc. Chem. Res. 25 (1992) 504-512. [133] D.H.R. Barton, W. Chavasiri, Tetrahedron 50 (1994) 19-30. [134] F. Minisci, F. Fontana, S. Araneo, F. Recupero, L. Zhao, Synlett 2 (1996) 119-125. [135] D.W. Snelgrove, P.A. MacFaul, K.U. Ingold, D.D.M. Wayner, Tetrahedron Lett. 37 (1996) 823-826. [136] D.H.R. Barton, F. Launay, Terahedron 54 (1998) 3379-3390. [137] S. Kiani, A. Tapper, R.J. Staples, P. Stravopoulos, J. Am. Chem. Soc. 122 (2000) 75037517. [138] P. Stavropoulos, R. Celenigil-Cetin, A.E. Tapper, Acc. Chem. Res. 34 (2001) 745-752. [139] U. Schuchardt, M.J.D.M. Jannini, P.T. Richens, M.C. Guerreiro, E.V. Spinace, Tetrahedron 57 (2001) 2685-2688. [140] S.J. Blanksby, G.B. Ellison, Acc. Chem. Res. 36 (2003) 255-263. [141] A. Pierpont, T. Cundari, Inorg. Chem.49 (2010) 2038-2046. [142] W. Donald, C. McKenzie, R. O'Hair, Angew. Chem. Int. Ed. 50 (2011) 8379-8383. [143] Q. Sun, Z. Li, A. Du, J. Chen, Z. Zhu, S. Smith, Fuel 96 (2012) 291-297. [144] X. Sun, X. Sun, C. Geng, H. Zhao, J. Li, J. Phys. Chem. A 118 (2014) 7146-7158. [145] M. Ansari, N. Vyas, A. Ansari, G. Rajaraman, Dalton Trans. 44 (2015) 15232-15243. [146] P. Verma, K. Vogiatzis, N. Planas, J. Borycz, D. Xiao, J. Long, L. Gagliardi, D. Truhlar, J. Am. Chem. Soc. 137 (2015) 5770-5781. 294

[147] R.J. Deeth, H. Dalton, J. Biol. Inorg. Chem. 3 (1998) 302-306. [148] K. Yoshizawa, J. Biol. Inorg. Chem. 3 (1998) 318-324. [149] X. Hu, C. Wang, Y. Sun, H. Sun, H. Li, J. Phys. Chem. B. 112 (2008) 10684-10688. [150] J. Bollinger, Y. Diao, M. Matthews, G. Xing, C. Krebs, Dalton Trans. (2009) 905-914. [151] C. Krest, A. Silakov, J. Rittle, T. Yosca, E. Onderko, J. Calixto, M. Green, Nat. Chem. 7 (2015) 696-702. [152] L. Wu, S. Meng, G. Tang, Biochimica et Biophysica Acta 1864 (2016) 453-470. [153] A. Bassan, M. Blomberg, P. Siegbahn, L. Que, Chem. Eur. J. 11 (2005) 692-705. [154] H. Tang, J. Guan, H. Liu, X. Huang, Dalton Trans. 42 (2013) 10260-10270. [155] S. Impeng, P. Khongpracha, C. Warakulwit, B. Jansang, J. Sirijaraensre, M. Ehara, J. Limtrakul, RSC Adv. 4 (2014) 12572-12578. [156] S. Impeng, P. Khongpracha, J. Sirijaraensre, B. Jansang, M. Ehara, J. Limtrakul, RSC Adv. 5 (2015) 97918-97927. [157] Y. Zuo, X. Huang, L. Li, G. Li, J. Mater. Chem. A 1 (2013) 374-380. [158] M.S. Chen, M.C. White, Science 327 (2010) 566-571. [159] D. Clemente-Tejeda, A. López-Moreno, F.A. Bermejo, Tetrahedron 69 (2013) 29772986. [160] J. Xiang, H. Li, J.S. Wu, Z. Anorg. Allg. Chem. 640 (2014) 1670-1674. [161] G. Olivo, M. Nardi, D. Vìdal, A. Barbieri, A. Lapi, L. Gómez, O. Lanzalunga, M. Costas, S. Di Stefano, Inorg. Chem. 54 (2015) 10141-10152.

295

[162] S. Haslinger, A. Raba, M. Cokoja, A. Pöthig, F.E. Kühn, J. Catal. 331 (2015) 147-153. [163] M. Nakanishi, C. Bolm, Adv. Synth. Catal. 349 (2007) 861-864. [164] A. Correa, O.C. Mancheno, C. Bolm, Chem. Soc. Rev. 37 (2008) 1108-1117. [165] Z. Li, R. Yu, H. Li, Angew. Chem. Int. Ed. 47 (2008) 7497-7500. [166] C.-X. Song, G.-X. Cai, T.R. Farrell, Z.-P. Jiang, H. Li, L.-B. Gan, Z.-J. Shi, Chem. Commun. 40 (2009) 6002-6004. [167] R. Mayilmurugan, H. Stoeckli-Evans, E. Suresh, M. Palaniandavar, Dalton Trans. (2009) 5101-5114. [168] S. Zhang, Y. Tu, C. Fan, F. Zhang, L. Shi, Angew. Chem. Int. Ed. 48 (2009) 87618765. [169] H. Richter, G.O. Mancheño, Eur. J. Org. Chem. 2010 (2010) 4460-4467. [170] N. Yoshikai, A. Mieczkowski, A. Matsumoto, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 132 (2010) 5568-5569. [171] Q. Xia, W. Chen, H. Qiu, J. Org. Chem. 76 (2011) 7577-7582. [172] B. Qian, P. Xie, Y. Xie, H. Huang, Org. Lett. 13 (2011) 2580-2583. [173] M. Sekine, L. Ilies, E. Nakamura, Org. Lett. 15 (2013) 714-717. [174] S. Verma, R. Nasir Baig, C. Han, M. Nadagouda, R. Varma, Chem. Commun .51 (2015) 15554-15557. [175] H. Wu, H. Huang, C. Ren, L. Liu, D. Wang, C. Li, Chem. Eur. J. 21 (2015) 1674416748.

296

[176] R. Shang, L. Ilies, A. Matsumoto, E. Nakamura J. Am. Chem. Soc. 135 (2013) 6030– 6032. [177] K. Graczyk, T. Haven, L. Ackermann, Chem. Eur. J. 21 (2015) 8812-8815. [178] L. Ilies, Y. Itabashi, R. Shang, E. Nakamura, ACS Catal. 7 (2017) 89–92. [179] C.A. Tolman, S.D. Ittel, A.D. English, J.P. Jesson, J. Am. Chem. Soc. 101 (1979) 1742-1751. [180] M.V. Baker, L.D. Field, J. Am. Chem. Soc. 108 (1986) 7436-7438. [181] H.F. Klein, S. Camadanli, R. Beck, D. Leukel, U. Flörke, Angew. Chem., Int. Ed. 44 (2005) 975-977. [182] S. Camadanli, R. Beck, U. Flörke, H.F. Klein, Organometallics 28 (2009) 2300-2310. [183] G. Xu, H. Sun, X. Li, Organometallics 28 (2009) 6090-6095. [184] For a recent theoretical study on iron-catalyzed C-H activation see: Y. Sun, H. Tang, K. Chen, L. Hu, J. Yao, S. Shaik, H. Chen, J. Am. Chem. Soc. 138 (2016) 3715-3730. [185] J. Norinder, A. Matsumoto, N. Yoshikai, E. Nakamura, J. Am. Chem. Soc 130 (2008) 5858-5859. [186] J. Wen, J. Zhang, S.-Y. Chen, J. Li, X.-Q. Yu, Angew. Chem. Int. Ed. 47 (2008) 88978900. [187] N. Yoshikai, A. Matsumoto, J. Norinder, E. Nakamura, Angew. Chem. Int. Ed. 48 (2009) 2925-2928. [188] W. Liu, H. Cao, A. Lei, Angew. Chem. Int. Ed 49 (2010) 2004-2008. [189] N. Yoshikai, A. Matsumoto, J. Norinder, E. Nakamura, Synlett 2 (2010) 313-316. 297

[190] N. Yoshikai, S. Asako, T. Yamakawa, L. Ilies, E. Nakamura, Chem. Asian J. 6 (2011) 3059-3065. [191] L. Ilies, S. Asako, E. Nakamura, J. Am. Chem. Soc. 133 (2011) 7672-7675. [192] L. Ilies, M. Kobayashi, A. Matsumoto, N. Yoshikai, E. Nakamura, Adv. Synth. Catal. 354 (2012) 593-596. [193] L. Ilies, E. Konno, Q. Chen, E. Nakamura, Asian J. Org. Chem. 2 (2012) 142-145. [194] Q. Gu, H.H.A. Mamari, K. Graczyk, E. Diers, L. Ackermann, Angew. Chem. Int. Ed. 53 (2014) 3868-3871. [195] J.J. Sirois, R. Davis, B. DeBoef, Org. Lett. 16 (2014) 868-871. [196] R. Shang, L. Ilies, S. Asako, E. Nakamura, J. Am. Chem. Soc. 136 (2014) 1434914352. [197] Y. Gartiaa, P. Ramidia, S. Cheerlaa, C.M. Feltona, D.E. Jonesa, B.C. Dasb, A. Ghosh, J. Mol. Catal. A: Chem. 392 (2014) 253-259. [198] J.C. Wasilke, G. Wu, X. Bu, G. Kehr, G. Erker, Organometallics 24 (2005), 4289-4297. [199] E. Salanouve, G. Bouzemame, S. Blanchard, E. Derat, M. Desage-El Murr, L. Fensterbank, Chem. Eur. J. 20 (2014) 4754–4761. [200] G. Zhang, G. Lv, C. Pan, J. Cheng, F. Chen, Synlett 20 (2011) 2991-2994. [201] Z. Shu, W. Ji, X. Wang, Y. Zhou, Y. Zhang, J. Wang, Angew. Chem. Int. Ed. 53 (2014) 2186-2189. [202] T. Hatanaka, Y. Ohki, K. Tatsumi, Chem Asian J 5 (2010), 1657-1666.

298

[203] T. Dombray, C. Gunnar Werncke, S. Jiang, M. Grellier, L. Vendier,S. Bontemps, J.B. Sortais, S. Sabo-Etienne, C. Darcel, J. Am. Chem. Soc. 137 (2015) 4062−4065. [204] J. Jiao, K. Murakami, K. Itami, ACS Catal. 6 (2016) 610−633. [205]

Y.

Park,

Y.

Kim,

S.

Chang,

Chem.

Rev.

117

(2017)

DOI:

10.1021/acs.chemrev.6b00664. [206] T. Matsubara, S. Asako, L. Ilies E. Nakamura, J. Am. Chem. Soc. 136 (2014) 646−649. [207] M. Zhang, S. Zhang, C. Pan, F. Chen, Synth. Commun. 42 (2012) 2844-2853. [208] S. Asako, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 135 (2013) 17755-17757. [209] S. Asako, J. Norinder, L. Ilies, N. Yoshikai, E. Nakamura, Adv. Synth. Catal. 356 (2014) 1481-1485. [210] B.M. Monks, E.R. Fruchey, S.P. Cook, Angew. Chem. Int. Ed. 53 (2014) 11065-11069. [211] E.R. Fruchey, B.M. Monks, S.P. Cook, J. Am. Chem. Soc. 136 (2014) 13130−13133. [212] L. Ilies, T. Matsubara, S. Ichikawa, S. Asako, E. Nakamura, J. Am. Chem. Soc. 136 (2014) 13126–13129. [213] M.Y. Wong, T. Yamakawa, N. Yoshikai, Org. Lett. 17 (2015) 442-445. [214] L. Ilies, S. Ichikawa, S. Asako, T. Matsubara, E. Nakamura, Adv. Synth. Catal. 357 (2015) 2175-2179. [215] M. Zhong, S. Sun, J. Cheng, Y. Shao, J. Org. Chem. 81 (2016) 10825-10831. [216] T. Matsubara, L. Ilies, E. Nakamura, Chem. Asian J. 11 (2016) 380–384. [217] G. Cero, T. Haven, L. Ackermann, Chem. Eur. J. 23 (2017) 3577–3582.

299

[218] W. Chen, R. Nguyen, C. Li, Tetrahedron Lett. 50 (2009) 2895-2898. [219] C.M.R. Volla, P. Vogel, Org. Lett. 11 (2009) 1701-1704. [220] G.S. Kumar, C. Kurumurthy, P.S. Rao, B. Veeraswamy, P.S. Rao, B. Narsaiah, Helv. Chim. Acta 94 (2011) 1692-1696. [221] J. Gao, Q.W. Song, L.N. He, Z.Z. Yang, X.Y. Dou, Chem. Commun. 48 (2012) 20242026. [222] C. Yao, B. Qin, H. Zhang, J. Lu, D. Wang, S. Tu, RSC Adv. 2 (2012) 3759-3764. [223] H. Do, O. Daugulis, J. Am. Chem. Soc. 133 (2011) 13577-13586. [224] B. Das, G.-C. Redy, P. Balasubramanyan, N. Salvanna, Tetrahedron 68 (2012) 300305. [225] Y. Ji, T. Brueckl, R.D. Baxter, Y. Fujiwara, I.B. Seiple, S. Su, D.G. Blackmond, P.S. Baran, Proc. Natl. Acad. Sci. U.S.A. 108 (2011) 14411-14415. [226] S. Zhu, X. Xu, F. Qing, Org. Chem. Front. 2 (2015) 1022-1025. [227] B.M. Trost, M. Osipov, Chem. Eur. J. 21 (2015) 16318-16343. [228] N. Willis, C. Fisher, C. Alder, A. Harsanyi, L. Shukla, J. Adams, G. Sandford, Green Chem. 18 (2016) 1313-1318. [229] W. Chung, C. Vanderwal, Angew. Chem. Int. Ed. 55 (2016) 4396-4434. [230] L. Chu, F.-L. Qing, J. Am. Chem. Soc. 134 (2012) 1298-1304. [231] M. Shang, S.-Z. Sun, H.-L. Wang, B.N. Laforteza, H.-X. Dai, J.-Q. Yu, Angew. Chem. 126 (2014) 10607-10610.

300

[232] C. Zhu, Y. Zhang, Y. Yuan, H. Xu, Synlett 26 (2015) 345-349. [233] M.-C Belhomme, D. Dru, H.-Y Xiong, D. Cahard, T. Besset, T. Poisson, X. Pannecoucke, Synthesis 46 (2014) 1859-1870. [234] G. Rong, J. Mao, Y. Zheng, R. Yao, X. Xu, Chem. Commun. 51 (2015) 13822-13825. [235] W. Li, C.-M. Schneider, G.-I. Georg, Org. Lett.17 (2015) 3902-3905. [236] C. Kanazawa, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc. 128 (2006) 10662-10663.]. [237] L. Wang, H. Huang, D.-L. Priebbenow, F.-F. Pan, C. Bolm, Angew. Chem. Int. Ed. 52 (2013) 3478-3480. [238] T. Hamada, X. Ye, S.S. Stahl, J. Am. Chem. Soc. 130 (2008) 833-835. [239] A. Laouti, M.M. Rammah, M.B. Rammah, J. Marrot, F. Couty, G. Evano, Org. Lett. 14 (2002) 6-9. [240] X. Pan, Y. Luo, J. Wu, J. Org. Chem. 78 (2013) 5756-5760. [241] D.C. Mohan, R.R.Donthiri, S.N. Rao, S. Adimurthy, Adv. Synth. Catal. 355 (2013) 2217-2221. [242] D.C. Mohan, S.N. Rao, C. Ravi, S. Adimurthy, Asian J. Org. Chem. 3 (2014) 609-613. [243] K. Morinoto, M. Itoh, K. Hirano, T. Satoh, Y. Shibata, K. Tanaka, M. Miura, Angew. Chem. 124 (2012) 5455-5458. [244] R. Morioka, K. Hirano, T. Satoh, M. Miura. Chem. Eur. J. 20 (2014) 12720-12724. [245] C. Cai, J. Gu, Synlett 26 (2015) 639-642.

301

[246] B.-Q. Hu, L.-X. Wang, G. Shen, Y.-L. Tang, L.Yang, RSC Adv. 5 (2015) 100097100101. [247] H. Yu, A. Dannenberg, Z. Li, C. Bolm, Chem. Asian J. 11 (2016) 54-57. [248] Z. Huang, Y. Bian, C. Xiang, Z. Chen, Synlett 16 (2011) 2407-2409. [249] A. Khemnar, B. Bhanage, Org. Biomol. Chem. 12 (2014) 9631-9637. [250] S. Zhao, F. Chen, B. Liu, B. Shi, Sci. China Chem. 58 (2015) 1302-1309. [251] S. Rout, S. Guin, A. Gogoi, G. Majji, B. Patel, Org. Lett. 16 (2014) 1614-1617. [252] N. Khatun, A. Banerjee, S. Santra, W. Ali, B. Patel, RSC Adv. 5 (2015) 36461-36466. [253] A. Behera, S.K. Rout, S. Guin, B.K. Patel, RSC Adv. 4 (2014) 55115-55118. [254] B. Bhanage, S. Yedage, Synlett 26 (2015) 2161-2169. [255] B.K. Singh, R. Jana, J. Org. Chem. 81 (2016) 831-834. [256] M. Wang, Y. Hu, Z. Jiang, H.C. Shen, X. Sun, Org. Biomol. Chem. 14 (2016) 42394246. [257] I. Beletskaya, V. Afanasiev, M. Kazankova, I. Efimova, M. Antipin, Synthesis 18 (2003) 2835-2838. [258] G. Kumaraswamy, G.V. Rao, A.N. Murthy, B. Sridhar, Synlett 7 (2009) 1180-1184. [259] S. Wang, W. Liu, Z. Cai, S. Li, J. Liu, A. Wang, Synlett 27 (2016) 2264-2268. [260] J. Liu, Z. Xue, Z. Zeng, Y. Chen, G. Chen, Adv. Synth. Catal. 358 (2016) 3694-3699. [261] A. Chabrier, A. Bruneau, S. Benmahdjoub, B. Benmerad, S. Belaid, J.D. Brion, M. Alami, S. Messaoudi, Chem. Eur. J. 22 (2016) 15006-15010. 302

[262] B. Movassagh, A. Yousefi, B.Z. Momeni, S. Heydari, Synlett 25 (2014) 1385-1390. [263] Q. Lefebvre, R. Pluta, M. Rueping, Chem. Commun. 51 (2015) 4394-4397. [264] G. Cera, L. Ackermann, Chem. Eur. J. 22 (2016) 8475-8478. [265] A.C. Correia, C.J. Li, Adv. Synth. Catal. 352 (2010) 1446-1450. [266] T. Xiong, Y. Li, X. Bi, Y. Lv, Q. Zhang, Angew. Chem., Int. Ed. 50 (2011) 7140-7143. [267] S. Bhadra, C. Matheis, D. Katayev, L.J. Gooßen, Angew. Chem. 125 (2013) 94499453. [268] X. Wang, Z. Wang, Tetrahedron 70 (2014) 6728-6732. [269] G. Li, C. Jia, Q. Chen, K. Sun, F. Zhao, H. Wu, Z. Wang, Y. Lv, X. Chen, Adv. Synth. Catal. 357 (2015) 1311-1313. [270] Z. Xie, X. Liu, L. Liu, Org. Lett. 18 (2016) 2982-2985. [271] T. Li, X. Qu, G. Xie, J. Mao, Chem. Asian J. 6 (2011) 1325-1330. [272] J. Petrignet, S.I. Ngi, M. Abarbri, J. Thibonnet, Tetrahedron Lett. 55 (2014) 982-984. [273] W. Xu, B. Yu, H. Sun, G. Zhang, W. Zhang, Z. Gao, Appl. Organometal. Chem. 29 (2015) 353-356. [274] J. Moegling, A.D. Benischke, J.M. Hammann, N.A. Veprek, F. Zoller, B. Rendenbach, A. Hoffmann, H. Sievers, M. Schuster, P. Knochel, S. Herres-Pawlis, Eur. J. Org. Chem. 2015 (2015) 7475-7483. [275] G. Cheng, H. Zhang, X. Cui, RSC Adv. 4 (2014) 1849-1852.

303

[276] W.-B. Sheng, T.-Q. Chen, M.-Z. Zhang, M. Tian, G.-F. Jiang, C.-C Guo, Tetrahedron Lett. 57 (2016) 1641-1643. [277] L.-J. Zhang, Y.-H. Wang, J. Liu, M.-C. Xu, X.-M. Zhang, RSC Adv. 6 (2016) 2865328657. [278] D. Yu, Y. Zhang, Proc. Natl. Acad. Sci. U.S.A. 107 (2010) 20184-20189. [279] J.-N. Xie, B. Yu, Z.-H. Zhou, H.-C. Fu, N. Wang, L.-N. He, Tetrahedron Lett. 56 (2015) 7059-7062. [280] B. Yu, J.N. Xie, C.L. Zhong, W. Li, L.N. He, ACS Catal. 5 (2015) 3940-3944. [281] B. Yu, Z.F. Diao, C.X. Guo, C.L. Zhong, L.N. He, Y.N. Zhao, Q.W. Song, A.H. Liu, J.Q. Wang, Green Chem. 15 (2013) 2401-2407. [282] S.-I. Ngi, V. Guilloteau, M. Abarbri, J. Thibonnet, J. Org. Chem. 76 (2011) 8347-8354. [283] M.L. Hossain, F. Ye, Y. Zhang, J. Wang, Tetrahedron 70 (2014) 6957-6962. [284] M.S. Rao, M. Haritha, N. Chandrasekhar, M.V.B. Rao, M. Pal, Tetrahedron Lett. 55 (2014) 1660-1663. [285] L. Zhao, G. Huang, B. Guo, L. Xu, J. Chen, W. Cao, G. Zhao, X. Wu, Org. Lett. 16 (2014) 5584-5587. [286] Z. Zhang, Q. Zhou, W. Yu, T. Li, G. Wu, Y. Zhang, J. Wang, Org. Lett. 17 (2015) 2474-2477. [287] N. Gommermann, C. Koradin, K. Polborn, P. Knochel, Angew. Chem. Int. Ed. 42 (2003) 5763-5766. [288] D. Yu, Y. Zhang, Adv. Synth. Catal. 353 (2011) 163-169. 304

[289] I. Yavari, S. Ahmadian, M. Ghazanfarpur-Darjani, Y. Solgi, Tetrahedron Lett. 52 (2011) 668-670. [290] E. Schreiner, S. Braun, C. Kwasnitschka, W. Franl, T. J. J. Müller, Adv. Synth. Catal. 356 (2014) 3135-3147. [291] J.-N. Xie, B. Yu, C.-X. Guo, L.-N. He, Green Chem. 17 (2015) 4061-4067. [292] A. Sagadevan, A. Ragupathi, K.C. Hwang, Angew. Chem. Int. Ed. 54 (2015) 1389613901. [293] M.I.D. Mardjan, J.L. Parrain, L. Commeiras, Adv. Synth. Catal 358. (2016) 543-548. [294] M. Selvaraju, T.Y. Ye, C.H. Li, P.H. Hoa, C.M. Sun, Chem. Commun. 52 (2016) 66216624. [295] Y. Cai, X. Tang, S. Ma, Chem. Eur. J. 22 (2016) 2266-2269. [296] H.-Q Do, O. Daugulis, J. Am. Chem. Soc. 129 (2007), 12404-12405. [297] H.-Q. Do, R.M. K. Khan, O. Daugulis J. Am. Chem. Soc. 130 (2008) 15185-15192. [298] M. Lesieur, F. Lazreg, C.S. Cazin, Chem. Commun. 50 (2014) 8927-8929. [299] F. Yang, J. Koeller, L. Ackermann, Angew. Chem. 128 (2016) 4837-4840. [300] Q. Gui, X. Chen, L. Hu, D. Wang, J. Liu, Z. Tan, Adv. Synth. Catal. 358 (2016) 509514. [301] M. Harari, F. Couly, C. Fruit, T. Besson, Org. Lett. 18 (2016) 3282-3285. [302] S. Teong, D. Yu, Y. Sum, Y. Zhang, Green Chem. 18 (2016) 3499-3502. [303] F. Peng, Z. Shao, A. Chan, Tetrahedron: Asymmetry 21 (2010) 465-468.

305

[304] J. Wang, Z. Shao, K. Yu, A. Chan, Adv. Synth. Catal. 351 (2009) 1250-1254. [305] P. Maity, H.D. Srinivas, M.P. Watson, J. Am. Chem. Soc. 133 (2011) 17142-17045. [306] D. Das, A. Sun, D. Seidel, Angew. Chem. 125 (2013) 3853-3857. [307] N. Rajesh, D. Prajapati, Org. Biomol. Chem. 13 (2015) 4668-4672. [308] Z. Xu, F. Ni, J. Han, L. Tao, H. Deng, M. Shao, J. Chen, H. Zhang, W. Cao, Eur. J. Org. Chem. 2016 (2016) 2959-2965. [309] Y. Makida, Y. Takayama, H. Ohmiya, M. Sawamura, Angew. Chem. Int. Ed. 52 (2013) 5350-5354. [310] A. Harada, Y. Makida, T. Sato, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 136 (2014) 13932-13939. [311] S. Dasgupta, T. Rivas, M. Watson, Angew. Chem. Int. Ed. 54 (2015) 14154-14158. [312] M. Pappoppula, F. Cardoso, B. Garrett, A. Aponick, Angew. Chem. Int. Ed. 54 (2015) 15202-15206. [313] Ł. Woźniak, O. Staszewska-Krajewska, M. Michalak, Chem. Commun. 51 (2015) 1933-1936. [314] V. Nair, M. Chouhan, K. Senwar, K. Kumar, R. Sharma, Synthesis 46 (2014) 195-202. [315] A. Kumar, M. Kumar, L. Gupta, M. Gupta, RSC Advances 4 (2014) 9412-9415. [316] Q. Chen, Y. Tang, T. Huang, X. Liu, L. Lin, X. Feng, Angew. Chem. Int. Ed. 55 (2016) 5286-5289. [317] N. Xu, D. Gu, J. Zi, X. Wu, X. Guo, Org. Lett. 18 (2016) 2439-2442.

306

[318] P. Czerwiński, E. Molga, L. Cavallo, A. Poater, M. Michalak, Chem. Eur. J. 22 (2016) 8089-8094. [319] Q. Xiao, Y. Xia, H. Li, Y. Zhang, J. Wang, Angew. Chem. Int. Ed. 50 (2011) 11141117. [320] A. Suárez, G.C. Fu, Angew. Chem. Int. Ed. 43 (2004) 3580-3582. [321] J. Kuang, H.Luo, S. Ma, Adv. Synth. Catal. 354 (2012) 933-944. [322] F. Hu, Y. Xia, C. Ma, Y. Zhang, J. Wang, Org. Lett. 16 (2014) 4082-4085. [323] M.L. Hossain, F. Ye, Z. Liu, Y. Xia, Y. Shi, L. Zhou, Y. Zhang, J. Wang, J. Org. Chem. 79 (2014) 8689-8699. [324] D. Vachhani, A. Sharma, E. Van der Eycken, Angew. Chem. Int. Ed. 52 (2013) 25472550. [325] S. Xu, G. Wu, F. Ye, X. Wang, H. Li, X. Zhao, Y. Zhang, J. Wang, Angew. Chem. Int. Ed. 54 (2015) 4669-4672. [326] A. Biswas, U. Karmakar, A. Pal, R. Samanta, Chem. Eur. J. 22 (2016) 13826–13830. [327] T. Yao, K. Hirano, T. Satoh, M. Miura, Angew. Chem., Int. Ed. 50 (2011) 2990-2994. [328] Y. Makida, H. Ohmiya, M. Sawamura, Angew. Chem., Int. Ed. 151 (2012) 4122-4127. [329] L.D. Tran, J. Roane, O. Daugulis, Angew. Chem. 125 (2013) 6159-6162. [330] J. Roane O. Daugulis, J. Am. Chem. Soc. 138 (2016) 4601-4607. [331] B.K. Singh, A. Polley, R. Jana, J. Org. Chem 81 (2016) pp 4295-4303. [332] J. Huang, C. Wan, M.-F. Xu, Q. Zhu, Eur. J. Org. Chem. 10 (2013) 1876-1880.

307

[333] C. Yamamoto, K. Takamatsu, K. Hirano, M. Miura, J. Org. Chem. 81 (2016) 76757684. [334] A. Banerjee, P. Subramanian, K. Kaliappan, J. Org. Chem. 81 (2016) 10424-10432. [335] R.T. Gephart, T.H. Warren, Organometallics 31 (2012) 7728-7752. [336] Y.M. Badiei, A. Dinescu, X. Dai, R.M. Palomino, F.W. Heinemann, T.R. Cundari, T.H. Warren, Angew. Chem., Int. Ed. 47 (2008) 9961-9964. [337] S. Wiese, Y.M. Badiei, R.T. Gephart, S. Mossin, M.S. Varonka, M.M. Melzer, M. Meyer, T.R. Cundari, T.H. Warren, Angew. Chem., Int. Ed. 49 (2010) 8850-8855. [338] R.T. Gephart, D.L. Huang, M.J.B. Aguila, G. Schmidt, A. Shahu, T.H. Warren, Angew. Chem., Int. Ed. 51 (2012) 6488-6492. [339] M.J.B. Aguila, Y.M. Badiei, T.H. Warren, J. Am. Chem. Soc. 135 (2013) 9399-9406. [340] E.S. Jang, C.L. McMullin, M. Käß, K. Meyer, T.R. Cundari, T.H. Warren, J. Am. Chem. Soc. 136 (2014) 10930-10940. [341] R.T. Gephart, C.L. McMullin, N.G. Sapiezynski, E.S. Jang, M.J.B. Aguila, T.R. Cundari, T.H. Warren, J. Am. Chem. Soc. 134 (2012) 17350-17353. [342] T.K. Salvador, C.H. Arnett, S. Kundu, N.G. Sapiezynski, J.A. Bertke, M. Raghibi Boroujeni, T.H. Warren, J. Am. Chem. Soc. 138 (2016) 16580-16583. [343] S. Nawratil, M. Grypioti, C. Menendez, S. Mallet-Ladeira, C. Lherbet, M. Baltas, Eur. J. Org. Chem. 2014 (2014) 654-659. [344] J. Zhu, Y. Kong, F. Lin, B. Wang, Z. Chen, L. Liu, Eur. J. Org. Chem. 2015 (2015) 1507-1515.

308

[345] D.E. Frantz, R. Fässler, E.M. Carreira, J. Am. Chem. Soc. 121 (1999) 11245-11246. [346] N.K. Anand, E.M. Carreira, J. Am. Chem. Soc. 123 (2001) 9687-9688. [347] S. Reber, T.F. Knöpfel, E.M. Carreira, Tetrahedron 59 (2003) 6813-6817. [348] C.W. Downey, B.D. Mahoney, V.R. Lipari, J. Org. Chem. 74 (2009) 2904-2906. [349] R. Fässler, D.E. Frantz, J. Oetier, E.M. Carreira, Angew. Chem., Int. Ed. 41 (2002) 3054-3056. [350] S. Pinet, S.U. Pandya, P.Y. Chavant, A. Ayling, Y. Vallée, Org. Lett. 4 (2002) 14631466. [351] S.K. Patel, S. Py, S.U. Pandya, P.Y. Chavant, Y. Vallée, Tetrahedron: Asymmetry 14 (2003) 525-528. [352] N. Chinkov, A. Warm, E.M. Carreira, Angew. Chem. Int. Ed. 50 (2011) 2957-2961. [353] B. Jiang, Z. Chen, X. Tang, Org. Lett. 4 (2002) 3451-3453. [354] T.F. Knöpfel, D. Boyall, E.M. Carreira, Org. Lett. 6 (2004) 2281-2283. [355] E. Ramu, R. Varala, N. Sreelatha, S.R. Adapa, Tetrahedron Lett. 48 (2007) 7184-7190. [356] J. Kuang, S. Ma, J. Am. Chem. Soc. 132 (2010) 1786-1787. [357] M. Periasamy, P.O. Reddy, A. Edukondalu, M. Dalai, L. Alakonda, B. Udaykumar, Eur. J. Org. Chem. 2014 (2014) 6067-6076. [358] P.B. Sarode, S.P. Bahekar, H.S. Chandak, Synlett 27 (2016) 2209-2212. [359] P.B. Sarode, S.P. Bahekar, H.S. Chandak, Tetrahedron Lett. 57 (2016) 5753-5756. [360] I. Suzuki, M. Yasuda, A. Baba, Chem. Commun. 49 (2013) 11620-11622. 309

[361] S. Murarka, A. Studer, Org. Lett. 13 (2011) 2746-2749. [362] T. Sugiishi, H. Nakamura, J. Am. Chem. Soc. 134 (2012) 2504-2507. [363] S. Tang, L. Zeng, Y. Liu, A. Lei, Angew. Chem. Int. Ed. 54 (2015) 15850-15853. [364] G. Li, H. Nakamura, Angew. Chem. Int. Ed. 55 (2016) 6758-6761. [365] R.J. Rahaim, J.T. Shaw, J. Org. Chem. 73 (2008) 2912-2915. [366] K. Kiyokawa, N. Tachikake, M. Yasuda, A. Baba, Angew. Chem. Int. Ed. 50 (2011) 10393-10396. [367] E. Negishi, L. Anastasia, Chem. Rev. 103 (2003) 1979-2017. [368] M. Costas, Coord. Chem. Rev. 255 (2011) 2912-2932. [369] S.M. Paradine, J.R. Griffin, J. Zhao, A.L. Petronico, S.M. Miller, M.C. White, Nat. Chem. 7 (2015) 987-994.

310

The C-H functionalization activity of catalytic systems based on Mg, Ca, Mn, Fe, Cu, and Zn is reviewed.

These catalytic systems are in general not-toxic, abundant, and inexpensive.

C-H activation is highly useful in the synthesis of fine chemicals, natural products, and advanced materials.

Mechanisms of action, strengths, and limitations are thoroughly discussed.

311

312