- Email: [email protected]
Metal-catalyzed C–H bond functionalization of phenol derivatives
Journal Pre-proof Metal-catalyzed C–H bond functionalization of phenol derivatives Hamad H. Al Mamari, Bogdan Štefane, Helena Brodnik Žugelj PII:
S0040-4020(20)30005-3
DOI:
https://doi.org/10.1016/j.tet.2020.130925
Reference:
TET 130925
To appear in:
Tetrahedron
Received Date: 23 August 2019 Revised Date:
31 December 2019
Accepted Date: 5 January 2020
Please cite this article as: Al Mamari HH, Štefane B, Žugelj HB, Metal-catalyzed C–H bond functionalization of phenol derivatives, Tetrahedron (2020), doi: https://doi.org/10.1016/ j.tet.2020.130925. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Published by Elsevier Ltd.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Metal-Catalyzed C–H Bond Functionalization of Phenol Derivatives
Leave this area blank for abstract info.
Hamad H. Al Mamaria,*, Bogdan Štefaneb, and Helena Brodnik Žugeljb a Department of Chemistry, College of Science, Sultan Qaboos University, PO Box 36, Al Khoudh 123, Muscat, Sultanate of Oman. b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI 1001, Ljubljana, Slovenia.
1
Tetrahedron journal homepage: www.elsevier.com
Metal-Catalyzed C–H Bond Functionalization of Phenol Derivatives 0 1 2 3 4 5
Hamad H. Al Mamaria,*, Bogdan Štefaneb, and Helena Brodnik Žugeljb a
Department of Chemistry, College of Science, Sultan Qaboos University, PO Box 36, Al Khoudh 123, Muscat, Sultanate of Oman
b
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI 1001, Ljubljana, Slovenia.
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Phenols and phenol derivatives constitute important starting materials, synthetic intermediates, and functional moieties of a broad range of chemicals and materials. They represent large production products of benzene and benzene derivative oxidation and are nowadays progressively available from biomass sources. In last decades or so, there have been tremendous advances in the field of catalytic C–H bond functionalization, among which metal-catalyzed C– H bond functionalization of phenol derivatives plays a substantial role. In this review, the latest transition metal catalyzed C–H bond functionalizations of phenol derivatives are summarized. These methods are powerful tools for the arylation, alkenylation, and acylation as well as annulation of phenol derivatives, especially as they can be carried out in a highly stepeconomical manner with readily available starting materials based on simple aryl (pseudo)halides, alkenes as reagents. Additionally, this review summarizes the main mechanistic aspects of the covered topic.
Keywords: Phenol Derivatives C–H Bond Functionalization Chelation-Assistance Transition Metals Monodentate Directing Groups Bidentate Directing Groups
2009 Elsevier Ltd. All rights reserved.
Contents: 1. 2.
Introduction Pd-Catalyzed C–H Bond Functionalization 3. Rh-Catalyzed C–H Bond Functionalization 4. Ru-Catalyzed C–H Bond Functionalization 5. Ir-Catalyzed C–H Bond Functionalization 6. Au-Catalyzed C–H Bond Functionalization 7. Fe-Catalyzed C–H Bond Functionalization 8. Conclusion 9. References ___________________________ * Corresponding author, Tel: +96824142471, Fax: +96824141469, Email: [email protected]
2
Tetrahedron 1. Introduction
Phenol-based molecules are ubiquitous in nature. Although phenol itself is toxic and corrosive, it shows antiseptic effects and is used as a disinfectant. Derivatives of phenol manifest themselves in a broad range of natural products, materials, and pharmaceuticals. [1] For example, gallic and ferulic acid are frequently occurring natural phenol derivatives found in plant cells, phenol-based natural opiate morphine is commonly used for the treatment of pain, whereas dopamine functions as an important hormone and neurotransmitter in the brain and body (Scheme 1A). A consequence of phenols being naturally abundant, the interest of using phenolic building blocks in materials science has also emerged, showing successful results in the development of biopolymers [2a], polyphenylene oxides (PPOs) [2b], and phenol-based resins (Scheme 1B). [2c] A) Naturally-occuring phenol derivatives O
OH
OH
C-H DG Functionalization
R
O
R
OH HO
major issue in the science of C–H bond functionalization. Over the past two decades, scientists have addressed the site-selectivity issue of C–H bond functionalization. One way to provide control of the issue is to use an electron donor atom or a Lewis basic atom (monodentate directing groups) that can coordinate the Lewis acidic transition metal typically used in C–H bond functionalization. [4] Coordination of the metal by the Lewis basic atom brings the metal in proximity to a certain C–H bond. A certain C–H bond appropriately located and distanced from the Lewis basic atom can be cleaved to promote formation of a fivemembered thermodynamically chelate or cyclometalated complex (Scheme 2). [5] Therefore, it is the formation of such stable five-membered chelates that is the driving force or an incentive for C–H bond cleavage at a certain carbon site, controlled by its carbon distance from the Lewis basic atom in the monodentate directing group.
H
M FG
R
R
DG
Ferulic acid
FG M
DG = directing group M = transition metal FG = functional group
HO Phenol
NH2 HO
NCH3
Based on the efficient concept of monodentate directing groups, bidentate directing groups have been developed. [6-8] The chelation-assisting group contains two Lewis basic atoms appropriately distanced from each other as well from the reacting substrate. The inception of the bidentate chelation assistance is driven by the formation of a thermodynamically stable bis-fivemembered chelate (Scheme 3). [5] With two five-membered chelates fused together, the bis-chelate is conformationally rigid.
OH
Morphine
Dopamine
B) Phenol-based materials H N
OH Me N H
HO HO
OH NH
H N
O
Me
Me
O
R
Me
n
polyphenylene oxide (PPO)
HO HO
DG M FG R Five-membered chelate
Scheme 2. Chelation-assistance by monodentate directing groups in C–H bond functionalization.
H
HO
HO
M FG
cyclometalation
OCH3 OH
DG H
DG = N, P, O, S, As coordination
R
H
R
HO
OH Gallic acid
O
R
R
D G H
C-H Functionalization
R
M FG coordination
R
DG
DG = N, P, O, S, As
Scheme 1. Examples of phenols in nature and materials science.
With developments made in organic synthesis, accessing phenol derivatives can be achieved in many ways. Recently, carbon– hydrogen (C–H) bond functionalization has emerged as a powerful strategy for the formation of carbon–carbon (C–C) or carbon–heteroatom (C–Het) bonds. [3] The chemical science allows transformation of otherwise inert nonfunctional C–H bonds into functional reactive counterparts. Consequently, C–H bond functionalization provides and offers new gateways to functional chemicals, molecules, and materials of various applications and interests in chemical, biochemical, biological, pharmaceutical, petrochemical, medicinal, agricultural, materials sciences, and industries. Due to its rapid and direct transformation approach, C–H bond functionalization reduces steps, chemicals, materials, solvents, energy, and time. Thus, it is a step- and atom-economical chemical science. As a result, C–H functionalization it could in some cases meet the definition of a green and environmentally benign synthetic approach. Hydrocarbons contain several types of inert C–H bonds of various electronic and steric bulk. Selective C–H bond functionalization of a certain type imposes a significant challenge. [3,4] Thus, regioselectivity or site-selectivity is a
DG
M FG
OH
An example of a substructure of a biopolymer
D G H
cyclometalation R R
D G FG
R DG
D G
DG M FG Double five-membered chelate R
Scheme 3. Chelation-assistance by bidentate directing groups in C–H bond functionalization.
The additional rigidity of such bis-chelates in bidentate directing groups, has resulted in developing new C–H bond functionalization reactions, non-realized before with monodentate directing groups. Bidentate directing groups in some cases proved to be beneficial than the monodentate counterparts in metal-catalyzed C–H bond functionalization. There have numerous reviews in the field of the C-H activation science, whether in monodentate directing group-assisted C–H functionalization or in the use of bidentate directing groups. [4-7] C–H bond functionalization can be catalyzed by various metals such as frequently used second row transition metals (Pd, Ru, and Rh) and less by cheaper, earth abundant, environmentally benign first row transition metals (Mn, Fe, Co, Ni and Cu). [4-7] To the best of our knowledge, there has been no reviews reported on the development of transition-metal catalyzed C–H bond functionalization of phenol derivatives apart from the recently published review by Lumb on phenol-directed C–H
3 functionalization, [9] which describes methodologies addressing phenol-directed transformations. Thus, the present review demonstrates a selection of relevant results and developments made in metal-catalyzed C–H bond functionalization of phenol derivatives. Specifically, developments and advances in C–H bond functionalization of phenol derivative A to provide the C–H functionalized product B (Scheme 4). OR
electron-deficient substrates (4c; 49%). As expected, sterically hindered bromophenol 3f was less efficient under the established reaction conditions. After the successful Pd-catalyzed intramolecular arylation, deprotection of the silicon tether on products 4 was performed using a standard TBAF procedure yielding the final unprotected phenols in excellent yields.
H
tBu Si Ph
O
OR FG
C-H Functionalization
Br PivOH, Cs2CO3 3Å MS, p-xylene, 140 oC
R
R
R
A
tBu O Si Ph
Pd(OAc)2 (5 mol%) PCy3*HBF4 (10 mol%)
3
R 4
B
Scheme 4. Schematic representation of C–H bond functionalization of phenol derivatives.
tBu O Si Ph
tBu O Si Ph
tBu O Si Ph
O2N
tBu O Si Ph
R2
F
2. Pd-Catalyzed C–H Bond Functionalization A mild, selective procedure for Pd-catalyzed intramolecular coupling of phenol with aryl halides is reported to proceed efficiently (Scheme 5). [10] Unlike Pd(OAc)2, Pd2(dba)3, or PdCl2, a well-defined palladacycle A, also known as Herrmann’s catalyst, is formed from Pd(OAc)2 and P(o-tolyl)3 and is crucial for the reaction to proceed with high conversion. The choice of base was also found to be essential for the Pd-catalyzed intramolecular cyclization of aryl halides 1 to the cyclized product 2, supporting the hypothesis that the reaction is accelerated through the phenolate anion as the nucleophile. Furthermore, when a hydroxyl group is attached to the aryl unit, then the nature of the phenolate furnishes the aryl ring as more electron-rich, consequently making it more reactive for the coupling reaction. The reaction was found to be of good scope. When the ortho position is blocked, then the substrate is forced to cyclize at the para position into product 2c. The cyclization reaction of the naphthyl substrate 2b required longer time, although cyclized in an overall excellent 96% yield to afford a mixture of the ortho and para products 2b in a ratio of 1:2. Deoxygenated aryl halide 1d was also reactive and provided the corresponding product 2d in a decent 75% yield, although higher reaction temperature was required. Moreover, the reaction gave good results in the presence of a protected nitrogen atom to provide a N-containing product 2e in a 76% yield.
R1
R1 4a; R1=H, 73% 4b; R1=OMe, 78%
A practical and mild Pd(II)-catalyzed ortho C–H arylation protocol for phenol esters using Ph2IOTf as the aryl pseudohalide was published by Liu et al. [12] With the discovery of crystalline complex A (confirmed by X-ray analysis), it is the first example of an acyloxy-directed Pd insertion into a C–H bond. The result indicates that the presence of HOTf may influence the electrophilicity of Pd(II) to improve such metal-catalyzed reactions. Further studies indicated, that HOAc is also relevant either for the C–H deprotonation step or for the stabilization of some active palladium intermediates. The reaction showed good substrate scope giving arylated pivalate esters 6 in good to excellent yields. Notably, halo substituents (7e–h) were well tolerated, making it possible for further modifications on the halogenated positions (Scheme 7). The selectivity of the reaction (mono- vs. diarylation) could be controlled by varying the temperature (from r.t. to 60 ºC) and the ratio of the reactants (7i and 7i’). OPiv
1
OH
O
Cs2CO3 (3 equiv.) DMA, 95-115 oC
O 2
OH
HO
O
O
OH
Ar Ar P O Pd O
Me
O Pd O P Ar Ar Me palladacycle A
N CO2Me
Me 2c; 84%
HO 2b; (1:2) 96%
2d; 75%
2e; 76%
Scheme 5. Pd-catalyzed intramolecular coupling of phenol with aryl halides.
In 2009, Gevorgyan and co-workers reported a Pd-catalyzed intramolecular C–H bond arylation of TBS-protected obromophenols. [11] The reaction features the use of an easily introducible and removable silicon tether, tert-butyldiphenylsilyl (TBDPS) protecting group, as the aryl coupling source. Accordingly, they examined the palladium-catalyzed intramolecular arylation reaction on a set of chosen TBDPSprotected o-bromophenols 3 (Scheme 6). The reaction scope showed some extent of variability as the yields proved to be higher with electron-rich arenes (4b; 78%) in comparison to
R1
OPiv tBu
25 ºC, 7i; 55% and 7i’; 14% 60 ºC, 7i; 10% and 7i’; 63%
Ph
p-Tol O
+ tBu
OPiv
7g; R1=Br, 82% 7h; R1=Cl, 94%
Ph OH
Ph 7
Me
7c; R1=OMe, 75% 7d; R1=Ph, 95% 7e; R1=Br, 88% 7f; R1=I, 24%
Ph
O
OPiv Ph
Ph 7a; 92% 7b; R1=Ph, 86%
OH
O 2a; 84%
R1
R1=Me,
+ HO
R
HOTf (10 mol%), Ph2IOTf (1.2 equiv.) Ac2O (0.5 equiv.), DCE, 25-60 oC, 3-48 h
6
OPiv
palladacycle A (5 mol%)
X= Br, I
OPiv
Pd(OAc)2 (10 mol%)
R
R1
X
4e; R1=CHO, R2=MeO, 52% 4f; R1=R2=tBu, 30%
Scheme 6. Intramolecular C–H bond arylation of TBS-protected obromophenols.
OH
OH
4d; 51%
4c; 49%
OTf O H Pd O H OH2
Ph Me
complex A
Scheme 7. C–H arylation protocol of phenol esters using Ph2+IOTf– as the aryl pseudohalide.
In 2010, Dong and co-workers reported a remarkable and very detailed study on Pd-catalyzed ortho-arylation of ophenylcarbamates with simple arenes using sodium persulfate (Na2S2O8) as the oxidant of choice to produce o-arylphenol derivatives (Scheme 8). [13] The reaction features employing simple and inexpensive arenes as reaction partners rather than pre-functionalized aryl iodides or hypervalent iodine reagents. Moreover, as a side product, only one equivalent of H2 is released. Optimization of the reaction conditions showed that both TFA and sodium persulfate were needed for achieving high conversion for the oxidative coupling reaction to occur. Previous studies have proposed that acetate anions can facilitate the intramolecular transfer of protons in the formation of a six-
4
Tetrahedron
membered transition state. In addition, TFA was found to enhance the electrophilicity of Pd(II), assisting the electrophilic metalation step. [13] Furthermore, the strong oxidant (Na2S2O8) is needed to reoxidize Pd(0) to Pd(II) in the catalytic cycle, as the authors propose a mechanism involving two discrete C–H bond activations via Pd(0)/II catalysis. The reaction methodology showed great scope with various functional group tolerance. Thus, different substitutions on the masked phenol such as 9a, 9c, and 9d were produced in 80%, 73%, and 75% yields respectively. Replacing the Cl with F on the arene was also possible as products 9h, 9i and 9j were produced in 79%, 82%, and 87% yields. The aryl coupling partners with present electrondonating functionalities yielded the corresponding products under the given reaction conditions in moderate to good yields (9k; 76% and 9l; 47%) (Scheme 8). O R
NMe2 (ca. 40 equiv.)
8 R1 R2
TFA (5 equiv.), Na2S2O8 (3 equiv.) 70 oC, 30-68 h R1
OCONMe2
R
Cl 9a; R1=Me, R2=H, 80% 9b; R1=iPr, R2=H, 55% 9c; R1=Ph, R2=H, 73% 9d; R1=R2=Me, 75% 9e; R1=H, R2=Me, 85% 9f; R1=H, R2=Cl, 76% 9g; R1=H, R2=F, 84%
R1 R1
F
9k; R1Me, 76% 9l; R1=OMe, 47%
9h; R1=Me, 79% 9i; R1=tBu, 82% 9j; R1=Ph, 87%
R2 Pd(OAc)2 or PdCl2 (5 mol%)
R3
+ OH
Cs2CO3 (1.2 or 4 equiv.), 4Å MS, DMF, 100 oC, 7-44 h
R3
OH
R3
(1.2 or 4 equiv.) 10
12
11 R1
R1
R2
R2
R3 OH
R3
OH
R3
12a’; R1=R2=R3=H, 56% 12b’; R1=Me, R2=H, R3=H, 63% 12e’; R1=H, R2=H, R3=OMe, 57%
12a; R1=R2=R3=H, 63% 12b; R1=Me, R2=H, R3=H, 60% 12c; R1=H, R2=OMe, R3=H, 73% 12d; R1=H, R2=NO2, R3=H, 72% 12e; R1=H, R2=H, R3=OMe, 70%
Scheme 10. Mono and diarylation of 2-phenylphenols with aryl iodides.
OCONMe2
F
R1
I
R2
O
9
MeO
OCONMe2
Cl
Ar
R1
NMe2
O
Pd(OAc)2 (10 mol%)
ArH
+
O
were formed as major products deriving 12a’, 12b’, and 12c’ in 56%, 63%, and 57% yields, respectively.
Scheme 8. ortho-Arylation of o-phenylcarbamates with simple arenes using sodium persulfate.
Mechanistic studies support a distinct mechanistic proposal shown in Scheme 9. The oxidative cross-coupling occurs via a Pd(0/II) catalytic cycle involving a C–H bond activation by carbamate-assisted cyclopalladation to afford complex A, followed by a C–H functionalization reaction by electrophilic metalation, reductive elimination elementary steps yielding the desired arylated carbamate 9, and finally re-oxidation of Pd(0) to the active Pd(II) with sodium persulfate. [13,14]
Phenols can easily be converted to 2-phenoxypyrimidines via copper-catalyzed coupling with 2-halopyrimidines (Ullmann reaction), obtaining valuable directing groups which have been used to develop many C–H bond functionalization protocols. In 2009 Chen and co-workers explored the possibility of introducing a 2-pyridinyl group as a directing group in a palladium-catalyzed direct arylation and acetoxylation reaction of 2-aryloxypyrimidines. [16] It was found that both Cu(OTf)2 and Ag2O are essential for the catalytic system. Other combinations of copper and silver salts led to much lower conversions of starting material. The scope of the reaction, with respect to the heteroaryl ether substrates, was investigated (Scheme 11). However, the coupling reactions of electron-rich arylethers were more efficiently achieved under the established conditions (Scheme 11, 14a and 14b). Furthermore, coupling reactions of different phenylboronic acids was also investigated. Both electron-rich and electron-deficient arylboronic acids gave monoarylated products in good yields. However, the relatively sterically hindered boronic acid (2-tolylboronic acid) demonstrated poor reactivity (14i; 17%).
Pd(OAc)2 2HX 2HOAc “H2O”
LnPdIIX2
oxidation
NMe2
O R1 H
8
N
O
R1 reductive elimination
Ar 9
NMe2 O
O R1 Pd Ar
R1
N 14 R3
NMe2
O PdII A X
NMe2 O
Ar O
N
toluene, 120 oC, 24 h
13
Ph
O
R1
+ Ar B(OH)2
Pd(OAc)2 (5 mol%) Cu(OTf)2 (1 equiv.) Ag2O (1 equiv.)
HX
Pd0
O
R1
N
cyclopalladation
[O]
O
O
N N
R1
14a; R1=Me, R2=H, 54% 14b; R1=R2=Me, 73% 14c; R1=Ph, R2=Me, 30% 14d; R1=Cl, R2=H, 38% R2 14e; R1=CO2Me, R2=H, 33%
Scheme 11. Pd-catalyzed phenylboronic acid.
arylation
R4 O
N N
Me
of
Me
14f; R3=Me, R4=H, 58% 14g; R3=Cl, R4=H, 41% 14h; R3=CF3, R4=H, 60% 14i; R3=H, R4=Me, 17%
2-phenoxypyrimidine
with
ArH HX electrophilic metalation
Scheme 9. Proposed mechanism for Pd-catalyzed ortho-arylation of ophenylcarbamates.
A Pd-catalyzed regioselective mono- and diarylation of unprotected 2-phenylphenols with aryl iodides is described. [15] The authors propose, that the phenolic function seems to act as an efficient anchor for such a metal-catalyzed arylation reaction. The reaction employs Pd(OAc)2 as the catalyst and Cs2CO3 as the chosen base in DMF (Scheme 10). The reaction showed good scope varying substituents R1, R2 and R3. Employing 1.2 equivalents of the iodobenzene 11, the monoarylated phenols 12a–e were selectively obtained in good yields (60–73%) (Scheme 10). In the case of using PdCl2 instead of Pd(OAc)2 and with 4 equivalents of the aryl iodide 11, diarylation products
ortho-Chelation-directed C–H activation has been widely exploited in developing numerous highly efficient C–H functionalization protocols. However, activating C–H bonds which are quite distal to the existing functional groups remains a challenge. The development of remote C–H functionalization reactions based on C–H palladation processes suffers from the difficulty of forming these metalacycles larger than sixmembered rings, which can present a major obstacle in the activation step. Thus, Yu et al. reported the first example of a Pdcatalyzed cross-coupling reaction of meta-C–H bonds with arylboronic acids. [17] The meta-selectivity was achieved through the use of a U-shaped nitrile template weakly coordinated to the Pd(II) catalyst (Scheme 12). Furthermore, the addition of a monoprotected amino acid (MPAA) was found to be significant for creating an efficient coupling protocol.
5 Additionally, TBAPF6 was also essential for enhancing the reactivity of the reaction, since tetrabutylammonium salts can attribute to the ability of surfactants to prevent undesired agglomeration of Pd(0) species to form unreactive palladium black. [18] The choice of base was also found to be pivotal. In this case, CsF proved to be the most effective in comparison to carbonates and acetates. It has been reported that fluoride ions can play an important role in activating boronic acid esters and therefore facilitating the transmetalation step. The protocol showed to be quite general for both electron-withdrawing (15a–f) and electron-donating substituents (15g–h). As expected, only mono-meta-arylation was observed in the cases of orthosubstituted substrates (15a, 15e, 15g), with the exception the of ortho-fluorinated substrate 15c, where the diarylated product was isolated in a 13% yield. Unfortunately, the di-ortho-substituted substrate 15j showed poor reactivity under the established reaction conditions, presumably due to steric hindrance. Furthermore, the scope of arylboronic acids was also tested, proving good reactivity with both electron-withdrawing (15k and 15l) and electron-donating (15m and 15n) coupling partners. Finally, the U-shaped template could easily be removed under mild basic reaction conditions (LiOH • H2O), furnishing the final unprotected carboxylic acid in an excellent 96% yield. O T + Ar Bpin (3 equiv.)
R
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) Ag2CO3 (2 equiv.) CsF (2 equiv.) TBAPF6 (3 equiv.)
O
CO2Me 16a; R1=Cl, R2=H, 56% 16g; R1=Me, R2=H, 85% 1 2 16b; R =H, R =Cl, 44% 16h; R1=H, R2=Me, 81% m:(p+o+o’)=93:7 m:(p+o+o’)=85:15 16cmono; R1=F, R2=H, 43% 16i; R1=H, R2=OMe, 48% 16cdi; R1=F, R2=H, 13% m:(p+o+o’)=91:9 16d; R1=H, R2=F, 63% m:(p+o+o’)=87:13 16e; R1=CF3, R2=H, 58% 16f; R1=H, R2=CF3, 65%
NC
Ar
OMe
16 Me
O
T
R2
OMe N
T=
R
HFIP, 70 oC, 24 h
15
R1
NC
O T
O T
Me
T
Me
CO2Me 16j; traces
R3 16k; R3=F, 83% 16l; R3=CF3, 60% 16m; R3=Me, 72% 16n; R1=OMe, 70%
Pd(OAc)2 (10 mol%) F3C NHAc
O R
T
Ar +
I
O R
Me
T
T= N
(3 equiv.)
Ar=2-MeO2C-C6H4-
17
Ar 18
CHCl3, air, 100 oC, 24 h
R1 R2
O
O
T
O
O
Ar
T
T
T
MeO Ar
Ar
Ar
18a; R1=H, R2=Me, 87% 18b; R1=H, R2=OMe, 91% 18c; R1=Me, R2=H, 85% 18d; R1=iPr, R2=H, 89% 18e; R1=OMe, R2=H, 54%
Ar
18g; 58% mono:di > 20:1
18f; 87%
18h+18h’; 78% mono:di = 1:1
Scheme 13. Ligand-promoted meta-arylation of phenolic derivatives with aryl iodides.
Recently, Yu and co-workers reported the first catalytic system that enables selective meta-arylation of a variety of electron-rich alkoxy aromatics. [20] The use of a modified norbornene (NBECO2) was crucial to achieve regioselective meta-arylation. Thorough screening of the reaction conditions revealed that the combination of two ligands (6-cyanoquinaxoline and 3pyridinesulfonic acid) noticeably improved the efficiency of this nondirected arylation reaction. The importance of both ligands is likely due to the formation of a reactive cationic Pd-complex A, which could bind to the substrate more efficiently (Scheme 14). High regioselectivity was found with a variety of aryl iodides regardless of their electronic properties (19a–19d). Furthermore, a series of C3-substituted anisole derivatives were compatible under the optimized reaction conditions giving the final monoC5-arylated product (20e–j) in good yields. Unfortunately, parasubstituted anisole gave only trace amount of the desired metaarylated product, due to the steric hindrance of the methyl group. Furthermore, no product was observed with substrates containing strong electron-withdrawing groups. N OMe R1 + 19
Scheme 12. meta-Arylation of phenolic derivatives with arylborornic acid esters.
Ar I (2 equiv.)
OMe
HFIP, 95 oC, 20 h
CN
L1 =
Pd(OAc)2 (10 mol%) NBE-CO2Me (1.5 equiv.) L1 (30 mol%), L2 (15 mol%) AgOAc (3 equiv.)
OMe
N
OMe R1 Ar
F3C L2 =
SO3H N
20 OMe
SO3 R3
R1
Soon after, the same research group published an article on a series of highly versatile 3-acetylamino-2-hydroxypyridine ligands which promote meta-arylation of phenols, anilines and heteroaromatic amines using norbornene as a transient mediato. [19] After a survey of several directing groups, a benzylicpyridine based directing group was found to be the most efficient for the formation of meta-arylated products. Furthermore, a number of different ligands, containing an NHAc moiety was tested. The authors hypothesized that the installation of an NHAc group would provide a secondary binding site which could serve as an important function in the catalytic system. A bisdentate coordination would be possible between the NAc group and the oxygen atom, which would form a structure similar to monoprotected amino acid (MPAA) ligands; ligands developed by the same research group. The synergy between the pyridinebased directing groups and ligands allowed the formation of a broad scope of meta-arylated products (Scheme 13). Although, the developed protocol was exploited on a broader scope of anilines, phenol derivatives also proved to be compatible with the C–H cross-coupling methodology, yielding the final monoarylated products in good to excellent yields. Not surprisingly, when subjecting unsubstituted phenol substrate 17h, a mixture of mono- and diarylated products 18h and 18h’ was isolated in a ratio of 1:1. Interestingly, in the case of 17g, the desired monofunctionalized compound was predominantly formed.
N OH (10 mol%) AgOAc (3 equiv.) NBE-CO2Me (1.5 equiv.)
R2 20a; R2=CO2Me, 70% 20b; R2=CF3, 62% 20c; R2=Me, 62% 20d; R2=OTs, 54%
MeO2C
MeO2C 20e; R3=CO2Me, 70% 20f; R3=OMe, 58% 20g; R3=OBn, 56%
20h; R4=H, 78% 20i; R4=Cl, 65% 20j; R4=CF3, 61%
R4
N
N H N Pd OAc
Reactive complex A
Scheme 14. meta-Arylation of electron-rich arenes.
The mechanism for meta-C–H arylation of anisoles is proposed to proceed with the initial palladation at the ortho-position, which is intercepted by the norbornene insertion followed by subsequent Catellani C–H arylation (Scheme 15). To obtain evidence for the proposed mechanism, deuterium incorporation experiments were performed with ethoxybenezene under standard reaction conditions in the presence of HFIP-ol-D. The presence of 70% of deuterium being incorporated at the C2position exclusively in the meta-arylated product suggests, that the arylated product is derived from ortho-C–H palladation and the catalytic cycle is terminated by the C2 protonation (deuterium incorporation step) of the arylpalladium intermediate A.
6
Tetrahedron OMe R1
R
OMe
Ar
norbornene extrusion
20
OMe PdIILn Ar reductive elimination
19
PdIILn
C-H activation
OH
PdIILn
OH
OMe R1 PdIILn
R1 PdIILn
OH Me
Me F
R1
norbornene insertion
OMe
Me
R2
R1
PdIVLn I
R’
22
R3
OMe
A
R1
Ar I oxidative addition
(1 equiv.)
R 2. PEPPSI-IPr (2 mol%), Ag2CO3 (0.5 equiv.), AcOH, 130 ºC, 16 h one-pot process
OH
OMe
Ar
OH 1. KOH (3 equiv.), CO2 (25 atm), 190 ºC, 2h
R’
+
21 (3 equiv.)
R1
R1
I
OH
C-H activation
Scheme 15. Proposed mechanism for Pd-catalyzed meta-arylation via orthoC–H activation with norbornene insertion.
The methodology of direct regioselective functionalization of arenes is generally based on the use of various directing groups, which are preinstalled on the substrate and are removed only after the C–H functionalization step in completed. This kind of approach creates lengthy synthetic sequences. In 2014, Larrosa et al. reported the first strategy of a one-pot direct meta-arylation of phenols based on the use of CO2 as a traceless directing group. [21] The well-known reactivity of phenols toward orthocarboxylation with CO2 (i.e., Kolbe–Schmitt reaction) inspired the authors to develop a simple single-pot three-step methodology, combining carboxylation/arylation/decarboxylation to access metafunctionalized unprotected phenols. Studies revealed, that the source of the Pd catalyst proved to be crucial, with PEPPSI-IPr leading to the best results. The sequence began by treating 21 with KOH under 25 atm of CO2 at 190 ºC for 2 h, followed by the addition of the corresponding iodoarene, Pd catalyst, Ag2CO3, and AcOH, and further heating the reaction mixture at 130 ºC for 16 h (Scheme 16). Pleasingly, the developed methodology found to be completely selective for mono- vs. bis-arylation. Both electron-withdrawing and -donating groups, as well as substrates containing Cl and Br substitutes were compatible with the established protocol. Unfortunately, ortho-substituted iodoarenes were not appropriate coupling partners for this reaction, presumably due to a sterically crowded intermediate being formed in the catalytic cycle. On the other hand, the presence of an electron-donating MeO group afforded the product in a low yield, as a fast protodecarboxylation reaction of the salicylic acid intermediate occurs. This side reaction could be prevented by substituting the methoxy group with a CF3O group, which allowed the formation of the desired arylated product 22h in a 69 % yield. Electron-withdrawing groups at the C3 position were compatible with the reaction (21i and 21j), but strong electronwithdrawing group (NO2 group) showed no reaction (21k). However, substitution at the C4-position of the phenol proved to be incompatible with the arylation step, as the para-fluorophenol afforded the final product 22o in only 11% yield, whereas the para-methyl analogue showed no reactivity under the applied reaction conditions.
Me 22g; R2=OMe, 25% 22h; R2=OCF3, 69% 22i; R2=Cl, 69% 22j; R1=Br, 60% 22k; R1=NO2, 0%
22a; R1=OMe, 63% 22b; R1=F, 46% 22c; R1=Cl, 65% 22d; R1=Br, 61% 22e; R1=NO2, 54% 22f; R1=CHO, 50%
Me 22l; R3=Et, 46% 22m; R3=OCF3, 83% 22n; R3=F, 68%
Me 22o; 11%
Scheme 16. meta-Arylation of phenols via traceless CO2 directing group.
It is often strived to use directing groups, which can easily be removed after the C–H functionalization step is completed. Hence, Gevorgyan and co-workers reported a Pd-catalyzed ortho-alkenylation of phenols using a silanol-directing group, which was in the end simply removed to provide alkenylated phenols as a semi-one-pot procedure. [22] Silanol-protected phenols 23 were reacted with a chosen alkene 24 using 10 mol% of Pd(OAc)2 in combination with 20 mol% of (+)-menthyl(O2C)Leu-OH as the chosen ligand. After direct alkenylation, the silanol moiety was easily removed with the addition of TBAF as the deprotecting agent to provide the final alkenylated phenols 25. The reaction showed good scope and compatibility for different substitution patterns and electronic features (Scheme 17). Notably, meta-substituted phenols reacted at the less hindered C–H site, forming products in good to excellent yields (25a; 94%, 25b; 53%). Similarly, para-substituted phenols were also found to be compatible with the established protocol, as the final olefinated products were obtained in very good yields (25c– f). However in general, electron-rich phenols gave higher yields compared to their electron-deficient counterparts. Remarkably, this Pd-catalyzed olefination reaction proved to be completely monoselective, which is most likely due to the bulky tert-butyl groups at the silanol moiety that prevent the orientation of the silanol directing group towards the less hindered C–H site. The olefin scope was also investigated. 3,4-Dimethyl substituted silanol-protected phenol 23 was used in reaction with different electron-deficient olefins 24 to give a number of alkenylated phenols (25g–l) after the deprotection step (Scheme 17).
tBu O Si HO tBu
R1
+
R2
OH
OH CO2nBu R1=Me,
25a; 94% 25b; R1=Cl, 53%
OH R1
2. TBAF/THF
24
23 R1
R2
1. Pd(OAc)2 (10 mol%) (+)-menthyl(O2C)-Leu-OH (20 mol%) Li2CO3 (1 equiv.), AgOAc (4 equiv.) DCE, 100 oC, 24 h
R1
25 Me
CO2nBu R1=OMe,
25c; 81% 25d; R1=tBu, 89% 25e; R1=F, 58% 25f; R1=OCF3, 52%
OH R2
Me R2=SO
25g; 3Ph, 96% 25h; R2=CHO, 70% 25i; R2=COMe, 67% 25j; R2=Ph, 64% 25k; R2=4-F-C6H4, 79% 25l; R2=C6F5, 83%
Scheme 17. Pd-catalyzed alkenylation of silanol-protected phenols.
Another traceless organosilicon template was developed for directed meta-C–H alkenylation of phenols. [23] To find an effective directing group, a series of silicon-based templates bearing a nitrile moiety was synthesized. The selectivity towards meta-olefination was achieved when T (Scheme 18) was used as the optimized directing group. Presumably, the two ethyl groups on the template T provide a bond angle expansion between the phenyl ring and nitrile, favoring meta-selectivity. Therefore, using this easily introducible and also removable directing group,
7 selective meta-C–H alkenylation of phenols bearing various electron-donating and electron-withdrawing groups was achieved (Scheme 18). Furthermore, halo-substituted phenols 26 as well as sterically demanding 26 also led to satisfactory results. Moreover, the alkene substrate scope was also examined. Cyano, phosphonate, and sulfone substituted olefins were tolerated and produced 28 in good yields and satisfactory meta-selectivities. After meta-alkenylation, the organosilicon template T was removed either in the presence of p-toluene sulfonic acid or by reacting 28 with TBAF. O
T
R1
O +
R2
O R1
CO2Et T
Et
N Si(iPr) 2
28e; R1=COMe, 75% (m/others = 95:5) 28f; R1=CO2Me, 65% (m/others = 98:2) 28g; R1=CF3, 59% (m/others = 95:5) 28h; R1=Br, 78% (m/others = 91:9) 28i; R1=Cl, 75% (m/others = 95:5)
T
O
T=
28
R1 O
Et
R2
28a; R1=COMe, 73% (m/others = 92:8) 28b; R1=Me, 83% (m/others = 92:8) 28c; R1=Br, 77% (m/others = 90:10) 28d; R1=Cl, 71% (m/others = 88:12)
T
T
R1
DCE/HFIP (1:0.3), 60 oC, 24 h
27
26
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv.)
The same research group developed a similar nitrile-based template for Pd-catalyzed selective distal C–H olefination of biphenyl systems with high regio- and stereo-selectivity. [25] The study was carried out on a biphenyl phenol system due to its intrinsic importance in synthetic chemistry. Notably, the medium played a significant role, as DCE in combination with HFIP (7:1 v/v) improved the yield and selectivity. Presumably, protic solvent HFIP improves the catalytic efficiency through better solubilization of the palladium catalyst. Distal C–H olefination of biphenyl phenols 31 was tested on a series of different activated alkenes such as acrylates, ketones, and sulfones (Scheme 20). Although the minor ortho-regioisomer could be detected in the NMR spectra of the isolated compounds, the reactions gave moderate to good efficiency in forming the desired metaolefinated biphenyl products 32. Moreover, an acrylate bearing a highly fluorinated side chain was also successfully reacted (32g). Unfortunately, electron-rich olefins and electron-neutral styrenes could not be applied under the established reaction conditions.
CO2Et
28j; R2=CN, 71% (m/others = 90:10) 28k; R2=PO(OEt)2, 61% (m/others = 95:5) 28l; R2=SO2Ph, 66% (m/others = 90:10)
O
R2
T
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv.)
+
Scheme 18. meta-Alkenylation of silanol-protected phenols.
R1 (2 equiv.)
O
T= DCE/HFIP (7:1), 65 oC, 42 h, air
R1
31
The last two decades selective ortho- and more recently meta-C– H bond functionalization of arenes has been significantly exploited. However, the implementation of such a strategy for regioselective functionalization of a para-C–H bond remains extremely difficult. The reason lies in the formation of a large cyclophane-like metallacycle, which is the driving force for the successful direct C–H functionalization of arenes. In 2016 Maiti and co-workers developed a highly selective method for para-C– H olefination of phenol derivatives based on the use of a recyclable silicon-containing biphenyl-based template containing a nitrile group, which is placed at the position suitable for the formation of a cyclophane 17-membered transition state. [24] The reaction was carried out in the presence of Pd(OAc)2, Nacetylglicine as the ligand and AgOAc as the most effective base. A wide range of arenes 29 was investigated as the final products 30 were formed in good yields (Scheme 19). Mono-substituted derivatives (at the ortho- or meta-position with respect to the hydroxy group) were applicable, as sterically demanding substituents gave the final products in satisfying yields (30h; 65%). The method was also employed with a diverse set of olefins bearing different functional groups. Amides, aldehydes, ketones, sulfonyls, phosphonates as well as olefins with longchain alkyl substituents gave the desired products in good yields (30i–n; 66–88%). O T
O R1
+
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv.)
R2
R3
O
T= R2
DCE/TFE, 60 oC, 32 h
m
p
R3
30
T
O 30a; R=Me, 79% (p/others = 15:1) 30b; R=Br, 68% (p/others = 8:1) m’ 30c; R=OMe, 78% (p/others = 4:1) 30d; R=Ph, 63% (p/others = 10:1)
o’
CO2Et
O
p
p
R1
32a; R=CO2Me, 62% (m/o = 14:1) 32b; R=CO2Et, 65% (m/o = 13:1) 32c; R=CO2tBu, 60% (m/o = 16:1) 32d; R=SO2Ph, 61% (m/o = 14:1) 32e; R=SO2Me, 47% (m/o = 12:1) 32f; R=CO2CH2CF3, 67% (m/o = 12:1)
T
R1
O
T
32g; 57% (m/o = 11:1) F F F F F F F
O F F F F
O
A significant contribution towards the development of highly regioselective C–H functionalization protocols has been made by Yu et al. Thus, in 2013 a Pd-catalyzed ortho- and metaolefination of α-phenoxyacetic acids through remote C–H activation promoted by weak coordination and ligand acceleration was investigate. [26] Thus, the removal of the acetic acid auxiliaries affords synthetically valuable ortho- or metaolefinated phenols. Regioselective ortho-alkenylation was carried out on a set of various α-phenoxyacetic acids 33, which were reacted with ethyl acrylate under 1 atm of O2 in the presence of 5 mol% of Pd(OAc)2, 10 mol% of Boc-Val-OH and 2 equivalents of KHCO3 as the chosen base (Scheme 21). The Pd-catalyzed reaction was carried out in tert-amyl alcohol as the solvent to give ortho-olefinated α-phenoxyacetic acids 34. The reaction tolerated unsubstituted substrates exemplified by the formation of olefinated product 34a in a 91% yield. However, 3-methyl 34b and 4-methyl 34d substituted substrates were also successfully olefinated and α–phenoxyacetic acid products were isolated in 62% and 80% yields, respectively. Electron-withdrawing groups present in the substrates, such as 2-fluoro 34c, 4-trifluoromethyl (CF3) 34e, and 3 fluoro 34f, did not significantly alter the reaction outcome. CO2Et CO2H
R1
CO2H
Pd(OAc)2 (5 mol%), Boc-Val-OH (10 mol%)
+ 33 CO2Et
CO2Et
O
CO2H
R1
KHCO3, tAmylOH O2, 90 oC, 24 h
34 CO2Et
CO2Et
CO2Et
30i; R2=H, R3=CONMe2, 74% (p/others = 9:1) 30j; R2=Ph, R3=CHO, 84% (p/others = 19:1, E/Z = 6:1) m’ 30k; R2=H, R3=COMe, 74% (p/others = 11:1) 30l; R2=H, R3=SO2Ph, 88% (p/others = 13:1) 30m; R2=H, R3=PO(OEt)2, 86% (p/others = 11:1) 2 R 30n; R2=H, R3=CO2CH2-(CH2)8-CH3, 66% (p/others = 6:1)
Scheme 19. para-C–H Olefination of phenol derivatives with the use of a Sibiphenyl-based template.
F
Scheme 20. Distal C–H olefination of biphenyl phenol.
O 30e; R=Br, 68% (p/others = 15:1) 30f; R=Me, 76% (p/others = 12:1) m’ 30g; R=OMe, 74% (p/others = 14:1) 30h; R=t-Bu, 65% (p/others = 10:1)
N
32
T
o’
o m
T
N
o’
o R
(iPr)2Si
R1
29
R
T
O
O
T
O
34a; 91%
CO2H
O
CO2H
R1 34b; R=Me, 62% 34c; R=F, 65%
O
CO2H
R1 34d; R=Me, 80% 34e; R=CF3, 85%
Scheme 21. ortho-Olefination of α-phenoxyacetic acids.
O
CO2H
F 34f; 68%
8
Tetrahedron
In the same paper, Yu also reported a Pd-catalyzed metaselective olefination of α-phenoxyacetic acids. The strategy employs an end-on coordinating nitrile template on substrates 35 that enabled Pd-catalyzed olefination with ethyl acrylate to provide meta-olefinated α-phenoxyacetic acids 37 (Scheme 22). The Pd-catalyzed olefination reaction tolerated electron-donating groups as 2-Me 37a, 3-Me 37c, and 4-Me 37e substituted metaolefinated α-phenoxyacetic acid products were isolated in good to excellent yields (86%, 91%, and 72%; Scheme 22). The formation of such meta-olefinated products was highly selective as a very small amount of the ortho-isomer was formed. Phenol derivatives substituted with electron-withdrawing groups (2-CF3, 3-CF3, and 4-Cl) were mostly meta-olefinated giving products 37b, 37d, and 37f in 78%, 52%, and 65% yields, respectively. In addition, Yu also demonstrated a Pd-catalyzed meta-selective olefination of ortho-brominated α-phenoxyacetic acids with various alkenes. The incentive was the versatility and synthetic utility of the bromine moiety in the synthesis. The Pd-catalyzed olefination strategy was tested on ortho-brominated substrates that enabled olefination with various alkenes 36 to provide metaolefinated ortho-brominated α-phenoxyacetic acids 37 (Scheme 22). Olefination of substrate 35 with ethyl acrylate gave metafunctionalized product 37g in a 78% yield. The analogous butyl ester 37h and methyl ketone 37i were obtained in 78% and 62% yields, respectively. The reaction of substrate 35 with transmethyl 2-butenoate gave the corresponding meta-olefination product 37j in a 61% yield. The analogous olefination products 37k and 37l (containing an amide and phosphonate functionality) were also successfully reacted and gave products in good yields. Moreover, the scope of the Pd-catalyzed olefination reaction of α-phenoxyacetic acids was investigated with respect to the olefins. Styrenes 36 were used as olefination partners with 2methyl substrates 35 in an attempt to obtain olefination products 37. It was found that styrenes with only electron-withdrawing groups on the arene were reactive. The reaction with electrondeficient styrenes gave the corresponding products in moderate yields as exemplified by the formation of 37m–p in 31–75% yields. O
O O
T +
R1
Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%)
R2 R3
NC T
R1
AgOAc, HFIP 90 oC, 24 h
36
35
O
N
T= NC
37
R3 R2
R1
O O
m' p
m
R1
T
o
p
CO2Et 37a; R=Me, 86%, (m/others = 98:2) 37b; R=CF3, 78%, (m/others = 90:10) Br
m
O
m
O
o'
O
m'
T
o
R1
m
T
o
CO2Et
CO2Et 37c; R=Me, 91%, (m/others = 94:6) 37d; R=CF3, 52%, (m/others = 96:4)
37e; R=Me, 72%, (m/others = 89:11) 37f; R=Cl, 65%, (m/others = 98:2) Me
O O
m' p
O
o'
T
o
O O
m' p
m
T
o
R3 R2 37g; R2=CO2Et, R3=H, 78% (m/others = 88:12) 37h; R2=CO2Bu, R3=H, 78% (m/others = 92:8) 37i; R2=COMe, R3=H, 62% (m/others = 88:12) 37j; R2=CO2Et, R3=Me, 61% (m/others = 75:25) 37k; R2=CONMe2, R3=H, 82% (m/others = 91:9) 37l; R2=PO(OEt)2, R3=H, 83% (m/others = 93:11)
R2 37m; R2=C6F5, 75% (m/others = 83:17) 37n; R2=4-CF3-C6H4, 38% 37o; R2=4-OAc-C6H4, 31% 37p; R2=2,5-Cl-C6H4, 48%
Scheme 22. Pd-catalyzed meta-selective olefination of α-phenoxyacetic acids.
The proposed mechanism for this Pd-catalyzed C–H olefination reaction is based on the observed isotope effects (kH/kD = 3.8) of the nitrile-directed meta-selective C–H functionalization with
analogues substrates suggesting that the reaction proceeds via cyclopalladation through C–H cleavage and that the C–H bond cleavage may be involved in the rate-determining step. Olefin coordination by the palladacycle followed by 1,2-migratory insertion and subsequent β–hydride elimination gives the final meta-olefinated product 37 (Scheme 23). O reoxidation Ag AgOAc [Pd0]
R1 C N H 35 C-H activation
[PdIIL] +L
reductive elimination [LPdIIX]H HX
O R1 N 37 R2
O R1
β-hydride elimination
C
LPdII
N
C
O R1 N
LPd II R2
C
1,2-migratory insertion
2
O R1 LPdII
N
C
36 R olefin coordination
R2
Scheme 23. Proposed mechanism for nitrile-directed meta C–H olefination.
A similar arene C–H-olefination methodology was also developed by the Yu group. [27] The limiting reagent for this efficient protocol was the presence of a 2-pyridone ligand which binds to palladium and therefore accelerates a non-directed C–H functionalization reaction of simple arenes with the corresponding alkene. The method was applied on a vast set of simple arenes, even phenol derivatives, whereas the paraolefinated phenol was the major product formed. Moreover, the group very recently published an innovative protocol, based on sequential functionalization of meta-C–H and ipso-C–O bonds of phenols. [28] The advantage of this methodology is the use of a rigid backbone in the directing group template, which forms a large yet less strained macrocyclic pretransition state, and therefore forms the palladacycle intermediate with higher stability and a presumably longer lifetime. The idea of designing an efficient template, which would form the final product in good selectivity, was based on the influence of electronic effects. However, adding more electron-donating groups (methoxy groups) on the phenyl ring in template T (Scheme 24) did not significantly improve the reactivity. Moreover, it even led to a lower ratio of mono- to di-olefinated products (Scheme 24). Having the optimal template in hand (T), the scope of different phenol derivatives was investigated. Pleasingly, both electronrich and electron-deficient groups were well tolerated with the meta-alkenylated phenol being the major product formed. Even, sterically hindered substrates showed compatibility with the protocol. Compared to ortho-substitutes phenols, meta- and paraanalogues gave lower yields. Presumably, the presence of an ortho-substituent significantly improves the monoselectivity of the reaction, as the di-meta-C–H-olefination would be subjected to steric hindrance from the adjunct ortho-substituent. Also, various α,β-unsaturated ester, sulfone, and phosphonate olefins were reactive, affording meta-olefinated products (39n–q) in good yields. After completing the C–H-alkenylation step, the protocol was further developed to involve a Ni-catalyzed arylation reaction, where template T served as a pseudohalide in the cross-coupling reaction with corresponding arylboronic acids, to yield the final biphenyl products. Furthermore, a sequential one-pot synthetic procedure was also developed, including both palladium and nickel catalytic steps, demonstrating no major change in the final reaction yields.
9 OMe O
T
R1
Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%) AgOAc (1.5 equiv.) +
O
N
HFIP 80 oC, 36 h
T
39g; R1=F, 67% 39h; R1=CF3, 62%
CO2Et R1
T=
R2
N
39
T
O
R1
N N
R1
R2 (3 equiv.)
38
T
O
T
O
39l; R1=Me, 70% 39m; R1=Cl, 55%
R1
CO2Et
CO2Et R1
39a; R1=Me, 81% 39b; R1=tBu, 89% 39c; R1=OMe, 75% 39d; R1=F, 75% 39emono; R1=Cl, 68% 39edi; R1=Cl, 17% 39fmono; R1=CO2Et, 61% 39fdi; R1=CO2Et, 17
O
T
39i; R1=Cl, 57% 39j; R1=COMe, 49% 39k; R1=OMe, 69%
O
T
Me
CO2Et
39n; R2=CO2Me, 73% 39o; R2=CO2tBu, 44% 39p; R2=SO2Ph, 76% 39q; R2=P(O)(OEt)2, 79% R2
R1
Scheme 24. Pd-catalyzed template-directed meta-C–H-olefination of phenols.
A very recent paper worth mentioning by Zhu et al. describes a highly selective ortho-alkenylation of unprotected phenols as the directing group under mild synthetic conditions. [29] The C–H functionalization of unprotected phenols 40 gave the corresponding products in moderate to excellent yield at 60 °C. The choice of oxidant was also crucial, as K2S2O8 provided the highest yields. Even different metal species were tested (Fe, Ni), whereas Pd(acac)2 showed superior catalytic activity. Interestingly, the reaction performed in AcOH resulted in the highest yield as oppose to other solvents (H2O, DCE, MeCN, and DMF), which gave poor yields or even no product. As the scope of phenols was investigated, the positions of the substituents on the phenyl ring did not affect the efficiency of the reaction (Scheme 25). In general, electron-rich substrates contributed to forming the desired products in higher yields (41a–c; 90–94%) in comparison to electron-deficient phenols (41d–f; 55–77%). The scope of olefins was also examined. As expected, acrylates with similar reactivity to ethyl acrylate were compatible with the reaction. Even styrene derivatives containing electron-donating and electron-withdrawing substituents on the phenyl moiety reacted well with the substrates (41s and 41t).
26A). Furthermore, different terminal and internal aliphatic olefins were subjected under the optimized reaction conditions. Gratifyingly, the reaction of 10-bromodec-1-ene with 2-naphthol provided 43h as a single product. Although, in the case of simple terminal olefins (1-octene), a 2-substituted benzofuran having an exocyclic double bond at C2 (43jB) was observed along with the desired product 43jA (43jA/43jB=1:1.3). After describing a vast scope of different benzofurans, a set of coumarin derivatives was prepared under the optimal reaction conditions (Scheme 26B). Substituents such as Me, OMe, NO2, and Br at either ortho, meta, or para position on the phenols derives the corresponding coumarins in good yields (43l–u). The most important finding of the described catalytic method is the compatibility of various electron-withdrawing groups (NO2, CN, CHO, COMe, CH2CN). Interestingly, when reacting unprotected phenols with ethyl acrylate (under Pd-catalyzed C–H-olefination conditions) the coumarins derivatives were formed, whereas results of Stanford et al. [32] showed that reacting phenol analogues such as anisoles and 4-methoxyanisoles, under similar reaction conditions provided the corresponding mono-olefinated products in good yields (69–75%). A) Benzofurans: R1 R2
+
(1 equiv.)
42 OH (2 equiv.) R1
R1
+
R2
AcOH/H2O, 60 oC
R2 R1
R2
Br
Me
O
CO2Me
O
5 O 6 O 43h; 76% 43i; 55% R2 43a; R1=NO2, R2=Cl, 55% O2N O2N C2 43b; R1=CN, R2=Br, 58% Me 43c; R1=CN, R2=Cl, 51% 43d; R1=CHO, R2=OMe, 73% 4 43e; R1=COMe, R2=H, 64% O O 43jB 43jA 43f; R1=R2=H, 30% 1 2 72%; 43jA/43jB = 1:1.3 43g; R =Br, R =Cl, 64%
C1 Me 4
B) Coumarins:
+ 42 OH
CO2Me (1 equiv.)
Pd(OAc)2 (5 mol%) 1,10-phenanthroline (10 mol%) Cu(OAc)2 (1 equiv.) NaOAc (3 equiv.)
R1
43 O
ClCH2CH2Cl, 110 oC, air
(2 equiv.)
O
41
40 OH
OH R1
O 43
O
OH
Pd(acac)2 (5 mol%) AgOAc (1.2 equiv.)
R1
ClCH2CH2Cl, 110 oC, air
R1
OH
Pd(OAc)2 (5 mol%) 1,10-phenanthroline (10 mol%) Cu(OAc)2 (1 equiv.) NaOAc (3 equiv.)
OH CO2Et
CO2Et
CO2Et
R1 41a; R1=H, 95% 41b; R1=Me, 94% 41c; R1=Br, 81% 41d; R1=Cl, 77% 41e; R1=F, 81%
41f; R1=Me, 88% 41g; R1=CF3, 81% 41h; R1=F, 85% 41i; R1=Cl, 88%
OH R2
R1
R1
1 R1 41j; R =Me, 90% 41k; R1=OMe, 94% 41l; R1=NO2, 55% 41m; R1=COOH, 75%
41n; R2=CO2Me, 78% 41o; R2=CO2Ph, 75% 41p; R2=CONHPh, 85% 41q; R2=SO2F, 60% 41r; R2=CN, 70% 41s; R2=4-OMe-C6H4, 65% 41t; R2=4-Cl-C6H4, 82%
Scheme 25. Phenol scope for Pd-catalyzed direct ortho-alkenylation.
A palladium-catalyzed synthesis of benzofurans and coumarins from phenols and olefins has been reported. [30] Benzofuran and coumarin derivatives are compounds of great synthetic value. Particularly, 2-arylbenzofurans are frequently found in nature and possess various biological activities. [31] The reported procedure is based on an active catalytic system which involves Pd(OAc)2 as the catalyst in combination with 1,10-phenantroline, Cu(OAc)2 and NaOAc. The authors stress, that the addition of NaOAc is crucial to achieve high conversions. The scope of styrene as well as phenol derivatives was evaluated. Halogen-substitutes phenols gave benzofuran derivatives in good yields without dehalogenation (43a–c and 43g). Unfortunately, only 30% yield of unsubstituted 2-phenylbenzofuran (43f) was formed (Scheme
O 43k; R1=H, 67% 43l; R1=Me, 78% 43m; R1=OMe, 81% 43n; R1=Br, 57%
O 43o; R1=NO2, 61% 43p; R1=CN, 78% 43q; R1=CHO, 70% 43r; R1=COMe, 72% 43s; R1=CH2CN, 64%
O
O
R2 43t; R1=NO2, R2=Cl, 55% 1 43u; R =CHO, R2=OMe, 52%
Scheme 26. A) Pd-catalyzed synthesis of benzofurans. B) Pd-catalyzed synthesis of coumarins.
Furthermore, a procedure for the synthesis of dibenzopyranones through palladium catalyzed directed C–H activation/carbonylation of 2-arylphenols was developed. [33] The most reactive catalytic system for this transformation proved to be Pd(OAc)2/Cu(OAc)2/PivOH, Na2CO3 under an atmospheric pressure of CO in mesitylene at 120 ºC. A variety of 2arylphenols could be converted to the desired dibenzopyranones in good to moderate yields (Scheme 27). Different substituents on the Ar2 ring were tolerated, including electron-donating (45c– f) and electron-withdrawing groups (45g–l). Substituents on the ortho position were, however, unfavorable which might arise from steric hinderance (45a and 45b). The regioselectivity of the reaction is preferred toward the formation of sterically less hindered products (45m and 45n), as the other isomers were not observed. Notably, in the cases were the yields of the products were low, no starting material was recovered, which can be attributed to phenols being prone to decomposition under the
10
Tetrahedron
applied oxidative reaction conditions. Interestingly, the reaction was found to be more sensitive to the electronic nature of substituents on the Ar1 ring comparing to the substituents on the Ar2 ring. Thus, electron neutral groups (45o–q) gave higher yields than electron-donating or -withdrawing groups. Pd(OAc)2 (5 mol%) Cu(OAc)2 (10 mol%) Na2CO3 (2 equiv.) PivOH (0.5 equiv.)
OH Ar1
Ar2
O O
CO (1 atm), mesitylene, 120 oC, 6 h
44 O
Ar1
Ar2
yields (Scheme 29). However, as it was observed for the arylation examplesError! Bookmark not defined. also in this cases substrate bearing electron-withdrawing substituents gave the products in lower yields (49b, R1=Cl, and 49c, R1=CO2Me; 24% and 29%. For substrates containing electron-donating groups the desired products were isolated in higher yields (49d and 49e; 42% and 69%). Not surprisingly, for the sterically hindered substrates with substituents at the ortho- and meta-positions (49f and 49g), the yields were significantly reduced.
45
O
O
O
N
OAc N
R1 49a; R1=H, 50% 49b; R1=Cl, 24% 49c; R1=CO2Me, 27% 49d; R1=Me, 69% 49e; R1=OMe, 42%
O 45m; 87% Me O O
R1 45o; R1=Me, 69% 1 45p; R =Ph, 72% 45q; R1=tBu, 70%
45n; 79%
Scheme 27. Pd-catalyzed synthesis of dibenzopyranones.
In 2013 Kim and co-workers reported a Pd-catalyzed oxidative ortho-acylation reaction of 2-phenoxypyridines with benzylic and aliphatic alcohols. [34] In the optimization studies, Pd(OAc)2 was found to be the best catalyst and tert-butyl hydroperoxide (TBHP) the oxidant of choice for the reaction to provide the corresponding products in good yields. The protocol extends to range of substrates which showed great level of regio- and chemo-selectivity and functional group tolerance (Scheme 28). The scope of alcohols using 2-fluorophenoxypyridines presented broadness which is exemplified by products 47a–f in good yields (61–87%). Aliphatic alcohols were also demonstrated to be effective under the applied reaction conditions. Thus, products 47g and 47h were obtained in 78% and 50% yield, respectively. The reaction showed to be compatible with a variety of different substituents on the phenyl ring, giving rise to products in good to moderate yields (47i–m; 48–71%). R2 O R1
Pd(OAc)2 (10 mol%) +
N
R2
OH
TBHP (4 equiv.) DCE, 80 oC, 20 h
46 R2
R2
F
N
N 47
Ph
O N
R1
R1 OH
N Me
N Me
49g; 62% Me
49f; 45% OAc N O Me N
Pd(OAc)2 (5 mol%) IPr (10 mol%) MesCOONa (0.5 equiv.)
OAc N
Me
O N
Me
Cl
49i; 29% Me
47i; R1=Cl, R3=Me, 65% 47j; R1=R3=OMe, 58% 47k; R1=F, R3=H, 61% 47l; R1=OMe, R3=H, 48% 47m; R1=R2=H, 71%
R3
Scheme 28. Ortho-acylation of 2-phenoxypyridines with benzylic and aliphatic alcohols.
A procedure already described for the arylation of 2phenoxypyrimidines 13 (Scheme 11) was also used for Pdcatalyzed acetoxylation of the same set of substrates. [16] The reaction was carried out using 2 mol% of Pd(OAc)2 as the chosen catalyst and 1.1 equiv. of PhI(OAc)2 as the oxidant in a solvent system of Ac2O/AcOH. However, when 3.0 equiv. of PhI(OAc)2 was employed, the diacetoxylated phenoxypyrimidine was the major product formed. The protocol found to be broadly applicable to a variety of heteroaryl substrates affording the corresponding acetoxylated products 49 in good to excellent
O
K2CO3 (2 equiv.), MS 3Å 4,5-diazafluoren-9-one (10 mol%) mesityl, 120 oC, air, 24 h
50
R1
Ph
51a; R1=CF3, 68% 51b; R1=tBu, 76%
R1
R2 IPr =
51c; R1=Me, 65% 51d, R1=F, 78%
N
N
51 O
O
O
O R1
O
Me
O
Liu and co-workers reported a Pd-catalyzed phenol-directed C–H activation/C–O cyclization methodology to afford dibenzofurans 51 (Scheme 30). [35] Amongst the tested oxidants, air was found to be the best performing, whereas treatment of phenols with stronger oxidants (eg. PhI(OAc)2) caused complete decomposition of the substrates. In addition, the carbene ligand IPr (Scheme 30) was found to be the ligand of choice. When 4,5diazafluoren-9-one was added in 10 mol%, the yield improved noticeably. The reaction scope demonstrates generality and variety in substitution on both arene rings, as well as good functional group tolerance. meta-and para-substituted phenol rings gave products 51a–d good 65–78% yields. The other arene ring was also found to be tolerant towards various electronically different substituents giving rise to products 51 in moderate to good yields (48–88%). Dibenzofuran containing Weinreb amide 51i and substrate 51k with an electron-withdrawing NO2 group were obtained in 80% yields. Nevertheless, dibenzofuran possessing an α,β-unsaturated methyl ester moiety was also obtained in a good yield (51j, 83%).
47g; R2=Ph, 78% 47h; R2=Me, 50%
N
47a; R2=H, 71% 47b; R2=4-OMe, 72% 47c; R2=4-CO2Me, 61% 47d; R2=4-CF3, 72% 47e; R2=3-Me, 71% 47f; R2=2-F, 87%
OAc N
Scheme 29. Pd-catalyzed acetoxylation of 2-phenoxypyrimidine.
R2
O O
R1 49
O R1
O
O
F
O
O N
Me
O
49h; 82%
45r; R1=F, 41% 45s; R1=OMe, 25% 45t; R1=OPh, 25%
N
OAc N
O N
O
OAc
Pd(OAc)2 (2 mol%) PhI(OAc)2 (1.1 equiv.) Ac2O/AcOH = 1 : 1 100 oC
48
45h; R1=F, 66% 45i; R1=Cl, 68% 45j; R1=CO2Me, 64% 45k; R1=CHO, 50% 45l; R1=NO2, 31%
45c; R1=Me, 83% 45d; R1=OMe, 60% 45e; R1=tBu, 80% 45f; R1=OPh, 79% 45g; R1=CF3, 59%
R1
N
R1 R1 45a; R1=Me, 31% 45b; R1=Ph, 41% O O
O
R2
51e; R2=SiMe3, 82% 51f; R2=OMe, 71% 51g; R2=Cl, 48% 51h; R2=Ph, 88% 51i; R2=CON(OMe)Me, 80% 51j; R2=CH=CHCO2Me, 83%
R2 51k; R2=NO2, 80% 51l; R2=COMe, 71% 51m; R2=CN, 37%
Scheme 30. Pd-catalyzed phenol-directed C–H activation/C–O cyclization.
In 2011 a Pd-catalyzed silanol-directed phenol hydroxylation of phenols was reported. [36] The introduction of silanol as a traceless directing group has often been used in Pd-catalyzed C– H functionalization reactions. Therefore, the developed methodology consists direct C–H oxygenation reaction followed by a desilylation reaction (with TBAF) yielding the desired catechols 53. The scope of this semi one-pot hydroxylation/desilylation sequence was compatible with differently substituted silanol-protected substrates to give rise to the corresponding products. The selected reaction scope is shown in Scheme 31. Substrates having electron-rich substituents
11 showed comparable reactivity to electron-deficient analogues as the corresponding catechols such as 53b, 53f and 53j were isolated in good to excellent yields (94%, 57%, and 93%).
Pd(OAc)2 (5 mol%) PivOH (1 equiv.) Cs2CO3 (1.2 equiv.) TBHP (4 equiv.)
OH Ar1
Ar1 CH3CN, 80 oC, 18 h, air
54 1. Pd(OPiv)2 (5 mol%) PhI(OAc)2 (2 equiv.)
tBu Si HO tBu
O
R1
OH
R1
OH
OH
OH OH 53a; 81% 53b; R1=Me, 94% 53c; R1=Ph, 87% 53d; R1=Cl, 62% 53e; R1=CF3, 35%
Me
OH
OH Me OH R1 53f; R1=OMe, 57% 53j; 93% 53g; R1=tBu, 78% 53h; R1=F, 60% 53i; R1=CO2Et, 76%
A mechanistic reaction pathway for the Pd-catalyzed silanoldirected C–H oxygenation of phenols into catechols is proposed (Scheme 32). The reaction is assumed to proceed via a palladacycle followed by a reductive acetoxylation elementary step which produces a palladium acetoxylated complex that was experimentally observed. In order to verify whether the observed silacyle arises solely through a stepwise route involving acetoxylated intermediate or it is formed via a direct CO reductive cyclization, the 18O-labeled silanol 52 was subjected to the standard reaction conditions. The labeling experiment reviled that 18O-labeled acetoxylated product was formed and then gradually diminished during the reaction time upon which the final cyclized product with no 18O label was formed. Instead 18O labeled acetic acid was detected, thus ruling out reductive cyclization reaction pathway. O
Si
tBu
t O18 Bu
H
52
tBu Si tBu O18 Pd H palladacycle
R1
tBu Si tBu 18 O Pd H OAc
O
O
cyclopalladation
reductive
R1
acetoxylation
observed reduc
O R1
tBu Si t O Bu
protected catechol
tion ycliza tive c
tBu Si tBu 18 OAcO H
O -HO18Ac
R1
tBu Si tBu O18 O Me OH
O
transesterification R1
55
R2
HO
OH R2
HO HO 55i; R2=F, 75% 55a; R2=H, 76% 55j; R2=Cl, 73% 55b; R2=F, 80% 55k; R2=Me, 71% 55c; R2=Cl, 77% 55d; R2=CF3, 80% OH 55e; R2=Me, 77% 55f; R2=tBu, 75% 1 R 55g; R2=Ph, 77% 55h; R2=OMe, 75% HO
Scheme 31. Silanol-directed phenol hydroxylation of phenols.
R1
Ar2
R2
53
Me OH
OH
OH
toluene, 100 oC 2.TBAF/THF
52
OH
R1
OH
Ar2
Scheme 32. Proposed reaction pathway for the Pd-catalyzed silanol-directed C–H oxygenation of phenols into catechols.
An important procedure was published by Fan et al. describing a novel synthesis of 2,2’-biphenols through Pd(II)-catalysis, using a previously attached hydroxyl group in one of the phenyl rings in [1,1’-biphenyl]-2-ol as a directing group to introduce an additional hydroxyl functionality (Scheme 33). [37] The initial studies were performed on 2-phenylphenol and therefore proving Pd(OAc)2 to be the catalyst of choice in combination with PivOH as the ligand, improving the reaction significantly. Moreover, screening different oxidants (K2S2O8, oxone, m-CPBA, H2O2) revealed that using a 70% aqueous solution of tert-butyl hydroperoxide (TBHP) provided good conversion of the starting material. However, replacing 70% aqueous solution of TBHP with TBHP in decane, the corresponding product 55a in a 75% yield suggesting that TBHP, rather than air or water, is in fact the oxygen source of the newly introduced hydroxyl functionality. Different substituents on the 4’- and 3’-postions of the Ar1 as well as on Ar2 ring showed good performance under the established reaction conditions. However, substituents attached on the 2’-position on the Ar2 ring turned out to be less favorable which might arise from steric hinderance (55l–n).
HO 55l; R2=F, 58% 55m; R2=Cl, 55% 55n; R2=Me, 50% OH
HO R1 55r; R1=Cl, 76% 55s; R1=Me, 75% 55t; R1=OMe, 75%
55o; R1=F, 85% 55p; R1=Cl, 80% 55q; R1=OMe, 76%
Scheme 33. C–H hydroxylation of [1,1’-biphenyl]-2-ols.
The synthetic and economic potential of fluorinated phenol derivatives is of great importance for the construction of various building blocks for further formation of materials, pharmaceuticals, and agrochemicals. Among the numerous phenol derivatives, the first C–H bond fluorination of 2phenoxypyridines was introduced by Xu and co-workers. [38] They proposed, that having an oxy-bridge in the 2phenoxypyridine might alter the electronic nature on the nitrogen atom in the pyridine ring, causing the reaction to yield selective ortho-monofluorinated products as oppose to the difluorinated ones. Reaction condition screening showed that using 5-10 mol% of Pd(dba)2 in EtOAc and NFSI as the fluorinating agent afforded the desired mono-fluorinated products 57 in high yields (Scheme 34). Generally, there showed to be no difference in the reactivity when subjecting either electron-rich or electron-deficient substrates under the established reaction conditions. Notably, milder conditions were used in the cases of electron-rich aryl rings (57b–57e, at 80 ºC) in order to avoid undesired difluorination. However, harsher conditions and a catalytic amount of KNO3 (30 mol%) were required when reacting electron-deficient substrates (57h, 57i, and 57p, at 120 ºC) to achieve satisfying conversions. Moreover, mono-fluorination occurred smoothly even in the presence of bulky (57c) and halo (57f, 57k, 57l, and 57n) substituents. Finally, a set of diverse functionalized methyl 2-phenoxy nicotinates were submitted under the optimized reaction conditions, having great value especially in the pesticide industry. COR2 O R1
N
Pd(dba)2 (5-10 mol%) NFSI (1.5-2.0 equiv.)
COR2 O R1
EtOAc, 80-120 oC, 2-6 h
F 57
56
N
R1 O
O
R1
N
N F R1 F 57a; R1=H, 81% 57f; R1=Br, 77% 57j; R1=Ph, 79% 1 57b; R =Me, 76% 57g; R1=CO2Me, 75% 57k; R1=Cl, 80% 57c; R1=tBu, 74% 57h; R1=CN, 74% 57l; R1=Br, 85% 57i; R1=NO2, 73% 57d; R1=Ph, 80% 57e; R1=OMe, 71% CO2Me O O R1 N F R1 57q; R1=H, 78% 57r; R1=Me, 75% 57s; R1=OMe, 70% 57t; R1=F, 64%
O F
N
57m; R1=Me, 76% 57n; R1=Br, 78% 57o; R1=COMe, 77% 57p; R1=CF3, 75% CO2Me
N F 57u; R1=Br, 81% 57v; R1=CF3, 75%
Scheme 34. C–H bond fluorination of 2-aryloxypyridines and 2-phenoxyl nicotinic acid derivatives.
The same removable 2-pyridyl group was applied for the development of a regioselective C–H chlorination/sequential C– H functionalization procedure for phenols. [39] This convenient and straightforward strategy employed the presence of Pd(OAc)2 as the catalyst, NCS as the chlorinating agent, and TsOH as the
12
Tetrahedron
most efficient promoter for the transformation (Scheme 35). Interestingly, the degree of chlorination was found to be highly dependent on the nature of the substituent on the phenyl ring of the 2-phenoxypyridine derivatives. When the para position was substituted by a methyl, chloride, bromide, ester, nitro, trifluoromethyl and trifluoromethoxy group, the corresponding di-chlorinated product was formed (59a–g; 69–99% yield). On the other hand, when 2-aryloxypyridines bearing a phenyl, aldehyde, nitrile, methoxy, or fluoro group at the para-position the mono-chlorination was possible in reasonable to high yields (59h–l; 46–81% yield). The effect of different substituents on the pyridine ring was also examined. Notably, substrates bearing electron-rich substituents reacted smoothly, affording dichlorinated products in good yields (59u, 59v, 59y, and 59z), as reactions of electron-deficient substrates gave lower yields of products (59t and 59x) suggesting that the coordinating ability of the pyridine moiety to the palladium center plays an important role. R2
O R1
Cl O Cl 59
58
Cl
O
O
O
N N Cl R1 Cl R1 59a; R1=Me, 69% 59h; R1=Ph, 81% 1 59b; R =Cl, 74% 59i; R1=CHO, 46% 59c; R1=Br, 94% 59j; R1=CN, 51% 59d; R1=CO2Me, 99% 59k; R1=OMe, 63% 59e; R1=NO2, 99% 59l; R1=F, 76% 59f; R1=CF3, 92% Cl R2 1 59g; R =OCF3, 92% O
N R1 59m; R1=Cl, 80% 59n; R1=Br, 88% 59o; R1=Me, 79%
Cl O
O Cl
59t; R2=CF3, 23% 59u; R2=Me, 81% 59v; R2=F, 79%
N R1 59p; R1=Me, 81% 59q; R1=Br, 71% 59r; R1=CF3, 47% 59s; R1=tBu, 77%
Cl
N
N
Cl
R2
59w; R2=Cl, 98% 59x; R2=NO2, 33%
N
R2 59y; R2=OMe, 65% 2 59z; R =Me, 72%
Scheme 35. C–H chlorination/sequential of phenols with NCS.
In 2014 Rao and co-workers reported the first carbamate-directed Pd-catalyzed ortho-chlorination of phenol derivatives at ambient temperature. [40] Remarkably, no para- or meta-chlorination occurred and only ortho-chlorinated products were obtained under the developed reaction conditions. With 5 mol% of Pd(OAc)2, 0.5 equivalents of TfOH, and NBS as the bromine source, the ortho-chlorinated phenols were readily prepared (Scheme 36). The survey of the reaction scope revealed that a variety of phenol derivatives could be chlorinated. Substrates being substituted ortho-, meta-, and para-functionalities on the aryl moiety proved to be good substrates under the developed reaction conditions. Pleasingly, the regioselectivity of the reaction was high, since meta- and para-substituted substrates provided solely ortho-chlorinated products. O R1
NMe2
Pd(OAc)2 (10 mol%) TfOH (0.7-3.0 equiv.) NCS (1.1 equiv.)
O
NMe2
O R1 Cl
DCE, r.t.
O
61
60 R1
Cl NMe2 Cl
O
61a; R1=H, 75% 61b; R1=Cl, 54% 61c; R1=Br, 72%
R1
NMe2 O
O
63a; R1=H, 89% 63b; R1=Ph, 83% 63c; R1=CN, 81% 63d; R1=Br, 46%
R1 NBS (1.1 equiv.) p-TsOH (0.5 equiv.) DCE, 80-90 oC
62
R1
O
Pd(OAc)2 (5-10 mol%)
Br
NMe2 O
63e; R1=CO2Me, 62% 63f; R1=NO2, 42% 63g; R1=F, 52%
Br
NMe2 O
63 Cl
O
NMe2
O Br 63h; 71%
3. Rh-Catalyzed C–H Bond Functionalization
N
Cl
Cl O
NMe2 O
R2
R1 EtOAc, 110 oC
Cl
O R1
Scheme 37. Pd-catalyzed ortho-bromination of carbamates using NBS.
Pd(OAc)2 (10 mol%) TsOH (10 mol%) NCS (3 equiv.)
N
bromination. [41] The reaction employs carbamate 62, 5–10 mol % of Pd(OAc)2, 50 mol % of p-TsOH in DCE at 80–90 °C along with NBS as the brominating agent. Unsubstituted carbamate gave 63a in an 89% yield (Scheme 37). It is worth mentioning that meta-chlorinated substrate derived the corresponding the ortho- brominated product 63h in a yield of 71%. Concerning the electronic nature on the para-position, the strongly electronwithdrawing group (such as nitro) gave the desired product in a slightly lower yield (63f, 42%).
NMe2 O
Cl R1 61d; R1=OMe, 66% 61m; R1=Me, 73% 61e; R1=F, 83% 61n; R1=F, 77% 61o; R1=CO2Me, 63% 61f; R1=Br, 69% 61p; R1=tBu, 93% 61g; R1=I, 68% 1 61q; R1=Ph, 80% 61i; R =Me, 86% 61j; R1=Cl, 72% 61k; R1=CO2Me, 57% 61l; R1=CF3, 24%
Scheme 36. ortho-Chlorination of carbamates at room temperature.
Additionally, Nicholas reported a similar Pd-catalyzed functionalization of carbamates using NBS thus achieving ortho-
A detailed Rh-catalyzed intermolecular ortho-arylation of unprotected phenols was also reported. [42,43] The reaction employs treatment of a phenol 64 with an aryl halide in the presence of Wilkinson’s catalyst, [RhCl(PPh3)3], an aryl dialkylphosphinite as the ligand, and Cs2CO3 as the base to give the corresponding arylated product 65 (Scheme 38). It is purposed that the phosphinite ligand, PR2(OAr), also acts as a cocatalyst when the aryloxide group is incorporated into phosphorus donors, facile orthometalation can occur to give lowstrain, five-membered metallacycles. The developed protocol showed to be compatible with a variety of different aryl bromides. Even sterically hindered bromide 2-bromo-paraxylene was employed, forming the desired product 65k in quantitative yield. Furthermore, aryl chlorides can also be used as coupling partners, although much lower yields of the arylated phenols were obtained (65d; 25% and 65e; 15%). It must be noted, that in all cases the phenol substrate is unsubstituted at the 4-position and only ortho-arylation occurs proving, that the reaction is indeed ortho-selective which in turn means that the C– H activation of phenol occurs after it has been incorporated into the phosphinite co-catalyst. Furthermore, it is not necessary to have a bulky tert-butyl group on the 2-position for the reaction to proceed. Phenols bearing much smaller groups (iPr, Et, Me) also gave the desired arylated products in satisfying yields (65f–h). 1Bromonaphthalene was also reactive as a coupling partner and the corresponding arylated phenol 65l was isolated in an excellent 92% yield. Unfortunately, the reaction with a heterocyclic bromide (2-bromopyridine) gave product 65m in a lower 23% yield, which may be due to deactivation of the cocatalyst since both the product and, in particular, the intermediate modified phosphinite can form chelate complexes with the metal center.
13 OPiPr2
R1
[RhCl(PPh3)3] (5 mol%) +
64
tBu
OH
OH ArX X=Br, Cl (1.5 equiv.)
R1
PR2(OAr) (15 mol%), Cs2CO3 (1.7 equiv.), toluene, reflux, 18 h
R2
OH
Ar R1 PR2(OAr)
65
Me
OMe
OH
OH
R1
tBu
carried out. Phenyl carbamate 66 underwent Rh-catalyzed olefination with various styrenes to give the corresponding olefinated products 68l–o. Other acrylates such tert-butyl ester, methyl ester, methyl sulfonate, and phosphates gave the corresponding olefinated phenyl carbamates 68p, 68q, 68r, and 68s in 62%, 73%, 54% and 48% yields, respectively.
tBu
R2=COMe,
65f; R1=iPr, 68% 65g; R1=Et, 53% 65h; R1=Me, 21% 65i; R1=Ph, 53% 65j; R1=OMe, 71%
65a; 96% 65b; R2=OMe, 79% 65c; R2=CH=CH2, 75% 65d; R2=Me, X=Cl, 25% 65e; R2=OMe, X=Cl, 15%
O R1
Me
67
MeOC
NMe2
O
NMe2
O
nBuO C 2
A mechanism for the Rh-catalyzed ortho-arylation of phenols was proposed (Scheme 39). Initially, oxidative addition of the aryl halide by the Rh catalyst gives an oxidative addition product A which reacts with the starting phenol 64. Coordination of Rh by the oxygen atom in the phosphinite co-catalyst gives rise to a rhodacycle complex intermediate B. Next, reductive elimination furnishes the ortho-arylated phosphinite C which undergoes transesterification with the starting phenol to give rise to the ortho-arylated phenol 65 and the Rh catalyst to be reused in the catalytic cycle. RhLn oxidative addition
O R1
ArX
Ar
Ar RhLn X A
P RhLn R2
C
ortho-metalation OH
reductive elimination
O R1
B
PR2 RhLn Ar
R1 64
Scheme 39. Proposed mechanism for the Rh-catalyzed ortho-arylation of phenols
In 2011, Liu and co-workers reported a Rh(III)-catalyzed olefination of phenol carbamates with acrylates and styrenes. [44] A similar transformation was developed by Dong, [13] where he repoted a Pd-catalyzed ortho-arylation reaction of ophenylcarbamates with simple arenes. The reaction that Liu developed employs a phenyl carbamate 66 with an acrylate 67 in the presence of 1 mol% of [RhCp*Cl2]2, 4 mol% of silver hexafluoroantimonate (AgSbF6), copper(II) acetate in tetrahydropyran (THP) as the solvent, to give the orthoolefinated phenyl carbamate 68 (Scheme 40). The scope of the phenyl carbamate was performed using n-butyl acrylate as the olefin partner. Various electron-neutral and electron-rich phenol carbamates were to be favored in the reaction (66a–c), whereas some substrates bearing strong electron-withdrawing groups (e.g., NO2) could not be converted to the desired product. Interestingly, acetyl-substituted substrate 66g gave predominantly the corresponding bis-olefinated product. This observation is consistent with the findings that ketones also act as good directing groups in Rh-catalyzed C–H functionalization reactions. Moreover, halo functional groups were also tolerated (66d–f, 66h, 66i), with no Heck-type coupling or protodehalogenation products being formed. Furthermore, even BINOL (66j) and biologically relevant substrate 66k showed good reactivity under the established reaction conditions. The scope of the reaction with respect to the olefin reactant was also
O
Br
O O
O
NMe2 O
Me O
nBuO C 2
NMe2 NMe2
O
H
R2 68p; R2=CO2tBu, 62% 68q; R2=CO2Me, 73% 68r; R2=SO2Me, 54% 68s; R2=P(O)(OEt)2, 48%
68l; R2=Ph, 72% 68m; R2=4-F-C6H 4, 55% 68n; R2=4-Cl-C6H4, 63% 68o; R2=4-Br-C6H4, 53%
H
Me2N
O
CO2nBu
n 68h; 67% CO2 Bu
CO2nBu O
NMe2
O
NMe2
68i; 58%
68g’; 62% CO2nBu
H
Ar 65 transesterification
Cl O
68a; R1=H; 70% 68d; R1=Br; 53% 68b; R1=Me; 74% 68e; R1=I; 49% 68c; R1=OMe; 58% 68f; R1=Ph; 67%
65m; 23%
OH
68
O CO2nBu
N
Scheme 38. Rh-catalyzed arylation of unprotected phenols in the presence of a phosphinite ligand.
R1
O
O
O
tBu
NMe2
O R1
Cu(OAc)2 (2 equiv.) THP, 110 oC, 24 h
R2 R1
65l; 92%
[RhCp*Cl2]2 (1 mol%) AgSbF6 (4 mol%)
R2
66
65k; quant.
OH
OH tBu
O
NMe2 +
68k; 65%
CO2nBu 68j; 82% (ee=96%)
Scheme 40. Rh-catalyzed olefination of phenol carbamates with acrylates and styrenes.
The first alkynylation of 2-vinylphenols using a hypervalent iodine reagent TIPS-EBX* in combination with [(Cp*RhCl2)2] as the C–H activating transition metal catalyst at room temperature was developed by Nachtsheim et al. [45] At first, the optimization studies were carried out using TIPS-EBX as the coupling agent. However, detailed investigation of the reaction revealed two significant side-products being formed, which derived from the hypervalent iodine reagent. Thus, modification of the alkynyl benziodoxolone to the ortho-Me-substituted derivative, TIPS-EBX*, resulted in a more reactive reagent forming the desired product 70a in an excellent 91% yield. The optimized reaction conditions were tested on a set of different substrates (Scheme 41). Electron-poor phenols, in particular 4and 5-halogen-substituted (69b–e), as well as 4-NO2-substituted 69f reacted under established reaction conditions giving products in high yields (86–93%). Substrates bearing electron-donating substituents were also well tolerated (69g and 69h). However, when the substitution pattern of the exocyclic double bond was changed, the yield dropped noticeably. Product 70i could only be isolated in a moderate 40% yield after 72 h. Finally, when subjecting phenols 70o–q under the established reaction conditions, no product was formed, proving the significance of the 2-hydroxy functionality in the substrate. TIPS OH
R3 R2
R1
R3
[RhCp*Cl2]2 (2.5 mol%) TIPS-EBX* (1.2 equiv.) DIPEA (1.5 equiv.)
TIPS
I
O
R2
R1 MeCN, rt, 2-72 h
Me
OH
69
TIPS-EBX*
70 TIPS
TIPS
TIPS
O
TIPS OH
R1
Me
R2
OH OH 70i; R2=H, 40% 70a; R1=H, 91% 2 70j; R =Et, 78% 70b; R1=4-F, 86% 70k; R2=Ph, 83% 70c; R1=4-Cl, 90% 1 70d; R =4-Br, 93% TIPS 70e; R1=5-F, 90% 70f; R1=4-NO2, 92% OH 70g; R1=4-Me, 92% 70h; R1=4-OMe, 87%
Me OH R2 70l; R2=F, 71% 2 70m; R =CN, 78%
70o; 0% (no conversion)
70n; 95% TIPS
TIPS
HO
S
Me
Me 70p; 0% (no conversion)
Me OMe 70q; 0% (no conversion)
Scheme 41. Rh-catalyzed alkynylation of 2-vinylphenols with ethynyl benziodoxolones.
14
Tetrahedron
The proposed Rh-catalyzed alkynylation mechanism is initiated by a base-assisted ligand exchange with 69 followed by C–H bond activation through an addition/elimination step which leads to the formation of rhodacycle A (Scheme 42). Next, insertion of the triple bond adjacent to the hypervalent iodine of TIPS-EBX* affords complex B, which undergoes elimination of 2-iodo-6-methylbenzoate to give the rhodium vinylidene complex C. 1,2-Migration of the vinylic moiety followed by a ligand exchange finally releases the corresponding product 70 and regenerates the rhodium catalyst. TIPS
OH
Me
R1 70
OH
HX
Me
R1 69
[Cp*Rh(X)2]
2 HX
Cp* O Rh X TIPS
O
R1
R1 A
Me
Cp*
RhCp*
Me
O Rh X O
R1 TIPS C
Me
TIPS-EBX* Me
Cp*O O Rh
I
R1 TIPS B
Me
Scheme 42. Proposed reaction mechanism for Rh-catalyzed alkynylation of 2-vinylphenols with ethynyl benziodoxolones.
In 2018, Zhou and co-workers published a protocol on Rh(III)catalyzed meta-selective C–H alkenylation of phenol derivatives [46], a similar transformation also previously published by the same group, based on palladium catalysis using a designed traceless organosilicon template as the directing group. [23] This remote meta-C–H functionalization of phenols represents the first example employing Rh(III) as the transition metal catalyst (Scheme 43). Thorough screening of the reaction conditions proved [RhCp*Cl2]2 to be the catalyst of choice in combination with Cu(CO2CF3)2⋅xH2O and V2O5 in DCE as the solvent of choice. Phenols bearing electron-donating and electronwithdrawing groups reacted smoothly with ethyl acrylate to afford 73b–i in good yields with excellent meta-selectivities. The scope of alkenes was also investigated and under the standard reaction conditions majority of investigated alkenes reacted well with the selected phenols giving rise to the desired olefinated products in moderate to good yields (73j–o, 50–63%). O R1
T
O [RhCp*Cl2]2 (5 mol%) Cu(CO2CF3)2 xH2O (1 equiv.) 2 V2O5 (1 equiv.) R
+
O
Et
Et
N T=
R2
A) 2-Phenylphenols R1
R2
O
DMF, 90-120 oC, 24 or 48 h
74
O
R2 75
R1 R1
O O
O O
O
Me
O
O O
O
O R2
R2 75n; R2=Me; 94% 75o; R2=tBu; 87% 75p; R2=NMe2; 73% 75q; R2=OMe; 92% 75r; R2=F; 81% 75s; R2=CF3; 88%
Si(iPr)2
73
B) 2-Heteroarylphenols
T
R1 O
R1
T
OH
CO2Et 73a; R1=H, 66% (m/others = 90:10) 73b; R1=Me, 54% (m/others = 92:8) O
R1
Rh2(OAc)4 (5 or 1 mol%) OH SPhos or PCy3 (10 or 2 mol%) CO2 (1 atm) tBuOK (4.5 equiv.)
75a; R1=H; 95% 75g; R1=F; 87% 75j; R1=Me; 66% 75k; R2=Me; 91% 75b; R1=Me; 97% 75h; R1=CF3; 89% 75l; R2=OMe; 96% 75c; R1=OMe; 94% 75i; R1=CN; 54% 75m; R2=CF3; 57% 75d; R1=F; 89% 75e; R1=Cl; 76% 75f; R1=Ph; 96%
R1
DCE, 120 oC, 36 h
72
71
T
stable CO2, as the source of CO moiety. Recently, Li et al. developed a chelation-assisted Rh(II)-catalyzed C–H carboxylation of 2-arylphenols under atmospheric pressure of CO2. [47] Remarkably, the Rh-catalyzed reaction overrides the site selectivity dictated by the well-known Kolbe-Schmitt type reaction of 2-phenylphenols and therefore occurs on the less nucleophilic aryl ring. Detailed screening of the reaction conditions justified the choice of the transition metal, ligand, base, and solvent. Rh2(OAc)4 proved superior activity in the reaction. The bridging acetate ligand in the well-defined bimetallic dimer structure of the Rh-catalyst might play an important role to facilitate the C–H cleavage. Electron-rich monodentate phosphine ligands, specifically SPhos, promoted the activity of the Rh-catalyst, which lead to the formation of the desired products in high yields. Such ligands are presumed to increase the nucleophilicity of the Rh-complex intermediate towards CO2 after C–H cleavage. Furthermore, tert-BuOK was the chosen base, as its features might help trap more CO2 and therefore increase the concentration of CO2 in the solution. Finally, the highest conversions were determined when the reaction was carried out in dimethylformamide (DMF), also a good solvent for absorbing CO2. With the optimized conditions in hand, the substrate scope for the C–H carboxylation reaction was investigated (Scheme 44). 2-Phenylphenols bearing electrondonating (75b, 75c, and 75n–q) and electron-withdrawing (75d, 75e, 75i, 75m, 75r, and 75s) groups reacted smoothly. Even sterically hindered substrates were reactive (75j, 66%). Unfortunately, halides, such as bromide, were not suitable substrates, as decomposition and dehalogenation reactions may occur. Furthermore, the scope of different 2-heteroarylphenols was tested and notably, diglyme was chosen as the optimal solvent, whereas the reaction carried out in DMF produced more side products, possibly due to a higher tendency for the heterocycles to undergo a Kolbe-Schmitt type reaction in DMF (77a–j, 71–95%).
T
R2 73j; R2=CO2CH2CF3, 56% (m/others = 88:12) 2 73k; R =CO2Me, 63% (m/others = 93:7) 73l; R2=CN, 61% (m/others = 90:10) 73m; R2=PO(OEt)2, 50% (m/others = 97:3) 73n; R2=SO 2Ph, 49% (m/others = 94:6) 73o; R2=CHO, 55% (m/others = 94:6)
Rh2(OAc)4 (1 mol%) PCy3 (2 mol%) CO2 (1 atm) tBuOK (4.5 equiv.)
R1 O
Het
R1
CO2Et
73c; R1=Me, 61% (m/others = 94:6) 73d; R1=OMe, 63% (m/others = 95:5) 73e; R1=OC(O)Me, 54% (m/others = 91:9) 73f; R1=F, 45% (m/others = 95:5) 73g; R1=Cl, 60% (m/others = 94:6) 73h; R1=CO2Me, 55% (m/others = 92:8) 73i; R1=CF3, 50% (m/others = 94:6)
Scheme 43. Rh(III)-catalyzed meta-alkenylation of phenols.
Catalytic carboxylation of non-activated C–H bonds still remains a challenge, largely due to the thermodynamic and kinetically
R1
R1
77
R1
O O
O O
O
Het
diglyme, 100 oC, 48 h
76
S
O
O O
O
N O N
77a; R1=H, 86% 77b; R1=Me, 81% 77c; R1=OMe, 83% 77d; R1=F, 71%
77e; R1=H, 95% 77f; R1=OMe, 90%
77g; R1=H, 85% 77h; R1=Me, 85% 77i; R1=F, 72%
77j; 72%
Scheme 44. A) Rh(III)-catalyzed C–H carboxylation of 2-phenylphenols. B) Rh(III)-catalyzed C–H carboxylation of 2-heteroarylphenols.
Detailed experiments were made to support a purposed catalytic cycle for this transformation (Scheme 45). First, 74b is formed
15 from 74 which coordinates with complex A with the help of t BuOK to form complex B in situ. Then, the chelation-assisted aryl C–H bond activation of complex B via proton abstraction with the assistance of tBuOK affords complex C. Nucleophilic carboxylation of C with CO2 leads to the formation of the unstable eight-membered Rh-carboxylate complex D, which is converted to complex E by ligand exchange with KOAc. Possibly, a second ligand exchange with KOAc occurs and after protonolysis of the resulting carboxylate and subsequent lactonization, the desired product 75 forms and complex A reenters the catalytic cycle. R1
BuOH tBuOK R1
t
R1
O
OK
OK O
R2
R2
R2
lactonization
75
74b
complex A
ROH + KOAc Rh2(OAc)4 + SPhos
R1
R1
ORh2(OAc)3(SPhos)
OK CO2Rh2(OAc)3(SPhos) R2
E protonolysis
B
R2 ROK
ROK
ROH + KOAc
R1
O
R2
C-H bond cleavage
Rh2(OAc)2(SPhos) R1 O
ROH + KOAc O Rh2(OAc)2(SPhos)
O D
nucleophilic addition
74
KOAc
CO2
R2
C
Scheme 45. Proposed mechanism for Rh(III)-catalyzed C–H carboxylation of 2-phenylphenols.
The same group published a similar rhodium-catalyzed protocol on C–H bond carboxylation on heteroarenes with CO2. [47,48] The difference in their previously established protocol is the use of bidentate phosphine ligands (dppm or dpppe) oppose to monodentate (SPhos or PCy3), which proved to be vital importance for this reaction. The scope of this C–H carboxylation of substituted 2-(imidazo[1,2-a]pyridine-2-yl)phenols with CO2 showed good generality towards different substituents (Scheme 46). Both electron-withdrawing (78b–d, 78i) and electrondonating (78e–h, 78j) groups were tolerated, with the latter resulting in slightly higher yields of products. Substrates with different substituents on the phenolic ring also reacted smoothly, giving the desired products in good yields (79k–n). Comparably the reactions were also carried out without the addition of Rh2(OAc)2 and the corresponding ligand (yields in parenthesis are 1H NMR yields), therefore indicating the importance of the present Rh/phosphine catalytic system on the reaction yields. R2
N R1
OH
N
N
Rh2(OAc)4 (1-5 mol%) dppm or dpppe (2-10 mol%) CO2 (1 atm) tBuOK (4.5 equiv.)
Ar(Het)
[RhCl(cod)]2 (5-10 mol%) ligand (20-40 mol%) B2(pin)2 (2 or 3 equiv.)
O N
toluene, 100-160
80
N
Ph2P O
N 79
R1
oC,
n
PPh2
dppm: n=1 dpppe: n=5
O
81a; 89% (A)
O Ar(Het) B O
15 h
81
conditions A: PCy3, 100ºC conditions B: IMesMe, 100ºC conditions C: IMXyMe, 160ºC B(pin)
B(pin)
81b; R1=OPiv, 72% (A), 0% (B) 81c; R1=OCONMe2, 66% (A), 0% (B) 81d; R1=NMe2, 68 (B)
R2
R1 81e; R1=tBu, 77% (B) 81i; R1=OCF3, 62% (B) 1 81j; R1=F, 70% (B) 81f; R =Ph, 80% (B) 81g; R1=OMe, 68% (B) 81k; R1=CF3, 61% (B) 81h; R1=OPh, 71% (B) B(pin)
B(pin)
B(pin)
S
N
R1
N
N
O
N R1
X X=Me: IMesMe X=OMe: IMXyMe
R2
R1
N
X
B(pin)
DMF, 90-100 oC, 24 or 48 h
78
A rhodium-catalyzed reaction of aryl 2-pyridyl ethers with a diboron reagent for the formation of arylboronic acids via activation of the C(aryl)–O bond was developed by Chatani and co-workers. [49] The 2-pyridylodxy (OPy) group is a frequently used motif for ortho directed metal-catalyzed C–H functionalization and the standard method to remove the pyridine ring in 2-OPy involves a N-methylation step followed by a cleavage of the C(pyridinium)–O bond by NaOMe to give the corresponding phenol. Hence, the reported method by Chanati involves the conversion of the OPy group by substituting the OPy group with a synthetically useful boryl group in a single step and in a catalytic manner. The methodology consists of three different sets of reaction conditions (conditions A, B, and C), whereas the choice of the latter depends on the nature of the substrate. The main difference between the established reaction conditions is the ligand and reaction temperature (Scheme 40). At first, conditions A, as the mildest, were developed for the desired transformation (having PCy3 as the chosen ligand and temperature at 100 ºC). Unfortunately, conditions A were ineffective for several less reactive substrates. For this reason, reinvestigation of the reaction conditions was needed which lead to the development of conditions B (IMesMe, 130 ºC). The scope showed broader tolerance for pyridyl ethers containing a range of functional groups such as simple ethers (80g, 80h), fluorinated substituents (80i–k) and amines (80d). However, conditions B proved to be unsuitable for substrates containing carbonyl functionalities (80b, 80c). Moreover, this borylation reaction was found to be relatively sensitive toward steric effects, as ortho substituted substrates gave the desired products in lower yields (81l, 41%; 81m, 50%). The decrease in the yields is presumed to be due to the formation of a reductive cleavage product, which indicates that an ortho substituent does not significantly inhibit the C(aryl)–O activation process but rather slows down the subsequent oxidative addition step. For accelerating the transmetalation step, a new NHC ligand was designed which would serve as a stronger σ-donor. As a result, a methoxysubstituted analogue of IMesMe was prepared (conditions C; IMXyMe, 160 ºC). Satisfyingly, the yields of products 81l and 81m were increased to 63% and 70%. In addition, heteroaromatic substrates also underwent the borylation reaction smoothly, giving products in good yields (81n–p, 60–82%).
O
79a; R1=H, 81% (30%) 79b; R1=F, 57% (12%) 79c; R1=Cl, 55% (8%) 79d; R1CF3, 66% (5%) 79e; R1=Me, 78% (43%) 79f; R1=Et, 95% (65%) 79g; R1=Ph, 75% (11%) 79h; R1=p-tol, 73% (43%)
O
N O
79i; R1=CF3, 62% (15%) 79j; R1=Me, 86% (34%)
N
R1
O
O 79k; R2=Br, 47% (12%) 79l; R2=Me, 84% (45%) 79m; R2=Et, 89% (55%) 79n; R2=Ph, 70% (39%)
Scheme 46. C–H carboxylation of 2-(imidazo[1,2-a]pyridine-2-yl)phenols with CO2.
81l; R1=Me, 63% (C), 42% (B) 81m; R1=Ph, 70% (C), 50% (B)
Me
N 81n; 82% (B)
N Me 81o; 60% (B)
Me 81p; 65% (B)
Scheme 47. Rh-catalyzed borylation of (hetero)aryl pyridyl ethers with B2(pin)2.
4. Ru-Catalyzed C–H Bond Functionalization In 2012, Ackermann and co-workers reported a Ru-catalyzed C– H bond arylation of 2-pyridyl-substituted phenol derivatives, the
16
Tetrahedron
first example of a ruthenium-catalyzed direct arylation via sixmembered ruthenacycle. [50] The arylation reaction was catalyzed by an in-situ formed ruthenium(II)-carboxylate complex. Under optimal conditions, 2-pyridyl-substituted phenol derivatives 82 were arylated with 4-bromoanisole in the presence of 2.5 mol % [RuCl2(p-cymene)]2, MesCO2H and K2CO3 as the base to give the corresponding monoarylated product 83 (Scheme 48). The reaction with the 2-Me substituted substrate gave the corresponding arylated pyridyl phenol 83a in a decent 44% isolated yield. Electron-withdrawing groups such as CF3 and F did not influence the reaction performance deriving the corresponding arylated products 83b, 83c, and 83d in good to excellent yields (42%, 71%, and 99%; Scheme 25). The Rucatalyzed C–H bond arylation protocol was also applicable by using less expensive and reactive aryl chlorides (X=Cl) in reaction with a set of different O-pyridyl fluorophenols 82 affording the final products in good to excellent yields (83e–r, 52–99%). [RuCl2(p-cymene)]2 (2.5 mol% or 5 mol%)
R2
O
+
R1
N
ArX X = Br, Cl
82
N
Me
MesCO2H (30 mol%) toluene, K2CO3, 120 oC, 20 h
N
CF3 O
N
O
F
83a; (X=Br), 44%
N
N
F O F
F
OMe 83b; (X=Br), 42%
Ar 83
O
F OMe
R2
O R1
OMe
OMe
83c; (X=Br), 71%
83d; (X=Br), 99% Me
N
F
N
F O
N
F
O
O R3
R3 83e; R3=OMe, (X=Cl), 98% 83f; R3=COMe, (X=Cl), 88%
83g; R3=OMe, (X=Cl), 77% 83h; R3=COPh, (X=Cl), 63%
Me Me N
F
Me N
F
N
F
O
O
R3 83i; R3=OMe, (X=Cl), 95% 3 83j; R =COMe, (X=Cl), 94% 83k; R3=CO2Me, (X=Cl), 71%
O
R3
R3 R3
83l; R3=OMe, (X=Cl), 75% 83m; R3=COMe, (X=Cl), 52%
83n; R3=OMe, (X=Cl), 99% 83o; R3=COMe, (X=Cl), 94% 83p; R3=CO2Et, (X=Cl), 61%
(85j), and esters (85k–m). Unfortunately, the desired products were not obtained when alkyl chlorides were employed as the coupling partner. O R1
+
N 84
O R1
N 85
benzene, 120 oC, 24 h
R2
R3
R4
OPy
OPy
OPy
OPy
OPy MeO
R1
85a; R1=H, 73% 85b; R1=4-Cl, 38% 85c; R1=4-OMe, 81% 85d; R1=4-NO2, n.r. 85e; R1=2-Me, 51% 85f; R1=5-Me, n.r.
MeO
MeO
MeO
Cl
R2 85g; R2=nPr, 62% 2 i 85h; R = Pr, 63%
O 85i; 58%
MeO2C
R2
85k; R2=Me, 36% 85l; R2=nHep, 34% 85m; R2=iPr, 37%
85j; 37%
Scheme 49. Ruthenium-catalyzed meta-C–H phenoxypiridines with isopropyl bromide.
alkylation
of
2-
A series of designed experiments were conducted to support the proposed mechanism shown in Scheme 50. First, 2-(2,6dimethylphenoxy)pyridine, bearing two methyl substituents on the ortho positions of the phenyl ring, failed to react with alkyl bromide, supporting the importance of the ortho-CAr–H metalation in the process. Second, an active six-membered ruthenacycle was prepared from a chosen phenol and [Ru(pcymene)Cl2]2, which was submitted under the standard reaction C–H functionalization conditions providing the desired metaalkylated product and therefore indicating that the ruthenacycle might be the active catalyst in the reaction. Finally, the desired product was not obtained when radical scavengers were added to the reaction system, suggesting that the alkylation reaction might involve a radical process. On the basis of the above mentioned results a plausible mechanism involves an active six-membered ruthenacycle A, which is subjected to an electrophilic attack at the meta-position of the directing group through a strong ortho/para-directing effect of the Ru–CAr σ-bond. The alkyl radical originates from a ruthenium-mediated single-electrontransfer process. Finally, the deprotonation of species B with the assistance of Ru(III) and the base forms a stable complex C, which undergoes ligand exchange with 2-phenoxypyridine and releases the desired meta-alkylated product, whereas the active species re-enters the catalytic cycle.
83q; R3=OMe, (X=Cl), 59% 83r; R3=COMe, (X=Cl), 57%
O R1
Scheme 48. Ru-catalyzed C–H bond arylation of 2-pyridyl-substituted phenol derivatives.
The first example of the synthesis of meta-alkylphenols via ruthenium-catalyzed C–H functionalization of phenol derivatives with sec/tert-alkyl bromides was reported by the Wang group. [51] A number of 2-phenoxypyridines bearing substituents at different positions of the phenyl ring were examined as coupling partners (Scheme 49). Substituents at the para (84b, 84c) or ortho (84e) positions of the 2-pyridyloxy group did not influence the reaction outcome. However, the corresponding product 85f was not formed with the methyl group at the meta position, which is presumed to be difficult to react due to steric hindrance. The electronic properties of the substituents also drastically influenced the final outcome of the reaction, as electron-donating substituents favored the formation of the meta-alkylated product 85c oppose to those bearing electron-withdrawing groups where no reaction was observed (85d). Furthermore, several alkyl bromides were tested as coupling partners with 2-(4methoxyphenoxy)pyridine under the established reaction conditions. Both sec-alkyl and tert-alkyl bromides favored the meta-alkylation process as well as simple ethers (85i), halogens
[Ru(p-cymene)Cl2]2 (5 mol%) 1-AdCOOH (30 mol%) K2CO3 (2 equiv.)
R2 R3 R4 (3 equiv.)
Br
84
O
N R1
85 O -
R2
N Ru L C
O
Ru(II) + KHCO3
R3
N Ru L
N
R4
84, K2CO3 1-AdCOOH
[Ru(p-cymene)Cl2]2
A
Ru(III) + K2CO3 O -
N Ru L
[Ru(III)X]
[Ru(II)]
Br
B
Scheme 50. Purposed mechanism for ruthenium-catalyzed meta-C–H alkylation of 2-phenoxypiridines with isopropyl bromide.
A novel catechol synthesis through Ru(II)-catalyzed regio- and chemo-selective C–H hydroxylation reaction was developed. [52] The protocol was initially tested on a set of different protected phenols (esters, carbonates, and carbamates), among which phenyl dimethylcarbamate gave the best result. Condition screening showed [Ru(p-cymene)Cl2]2 to be the most effective
17 catalyst in combination with K2S2O8 as the oxidant in a 1:1 solvent mixture of TFA/TFAA (Scheme 43). Pleasingly, no double-hydroxylation products were observed in all examples. Moreover, the reaction could be carried out at room temperature, although at a much slower rate. The typical reaction temperature for achieving satisfying yields was determined to be 70–90 ºC. A survey of the reaction scope showed to be very broad, including ortho-, meta-, and para-substituted carbamates, as well as those with electron-donating (86b–d) and electron-withdrawing (86e– h) groups were well tolerated. Even, acetyl and aldehyde groups were compatible with the reaction conditions, yielding products 87i and 87q in 40% and 67%, respectively. Gratifyingly, all meta-substituted carbamates only gave one regioisomeric product (87k–r), due to steric hindrance. Interestingly, when reacting carbamates bearing ester or ketone substituents, the carbamate group showed to be superior in terms of directing ability (87i, 87j, and 87r). It must be noted, that a chosen set of phenol carbamates was also converted to the desired catechols effectively by palladium catalysis (5 mol% of Pd(OAc)2) at ambient temperature, although in lower yields. NMe2
O R1 86
O
87a; R1=Me, 79% 87b; R1=OMe, 58% 87c; R1=tBu, 61% 87d; R1=Ph, 53% 87e; R1=F, 70%
O R1
TFA/TFAA, 70-90 oC, 2-3 h 87 O
R1
[Ru(p-cymene)Cl2]2 (2.5 mol%) K2S2O8 (2 equiv.)
NMe2
R1
O OH 87f; R1=Cl, 70% 87g; R1=Br, 74% 87h; R1=NO2, 70% 87i; R1=COMe, 40% 87j; R1=CO2Me, 62%
O
NMe2
O OH
NMe2
O OH 87k; R1=Me, 77% 87l; R1=CF3, 76% 87m; R1=F, 75% 87n; R1=Cl, 77%
87o; R1=Br, 73% 87p; R1=I, 81% 87q; R1=CHO, 67% 87r; R1=CO2Me, 71%
O [Ru(p-cymene)Cl2]2 (5 mol%) + Ar S Cl xylene, 120 oC, 24 h O
O N R1
88
Me p-Tosyl
O
R1
R1 89
Cl
N
O
O
N Cl
1 89a; R1=H, 83% 89c; R =OMe, 86% 89b; R1=Me, 78% 89d; R1=NO2, n.r.
O
O
p-Tosyl
p-Tosyl
Cl
O S
Ar
N Cl Me 89f; trace
N
89e; 76% F
R2
F O
F O
F F
N
Cl 89g; R2=H, 82% 89k; R2=NO2, 60% 2 t 89h; R = Bu, 78% 89l; R2=F, 75% 89i; R2=Ph, 72% 89m; R2=Cl, 80% 89j; R2=OMe, 81%
Cl
N
89n; 75%
Scheme 52. Ru-catalyzed ortho-C–H chlorination and meta-C–H sulfonation of 2-phenoxypiridines.
Similar experiments as described above in Scheme 50 were also conducted to support this Ru-catalyzed dual C–H bond functionalization mechanism indicating (1) the necessity of ortho-CAr–H metalation in the reaction process, (2) the sixmembered ruthenacycle being a plausible key active intermediate, and (3) suggestion that the reaction involves a radical process. A plausible catalytic cycle was therefore proposed (Scheme 53). Initially, the key six-membered ruthenacycle A is formed and then attacked by an arylsulfonyl chloride at the para position on the Ru–CAr σ-bond after which an oxidative addition of the arylsulfonyl chloride in followed. Finally, reductive elimination of complex B yields the final product 89.
Scheme 51. Ruthenium-catalyzed C–H hydroxylation of phenyl carbamates. O
The first example of transition-metal-catalyzed ortho/metaselective dual C–H functionalization of 2-phenoxypyridines in one reaction was described by Yang and co-workers. [53] The transformation includes an ortho-C–H chlorination and meta-C– H sulfonation of the corresponding substrates which was achieved in the presence of 5 mol% [Ru(p-cymene)Cl2]2 in xylene as the chosen solvent. The selected arylsulfonyl chloride plays an extremely important role in the reaction, as it represents both, the sulfonation and chlorination reagent, and more importantly, also the oxidant in the developed process. As the scope of the substrates was examined, the methyl group on the ortho- and para-position of the 2-pyridyloxy directing group did not affect the reaction (89b; 78%, 89e; 76%), whereas only traces of the desired product 89f were obtained for substrate bearing the Me group on the meta-position (Scheme 52). Interestingly, strong electronic effects were observed in the reaction where electrondonating substituents showed to be favorable for the reaction (89c; 86%) in contrast to electron-withdrawing groups which deactivated the reaction (89d; no reaction). Moreover, the scope of the arylsulfonyl chlorides was also examined and according to the obtained results, alkyl (89h), aryl (89i), electron-donating (89j), electron-withdrawing (89k) groups, and halides (89l, 89m, and 89n) were compatible with the applied reaction conditions.
N Cl
Cl Ru SO2Ar
O S O
89
Me
i-Pr
C-H cleavage 2
reductive elimination
O S Ar
O
O N Cl Cl Ru SO2Ar O
B
H i-Pr
O O Ar S Cl O oxidative O S addition Ar O
N Ru Cl A
88 [Ru(p-cymene)2Cl2] i-Pr
O Ar S Cl meta-C-H O functionalization
N Ru Cl i-Pr
Scheme 53. Proposed catalytic cycle for Ru-catalyzed dual C–H bond functionalization of 2-phenoxypyrydynes.
5. Ir-Catalyzed C–H Bond Functionalization In 2008, Hartwig and co-workers reported a one-pot strategy for silyl-directed Ir-catalyzed ortho-C–H borylation of phenols. [54] The approach employs a diethyl silyl directing group to affect C– H borylation at the ortho position of the phenol derivative. Phenols 90 were treated with diethylsilane (Et2SiH2) in the presence of 0.5 mol% of [Ir(cod)Cl]2 as the catalyst to give silyl ether 91 (Scheme 54). After evaporation of the solvent and redissolution of the residue in THF, bis(pinacolato)diboron (B2pin2), pinacolborane (HBpin), [Ir(cod)Cl]2, and 4,4’-di-tbutyl-2,2’-dipyridyl (dtbpy), were added. Consequently, orthoborylated silyl ethers 92 were obtained. The treatment of this borylation product with potassium hydrogen fluoride (KHF2) formed stable trifluoroborate salts 93. The one-pot silylation/C–H borylation sequence was carried out on various substituted phenols. Electron-rich phenols derived the corresponding trifluoroborylated phenols (2-Me 93a, 2-OMe 93b, and 3-tert-Bu 93d) in good yields. Additionally, the presence of halogen atom on the phenol moiety was well tolerated under the established
18
Tetrahedron
reaction conditions since the product 93c was isolated in quantitative yield. OH R1
OH 1. Et2SiH2, [Ir(cod)Cl]2 (0.5 mol%), C6H6
R1
2. B2Pin2, HBpin (5 mol%), [Ir(cod)Cl]2 (1 mol%), dtbpy (2 mol%), THF, 80 oC 3. 4 M KHF2 , THF
90 EtSiH2 [Ir]
OSiEt2H R1
KHF2 H2O OSiEt2H
B2Pin2, HBpin
R1 Bpin
[Ir], dtbpy
91
BF3K
93
92
R1 OH
tBu
BF3K
O
93e; 94%
tBu
O
B B O
BF3K
BF3K 93d; 82%
93a; R=Me, 96% 93b; R=OMe, 89% 93c; R=Cl, quant.
O
OH
OH
tBu
thermodynamically favorable oxidative addition of a C–H bond to the iridium complex occurs if the phenantroline ligand contains both methyl groups on the exactly specified positions as oppose to such ligands which lack one or both Me-groups on the 2 and 9 positions. And secondly, the reaction also exhibits H2 as a byproduct, which was found to inhibit the activity of the iridium complex and therefore slow down the reaction rate. Consequently, a flow of nitrogen was applied to the reaction mixture to remove hydrogen from the system achieving high yields of the desired products. The silylation reaction of 1,3dimethoxybenzene (94a) occurred with >10:1 selectivity on the meta C–H bond over the ortho C–H bonds (Scheme 56). In the case of 2,6-dimethylanisole (94b) and 1,2,3-trimethoxybenzene (94c) the electron-rich para C–H bond to the methoxy groups were successfully silylated forming products 95b and 95c in high 83% and 84% yields, respectively. Unfortunately, the reaction of 3,4-dimethoxytoluene afforded 95d in a very low yield even at a higher catalyst loading (4 mol%) and longer reaction time (48 h).
B H
O
O
B2pin2
N N dtbpy
HBpin
Scheme 54. Silyl-directed Ir-catalyzed ortho-C–H borylation of phenols.
OMe
[Ir(cod)(OMe)]2 (1 mol%) 2,9-Me2Phen (2 mol%) N2
OMe R1
R1 Si
dioxane, 100 ºC, 20 h
TMSO 95
94
Two sets of experiments were conducted to confirm that the ortho-functionalization results from temporary formation of an Ir–Si bond, rather than formation of a silylborane. Furthermore, H/D exchange studies indicated that the ortho-substituted product results from selective C–H activation at the ortho-position directed by the hydrosilyl group, rather than selective functionalization of ortho-C–H bond cleavage by the silylborane moiety. The plausible mechanism is proposed to proceed through a trisboryl complex A as the key intermediate (Scheme 55). Furthermore, the ortho-borylation occurs by the generation of tha bisboryl monosilyl complex C, followed by selective ortho-C–H activation and functionalization to yield complex D. Thus, coordination between Si and B gives rise to bisboryl complex. Finally, the addition of B2pin2 would release the ortho-borylated phenol 93 with regeneration of the trisboryl complex intermediate B. OSiEt2H R
R O SiMe2
N H
91
Ir Bpin
N Bpin
tBu
C
N
Bpin
N
Bpin
N
Ir N tBu
Bpin Ir Bpin
Bpin
Bpin
A
B
Bpin R O SiMe2
N Ir OSiEt2H R Bpin
H
N Bpin D
93
Scheme 55. Proposed mechanism for the Ir-catalyzed silyl-directed orthoborylation of phenols.
Recently, a new procedure for the silylation of aryl C–H bonds employing a carefully designed catalytic system has been described. [55] The high efficiency, functional group tolerance, and regioselectivity of developed methodology in based on the combination of iridium complex [Ir(cod)(OMe)]2 with a sterically hindered phenantroline ligand, 2,9-Me2-phenantroline (2,9Me2Phen). Thorough condition screening revealed two crucial features for the reaction to proceed efficiently. First, the high activity of the catalyst is evident in the appropriately chosen ligand, which turned out to be a phenantroline containing methyl groups on the 2 and 9 positions. Apparently, a more
OTMS Me
N
Me 2,9-Me2Phen
R1
OMe
OMe
R2 MeO
Si TMSO 95a; 74%
OTMS Me
R1
N
Me
OMe Si TMSO
OTMS Me
95b; R1=Me, R2=OMe, 83% 95c; R1=R2=OMe, 84%
Me
OTMS Si TMSO Me 95d; 4%
Scheme 56. Ir-catalyzed C–H silylation of anisoles.
6. Au-Catalyzed C–H Bond Functionalization An important contribution was made by Russell et al., as they managed to develop a gold-catalyzed direct arylation reaction for the construction of biaryls which proceeds at ambient temperature. [56] The key developments of the method is the use of Ph3PAuOTs as the precatalyst, conducting the reaction at room temperature in the presence of a low concentration of methanol as a co-solvent, and forming the active oxidant in situ from iodobenzene diacetate (PhI(OAc)2) and camphorsulforic acid (CSA). Two sets of reaction conditions were established, depending on the degree of functionality of the substrate. Heavily functionalized or valuable arenes were reacted in a ratio of 1:1 with the coupling partner (conditions A), whereas simple or cheap arenes were submitted with the coupling reagent in a 2:1 stoichiometry and the precatalyst loading was reduced from 2 to 1 mol% (conditions B). Most reactions were carried out within 20–40 h at ambient temperature (97a–c, 97e–g). However, sterically hindered (97m and 97n) or electron-rich (97d and 97h) required longer reaction times (up to 80 h) and higher reaction temperatures (up to 65 ºC). Diverse functionality on the arylsilanes was well tolerated under the established reaction conditions, as halogens (97n–p), sulfonates (97q), aldehydes (97r), and pivaloyl esters (97s) gave the desired biaryls in good to excellent yields (99–99%) without oxidation or transesterifications, respectively (Scheme 57).
19 R2 OR1
SiMe3
+ R3
R2 96
Ph3PAuOTs(1 or 2 mol%) PhI(OAc)2 (1.3 equiv.) CSA (1.5 equiv.)
Conditions A:
F
R3
CHCl3/CH3OH = 50:1 r.t. or 65 ºC
(1 or 2 equiv.)
OMe
O
R2
Br
OR1
97
R1
MeO
Me Br
F
F
97m; 74% 97i; R1=OH, 82% 97a; R2=Cl, 85% 97j; R1=OMs, 71% 97b; R2=Br, 92% OMe 1 i 2 97k; R =OCON Pr2 , 69% 97c; R =I, 88% 97l; R1=NPhth, 83% 97d; R2=OMs, 81% Br 97e; R2=CO2Me, 92% R3 97f; R2=NMePiv, 94% 97g; R2=NPhth, 88% 97n; R3=2-F, 92% 97q; R3=4-OTf, 72% 97o; R3=4-Cl, 97% 97r; R3=3-CHO, 77% 97h; R2=CON(Me)CH2CH2NMe2, 65% 97p; R3=3-Br, 72% 97s; R3=4-OPiv, 80%
Conditions B: Me
MeO
Me
OMe
Me F
F
97t; 68%
F
97u; 63%
97v; 46%
Scheme 57. Au-catalyzed C–H arylation of phenol derivatives for the formation of biaryl systems.
Zhang and co-workers reported the first example of a goldcatalyzed intermolecular site-selective C–H bond functionalization of unprotected phenols by using diazo compounds as the coupling partner in the presence of a tris(2,4di-tert-butylphenyl) phosphite derived gold complex under mild conditions. [57,58] The reaction proceeded in a highly chemoselective manner furnishing the desired para C–H bond functionalization products 100 (Scheme 58). The crucial element for making the reaction regioselective was the addition of the sterically hindered phosphine ligand ((2,4-tBu2C6H3O)3P)), which solely lead to the formation of para C–H functionalized products, as no ortho and meta C–H functionalization or O–H insertion products were detected. Varying the scope of different diazo compounds 99 had no effect on the selectivity and yield of the reaction (100a–g). Moreover, different substituted phenols reacted smoothly, affording the corresponding C–H functionalization products in good to excellent yields (100h–l; 83–98%). Interestingly, phenol substrate bearing an ortho-allyl substituent only gave the para C–H functionalization product 100m without the formation of any product via cyclopropanation or O–H insertion. Furthermore, when meta-methylphenol 98n and meta-methoxyphenol 98o were employed, ortho C–H functionalization products could also be detected and isolated in decent yields indicating, that the methyl and methoxy group can also act as directing groups. Surprisingly, sterically hindered phenol still gave the desired para C–H functionalization product 100p in a good 75% yield rather than the less hindered O–H insertion product. OH OH
A highly chemo- and stereoselective gold catalyzed para-C–H bond functionalization of phenols with haloalkynes was recently developed. [59] Reaction conditions screening revealed that bulkier ligands, such as IPr, improved the yield but not the (E:Z)ratio of the reaction. However, by changing the counterion to BARF– in combination with IPrAuCl not only enhanced the yield but also achieved perfect diastereoselectivity at room temperature. With the optimal reaction conditions in hand, the scope of chlorophenyl acetylene with various phenol derivatives was explored (Scheme 59). Ortho-substituted phenols all delivered exclusively para-functionalized products in good to excellent yields (102a–e; 68–93%). However, in the cases of meta-substituted phenols, a mixture of ortho- and para-addition products was obtained with good overall yields of the corresponding products (102f and 102f’; 102g and 102g’). However, the reactions involving phenols substituted on the para-position always yielded ortho-substituted products in good to excellent yields (102h–j; 73–80%). The scope with respects to the chloroalkynes was also investigated. Overall, the substituents on the phenyl ring had only a slight effect on the selectivity and yields of the reaction. For example, electron-deficient chloroalkynes showed better reactivity (102n–q) than electronrich chloroalkynes (102k–m). Furthermore, it should be mentioned that chloroalkynes showed better reactivity than bromoalkynes (102r), possibly due to the higher electronegativity, whereas the corresponding iodoalkynes did not react at all. Cl OH
OH R2 R1 +
Cl
IPrAuCl (2 mol%) NaBARF (3 mol%) DCE, r.t., 3-6 h
101 OH
OH
Ph
102f; 51% OH
R2
102h; R1=Me, 73% Ph 102i; R1=OMe, 80% 102j; R1=Ph, 77% R1
Me
Me Cl
Ph
102
R2
Cl OH
102a; R1=Me, 84% 102b; R1=tBu, 86% 102c; R1=OMe, 93% 102d; R1=CH2-CH=CH2, 68% Cl 102e; R1=Ph, 77% R1
Ph
R1
OMe
OH
OH Cl
102f’; 35% R2=Me,
Ph
OMe Cl
102g; 32%
102k; 61% 102l; R2=tBu, 74% 102m; R2=OMe, 54% 102n; R2=F, 82% Cl 102o; R2=Cl, 85% 102p; R2=Br, 92% 102q; R2=CF3, 68%
OH Cl
Ph
102g’; 59% OH
Br 102r; 49%
Scheme 59. Au-catalyzed C–H functionalization of unprotected phenols with chlorophenyl acetylenes.
R1 N2 R1
+
CO2R2
Ar
98
LAuCl (5 mol%) AgSbF6 (30 mol%)
L = (2,4-tBu2C6H3O)3P Ar
DCM, r.t.
99
2
CO2R 100
OH OH
OH
OH R1
R3
Scheme 58. Au-catalyzed C–H functionalization of unprotected phenols with diazo compounds.
Me
CO2R2 Ph
CO2R2
Ph
100a; R3=H, R2=Et, 99% 100h; R1=Me, R2=Me, 98% 100b; R3=4-Cl, R2=Me, 99% 100i; R1=F, R2=Et, 85% 100j; R1=Cl, R2=Me, 83% 100c; R3=4-Br, R2=Et, 99% 100d; R3=4-Me, R2=Me, 98% 100k; R1=Br, R2=Me, 86% 3 2 100e; R =2-Cl, R =Me, 91% 100l; R1=I, R2=Me, 92% 100f; R3=3-OMe, R2=Me, 70% 100g; R3=3-CF3, R2=Me, 63%
CO2Me
100m; 68%
Me Ph
CO2Me
100p; 75% R1
OH
R1
OH
Ph CO2Me Ph CO2Me R1=Me: 100n; 57% R1=Me: 100n’; 39% 1 1 R =OMe: 100o; 34% R =OMe: 100o’; 57%
The preliminary competitive kinetic study showed no kinetic isotope effect and therefore revealing that the C–H bond cleavage of phenol is not involved in the rate-determining step. Hence, C– H activation of phenol by gold is unlikely and so the reaction should proceed via nucleophilic addition of phenol onto the πactivated alkyne (Scheme 60). A series of experiments with deuterated starting materials and solvents proved that no direct transfer of the proton released from the Wheland intermediate takes place. Instead, exchange processes with either the acidic phenol group or traces of water in the reaction media occurs. Based on the results the authors propose a mechanism in which Au coordinates to the chloro-substituted alkyne carbon which leads to a more stable π-activated alkyne A/vinyl cation B. The
20
Tetrahedron
phenol then attacks the highly electrophilic alkyne after which the final product 102 in formed. LAu+
Cl OH
phenol (anisole) gave the aminated product preferably at the para position of the methoxy group (106a), whereas in the cases of other disubstituted phenols the amination reaction proceeded rather at the ortho position to the methoxy functionality (106b–f).
R1 Ar
OMe
Cl
102
OMe
R1
+ 105
HO H
Carbocationic nature LAu+ Ar Cl
Cl [Au]
R1
Ar
NH3
MsO OTf (1.5-4 equiv.)
OMe Cl AuL
B
NH2 106a; 65% (o/m/p = 4/1/14.3) 101
Scheme 60. Proposed reaction mechanism for Au-catalyzed C–H functionalization of phenols with haloalkynes
106 NH2
OMe NH2
m
p
Ar OH
R1
MeCN/H2O, 16 h, r.t.
o
Ar
A
FeSO4 (5 mol%)
R1 106b; R1=Br, 78% 106c; R1=NH2, 70% 106d; R1=CO2Me, 64% 106e; R1=CN, CN% 106f; R1=Me, 53% (o/m = 4.8/1)
Scheme 62. Iron-catalyzed direct C–H amination of phenols.
7. Fe-Catalyzed C–H Bond Functionalization A chemoselective iron-catalyzed oxidative cross-coupling reaction, also known as cross-dehydrogenative coupling (CDC) was developed by Pappo and co-workers. [60] Such methods represent a practical and sustainable strategy in the formation of new C–C bonds as they are achieved directly from two C–H bonds without the need of prefunctionalization of the coupling partners. Iron complexes with high oxidations states are generated following the oxygen–oxygen bond scission of organic peroxides or molecular oxygen. Hence, these high-valent iron species are capable of inducing a single electron transfer (SET) process, which generates an active radical cation species that reacts with a nucleophile. The general system for such transformations usually relies on the use on Fe(III) salts, a terminal oxidant, and 1,2-dichloroethane (DCE) or toluene as the solvent. Furthermore, prolong reactions times and heating is required to initiate the oxidation process and to ensure satisfying results. Unfortunately, such harsh conditions result in the formation of side-products, typically homocoupling processes take place. The protocol developed by Pappo is based on an ironcatalyzed oxidative coupling of phenols carried out in fluorinated solvents, which significantly reduces the oxidative potential of the phenols and thereby facilitates the coupling reactions under mild conditions, avoiding the formation of homocoupled byproducts. Among the tested fluorinated solvents, 1,1,1,3,3,3hexafluoropropan-2-ol (HFIP) and 2,2,2-trifluoroethanol (TFE) were chosen as the optimal solvents as non-symmetrical biaryl products 104a–e were formed in good to excellent yields at room temperature (Scheme 61). OMe FeCl3 (5-15 mol%) tBuOOtBu (1.5-2 equiv.) Ar OH 103
+
MeO OMe (1-3 equiv.)
HFIP or TFE, r.t.
OMe HO Ar MeO
OH OMe
MeO
OMe 104a; R1=H, 79% 104b; R1=CO2Me, 93% 104c; R1=Br, 77%
MeO MeO
OMe
9. References
OH
OH OMe
OMe 104d; 37%
In this review our aim was to summarize the transition-metal catalysts applied for the C–H bond functionalization of phenol derivatives. In surveying the literature on the transition-metal C– H bond functionalization of phenol derivatives, we have recognized achievements and developments that have been realized by using transition metals such as Pd, Rh, Ru, Ir, Au, and Fe. A great number of C–H bond functionalization reactions have been possible using Pd as the chosen catalyst being capable of overcoming continuous challenges of selectivity. Thus, acylation, arylation, hydroxylation, bromination and olefination have been achieved via Pd-catalyzed C–H functionalization. Other metals such as Ir and Ru have been demonstrated to be effective especially in borylation and arylation reactions respectively. Additionally, C–H bond arylation and olefination have also been achieved using Rh catalysis. Metal-catalyzed C–H insertions of the discussed systems, being directed by increasingly complex templates, have given rise to selective meta- and para-functionalization, however, they are still remaining a challenging area for future development. Regarding the discussed methodologies, only some of them meet the criteria of green and environmentally benign synthetic strategies. Thus, those catalyzed transformations possessing relatively large directing groups hardly meet the definition. Consequently, the future developments should be directed towards a greener approach. Finally, known mechanistic insights for reactions catalyzed by Pd, Rh, Ru, Ir, and Au are summarized and in general involve metalacyclic intermediates forming more stable five-membered cyclometalated complexes or even less typical the corresponding six-membered metalacycles.
104
OMe
R1
8. Conclusion
MeO MeO
OMe OMe
1.
OMe 104e; 51%
Scheme 61. Iron-catalyzed oxidative cross-coupling of phenols with arenes.
Direct C–H amination of phenol derivatives without relying on a directing group is reported. [61] An inexpensive iron precatalyst, FeSO4, showed superior activity over other metals (MnSO4, Cu(MeCN)4PF6). Furthermore, the use of a newly developed amination reagent (MsO–NH3+ –OTf) afforded the desired aminated phenols in satisfying yields (Scheme 62). Unsubstituted
2.
Weber, M.; Kleine-Boymann, M. Phenol. In Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, Germany, 2000, pp. 503– 519; (b) Tyman, J. H. P. Synthetic and Natural Phenols; Studies in Organic Chemistry, Vol. 52, Elsevier, Amsterdam, 2014; (c) Z. Rappoport, The 1. Chemistry of Phenols, Ed. John Wiley & Sons, Chichester, UK, 2003. Chen, C.-T.; Martin-Martinez, F. J.; Jung, G. S.; Buehler, M. J. Chem. Sci. 2017, 8, 1631–1641; (b) Finkbeiner, H.; Hay, A. S.; Blanchard, H. S.; Endres, G. F. J. Org. Chem. 1996, 31, 549–555; (c) W. Hesse,W.; Lang, J. Phenolic Resins. In Ullmann’s
21 3.
4.
5.
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, Germany, 2000, pp. 583–600. (a) Top. Organomet. Chem.: Directed Metallation, Vol. 24 (Ed.: N. Chatani), Springer, Heidelberg/New York, 2007. (b) Top. Organomet. Chem.: C–H Activation, Vol. 292 (Ed.: J.-Q. Yu and Z. Shi), Springer, Heidelberg/Dordrecht/London/New York, 2010. (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879–2932; (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802; (c) Colby, D. A.; Tsai, A. S.; Bergman, R.G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814–825; (d) Giri, R.; Shi, N.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242–3272; (e) Liu W.; Ackermann, L. ACS Catal. 2016, 6, 3743– 3752; (f) He, J.; Wasa, M.; Chan, K. S. L.; Shao,Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754–8786. (a) Omae, I. Coord. Chem. Rev. 2004, 248, 995– 1023; (b) Al Mamari, H. H.; Al Awaimri, N.; Al Lawati, Y. Molbank, 2019, 2019(3), M1075; (c) Al Mamari, H. H.; Al Lawati, Y. Molbank 2020, 2020, M1099.
6.
7.
8.
9. 10. 11. 12. 13. 14.
15. 16. 17.
(a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155; (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965–3972; (c) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657–3659. (a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743; (b) Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664–670; (c) Rouquet, G.; Chatani, N. Chem. Sci. 2013, 4, 2201–2208; (d) Ano. Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354–359. (a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743; (b) Al Mamari, H. H.; Diers, E.; Ackermann, L. Chem. Eur. J. 2014, 20, 9739–9743; (c) Gu, Q.; Al Mamari, H.H.; Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem. Int. Ed. 2014, 53, 3868–3871. Angew. Chem. 2014, 126, 3949-3952. Huang, Z.; Lumb, J.-P. ACS Catal. 2019, 9, 521– 555. Hennings, D. D.; Iwasa, S.; Rawal,V. H. J. Org. Chem. 1997, 62, 2–3. Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844–10845. Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468–469. Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837–5844. (a) Jia, C.; Piao, D.: Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–1995, (b) Jia, C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252–7263. Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997, 36, 1740–1741. Gu, S.; Chen, C.; Chen, W. J. Org. Chem. 2009, 74,7203–7206. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 18056–18059.
18. (a) Moreno-Manas, M.; Pleixats, R. Acc. Chem. Res. 2003, 36, 638–643, (b) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 86–89. 19. Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 9269–9276. 20. Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing,W. R.; Yu, J.-Q. J. Am. Chem. Soc. 2019, 141, 14870– 14877. 21. Luo, J.; Preciado,S.; Larossa, I. J. Am. Chem. Soc. 2014, 136, 4109–4112. 22. Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406–12409. 23. Mi, R.-J.; Sun, J.; Kühn, E.; Zhou, M.-D.; Xu, Z. Chem. Commun. 2017, 53, 13209–13212. 24. Patra, T.; Bag, S.; Kancherla, R.; Mondal, A.; Dey, A.; Pimparkar, S.; Agasti, S.; Modak, A.; Maiti, D. Angew. Chem. Int. Ed. 2016, 55, 7751–7755. 25. Maity, S.; Hoque, E.; Dhawa, U.; Maiti, D. Chem. Commun. 2016, 52, 14003–14006. 26. Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 7567–7571. 27. Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. Nature 2017, 551, 489– 494. 28. Xu, J.; Chen, J.; Gao, F.; Xie, S.; Xu, X.; Jin, Z.; Yu, J.-Q. J. Am. Chem. Soc. 2019, 141, 1903–1907. 29. Dou, Y.; Kenry; Liu, J.; Jiang, J.; Zhu, Q. Chem. Eur. J. 2019, 25, 6896–6901. 30. Sharma, U.; Naveen, T.; Maji, A.; Manna, S.; Maiti, D. Angew. Chem. Int. Ed. 2013, 52, 12669–12673. 31. 1 For selected examples see: (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C.; J. Nat. Prod. 2000, 64,134–135, (b) Bowyer, P. W.;Tate, E. W.; Leatherbarrow, R. J.; Holder, A. A.; Smith, D. F.; Brown, K. A. ChemMedChem 2008, 3, 402–408, c) De Luca, L.; Nieddu, G.; Porcheddu, A.; Giacomelli, G. Curr. Med. Chem. 2009, 16, 1–20, d) Day, S.-H.; Chiu, N.-Y.; Tsao, L.-T.; Wang, J.-P.; Lin, C.-N. J. Nat. Prod. 2000, 63, 1560–1562. 32. Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14, 1760–1763. 33. Luo, S.; Luo, F.-X.; Zhang, X.-S.; Shi, Z.-J. Angew. Chem. Int. Ed. 2013, 2, 10598–10601. 34. Kim, M.; Sharma, S.; Park, J.; Kim, M.; Choi, Y.; Jeon, Y.; Kwak, J. H.; Kim, I. S. Tetrahedron 2013, 69, 6552–6559. 35. Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250–9253. 36. Huang, C.; Chavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 17630– 17633. 37. Duan, S.; Xu, Y.; Zhang, X.; Fan, X. Chem. Commun. 2016, 52, 10529–10532. 38. Lou, S.-J.; Chen, Q.; Wang, Y.-F.; Xu, D.-Q.; Du, X.-H.;. He, J.-Q.; Mao, Y.-j.; Xu, Z.-Y. ACS Catal. 2015, 5, 2846–2849.
22
Tetrahedron 39. Gao, C.; Li, H.; Liu, M.; Ding, J.; Huang, X.; Wu, H.; Gao, W.; Wu, G. RSC Adv. 2017, 7, 46636– 46643. 40. Sun, X.; Sun, Y.; Zhang, C.; Rao, Y. Chem. Commun. 2014, 50, 1262–1264. 41. John, A.; Nicholas, K. M. J. Org. Chem. 2017, 72, 5600–5605. 42. Bedford, B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem. Int. Ed. 2003, 42, 112–114. 43. Bedford, R. B.; Limmert, M. E. J. Org. Chem. 2003, 68, 8669–8682. 44. Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F. Org. Lett. 2011, 13, 3235–3237. 45. Finkbeiner, P.; Kloeckner, U.; Nachtsheim, B. J. Angew. Chem. Int. Ed. 2015, 54, 4949–4952. 46. Mi, R.-J.; Sun, Y.-Z.; Wang, J.-Y.; Sun, J.; Xu, Z.; Zhou, M.-D. Org. Lett. 2018, 20, 5126–5129. 47. Fu, L.; Li, S.; Cai, Z.; Ding, Y.; Guo, X.-Q.; Zhou, L.-P.; Yuan, D.; Sun, Q.-F.; Li, G. Nat. Catal. 2018, 1, 469–478. 48. Huang, R.; Li, S.; Fu, L.; Li, G. Asian J. Org. Chem. 2018, 7, 1376–1379. 49. Kinuta, H.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015, 137, 1593–1600. 50. Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012, 14, 1154–1157. 51. Li, G.; Gao, P.; Qu, C.; Yan, Q.; Wang, Y.; Yang, S.; Wang, J. Org. Lett. 2017, 19, 2682–2685. 52. Yang, X.; Sun, Y.; Chen, Z.; Rao, Y. Adv. Synth. Catal. 2014, 356, 1625–1630. 53. Li, G.; Zhu, B.; Ma, X.; Jia, C.; Lv, X.; Wang, J.; Zhao, F.; Lv,Y.; Yang, S. Org. Lett. 2017, 19, 5166– 5169. 54. Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534–7535. 55. Karmel, C.; Chen, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2019, 141, 7063–7072. 56. Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Science 2012, 337, 1644–1648. 57. Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136, 6904–6907. 58. Liu, Y.; Yu, Z.; Zhang, J. Z.; Liu, L.; Xia, F.; Zhang, J. Chem Sci. 2016, 7, 1988–1995. 59. Adak, T.; Schulmeister, J.; Dietl, M. C.; Rudolph, M.; Rominger, F.; Hashmi,A. S. K. Eur. J. Org. Chem. 2019, 3867–3876. 60. Gaster, E.; Vainer, Y.; Regev, A.; Narute, S.; Sudheendran, K.; Werbeloff, A.; Shalit, H.; Pappo, D. Angew. Chem. Int. Ed. 2015, 54, 4198–4202. 61. Legnani, L.; Cerai, G. P.; Morandi, B. ACS Catal. 2016, 6, 8162–8165.
Review Highlights: The review covers advances, and developments in the topic of metal-catalyzed C-H bond functionalization of phenol derivatives with the chelation assistance using directing groups. The review provides information and latest developments in C-H bond functionalization of phenol derivatives as catalyzed by various transition metals: • • • • • •
Pd-Catalyzed C–H Bond Functionalization Rh-Catalyzed C–H Bond Functionalization Ru-Catalyzed C–H Bond Functionalization Ir-Catalyzed C–H Bond Functionalization Au-Catalyzed C–H Bond Functionalization Fe-Catalyzed C–H Bond Functionalization
Hamad Al Mamari obtained his DPhil (PhD) degree (2006) at the University of Oxford under the supervision of Professor David Hodgson. Upon completion of his PhD, he returned to his home institution, Sultan Qaboos University, Muscat, Oman to hold the rank of an Assistant Professor. In 2012/2013 he spent oneyear sabbatical at Georg-August University, Göttingen, Germany. In that period, he worked in the field of C-H bond functionalization in the research group of Professor Lutz Ackermann. Later, he spent short-term visits at the Department of Chemistry, School of Science, University of Tokyo in the group of Professor Eiichi Nakamura (2015 & 2017), the Institut für Anorganische Chemie, JuliusMaximilians-Universität, Würzburg, Germany in the group Professor Todd Marder (2016), and at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia in the group of Professor Dr. Bogdan Štefane. His research interests are themed in organic synthesis with emphasis in developments of methods and reactions in the field of C-H bond functionalization and their applications in natural product synthesis.
Bogdan Štefane received his PhD in chemistry in 2000 at the University of Ljubljana under the supervision of Professor S. Polanc. From 2002 to 2004 he was a Marie Curie postdoctoral fellow at the University of Oxford, working with Professor D. M. Hodgson. In 2009 he continued his post-doctoral education as a Fulbright Fellow at the University of Maryland in the research group of Professor H. O. Sintim. In 2017 he spent 4 months as a visiting Professor at Sultan Qaboos University in Oman. In 2004 he became an Assistant Professor and 2011 received the position of an Associate Professor at the University of Ljubljana, where he is currently the head of the Department of Organic Chemistry. His research interests are the development of novel synthetic methods for the synthesis of heterocyclic compounds, transition metal catalysis and design of catalysts, activation of inert chemical bonds, and photochemistry.
Helena Brodnik Žugelj received her PhD at the Faculty of Chemistry and Chemical Technology, University of Ljubljana in 2017 under the supervision of Professor Bogdan Štefane. During her PhD studies she was a visiting scholar at the University of Toronto (Ontario, Canada) in the research group of prof. Mark Lautens. After completing her studies, she became a teaching assistant at the Department of Organic Chemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana. Her main research interests are developing novel and efficient synthetic methods for the activation of inert C–H bonds by employing various transition-metal complexes for the synthesis of structurally complex heterocyclic compounds of biological value and also studying the mechanistic background such transformations.
Declaration of Interest Statement
The authors declare no conflict of interest
Dr. Hamad Al Mamari Corresponding author
S0040-4020(20)30005-3
DOI:
https://doi.org/10.1016/j.tet.2020.130925
Reference:
TET 130925
To appear in:
Tetrahedron
Received Date: 23 August 2019 Revised Date:
31 December 2019
Accepted Date: 5 January 2020
Please cite this article as: Al Mamari HH, Štefane B, Žugelj HB, Metal-catalyzed C–H bond functionalization of phenol derivatives, Tetrahedron (2020), doi: https://doi.org/10.1016/ j.tet.2020.130925. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2020 Published by Elsevier Ltd.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Metal-Catalyzed C–H Bond Functionalization of Phenol Derivatives
Leave this area blank for abstract info.
Hamad H. Al Mamaria,*, Bogdan Štefaneb, and Helena Brodnik Žugeljb a Department of Chemistry, College of Science, Sultan Qaboos University, PO Box 36, Al Khoudh 123, Muscat, Sultanate of Oman. b Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI 1001, Ljubljana, Slovenia.
1
Tetrahedron journal homepage: www.elsevier.com
Metal-Catalyzed C–H Bond Functionalization of Phenol Derivatives 0 1 2 3 4 5
Hamad H. Al Mamaria,*, Bogdan Štefaneb, and Helena Brodnik Žugeljb a
Department of Chemistry, College of Science, Sultan Qaboos University, PO Box 36, Al Khoudh 123, Muscat, Sultanate of Oman
b
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI 1001, Ljubljana, Slovenia.
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Phenols and phenol derivatives constitute important starting materials, synthetic intermediates, and functional moieties of a broad range of chemicals and materials. They represent large production products of benzene and benzene derivative oxidation and are nowadays progressively available from biomass sources. In last decades or so, there have been tremendous advances in the field of catalytic C–H bond functionalization, among which metal-catalyzed C– H bond functionalization of phenol derivatives plays a substantial role. In this review, the latest transition metal catalyzed C–H bond functionalizations of phenol derivatives are summarized. These methods are powerful tools for the arylation, alkenylation, and acylation as well as annulation of phenol derivatives, especially as they can be carried out in a highly stepeconomical manner with readily available starting materials based on simple aryl (pseudo)halides, alkenes as reagents. Additionally, this review summarizes the main mechanistic aspects of the covered topic.
Keywords: Phenol Derivatives C–H Bond Functionalization Chelation-Assistance Transition Metals Monodentate Directing Groups Bidentate Directing Groups
2009 Elsevier Ltd. All rights reserved.
Contents: 1. 2.
Introduction Pd-Catalyzed C–H Bond Functionalization 3. Rh-Catalyzed C–H Bond Functionalization 4. Ru-Catalyzed C–H Bond Functionalization 5. Ir-Catalyzed C–H Bond Functionalization 6. Au-Catalyzed C–H Bond Functionalization 7. Fe-Catalyzed C–H Bond Functionalization 8. Conclusion 9. References ___________________________ * Corresponding author, Tel: +96824142471, Fax: +96824141469, Email: [email protected]
2
Tetrahedron 1. Introduction
Phenol-based molecules are ubiquitous in nature. Although phenol itself is toxic and corrosive, it shows antiseptic effects and is used as a disinfectant. Derivatives of phenol manifest themselves in a broad range of natural products, materials, and pharmaceuticals. [1] For example, gallic and ferulic acid are frequently occurring natural phenol derivatives found in plant cells, phenol-based natural opiate morphine is commonly used for the treatment of pain, whereas dopamine functions as an important hormone and neurotransmitter in the brain and body (Scheme 1A). A consequence of phenols being naturally abundant, the interest of using phenolic building blocks in materials science has also emerged, showing successful results in the development of biopolymers [2a], polyphenylene oxides (PPOs) [2b], and phenol-based resins (Scheme 1B). [2c] A) Naturally-occuring phenol derivatives O
OH
OH
C-H DG Functionalization
R
O
R
OH HO
major issue in the science of C–H bond functionalization. Over the past two decades, scientists have addressed the site-selectivity issue of C–H bond functionalization. One way to provide control of the issue is to use an electron donor atom or a Lewis basic atom (monodentate directing groups) that can coordinate the Lewis acidic transition metal typically used in C–H bond functionalization. [4] Coordination of the metal by the Lewis basic atom brings the metal in proximity to a certain C–H bond. A certain C–H bond appropriately located and distanced from the Lewis basic atom can be cleaved to promote formation of a fivemembered thermodynamically chelate or cyclometalated complex (Scheme 2). [5] Therefore, it is the formation of such stable five-membered chelates that is the driving force or an incentive for C–H bond cleavage at a certain carbon site, controlled by its carbon distance from the Lewis basic atom in the monodentate directing group.
H
M FG
R
R
DG
Ferulic acid
FG M
DG = directing group M = transition metal FG = functional group
HO Phenol
NH2 HO
NCH3
Based on the efficient concept of monodentate directing groups, bidentate directing groups have been developed. [6-8] The chelation-assisting group contains two Lewis basic atoms appropriately distanced from each other as well from the reacting substrate. The inception of the bidentate chelation assistance is driven by the formation of a thermodynamically stable bis-fivemembered chelate (Scheme 3). [5] With two five-membered chelates fused together, the bis-chelate is conformationally rigid.
OH
Morphine
Dopamine
B) Phenol-based materials H N
OH Me N H
HO HO
OH NH
H N
O
Me
Me
O
R
Me
n
polyphenylene oxide (PPO)
HO HO
DG M FG R Five-membered chelate
Scheme 2. Chelation-assistance by monodentate directing groups in C–H bond functionalization.
H
HO
HO
M FG
cyclometalation
OCH3 OH
DG H
DG = N, P, O, S, As coordination
R
H
R
HO
OH Gallic acid
O
R
R
D G H
C-H Functionalization
R
M FG coordination
R
DG
DG = N, P, O, S, As
Scheme 1. Examples of phenols in nature and materials science.
With developments made in organic synthesis, accessing phenol derivatives can be achieved in many ways. Recently, carbon– hydrogen (C–H) bond functionalization has emerged as a powerful strategy for the formation of carbon–carbon (C–C) or carbon–heteroatom (C–Het) bonds. [3] The chemical science allows transformation of otherwise inert nonfunctional C–H bonds into functional reactive counterparts. Consequently, C–H bond functionalization provides and offers new gateways to functional chemicals, molecules, and materials of various applications and interests in chemical, biochemical, biological, pharmaceutical, petrochemical, medicinal, agricultural, materials sciences, and industries. Due to its rapid and direct transformation approach, C–H bond functionalization reduces steps, chemicals, materials, solvents, energy, and time. Thus, it is a step- and atom-economical chemical science. As a result, C–H functionalization it could in some cases meet the definition of a green and environmentally benign synthetic approach. Hydrocarbons contain several types of inert C–H bonds of various electronic and steric bulk. Selective C–H bond functionalization of a certain type imposes a significant challenge. [3,4] Thus, regioselectivity or site-selectivity is a
DG
M FG
OH
An example of a substructure of a biopolymer
D G H
cyclometalation R R
D G FG
R DG
D G
DG M FG Double five-membered chelate R
Scheme 3. Chelation-assistance by bidentate directing groups in C–H bond functionalization.
The additional rigidity of such bis-chelates in bidentate directing groups, has resulted in developing new C–H bond functionalization reactions, non-realized before with monodentate directing groups. Bidentate directing groups in some cases proved to be beneficial than the monodentate counterparts in metal-catalyzed C–H bond functionalization. There have numerous reviews in the field of the C-H activation science, whether in monodentate directing group-assisted C–H functionalization or in the use of bidentate directing groups. [4-7] C–H bond functionalization can be catalyzed by various metals such as frequently used second row transition metals (Pd, Ru, and Rh) and less by cheaper, earth abundant, environmentally benign first row transition metals (Mn, Fe, Co, Ni and Cu). [4-7] To the best of our knowledge, there has been no reviews reported on the development of transition-metal catalyzed C–H bond functionalization of phenol derivatives apart from the recently published review by Lumb on phenol-directed C–H
3 functionalization, [9] which describes methodologies addressing phenol-directed transformations. Thus, the present review demonstrates a selection of relevant results and developments made in metal-catalyzed C–H bond functionalization of phenol derivatives. Specifically, developments and advances in C–H bond functionalization of phenol derivative A to provide the C–H functionalized product B (Scheme 4). OR
electron-deficient substrates (4c; 49%). As expected, sterically hindered bromophenol 3f was less efficient under the established reaction conditions. After the successful Pd-catalyzed intramolecular arylation, deprotection of the silicon tether on products 4 was performed using a standard TBAF procedure yielding the final unprotected phenols in excellent yields.
H
tBu Si Ph
O
OR FG
C-H Functionalization
Br PivOH, Cs2CO3 3Å MS, p-xylene, 140 oC
R
R
R
A
tBu O Si Ph
Pd(OAc)2 (5 mol%) PCy3*HBF4 (10 mol%)
3
R 4
B
Scheme 4. Schematic representation of C–H bond functionalization of phenol derivatives.
tBu O Si Ph
tBu O Si Ph
tBu O Si Ph
O2N
tBu O Si Ph
R2
F
2. Pd-Catalyzed C–H Bond Functionalization A mild, selective procedure for Pd-catalyzed intramolecular coupling of phenol with aryl halides is reported to proceed efficiently (Scheme 5). [10] Unlike Pd(OAc)2, Pd2(dba)3, or PdCl2, a well-defined palladacycle A, also known as Herrmann’s catalyst, is formed from Pd(OAc)2 and P(o-tolyl)3 and is crucial for the reaction to proceed with high conversion. The choice of base was also found to be essential for the Pd-catalyzed intramolecular cyclization of aryl halides 1 to the cyclized product 2, supporting the hypothesis that the reaction is accelerated through the phenolate anion as the nucleophile. Furthermore, when a hydroxyl group is attached to the aryl unit, then the nature of the phenolate furnishes the aryl ring as more electron-rich, consequently making it more reactive for the coupling reaction. The reaction was found to be of good scope. When the ortho position is blocked, then the substrate is forced to cyclize at the para position into product 2c. The cyclization reaction of the naphthyl substrate 2b required longer time, although cyclized in an overall excellent 96% yield to afford a mixture of the ortho and para products 2b in a ratio of 1:2. Deoxygenated aryl halide 1d was also reactive and provided the corresponding product 2d in a decent 75% yield, although higher reaction temperature was required. Moreover, the reaction gave good results in the presence of a protected nitrogen atom to provide a N-containing product 2e in a 76% yield.
R1
R1 4a; R1=H, 73% 4b; R1=OMe, 78%
A practical and mild Pd(II)-catalyzed ortho C–H arylation protocol for phenol esters using Ph2IOTf as the aryl pseudohalide was published by Liu et al. [12] With the discovery of crystalline complex A (confirmed by X-ray analysis), it is the first example of an acyloxy-directed Pd insertion into a C–H bond. The result indicates that the presence of HOTf may influence the electrophilicity of Pd(II) to improve such metal-catalyzed reactions. Further studies indicated, that HOAc is also relevant either for the C–H deprotonation step or for the stabilization of some active palladium intermediates. The reaction showed good substrate scope giving arylated pivalate esters 6 in good to excellent yields. Notably, halo substituents (7e–h) were well tolerated, making it possible for further modifications on the halogenated positions (Scheme 7). The selectivity of the reaction (mono- vs. diarylation) could be controlled by varying the temperature (from r.t. to 60 ºC) and the ratio of the reactants (7i and 7i’). OPiv
1
OH
O
Cs2CO3 (3 equiv.) DMA, 95-115 oC
O 2
OH
HO
O
O
OH
Ar Ar P O Pd O
Me
O Pd O P Ar Ar Me palladacycle A
N CO2Me
Me 2c; 84%
HO 2b; (1:2) 96%
2d; 75%
2e; 76%
Scheme 5. Pd-catalyzed intramolecular coupling of phenol with aryl halides.
In 2009, Gevorgyan and co-workers reported a Pd-catalyzed intramolecular C–H bond arylation of TBS-protected obromophenols. [11] The reaction features the use of an easily introducible and removable silicon tether, tert-butyldiphenylsilyl (TBDPS) protecting group, as the aryl coupling source. Accordingly, they examined the palladium-catalyzed intramolecular arylation reaction on a set of chosen TBDPSprotected o-bromophenols 3 (Scheme 6). The reaction scope showed some extent of variability as the yields proved to be higher with electron-rich arenes (4b; 78%) in comparison to
R1
OPiv tBu
25 ºC, 7i; 55% and 7i’; 14% 60 ºC, 7i; 10% and 7i’; 63%
Ph
p-Tol O
+ tBu
OPiv
7g; R1=Br, 82% 7h; R1=Cl, 94%
Ph OH
Ph 7
Me
7c; R1=OMe, 75% 7d; R1=Ph, 95% 7e; R1=Br, 88% 7f; R1=I, 24%
Ph
O
OPiv Ph
Ph 7a; 92% 7b; R1=Ph, 86%
OH
O 2a; 84%
R1
R1=Me,
+ HO
R
HOTf (10 mol%), Ph2IOTf (1.2 equiv.) Ac2O (0.5 equiv.), DCE, 25-60 oC, 3-48 h
6
OPiv
palladacycle A (5 mol%)
X= Br, I
OPiv
Pd(OAc)2 (10 mol%)
R
R1
X
4e; R1=CHO, R2=MeO, 52% 4f; R1=R2=tBu, 30%
Scheme 6. Intramolecular C–H bond arylation of TBS-protected obromophenols.
OH
OH
4d; 51%
4c; 49%
OTf O H Pd O H OH2
Ph Me
complex A
Scheme 7. C–H arylation protocol of phenol esters using Ph2+IOTf– as the aryl pseudohalide.
In 2010, Dong and co-workers reported a remarkable and very detailed study on Pd-catalyzed ortho-arylation of ophenylcarbamates with simple arenes using sodium persulfate (Na2S2O8) as the oxidant of choice to produce o-arylphenol derivatives (Scheme 8). [13] The reaction features employing simple and inexpensive arenes as reaction partners rather than pre-functionalized aryl iodides or hypervalent iodine reagents. Moreover, as a side product, only one equivalent of H2 is released. Optimization of the reaction conditions showed that both TFA and sodium persulfate were needed for achieving high conversion for the oxidative coupling reaction to occur. Previous studies have proposed that acetate anions can facilitate the intramolecular transfer of protons in the formation of a six-
4
Tetrahedron
membered transition state. In addition, TFA was found to enhance the electrophilicity of Pd(II), assisting the electrophilic metalation step. [13] Furthermore, the strong oxidant (Na2S2O8) is needed to reoxidize Pd(0) to Pd(II) in the catalytic cycle, as the authors propose a mechanism involving two discrete C–H bond activations via Pd(0)/II catalysis. The reaction methodology showed great scope with various functional group tolerance. Thus, different substitutions on the masked phenol such as 9a, 9c, and 9d were produced in 80%, 73%, and 75% yields respectively. Replacing the Cl with F on the arene was also possible as products 9h, 9i and 9j were produced in 79%, 82%, and 87% yields. The aryl coupling partners with present electrondonating functionalities yielded the corresponding products under the given reaction conditions in moderate to good yields (9k; 76% and 9l; 47%) (Scheme 8). O R
NMe2 (ca. 40 equiv.)
8 R1 R2
TFA (5 equiv.), Na2S2O8 (3 equiv.) 70 oC, 30-68 h R1
OCONMe2
R
Cl 9a; R1=Me, R2=H, 80% 9b; R1=iPr, R2=H, 55% 9c; R1=Ph, R2=H, 73% 9d; R1=R2=Me, 75% 9e; R1=H, R2=Me, 85% 9f; R1=H, R2=Cl, 76% 9g; R1=H, R2=F, 84%
R1 R1
F
9k; R1Me, 76% 9l; R1=OMe, 47%
9h; R1=Me, 79% 9i; R1=tBu, 82% 9j; R1=Ph, 87%
R2 Pd(OAc)2 or PdCl2 (5 mol%)
R3
+ OH
Cs2CO3 (1.2 or 4 equiv.), 4Å MS, DMF, 100 oC, 7-44 h
R3
OH
R3
(1.2 or 4 equiv.) 10
12
11 R1
R1
R2
R2
R3 OH
R3
OH
R3
12a’; R1=R2=R3=H, 56% 12b’; R1=Me, R2=H, R3=H, 63% 12e’; R1=H, R2=H, R3=OMe, 57%
12a; R1=R2=R3=H, 63% 12b; R1=Me, R2=H, R3=H, 60% 12c; R1=H, R2=OMe, R3=H, 73% 12d; R1=H, R2=NO2, R3=H, 72% 12e; R1=H, R2=H, R3=OMe, 70%
Scheme 10. Mono and diarylation of 2-phenylphenols with aryl iodides.
OCONMe2
F
R1
I
R2
O
9
MeO
OCONMe2
Cl
Ar
R1
NMe2
O
Pd(OAc)2 (10 mol%)
ArH
+
O
were formed as major products deriving 12a’, 12b’, and 12c’ in 56%, 63%, and 57% yields, respectively.
Scheme 8. ortho-Arylation of o-phenylcarbamates with simple arenes using sodium persulfate.
Mechanistic studies support a distinct mechanistic proposal shown in Scheme 9. The oxidative cross-coupling occurs via a Pd(0/II) catalytic cycle involving a C–H bond activation by carbamate-assisted cyclopalladation to afford complex A, followed by a C–H functionalization reaction by electrophilic metalation, reductive elimination elementary steps yielding the desired arylated carbamate 9, and finally re-oxidation of Pd(0) to the active Pd(II) with sodium persulfate. [13,14]
Phenols can easily be converted to 2-phenoxypyrimidines via copper-catalyzed coupling with 2-halopyrimidines (Ullmann reaction), obtaining valuable directing groups which have been used to develop many C–H bond functionalization protocols. In 2009 Chen and co-workers explored the possibility of introducing a 2-pyridinyl group as a directing group in a palladium-catalyzed direct arylation and acetoxylation reaction of 2-aryloxypyrimidines. [16] It was found that both Cu(OTf)2 and Ag2O are essential for the catalytic system. Other combinations of copper and silver salts led to much lower conversions of starting material. The scope of the reaction, with respect to the heteroaryl ether substrates, was investigated (Scheme 11). However, the coupling reactions of electron-rich arylethers were more efficiently achieved under the established conditions (Scheme 11, 14a and 14b). Furthermore, coupling reactions of different phenylboronic acids was also investigated. Both electron-rich and electron-deficient arylboronic acids gave monoarylated products in good yields. However, the relatively sterically hindered boronic acid (2-tolylboronic acid) demonstrated poor reactivity (14i; 17%).
Pd(OAc)2 2HX 2HOAc “H2O”
LnPdIIX2
oxidation
NMe2
O R1 H
8
N
O
R1 reductive elimination
Ar 9
NMe2 O
O R1 Pd Ar
R1
N 14 R3
NMe2
O PdII A X
NMe2 O
Ar O
N
toluene, 120 oC, 24 h
13
Ph
O
R1
+ Ar B(OH)2
Pd(OAc)2 (5 mol%) Cu(OTf)2 (1 equiv.) Ag2O (1 equiv.)
HX
Pd0
O
R1
N
cyclopalladation
[O]
O
O
N N
R1
14a; R1=Me, R2=H, 54% 14b; R1=R2=Me, 73% 14c; R1=Ph, R2=Me, 30% 14d; R1=Cl, R2=H, 38% R2 14e; R1=CO2Me, R2=H, 33%
Scheme 11. Pd-catalyzed phenylboronic acid.
arylation
R4 O
N N
Me
of
Me
14f; R3=Me, R4=H, 58% 14g; R3=Cl, R4=H, 41% 14h; R3=CF3, R4=H, 60% 14i; R3=H, R4=Me, 17%
2-phenoxypyrimidine
with
ArH HX electrophilic metalation
Scheme 9. Proposed mechanism for Pd-catalyzed ortho-arylation of ophenylcarbamates.
A Pd-catalyzed regioselective mono- and diarylation of unprotected 2-phenylphenols with aryl iodides is described. [15] The authors propose, that the phenolic function seems to act as an efficient anchor for such a metal-catalyzed arylation reaction. The reaction employs Pd(OAc)2 as the catalyst and Cs2CO3 as the chosen base in DMF (Scheme 10). The reaction showed good scope varying substituents R1, R2 and R3. Employing 1.2 equivalents of the iodobenzene 11, the monoarylated phenols 12a–e were selectively obtained in good yields (60–73%) (Scheme 10). In the case of using PdCl2 instead of Pd(OAc)2 and with 4 equivalents of the aryl iodide 11, diarylation products
ortho-Chelation-directed C–H activation has been widely exploited in developing numerous highly efficient C–H functionalization protocols. However, activating C–H bonds which are quite distal to the existing functional groups remains a challenge. The development of remote C–H functionalization reactions based on C–H palladation processes suffers from the difficulty of forming these metalacycles larger than sixmembered rings, which can present a major obstacle in the activation step. Thus, Yu et al. reported the first example of a Pdcatalyzed cross-coupling reaction of meta-C–H bonds with arylboronic acids. [17] The meta-selectivity was achieved through the use of a U-shaped nitrile template weakly coordinated to the Pd(II) catalyst (Scheme 12). Furthermore, the addition of a monoprotected amino acid (MPAA) was found to be significant for creating an efficient coupling protocol.
5 Additionally, TBAPF6 was also essential for enhancing the reactivity of the reaction, since tetrabutylammonium salts can attribute to the ability of surfactants to prevent undesired agglomeration of Pd(0) species to form unreactive palladium black. [18] The choice of base was also found to be pivotal. In this case, CsF proved to be the most effective in comparison to carbonates and acetates. It has been reported that fluoride ions can play an important role in activating boronic acid esters and therefore facilitating the transmetalation step. The protocol showed to be quite general for both electron-withdrawing (15a–f) and electron-donating substituents (15g–h). As expected, only mono-meta-arylation was observed in the cases of orthosubstituted substrates (15a, 15e, 15g), with the exception the of ortho-fluorinated substrate 15c, where the diarylated product was isolated in a 13% yield. Unfortunately, the di-ortho-substituted substrate 15j showed poor reactivity under the established reaction conditions, presumably due to steric hindrance. Furthermore, the scope of arylboronic acids was also tested, proving good reactivity with both electron-withdrawing (15k and 15l) and electron-donating (15m and 15n) coupling partners. Finally, the U-shaped template could easily be removed under mild basic reaction conditions (LiOH • H2O), furnishing the final unprotected carboxylic acid in an excellent 96% yield. O T + Ar Bpin (3 equiv.)
R
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) Ag2CO3 (2 equiv.) CsF (2 equiv.) TBAPF6 (3 equiv.)
O
CO2Me 16a; R1=Cl, R2=H, 56% 16g; R1=Me, R2=H, 85% 1 2 16b; R =H, R =Cl, 44% 16h; R1=H, R2=Me, 81% m:(p+o+o’)=93:7 m:(p+o+o’)=85:15 16cmono; R1=F, R2=H, 43% 16i; R1=H, R2=OMe, 48% 16cdi; R1=F, R2=H, 13% m:(p+o+o’)=91:9 16d; R1=H, R2=F, 63% m:(p+o+o’)=87:13 16e; R1=CF3, R2=H, 58% 16f; R1=H, R2=CF3, 65%
NC
Ar
OMe
16 Me
O
T
R2
OMe N
T=
R
HFIP, 70 oC, 24 h
15
R1
NC
O T
O T
Me
T
Me
CO2Me 16j; traces
R3 16k; R3=F, 83% 16l; R3=CF3, 60% 16m; R3=Me, 72% 16n; R1=OMe, 70%
Pd(OAc)2 (10 mol%) F3C NHAc
O R
T
Ar +
I
O R
Me
T
T= N
(3 equiv.)
Ar=2-MeO2C-C6H4-
17
Ar 18
CHCl3, air, 100 oC, 24 h
R1 R2
O
O
T
O
O
Ar
T
T
T
MeO Ar
Ar
Ar
18a; R1=H, R2=Me, 87% 18b; R1=H, R2=OMe, 91% 18c; R1=Me, R2=H, 85% 18d; R1=iPr, R2=H, 89% 18e; R1=OMe, R2=H, 54%
Ar
18g; 58% mono:di > 20:1
18f; 87%
18h+18h’; 78% mono:di = 1:1
Scheme 13. Ligand-promoted meta-arylation of phenolic derivatives with aryl iodides.
Recently, Yu and co-workers reported the first catalytic system that enables selective meta-arylation of a variety of electron-rich alkoxy aromatics. [20] The use of a modified norbornene (NBECO2) was crucial to achieve regioselective meta-arylation. Thorough screening of the reaction conditions revealed that the combination of two ligands (6-cyanoquinaxoline and 3pyridinesulfonic acid) noticeably improved the efficiency of this nondirected arylation reaction. The importance of both ligands is likely due to the formation of a reactive cationic Pd-complex A, which could bind to the substrate more efficiently (Scheme 14). High regioselectivity was found with a variety of aryl iodides regardless of their electronic properties (19a–19d). Furthermore, a series of C3-substituted anisole derivatives were compatible under the optimized reaction conditions giving the final monoC5-arylated product (20e–j) in good yields. Unfortunately, parasubstituted anisole gave only trace amount of the desired metaarylated product, due to the steric hindrance of the methyl group. Furthermore, no product was observed with substrates containing strong electron-withdrawing groups. N OMe R1 + 19
Scheme 12. meta-Arylation of phenolic derivatives with arylborornic acid esters.
Ar I (2 equiv.)
OMe
HFIP, 95 oC, 20 h
CN
L1 =
Pd(OAc)2 (10 mol%) NBE-CO2Me (1.5 equiv.) L1 (30 mol%), L2 (15 mol%) AgOAc (3 equiv.)
OMe
N
OMe R1 Ar
F3C L2 =
SO3H N
20 OMe
SO3 R3
R1
Soon after, the same research group published an article on a series of highly versatile 3-acetylamino-2-hydroxypyridine ligands which promote meta-arylation of phenols, anilines and heteroaromatic amines using norbornene as a transient mediato. [19] After a survey of several directing groups, a benzylicpyridine based directing group was found to be the most efficient for the formation of meta-arylated products. Furthermore, a number of different ligands, containing an NHAc moiety was tested. The authors hypothesized that the installation of an NHAc group would provide a secondary binding site which could serve as an important function in the catalytic system. A bisdentate coordination would be possible between the NAc group and the oxygen atom, which would form a structure similar to monoprotected amino acid (MPAA) ligands; ligands developed by the same research group. The synergy between the pyridinebased directing groups and ligands allowed the formation of a broad scope of meta-arylated products (Scheme 13). Although, the developed protocol was exploited on a broader scope of anilines, phenol derivatives also proved to be compatible with the C–H cross-coupling methodology, yielding the final monoarylated products in good to excellent yields. Not surprisingly, when subjecting unsubstituted phenol substrate 17h, a mixture of mono- and diarylated products 18h and 18h’ was isolated in a ratio of 1:1. Interestingly, in the case of 17g, the desired monofunctionalized compound was predominantly formed.
N OH (10 mol%) AgOAc (3 equiv.) NBE-CO2Me (1.5 equiv.)
R2 20a; R2=CO2Me, 70% 20b; R2=CF3, 62% 20c; R2=Me, 62% 20d; R2=OTs, 54%
MeO2C
MeO2C 20e; R3=CO2Me, 70% 20f; R3=OMe, 58% 20g; R3=OBn, 56%
20h; R4=H, 78% 20i; R4=Cl, 65% 20j; R4=CF3, 61%
R4
N
N H N Pd OAc
Reactive complex A
Scheme 14. meta-Arylation of electron-rich arenes.
The mechanism for meta-C–H arylation of anisoles is proposed to proceed with the initial palladation at the ortho-position, which is intercepted by the norbornene insertion followed by subsequent Catellani C–H arylation (Scheme 15). To obtain evidence for the proposed mechanism, deuterium incorporation experiments were performed with ethoxybenezene under standard reaction conditions in the presence of HFIP-ol-D. The presence of 70% of deuterium being incorporated at the C2position exclusively in the meta-arylated product suggests, that the arylated product is derived from ortho-C–H palladation and the catalytic cycle is terminated by the C2 protonation (deuterium incorporation step) of the arylpalladium intermediate A.
6
Tetrahedron OMe R1
R
OMe
Ar
norbornene extrusion
20
OMe PdIILn Ar reductive elimination
19
PdIILn
C-H activation
OH
PdIILn
OH
OMe R1 PdIILn
R1 PdIILn
OH Me
Me F
R1
norbornene insertion
OMe
Me
R2
R1
PdIVLn I
R’
22
R3
OMe
A
R1
Ar I oxidative addition
(1 equiv.)
R 2. PEPPSI-IPr (2 mol%), Ag2CO3 (0.5 equiv.), AcOH, 130 ºC, 16 h one-pot process
OH
OMe
Ar
OH 1. KOH (3 equiv.), CO2 (25 atm), 190 ºC, 2h
R’
+
21 (3 equiv.)
R1
R1
I
OH
C-H activation
Scheme 15. Proposed mechanism for Pd-catalyzed meta-arylation via orthoC–H activation with norbornene insertion.
The methodology of direct regioselective functionalization of arenes is generally based on the use of various directing groups, which are preinstalled on the substrate and are removed only after the C–H functionalization step in completed. This kind of approach creates lengthy synthetic sequences. In 2014, Larrosa et al. reported the first strategy of a one-pot direct meta-arylation of phenols based on the use of CO2 as a traceless directing group. [21] The well-known reactivity of phenols toward orthocarboxylation with CO2 (i.e., Kolbe–Schmitt reaction) inspired the authors to develop a simple single-pot three-step methodology, combining carboxylation/arylation/decarboxylation to access metafunctionalized unprotected phenols. Studies revealed, that the source of the Pd catalyst proved to be crucial, with PEPPSI-IPr leading to the best results. The sequence began by treating 21 with KOH under 25 atm of CO2 at 190 ºC for 2 h, followed by the addition of the corresponding iodoarene, Pd catalyst, Ag2CO3, and AcOH, and further heating the reaction mixture at 130 ºC for 16 h (Scheme 16). Pleasingly, the developed methodology found to be completely selective for mono- vs. bis-arylation. Both electron-withdrawing and -donating groups, as well as substrates containing Cl and Br substitutes were compatible with the established protocol. Unfortunately, ortho-substituted iodoarenes were not appropriate coupling partners for this reaction, presumably due to a sterically crowded intermediate being formed in the catalytic cycle. On the other hand, the presence of an electron-donating MeO group afforded the product in a low yield, as a fast protodecarboxylation reaction of the salicylic acid intermediate occurs. This side reaction could be prevented by substituting the methoxy group with a CF3O group, which allowed the formation of the desired arylated product 22h in a 69 % yield. Electron-withdrawing groups at the C3 position were compatible with the reaction (21i and 21j), but strong electronwithdrawing group (NO2 group) showed no reaction (21k). However, substitution at the C4-position of the phenol proved to be incompatible with the arylation step, as the para-fluorophenol afforded the final product 22o in only 11% yield, whereas the para-methyl analogue showed no reactivity under the applied reaction conditions.
Me 22g; R2=OMe, 25% 22h; R2=OCF3, 69% 22i; R2=Cl, 69% 22j; R1=Br, 60% 22k; R1=NO2, 0%
22a; R1=OMe, 63% 22b; R1=F, 46% 22c; R1=Cl, 65% 22d; R1=Br, 61% 22e; R1=NO2, 54% 22f; R1=CHO, 50%
Me 22l; R3=Et, 46% 22m; R3=OCF3, 83% 22n; R3=F, 68%
Me 22o; 11%
Scheme 16. meta-Arylation of phenols via traceless CO2 directing group.
It is often strived to use directing groups, which can easily be removed after the C–H functionalization step is completed. Hence, Gevorgyan and co-workers reported a Pd-catalyzed ortho-alkenylation of phenols using a silanol-directing group, which was in the end simply removed to provide alkenylated phenols as a semi-one-pot procedure. [22] Silanol-protected phenols 23 were reacted with a chosen alkene 24 using 10 mol% of Pd(OAc)2 in combination with 20 mol% of (+)-menthyl(O2C)Leu-OH as the chosen ligand. After direct alkenylation, the silanol moiety was easily removed with the addition of TBAF as the deprotecting agent to provide the final alkenylated phenols 25. The reaction showed good scope and compatibility for different substitution patterns and electronic features (Scheme 17). Notably, meta-substituted phenols reacted at the less hindered C–H site, forming products in good to excellent yields (25a; 94%, 25b; 53%). Similarly, para-substituted phenols were also found to be compatible with the established protocol, as the final olefinated products were obtained in very good yields (25c– f). However in general, electron-rich phenols gave higher yields compared to their electron-deficient counterparts. Remarkably, this Pd-catalyzed olefination reaction proved to be completely monoselective, which is most likely due to the bulky tert-butyl groups at the silanol moiety that prevent the orientation of the silanol directing group towards the less hindered C–H site. The olefin scope was also investigated. 3,4-Dimethyl substituted silanol-protected phenol 23 was used in reaction with different electron-deficient olefins 24 to give a number of alkenylated phenols (25g–l) after the deprotection step (Scheme 17).
tBu O Si HO tBu
R1
+
R2
OH
OH CO2nBu R1=Me,
25a; 94% 25b; R1=Cl, 53%
OH R1
2. TBAF/THF
24
23 R1
R2
1. Pd(OAc)2 (10 mol%) (+)-menthyl(O2C)-Leu-OH (20 mol%) Li2CO3 (1 equiv.), AgOAc (4 equiv.) DCE, 100 oC, 24 h
R1
25 Me
CO2nBu R1=OMe,
25c; 81% 25d; R1=tBu, 89% 25e; R1=F, 58% 25f; R1=OCF3, 52%
OH R2
Me R2=SO
25g; 3Ph, 96% 25h; R2=CHO, 70% 25i; R2=COMe, 67% 25j; R2=Ph, 64% 25k; R2=4-F-C6H4, 79% 25l; R2=C6F5, 83%
Scheme 17. Pd-catalyzed alkenylation of silanol-protected phenols.
Another traceless organosilicon template was developed for directed meta-C–H alkenylation of phenols. [23] To find an effective directing group, a series of silicon-based templates bearing a nitrile moiety was synthesized. The selectivity towards meta-olefination was achieved when T (Scheme 18) was used as the optimized directing group. Presumably, the two ethyl groups on the template T provide a bond angle expansion between the phenyl ring and nitrile, favoring meta-selectivity. Therefore, using this easily introducible and also removable directing group,
7 selective meta-C–H alkenylation of phenols bearing various electron-donating and electron-withdrawing groups was achieved (Scheme 18). Furthermore, halo-substituted phenols 26 as well as sterically demanding 26 also led to satisfactory results. Moreover, the alkene substrate scope was also examined. Cyano, phosphonate, and sulfone substituted olefins were tolerated and produced 28 in good yields and satisfactory meta-selectivities. After meta-alkenylation, the organosilicon template T was removed either in the presence of p-toluene sulfonic acid or by reacting 28 with TBAF. O
T
R1
O +
R2
O R1
CO2Et T
Et
N Si(iPr) 2
28e; R1=COMe, 75% (m/others = 95:5) 28f; R1=CO2Me, 65% (m/others = 98:2) 28g; R1=CF3, 59% (m/others = 95:5) 28h; R1=Br, 78% (m/others = 91:9) 28i; R1=Cl, 75% (m/others = 95:5)
T
O
T=
28
R1 O
Et
R2
28a; R1=COMe, 73% (m/others = 92:8) 28b; R1=Me, 83% (m/others = 92:8) 28c; R1=Br, 77% (m/others = 90:10) 28d; R1=Cl, 71% (m/others = 88:12)
T
T
R1
DCE/HFIP (1:0.3), 60 oC, 24 h
27
26
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv.)
The same research group developed a similar nitrile-based template for Pd-catalyzed selective distal C–H olefination of biphenyl systems with high regio- and stereo-selectivity. [25] The study was carried out on a biphenyl phenol system due to its intrinsic importance in synthetic chemistry. Notably, the medium played a significant role, as DCE in combination with HFIP (7:1 v/v) improved the yield and selectivity. Presumably, protic solvent HFIP improves the catalytic efficiency through better solubilization of the palladium catalyst. Distal C–H olefination of biphenyl phenols 31 was tested on a series of different activated alkenes such as acrylates, ketones, and sulfones (Scheme 20). Although the minor ortho-regioisomer could be detected in the NMR spectra of the isolated compounds, the reactions gave moderate to good efficiency in forming the desired metaolefinated biphenyl products 32. Moreover, an acrylate bearing a highly fluorinated side chain was also successfully reacted (32g). Unfortunately, electron-rich olefins and electron-neutral styrenes could not be applied under the established reaction conditions.
CO2Et
28j; R2=CN, 71% (m/others = 90:10) 28k; R2=PO(OEt)2, 61% (m/others = 95:5) 28l; R2=SO2Ph, 66% (m/others = 90:10)
O
R2
T
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv.)
+
Scheme 18. meta-Alkenylation of silanol-protected phenols.
R1 (2 equiv.)
O
T= DCE/HFIP (7:1), 65 oC, 42 h, air
R1
31
The last two decades selective ortho- and more recently meta-C– H bond functionalization of arenes has been significantly exploited. However, the implementation of such a strategy for regioselective functionalization of a para-C–H bond remains extremely difficult. The reason lies in the formation of a large cyclophane-like metallacycle, which is the driving force for the successful direct C–H functionalization of arenes. In 2016 Maiti and co-workers developed a highly selective method for para-C– H olefination of phenol derivatives based on the use of a recyclable silicon-containing biphenyl-based template containing a nitrile group, which is placed at the position suitable for the formation of a cyclophane 17-membered transition state. [24] The reaction was carried out in the presence of Pd(OAc)2, Nacetylglicine as the ligand and AgOAc as the most effective base. A wide range of arenes 29 was investigated as the final products 30 were formed in good yields (Scheme 19). Mono-substituted derivatives (at the ortho- or meta-position with respect to the hydroxy group) were applicable, as sterically demanding substituents gave the final products in satisfying yields (30h; 65%). The method was also employed with a diverse set of olefins bearing different functional groups. Amides, aldehydes, ketones, sulfonyls, phosphonates as well as olefins with longchain alkyl substituents gave the desired products in good yields (30i–n; 66–88%). O T
O R1
+
Pd(OAc)2 (10 mol%) Ac-Gly-OH (20 mol%) AgOAc (2 equiv.)
R2
R3
O
T= R2
DCE/TFE, 60 oC, 32 h
m
p
R3
30
T
O 30a; R=Me, 79% (p/others = 15:1) 30b; R=Br, 68% (p/others = 8:1) m’ 30c; R=OMe, 78% (p/others = 4:1) 30d; R=Ph, 63% (p/others = 10:1)
o’
CO2Et
O
p
p
R1
32a; R=CO2Me, 62% (m/o = 14:1) 32b; R=CO2Et, 65% (m/o = 13:1) 32c; R=CO2tBu, 60% (m/o = 16:1) 32d; R=SO2Ph, 61% (m/o = 14:1) 32e; R=SO2Me, 47% (m/o = 12:1) 32f; R=CO2CH2CF3, 67% (m/o = 12:1)
T
R1
O
T
32g; 57% (m/o = 11:1) F F F F F F F
O F F F F
O
A significant contribution towards the development of highly regioselective C–H functionalization protocols has been made by Yu et al. Thus, in 2013 a Pd-catalyzed ortho- and metaolefination of α-phenoxyacetic acids through remote C–H activation promoted by weak coordination and ligand acceleration was investigate. [26] Thus, the removal of the acetic acid auxiliaries affords synthetically valuable ortho- or metaolefinated phenols. Regioselective ortho-alkenylation was carried out on a set of various α-phenoxyacetic acids 33, which were reacted with ethyl acrylate under 1 atm of O2 in the presence of 5 mol% of Pd(OAc)2, 10 mol% of Boc-Val-OH and 2 equivalents of KHCO3 as the chosen base (Scheme 21). The Pd-catalyzed reaction was carried out in tert-amyl alcohol as the solvent to give ortho-olefinated α-phenoxyacetic acids 34. The reaction tolerated unsubstituted substrates exemplified by the formation of olefinated product 34a in a 91% yield. However, 3-methyl 34b and 4-methyl 34d substituted substrates were also successfully olefinated and α–phenoxyacetic acid products were isolated in 62% and 80% yields, respectively. Electron-withdrawing groups present in the substrates, such as 2-fluoro 34c, 4-trifluoromethyl (CF3) 34e, and 3 fluoro 34f, did not significantly alter the reaction outcome. CO2Et CO2H
R1
CO2H
Pd(OAc)2 (5 mol%), Boc-Val-OH (10 mol%)
+ 33 CO2Et
CO2Et
O
CO2H
R1
KHCO3, tAmylOH O2, 90 oC, 24 h
34 CO2Et
CO2Et
CO2Et
30i; R2=H, R3=CONMe2, 74% (p/others = 9:1) 30j; R2=Ph, R3=CHO, 84% (p/others = 19:1, E/Z = 6:1) m’ 30k; R2=H, R3=COMe, 74% (p/others = 11:1) 30l; R2=H, R3=SO2Ph, 88% (p/others = 13:1) 30m; R2=H, R3=PO(OEt)2, 86% (p/others = 11:1) 2 R 30n; R2=H, R3=CO2CH2-(CH2)8-CH3, 66% (p/others = 6:1)
Scheme 19. para-C–H Olefination of phenol derivatives with the use of a Sibiphenyl-based template.
F
Scheme 20. Distal C–H olefination of biphenyl phenol.
O 30e; R=Br, 68% (p/others = 15:1) 30f; R=Me, 76% (p/others = 12:1) m’ 30g; R=OMe, 74% (p/others = 14:1) 30h; R=t-Bu, 65% (p/others = 10:1)
N
32
T
o’
o m
T
N
o’
o R
(iPr)2Si
R1
29
R
T
O
O
T
O
34a; 91%
CO2H
O
CO2H
R1 34b; R=Me, 62% 34c; R=F, 65%
O
CO2H
R1 34d; R=Me, 80% 34e; R=CF3, 85%
Scheme 21. ortho-Olefination of α-phenoxyacetic acids.
O
CO2H
F 34f; 68%
8
Tetrahedron
In the same paper, Yu also reported a Pd-catalyzed metaselective olefination of α-phenoxyacetic acids. The strategy employs an end-on coordinating nitrile template on substrates 35 that enabled Pd-catalyzed olefination with ethyl acrylate to provide meta-olefinated α-phenoxyacetic acids 37 (Scheme 22). The Pd-catalyzed olefination reaction tolerated electron-donating groups as 2-Me 37a, 3-Me 37c, and 4-Me 37e substituted metaolefinated α-phenoxyacetic acid products were isolated in good to excellent yields (86%, 91%, and 72%; Scheme 22). The formation of such meta-olefinated products was highly selective as a very small amount of the ortho-isomer was formed. Phenol derivatives substituted with electron-withdrawing groups (2-CF3, 3-CF3, and 4-Cl) were mostly meta-olefinated giving products 37b, 37d, and 37f in 78%, 52%, and 65% yields, respectively. In addition, Yu also demonstrated a Pd-catalyzed meta-selective olefination of ortho-brominated α-phenoxyacetic acids with various alkenes. The incentive was the versatility and synthetic utility of the bromine moiety in the synthesis. The Pd-catalyzed olefination strategy was tested on ortho-brominated substrates that enabled olefination with various alkenes 36 to provide metaolefinated ortho-brominated α-phenoxyacetic acids 37 (Scheme 22). Olefination of substrate 35 with ethyl acrylate gave metafunctionalized product 37g in a 78% yield. The analogous butyl ester 37h and methyl ketone 37i were obtained in 78% and 62% yields, respectively. The reaction of substrate 35 with transmethyl 2-butenoate gave the corresponding meta-olefination product 37j in a 61% yield. The analogous olefination products 37k and 37l (containing an amide and phosphonate functionality) were also successfully reacted and gave products in good yields. Moreover, the scope of the Pd-catalyzed olefination reaction of α-phenoxyacetic acids was investigated with respect to the olefins. Styrenes 36 were used as olefination partners with 2methyl substrates 35 in an attempt to obtain olefination products 37. It was found that styrenes with only electron-withdrawing groups on the arene were reactive. The reaction with electrondeficient styrenes gave the corresponding products in moderate yields as exemplified by the formation of 37m–p in 31–75% yields. O
O O
T +
R1
Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%)
R2 R3
NC T
R1
AgOAc, HFIP 90 oC, 24 h
36
35
O
N
T= NC
37
R3 R2
R1
O O
m' p
m
R1
T
o
p
CO2Et 37a; R=Me, 86%, (m/others = 98:2) 37b; R=CF3, 78%, (m/others = 90:10) Br
m
O
m
O
o'
O
m'
T
o
R1
m
T
o
CO2Et
CO2Et 37c; R=Me, 91%, (m/others = 94:6) 37d; R=CF3, 52%, (m/others = 96:4)
37e; R=Me, 72%, (m/others = 89:11) 37f; R=Cl, 65%, (m/others = 98:2) Me
O O
m' p
O
o'
T
o
O O
m' p
m
T
o
R3 R2 37g; R2=CO2Et, R3=H, 78% (m/others = 88:12) 37h; R2=CO2Bu, R3=H, 78% (m/others = 92:8) 37i; R2=COMe, R3=H, 62% (m/others = 88:12) 37j; R2=CO2Et, R3=Me, 61% (m/others = 75:25) 37k; R2=CONMe2, R3=H, 82% (m/others = 91:9) 37l; R2=PO(OEt)2, R3=H, 83% (m/others = 93:11)
R2 37m; R2=C6F5, 75% (m/others = 83:17) 37n; R2=4-CF3-C6H4, 38% 37o; R2=4-OAc-C6H4, 31% 37p; R2=2,5-Cl-C6H4, 48%
Scheme 22. Pd-catalyzed meta-selective olefination of α-phenoxyacetic acids.
The proposed mechanism for this Pd-catalyzed C–H olefination reaction is based on the observed isotope effects (kH/kD = 3.8) of the nitrile-directed meta-selective C–H functionalization with
analogues substrates suggesting that the reaction proceeds via cyclopalladation through C–H cleavage and that the C–H bond cleavage may be involved in the rate-determining step. Olefin coordination by the palladacycle followed by 1,2-migratory insertion and subsequent β–hydride elimination gives the final meta-olefinated product 37 (Scheme 23). O reoxidation Ag AgOAc [Pd0]
R1 C N H 35 C-H activation
[PdIIL] +L
reductive elimination [LPdIIX]H HX
O R1 N 37 R2
O R1
β-hydride elimination
C
LPdII
N
C
O R1 N
LPd II R2
C
1,2-migratory insertion
2
O R1 LPdII
N
C
36 R olefin coordination
R2
Scheme 23. Proposed mechanism for nitrile-directed meta C–H olefination.
A similar arene C–H-olefination methodology was also developed by the Yu group. [27] The limiting reagent for this efficient protocol was the presence of a 2-pyridone ligand which binds to palladium and therefore accelerates a non-directed C–H functionalization reaction of simple arenes with the corresponding alkene. The method was applied on a vast set of simple arenes, even phenol derivatives, whereas the paraolefinated phenol was the major product formed. Moreover, the group very recently published an innovative protocol, based on sequential functionalization of meta-C–H and ipso-C–O bonds of phenols. [28] The advantage of this methodology is the use of a rigid backbone in the directing group template, which forms a large yet less strained macrocyclic pretransition state, and therefore forms the palladacycle intermediate with higher stability and a presumably longer lifetime. The idea of designing an efficient template, which would form the final product in good selectivity, was based on the influence of electronic effects. However, adding more electron-donating groups (methoxy groups) on the phenyl ring in template T (Scheme 24) did not significantly improve the reactivity. Moreover, it even led to a lower ratio of mono- to di-olefinated products (Scheme 24). Having the optimal template in hand (T), the scope of different phenol derivatives was investigated. Pleasingly, both electronrich and electron-deficient groups were well tolerated with the meta-alkenylated phenol being the major product formed. Even, sterically hindered substrates showed compatibility with the protocol. Compared to ortho-substitutes phenols, meta- and paraanalogues gave lower yields. Presumably, the presence of an ortho-substituent significantly improves the monoselectivity of the reaction, as the di-meta-C–H-olefination would be subjected to steric hindrance from the adjunct ortho-substituent. Also, various α,β-unsaturated ester, sulfone, and phosphonate olefins were reactive, affording meta-olefinated products (39n–q) in good yields. After completing the C–H-alkenylation step, the protocol was further developed to involve a Ni-catalyzed arylation reaction, where template T served as a pseudohalide in the cross-coupling reaction with corresponding arylboronic acids, to yield the final biphenyl products. Furthermore, a sequential one-pot synthetic procedure was also developed, including both palladium and nickel catalytic steps, demonstrating no major change in the final reaction yields.
9 OMe O
T
R1
Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%) AgOAc (1.5 equiv.) +
O
N
HFIP 80 oC, 36 h
T
39g; R1=F, 67% 39h; R1=CF3, 62%
CO2Et R1
T=
R2
N
39
T
O
R1
N N
R1
R2 (3 equiv.)
38
T
O
T
O
39l; R1=Me, 70% 39m; R1=Cl, 55%
R1
CO2Et
CO2Et R1
39a; R1=Me, 81% 39b; R1=tBu, 89% 39c; R1=OMe, 75% 39d; R1=F, 75% 39emono; R1=Cl, 68% 39edi; R1=Cl, 17% 39fmono; R1=CO2Et, 61% 39fdi; R1=CO2Et, 17
O
T
39i; R1=Cl, 57% 39j; R1=COMe, 49% 39k; R1=OMe, 69%
O
T
Me
CO2Et
39n; R2=CO2Me, 73% 39o; R2=CO2tBu, 44% 39p; R2=SO2Ph, 76% 39q; R2=P(O)(OEt)2, 79% R2
R1
Scheme 24. Pd-catalyzed template-directed meta-C–H-olefination of phenols.
A very recent paper worth mentioning by Zhu et al. describes a highly selective ortho-alkenylation of unprotected phenols as the directing group under mild synthetic conditions. [29] The C–H functionalization of unprotected phenols 40 gave the corresponding products in moderate to excellent yield at 60 °C. The choice of oxidant was also crucial, as K2S2O8 provided the highest yields. Even different metal species were tested (Fe, Ni), whereas Pd(acac)2 showed superior catalytic activity. Interestingly, the reaction performed in AcOH resulted in the highest yield as oppose to other solvents (H2O, DCE, MeCN, and DMF), which gave poor yields or even no product. As the scope of phenols was investigated, the positions of the substituents on the phenyl ring did not affect the efficiency of the reaction (Scheme 25). In general, electron-rich substrates contributed to forming the desired products in higher yields (41a–c; 90–94%) in comparison to electron-deficient phenols (41d–f; 55–77%). The scope of olefins was also examined. As expected, acrylates with similar reactivity to ethyl acrylate were compatible with the reaction. Even styrene derivatives containing electron-donating and electron-withdrawing substituents on the phenyl moiety reacted well with the substrates (41s and 41t).
26A). Furthermore, different terminal and internal aliphatic olefins were subjected under the optimized reaction conditions. Gratifyingly, the reaction of 10-bromodec-1-ene with 2-naphthol provided 43h as a single product. Although, in the case of simple terminal olefins (1-octene), a 2-substituted benzofuran having an exocyclic double bond at C2 (43jB) was observed along with the desired product 43jA (43jA/43jB=1:1.3). After describing a vast scope of different benzofurans, a set of coumarin derivatives was prepared under the optimal reaction conditions (Scheme 26B). Substituents such as Me, OMe, NO2, and Br at either ortho, meta, or para position on the phenols derives the corresponding coumarins in good yields (43l–u). The most important finding of the described catalytic method is the compatibility of various electron-withdrawing groups (NO2, CN, CHO, COMe, CH2CN). Interestingly, when reacting unprotected phenols with ethyl acrylate (under Pd-catalyzed C–H-olefination conditions) the coumarins derivatives were formed, whereas results of Stanford et al. [32] showed that reacting phenol analogues such as anisoles and 4-methoxyanisoles, under similar reaction conditions provided the corresponding mono-olefinated products in good yields (69–75%). A) Benzofurans: R1 R2
+
(1 equiv.)
42 OH (2 equiv.) R1
R1
+
R2
AcOH/H2O, 60 oC
R2 R1
R2
Br
Me
O
CO2Me
O
5 O 6 O 43h; 76% 43i; 55% R2 43a; R1=NO2, R2=Cl, 55% O2N O2N C2 43b; R1=CN, R2=Br, 58% Me 43c; R1=CN, R2=Cl, 51% 43d; R1=CHO, R2=OMe, 73% 4 43e; R1=COMe, R2=H, 64% O O 43jB 43jA 43f; R1=R2=H, 30% 1 2 72%; 43jA/43jB = 1:1.3 43g; R =Br, R =Cl, 64%
C1 Me 4
B) Coumarins:
+ 42 OH
CO2Me (1 equiv.)
Pd(OAc)2 (5 mol%) 1,10-phenanthroline (10 mol%) Cu(OAc)2 (1 equiv.) NaOAc (3 equiv.)
R1
43 O
ClCH2CH2Cl, 110 oC, air
(2 equiv.)
O
41
40 OH
OH R1
O 43
O
OH
Pd(acac)2 (5 mol%) AgOAc (1.2 equiv.)
R1
ClCH2CH2Cl, 110 oC, air
R1
OH
Pd(OAc)2 (5 mol%) 1,10-phenanthroline (10 mol%) Cu(OAc)2 (1 equiv.) NaOAc (3 equiv.)
OH CO2Et
CO2Et
CO2Et
R1 41a; R1=H, 95% 41b; R1=Me, 94% 41c; R1=Br, 81% 41d; R1=Cl, 77% 41e; R1=F, 81%
41f; R1=Me, 88% 41g; R1=CF3, 81% 41h; R1=F, 85% 41i; R1=Cl, 88%
OH R2
R1
R1
1 R1 41j; R =Me, 90% 41k; R1=OMe, 94% 41l; R1=NO2, 55% 41m; R1=COOH, 75%
41n; R2=CO2Me, 78% 41o; R2=CO2Ph, 75% 41p; R2=CONHPh, 85% 41q; R2=SO2F, 60% 41r; R2=CN, 70% 41s; R2=4-OMe-C6H4, 65% 41t; R2=4-Cl-C6H4, 82%
Scheme 25. Phenol scope for Pd-catalyzed direct ortho-alkenylation.
A palladium-catalyzed synthesis of benzofurans and coumarins from phenols and olefins has been reported. [30] Benzofuran and coumarin derivatives are compounds of great synthetic value. Particularly, 2-arylbenzofurans are frequently found in nature and possess various biological activities. [31] The reported procedure is based on an active catalytic system which involves Pd(OAc)2 as the catalyst in combination with 1,10-phenantroline, Cu(OAc)2 and NaOAc. The authors stress, that the addition of NaOAc is crucial to achieve high conversions. The scope of styrene as well as phenol derivatives was evaluated. Halogen-substitutes phenols gave benzofuran derivatives in good yields without dehalogenation (43a–c and 43g). Unfortunately, only 30% yield of unsubstituted 2-phenylbenzofuran (43f) was formed (Scheme
O 43k; R1=H, 67% 43l; R1=Me, 78% 43m; R1=OMe, 81% 43n; R1=Br, 57%
O 43o; R1=NO2, 61% 43p; R1=CN, 78% 43q; R1=CHO, 70% 43r; R1=COMe, 72% 43s; R1=CH2CN, 64%
O
O
R2 43t; R1=NO2, R2=Cl, 55% 1 43u; R =CHO, R2=OMe, 52%
Scheme 26. A) Pd-catalyzed synthesis of benzofurans. B) Pd-catalyzed synthesis of coumarins.
Furthermore, a procedure for the synthesis of dibenzopyranones through palladium catalyzed directed C–H activation/carbonylation of 2-arylphenols was developed. [33] The most reactive catalytic system for this transformation proved to be Pd(OAc)2/Cu(OAc)2/PivOH, Na2CO3 under an atmospheric pressure of CO in mesitylene at 120 ºC. A variety of 2arylphenols could be converted to the desired dibenzopyranones in good to moderate yields (Scheme 27). Different substituents on the Ar2 ring were tolerated, including electron-donating (45c– f) and electron-withdrawing groups (45g–l). Substituents on the ortho position were, however, unfavorable which might arise from steric hinderance (45a and 45b). The regioselectivity of the reaction is preferred toward the formation of sterically less hindered products (45m and 45n), as the other isomers were not observed. Notably, in the cases were the yields of the products were low, no starting material was recovered, which can be attributed to phenols being prone to decomposition under the
10
Tetrahedron
applied oxidative reaction conditions. Interestingly, the reaction was found to be more sensitive to the electronic nature of substituents on the Ar1 ring comparing to the substituents on the Ar2 ring. Thus, electron neutral groups (45o–q) gave higher yields than electron-donating or -withdrawing groups. Pd(OAc)2 (5 mol%) Cu(OAc)2 (10 mol%) Na2CO3 (2 equiv.) PivOH (0.5 equiv.)
OH Ar1
Ar2
O O
CO (1 atm), mesitylene, 120 oC, 6 h
44 O
Ar1
Ar2
yields (Scheme 29). However, as it was observed for the arylation examplesError! Bookmark not defined. also in this cases substrate bearing electron-withdrawing substituents gave the products in lower yields (49b, R1=Cl, and 49c, R1=CO2Me; 24% and 29%. For substrates containing electron-donating groups the desired products were isolated in higher yields (49d and 49e; 42% and 69%). Not surprisingly, for the sterically hindered substrates with substituents at the ortho- and meta-positions (49f and 49g), the yields were significantly reduced.
45
O
O
O
N
OAc N
R1 49a; R1=H, 50% 49b; R1=Cl, 24% 49c; R1=CO2Me, 27% 49d; R1=Me, 69% 49e; R1=OMe, 42%
O 45m; 87% Me O O
R1 45o; R1=Me, 69% 1 45p; R =Ph, 72% 45q; R1=tBu, 70%
45n; 79%
Scheme 27. Pd-catalyzed synthesis of dibenzopyranones.
In 2013 Kim and co-workers reported a Pd-catalyzed oxidative ortho-acylation reaction of 2-phenoxypyridines with benzylic and aliphatic alcohols. [34] In the optimization studies, Pd(OAc)2 was found to be the best catalyst and tert-butyl hydroperoxide (TBHP) the oxidant of choice for the reaction to provide the corresponding products in good yields. The protocol extends to range of substrates which showed great level of regio- and chemo-selectivity and functional group tolerance (Scheme 28). The scope of alcohols using 2-fluorophenoxypyridines presented broadness which is exemplified by products 47a–f in good yields (61–87%). Aliphatic alcohols were also demonstrated to be effective under the applied reaction conditions. Thus, products 47g and 47h were obtained in 78% and 50% yield, respectively. The reaction showed to be compatible with a variety of different substituents on the phenyl ring, giving rise to products in good to moderate yields (47i–m; 48–71%). R2 O R1
Pd(OAc)2 (10 mol%) +
N
R2
OH
TBHP (4 equiv.) DCE, 80 oC, 20 h
46 R2
R2
F
N
N 47
Ph
O N
R1
R1 OH
N Me
N Me
49g; 62% Me
49f; 45% OAc N O Me N
Pd(OAc)2 (5 mol%) IPr (10 mol%) MesCOONa (0.5 equiv.)
OAc N
Me
O N
Me
Cl
49i; 29% Me
47i; R1=Cl, R3=Me, 65% 47j; R1=R3=OMe, 58% 47k; R1=F, R3=H, 61% 47l; R1=OMe, R3=H, 48% 47m; R1=R2=H, 71%
R3
Scheme 28. Ortho-acylation of 2-phenoxypyridines with benzylic and aliphatic alcohols.
A procedure already described for the arylation of 2phenoxypyrimidines 13 (Scheme 11) was also used for Pdcatalyzed acetoxylation of the same set of substrates. [16] The reaction was carried out using 2 mol% of Pd(OAc)2 as the chosen catalyst and 1.1 equiv. of PhI(OAc)2 as the oxidant in a solvent system of Ac2O/AcOH. However, when 3.0 equiv. of PhI(OAc)2 was employed, the diacetoxylated phenoxypyrimidine was the major product formed. The protocol found to be broadly applicable to a variety of heteroaryl substrates affording the corresponding acetoxylated products 49 in good to excellent
O
K2CO3 (2 equiv.), MS 3Å 4,5-diazafluoren-9-one (10 mol%) mesityl, 120 oC, air, 24 h
50
R1
Ph
51a; R1=CF3, 68% 51b; R1=tBu, 76%
R1
R2 IPr =
51c; R1=Me, 65% 51d, R1=F, 78%
N
N
51 O
O
O
O R1
O
Me
O
Liu and co-workers reported a Pd-catalyzed phenol-directed C–H activation/C–O cyclization methodology to afford dibenzofurans 51 (Scheme 30). [35] Amongst the tested oxidants, air was found to be the best performing, whereas treatment of phenols with stronger oxidants (eg. PhI(OAc)2) caused complete decomposition of the substrates. In addition, the carbene ligand IPr (Scheme 30) was found to be the ligand of choice. When 4,5diazafluoren-9-one was added in 10 mol%, the yield improved noticeably. The reaction scope demonstrates generality and variety in substitution on both arene rings, as well as good functional group tolerance. meta-and para-substituted phenol rings gave products 51a–d good 65–78% yields. The other arene ring was also found to be tolerant towards various electronically different substituents giving rise to products 51 in moderate to good yields (48–88%). Dibenzofuran containing Weinreb amide 51i and substrate 51k with an electron-withdrawing NO2 group were obtained in 80% yields. Nevertheless, dibenzofuran possessing an α,β-unsaturated methyl ester moiety was also obtained in a good yield (51j, 83%).
47g; R2=Ph, 78% 47h; R2=Me, 50%
N
47a; R2=H, 71% 47b; R2=4-OMe, 72% 47c; R2=4-CO2Me, 61% 47d; R2=4-CF3, 72% 47e; R2=3-Me, 71% 47f; R2=2-F, 87%
OAc N
Scheme 29. Pd-catalyzed acetoxylation of 2-phenoxypyrimidine.
R2
O O
R1 49
O R1
O
O
F
O
O N
Me
O
49h; 82%
45r; R1=F, 41% 45s; R1=OMe, 25% 45t; R1=OPh, 25%
N
OAc N
O N
O
OAc
Pd(OAc)2 (2 mol%) PhI(OAc)2 (1.1 equiv.) Ac2O/AcOH = 1 : 1 100 oC
48
45h; R1=F, 66% 45i; R1=Cl, 68% 45j; R1=CO2Me, 64% 45k; R1=CHO, 50% 45l; R1=NO2, 31%
45c; R1=Me, 83% 45d; R1=OMe, 60% 45e; R1=tBu, 80% 45f; R1=OPh, 79% 45g; R1=CF3, 59%
R1
N
R1 R1 45a; R1=Me, 31% 45b; R1=Ph, 41% O O
O
R2
51e; R2=SiMe3, 82% 51f; R2=OMe, 71% 51g; R2=Cl, 48% 51h; R2=Ph, 88% 51i; R2=CON(OMe)Me, 80% 51j; R2=CH=CHCO2Me, 83%
R2 51k; R2=NO2, 80% 51l; R2=COMe, 71% 51m; R2=CN, 37%
Scheme 30. Pd-catalyzed phenol-directed C–H activation/C–O cyclization.
In 2011 a Pd-catalyzed silanol-directed phenol hydroxylation of phenols was reported. [36] The introduction of silanol as a traceless directing group has often been used in Pd-catalyzed C– H functionalization reactions. Therefore, the developed methodology consists direct C–H oxygenation reaction followed by a desilylation reaction (with TBAF) yielding the desired catechols 53. The scope of this semi one-pot hydroxylation/desilylation sequence was compatible with differently substituted silanol-protected substrates to give rise to the corresponding products. The selected reaction scope is shown in Scheme 31. Substrates having electron-rich substituents
11 showed comparable reactivity to electron-deficient analogues as the corresponding catechols such as 53b, 53f and 53j were isolated in good to excellent yields (94%, 57%, and 93%).
Pd(OAc)2 (5 mol%) PivOH (1 equiv.) Cs2CO3 (1.2 equiv.) TBHP (4 equiv.)
OH Ar1
Ar1 CH3CN, 80 oC, 18 h, air
54 1. Pd(OPiv)2 (5 mol%) PhI(OAc)2 (2 equiv.)
tBu Si HO tBu
O
R1
OH
R1
OH
OH
OH OH 53a; 81% 53b; R1=Me, 94% 53c; R1=Ph, 87% 53d; R1=Cl, 62% 53e; R1=CF3, 35%
Me
OH
OH Me OH R1 53f; R1=OMe, 57% 53j; 93% 53g; R1=tBu, 78% 53h; R1=F, 60% 53i; R1=CO2Et, 76%
A mechanistic reaction pathway for the Pd-catalyzed silanoldirected C–H oxygenation of phenols into catechols is proposed (Scheme 32). The reaction is assumed to proceed via a palladacycle followed by a reductive acetoxylation elementary step which produces a palladium acetoxylated complex that was experimentally observed. In order to verify whether the observed silacyle arises solely through a stepwise route involving acetoxylated intermediate or it is formed via a direct CO reductive cyclization, the 18O-labeled silanol 52 was subjected to the standard reaction conditions. The labeling experiment reviled that 18O-labeled acetoxylated product was formed and then gradually diminished during the reaction time upon which the final cyclized product with no 18O label was formed. Instead 18O labeled acetic acid was detected, thus ruling out reductive cyclization reaction pathway. O
Si
tBu
t O18 Bu
H
52
tBu Si tBu O18 Pd H palladacycle
R1
tBu Si tBu 18 O Pd H OAc
O
O
cyclopalladation
reductive
R1
acetoxylation
observed reduc
O R1
tBu Si t O Bu
protected catechol
tion ycliza tive c
tBu Si tBu 18 OAcO H
O -HO18Ac
R1
tBu Si tBu O18 O Me OH
O
transesterification R1
55
R2
HO
OH R2
HO HO 55i; R2=F, 75% 55a; R2=H, 76% 55j; R2=Cl, 73% 55b; R2=F, 80% 55k; R2=Me, 71% 55c; R2=Cl, 77% 55d; R2=CF3, 80% OH 55e; R2=Me, 77% 55f; R2=tBu, 75% 1 R 55g; R2=Ph, 77% 55h; R2=OMe, 75% HO
Scheme 31. Silanol-directed phenol hydroxylation of phenols.
R1
Ar2
R2
53
Me OH
OH
OH
toluene, 100 oC 2.TBAF/THF
52
OH
R1
OH
Ar2
Scheme 32. Proposed reaction pathway for the Pd-catalyzed silanol-directed C–H oxygenation of phenols into catechols.
An important procedure was published by Fan et al. describing a novel synthesis of 2,2’-biphenols through Pd(II)-catalysis, using a previously attached hydroxyl group in one of the phenyl rings in [1,1’-biphenyl]-2-ol as a directing group to introduce an additional hydroxyl functionality (Scheme 33). [37] The initial studies were performed on 2-phenylphenol and therefore proving Pd(OAc)2 to be the catalyst of choice in combination with PivOH as the ligand, improving the reaction significantly. Moreover, screening different oxidants (K2S2O8, oxone, m-CPBA, H2O2) revealed that using a 70% aqueous solution of tert-butyl hydroperoxide (TBHP) provided good conversion of the starting material. However, replacing 70% aqueous solution of TBHP with TBHP in decane, the corresponding product 55a in a 75% yield suggesting that TBHP, rather than air or water, is in fact the oxygen source of the newly introduced hydroxyl functionality. Different substituents on the 4’- and 3’-postions of the Ar1 as well as on Ar2 ring showed good performance under the established reaction conditions. However, substituents attached on the 2’-position on the Ar2 ring turned out to be less favorable which might arise from steric hinderance (55l–n).
HO 55l; R2=F, 58% 55m; R2=Cl, 55% 55n; R2=Me, 50% OH
HO R1 55r; R1=Cl, 76% 55s; R1=Me, 75% 55t; R1=OMe, 75%
55o; R1=F, 85% 55p; R1=Cl, 80% 55q; R1=OMe, 76%
Scheme 33. C–H hydroxylation of [1,1’-biphenyl]-2-ols.
The synthetic and economic potential of fluorinated phenol derivatives is of great importance for the construction of various building blocks for further formation of materials, pharmaceuticals, and agrochemicals. Among the numerous phenol derivatives, the first C–H bond fluorination of 2phenoxypyridines was introduced by Xu and co-workers. [38] They proposed, that having an oxy-bridge in the 2phenoxypyridine might alter the electronic nature on the nitrogen atom in the pyridine ring, causing the reaction to yield selective ortho-monofluorinated products as oppose to the difluorinated ones. Reaction condition screening showed that using 5-10 mol% of Pd(dba)2 in EtOAc and NFSI as the fluorinating agent afforded the desired mono-fluorinated products 57 in high yields (Scheme 34). Generally, there showed to be no difference in the reactivity when subjecting either electron-rich or electron-deficient substrates under the established reaction conditions. Notably, milder conditions were used in the cases of electron-rich aryl rings (57b–57e, at 80 ºC) in order to avoid undesired difluorination. However, harsher conditions and a catalytic amount of KNO3 (30 mol%) were required when reacting electron-deficient substrates (57h, 57i, and 57p, at 120 ºC) to achieve satisfying conversions. Moreover, mono-fluorination occurred smoothly even in the presence of bulky (57c) and halo (57f, 57k, 57l, and 57n) substituents. Finally, a set of diverse functionalized methyl 2-phenoxy nicotinates were submitted under the optimized reaction conditions, having great value especially in the pesticide industry. COR2 O R1
N
Pd(dba)2 (5-10 mol%) NFSI (1.5-2.0 equiv.)
COR2 O R1
EtOAc, 80-120 oC, 2-6 h
F 57
56
N
R1 O
O
R1
N
N F R1 F 57a; R1=H, 81% 57f; R1=Br, 77% 57j; R1=Ph, 79% 1 57b; R =Me, 76% 57g; R1=CO2Me, 75% 57k; R1=Cl, 80% 57c; R1=tBu, 74% 57h; R1=CN, 74% 57l; R1=Br, 85% 57i; R1=NO2, 73% 57d; R1=Ph, 80% 57e; R1=OMe, 71% CO2Me O O R1 N F R1 57q; R1=H, 78% 57r; R1=Me, 75% 57s; R1=OMe, 70% 57t; R1=F, 64%
O F
N
57m; R1=Me, 76% 57n; R1=Br, 78% 57o; R1=COMe, 77% 57p; R1=CF3, 75% CO2Me
N F 57u; R1=Br, 81% 57v; R1=CF3, 75%
Scheme 34. C–H bond fluorination of 2-aryloxypyridines and 2-phenoxyl nicotinic acid derivatives.
The same removable 2-pyridyl group was applied for the development of a regioselective C–H chlorination/sequential C– H functionalization procedure for phenols. [39] This convenient and straightforward strategy employed the presence of Pd(OAc)2 as the catalyst, NCS as the chlorinating agent, and TsOH as the
12
Tetrahedron
most efficient promoter for the transformation (Scheme 35). Interestingly, the degree of chlorination was found to be highly dependent on the nature of the substituent on the phenyl ring of the 2-phenoxypyridine derivatives. When the para position was substituted by a methyl, chloride, bromide, ester, nitro, trifluoromethyl and trifluoromethoxy group, the corresponding di-chlorinated product was formed (59a–g; 69–99% yield). On the other hand, when 2-aryloxypyridines bearing a phenyl, aldehyde, nitrile, methoxy, or fluoro group at the para-position the mono-chlorination was possible in reasonable to high yields (59h–l; 46–81% yield). The effect of different substituents on the pyridine ring was also examined. Notably, substrates bearing electron-rich substituents reacted smoothly, affording dichlorinated products in good yields (59u, 59v, 59y, and 59z), as reactions of electron-deficient substrates gave lower yields of products (59t and 59x) suggesting that the coordinating ability of the pyridine moiety to the palladium center plays an important role. R2
O R1
Cl O Cl 59
58
Cl
O
O
O
N N Cl R1 Cl R1 59a; R1=Me, 69% 59h; R1=Ph, 81% 1 59b; R =Cl, 74% 59i; R1=CHO, 46% 59c; R1=Br, 94% 59j; R1=CN, 51% 59d; R1=CO2Me, 99% 59k; R1=OMe, 63% 59e; R1=NO2, 99% 59l; R1=F, 76% 59f; R1=CF3, 92% Cl R2 1 59g; R =OCF3, 92% O
N R1 59m; R1=Cl, 80% 59n; R1=Br, 88% 59o; R1=Me, 79%
Cl O
O Cl
59t; R2=CF3, 23% 59u; R2=Me, 81% 59v; R2=F, 79%
N R1 59p; R1=Me, 81% 59q; R1=Br, 71% 59r; R1=CF3, 47% 59s; R1=tBu, 77%
Cl
N
N
Cl
R2
59w; R2=Cl, 98% 59x; R2=NO2, 33%
N
R2 59y; R2=OMe, 65% 2 59z; R =Me, 72%
Scheme 35. C–H chlorination/sequential of phenols with NCS.
In 2014 Rao and co-workers reported the first carbamate-directed Pd-catalyzed ortho-chlorination of phenol derivatives at ambient temperature. [40] Remarkably, no para- or meta-chlorination occurred and only ortho-chlorinated products were obtained under the developed reaction conditions. With 5 mol% of Pd(OAc)2, 0.5 equivalents of TfOH, and NBS as the bromine source, the ortho-chlorinated phenols were readily prepared (Scheme 36). The survey of the reaction scope revealed that a variety of phenol derivatives could be chlorinated. Substrates being substituted ortho-, meta-, and para-functionalities on the aryl moiety proved to be good substrates under the developed reaction conditions. Pleasingly, the regioselectivity of the reaction was high, since meta- and para-substituted substrates provided solely ortho-chlorinated products. O R1
NMe2
Pd(OAc)2 (10 mol%) TfOH (0.7-3.0 equiv.) NCS (1.1 equiv.)
O
NMe2
O R1 Cl
DCE, r.t.
O
61
60 R1
Cl NMe2 Cl
O
61a; R1=H, 75% 61b; R1=Cl, 54% 61c; R1=Br, 72%
R1
NMe2 O
O
63a; R1=H, 89% 63b; R1=Ph, 83% 63c; R1=CN, 81% 63d; R1=Br, 46%
R1 NBS (1.1 equiv.) p-TsOH (0.5 equiv.) DCE, 80-90 oC
62
R1
O
Pd(OAc)2 (5-10 mol%)
Br
NMe2 O
63e; R1=CO2Me, 62% 63f; R1=NO2, 42% 63g; R1=F, 52%
Br
NMe2 O
63 Cl
O
NMe2
O Br 63h; 71%
3. Rh-Catalyzed C–H Bond Functionalization
N
Cl
Cl O
NMe2 O
R2
R1 EtOAc, 110 oC
Cl
O R1
Scheme 37. Pd-catalyzed ortho-bromination of carbamates using NBS.
Pd(OAc)2 (10 mol%) TsOH (10 mol%) NCS (3 equiv.)
N
bromination. [41] The reaction employs carbamate 62, 5–10 mol % of Pd(OAc)2, 50 mol % of p-TsOH in DCE at 80–90 °C along with NBS as the brominating agent. Unsubstituted carbamate gave 63a in an 89% yield (Scheme 37). It is worth mentioning that meta-chlorinated substrate derived the corresponding the ortho- brominated product 63h in a yield of 71%. Concerning the electronic nature on the para-position, the strongly electronwithdrawing group (such as nitro) gave the desired product in a slightly lower yield (63f, 42%).
NMe2 O
Cl R1 61d; R1=OMe, 66% 61m; R1=Me, 73% 61e; R1=F, 83% 61n; R1=F, 77% 61o; R1=CO2Me, 63% 61f; R1=Br, 69% 61p; R1=tBu, 93% 61g; R1=I, 68% 1 61q; R1=Ph, 80% 61i; R =Me, 86% 61j; R1=Cl, 72% 61k; R1=CO2Me, 57% 61l; R1=CF3, 24%
Scheme 36. ortho-Chlorination of carbamates at room temperature.
Additionally, Nicholas reported a similar Pd-catalyzed functionalization of carbamates using NBS thus achieving ortho-
A detailed Rh-catalyzed intermolecular ortho-arylation of unprotected phenols was also reported. [42,43] The reaction employs treatment of a phenol 64 with an aryl halide in the presence of Wilkinson’s catalyst, [RhCl(PPh3)3], an aryl dialkylphosphinite as the ligand, and Cs2CO3 as the base to give the corresponding arylated product 65 (Scheme 38). It is purposed that the phosphinite ligand, PR2(OAr), also acts as a cocatalyst when the aryloxide group is incorporated into phosphorus donors, facile orthometalation can occur to give lowstrain, five-membered metallacycles. The developed protocol showed to be compatible with a variety of different aryl bromides. Even sterically hindered bromide 2-bromo-paraxylene was employed, forming the desired product 65k in quantitative yield. Furthermore, aryl chlorides can also be used as coupling partners, although much lower yields of the arylated phenols were obtained (65d; 25% and 65e; 15%). It must be noted, that in all cases the phenol substrate is unsubstituted at the 4-position and only ortho-arylation occurs proving, that the reaction is indeed ortho-selective which in turn means that the C– H activation of phenol occurs after it has been incorporated into the phosphinite co-catalyst. Furthermore, it is not necessary to have a bulky tert-butyl group on the 2-position for the reaction to proceed. Phenols bearing much smaller groups (iPr, Et, Me) also gave the desired arylated products in satisfying yields (65f–h). 1Bromonaphthalene was also reactive as a coupling partner and the corresponding arylated phenol 65l was isolated in an excellent 92% yield. Unfortunately, the reaction with a heterocyclic bromide (2-bromopyridine) gave product 65m in a lower 23% yield, which may be due to deactivation of the cocatalyst since both the product and, in particular, the intermediate modified phosphinite can form chelate complexes with the metal center.
13 OPiPr2
R1
[RhCl(PPh3)3] (5 mol%) +
64
tBu
OH
OH ArX X=Br, Cl (1.5 equiv.)
R1
PR2(OAr) (15 mol%), Cs2CO3 (1.7 equiv.), toluene, reflux, 18 h
R2
OH
Ar R1 PR2(OAr)
65
Me
OMe
OH
OH
R1
tBu
carried out. Phenyl carbamate 66 underwent Rh-catalyzed olefination with various styrenes to give the corresponding olefinated products 68l–o. Other acrylates such tert-butyl ester, methyl ester, methyl sulfonate, and phosphates gave the corresponding olefinated phenyl carbamates 68p, 68q, 68r, and 68s in 62%, 73%, 54% and 48% yields, respectively.
tBu
R2=COMe,
65f; R1=iPr, 68% 65g; R1=Et, 53% 65h; R1=Me, 21% 65i; R1=Ph, 53% 65j; R1=OMe, 71%
65a; 96% 65b; R2=OMe, 79% 65c; R2=CH=CH2, 75% 65d; R2=Me, X=Cl, 25% 65e; R2=OMe, X=Cl, 15%
O R1
Me
67
MeOC
NMe2
O
NMe2
O
nBuO C 2
A mechanism for the Rh-catalyzed ortho-arylation of phenols was proposed (Scheme 39). Initially, oxidative addition of the aryl halide by the Rh catalyst gives an oxidative addition product A which reacts with the starting phenol 64. Coordination of Rh by the oxygen atom in the phosphinite co-catalyst gives rise to a rhodacycle complex intermediate B. Next, reductive elimination furnishes the ortho-arylated phosphinite C which undergoes transesterification with the starting phenol to give rise to the ortho-arylated phenol 65 and the Rh catalyst to be reused in the catalytic cycle. RhLn oxidative addition
O R1
ArX
Ar
Ar RhLn X A
P RhLn R2
C
ortho-metalation OH
reductive elimination
O R1
B
PR2 RhLn Ar
R1 64
Scheme 39. Proposed mechanism for the Rh-catalyzed ortho-arylation of phenols
In 2011, Liu and co-workers reported a Rh(III)-catalyzed olefination of phenol carbamates with acrylates and styrenes. [44] A similar transformation was developed by Dong, [13] where he repoted a Pd-catalyzed ortho-arylation reaction of ophenylcarbamates with simple arenes. The reaction that Liu developed employs a phenyl carbamate 66 with an acrylate 67 in the presence of 1 mol% of [RhCp*Cl2]2, 4 mol% of silver hexafluoroantimonate (AgSbF6), copper(II) acetate in tetrahydropyran (THP) as the solvent, to give the orthoolefinated phenyl carbamate 68 (Scheme 40). The scope of the phenyl carbamate was performed using n-butyl acrylate as the olefin partner. Various electron-neutral and electron-rich phenol carbamates were to be favored in the reaction (66a–c), whereas some substrates bearing strong electron-withdrawing groups (e.g., NO2) could not be converted to the desired product. Interestingly, acetyl-substituted substrate 66g gave predominantly the corresponding bis-olefinated product. This observation is consistent with the findings that ketones also act as good directing groups in Rh-catalyzed C–H functionalization reactions. Moreover, halo functional groups were also tolerated (66d–f, 66h, 66i), with no Heck-type coupling or protodehalogenation products being formed. Furthermore, even BINOL (66j) and biologically relevant substrate 66k showed good reactivity under the established reaction conditions. The scope of the reaction with respect to the olefin reactant was also
O
Br
O O
O
NMe2 O
Me O
nBuO C 2
NMe2 NMe2
O
H
R2 68p; R2=CO2tBu, 62% 68q; R2=CO2Me, 73% 68r; R2=SO2Me, 54% 68s; R2=P(O)(OEt)2, 48%
68l; R2=Ph, 72% 68m; R2=4-F-C6H 4, 55% 68n; R2=4-Cl-C6H4, 63% 68o; R2=4-Br-C6H4, 53%
H
Me2N
O
CO2nBu
n 68h; 67% CO2 Bu
CO2nBu O
NMe2
O
NMe2
68i; 58%
68g’; 62% CO2nBu
H
Ar 65 transesterification
Cl O
68a; R1=H; 70% 68d; R1=Br; 53% 68b; R1=Me; 74% 68e; R1=I; 49% 68c; R1=OMe; 58% 68f; R1=Ph; 67%
65m; 23%
OH
68
O CO2nBu
N
Scheme 38. Rh-catalyzed arylation of unprotected phenols in the presence of a phosphinite ligand.
R1
O
O
O
tBu
NMe2
O R1
Cu(OAc)2 (2 equiv.) THP, 110 oC, 24 h
R2 R1
65l; 92%
[RhCp*Cl2]2 (1 mol%) AgSbF6 (4 mol%)
R2
66
65k; quant.
OH
OH tBu
O
NMe2 +
68k; 65%
CO2nBu 68j; 82% (ee=96%)
Scheme 40. Rh-catalyzed olefination of phenol carbamates with acrylates and styrenes.
The first alkynylation of 2-vinylphenols using a hypervalent iodine reagent TIPS-EBX* in combination with [(Cp*RhCl2)2] as the C–H activating transition metal catalyst at room temperature was developed by Nachtsheim et al. [45] At first, the optimization studies were carried out using TIPS-EBX as the coupling agent. However, detailed investigation of the reaction revealed two significant side-products being formed, which derived from the hypervalent iodine reagent. Thus, modification of the alkynyl benziodoxolone to the ortho-Me-substituted derivative, TIPS-EBX*, resulted in a more reactive reagent forming the desired product 70a in an excellent 91% yield. The optimized reaction conditions were tested on a set of different substrates (Scheme 41). Electron-poor phenols, in particular 4and 5-halogen-substituted (69b–e), as well as 4-NO2-substituted 69f reacted under established reaction conditions giving products in high yields (86–93%). Substrates bearing electron-donating substituents were also well tolerated (69g and 69h). However, when the substitution pattern of the exocyclic double bond was changed, the yield dropped noticeably. Product 70i could only be isolated in a moderate 40% yield after 72 h. Finally, when subjecting phenols 70o–q under the established reaction conditions, no product was formed, proving the significance of the 2-hydroxy functionality in the substrate. TIPS OH
R3 R2
R1
R3
[RhCp*Cl2]2 (2.5 mol%) TIPS-EBX* (1.2 equiv.) DIPEA (1.5 equiv.)
TIPS
I
O
R2
R1 MeCN, rt, 2-72 h
Me
OH
69
TIPS-EBX*
70 TIPS
TIPS
TIPS
O
TIPS OH
R1
Me
R2
OH OH 70i; R2=H, 40% 70a; R1=H, 91% 2 70j; R =Et, 78% 70b; R1=4-F, 86% 70k; R2=Ph, 83% 70c; R1=4-Cl, 90% 1 70d; R =4-Br, 93% TIPS 70e; R1=5-F, 90% 70f; R1=4-NO2, 92% OH 70g; R1=4-Me, 92% 70h; R1=4-OMe, 87%
Me OH R2 70l; R2=F, 71% 2 70m; R =CN, 78%
70o; 0% (no conversion)
70n; 95% TIPS
TIPS
HO
S
Me
Me 70p; 0% (no conversion)
Me OMe 70q; 0% (no conversion)
Scheme 41. Rh-catalyzed alkynylation of 2-vinylphenols with ethynyl benziodoxolones.
14
Tetrahedron
The proposed Rh-catalyzed alkynylation mechanism is initiated by a base-assisted ligand exchange with 69 followed by C–H bond activation through an addition/elimination step which leads to the formation of rhodacycle A (Scheme 42). Next, insertion of the triple bond adjacent to the hypervalent iodine of TIPS-EBX* affords complex B, which undergoes elimination of 2-iodo-6-methylbenzoate to give the rhodium vinylidene complex C. 1,2-Migration of the vinylic moiety followed by a ligand exchange finally releases the corresponding product 70 and regenerates the rhodium catalyst. TIPS
OH
Me
R1 70
OH
HX
Me
R1 69
[Cp*Rh(X)2]
2 HX
Cp* O Rh X TIPS
O
R1
R1 A
Me
Cp*
RhCp*
Me
O Rh X O
R1 TIPS C
Me
TIPS-EBX* Me
Cp*O O Rh
I
R1 TIPS B
Me
Scheme 42. Proposed reaction mechanism for Rh-catalyzed alkynylation of 2-vinylphenols with ethynyl benziodoxolones.
In 2018, Zhou and co-workers published a protocol on Rh(III)catalyzed meta-selective C–H alkenylation of phenol derivatives [46], a similar transformation also previously published by the same group, based on palladium catalysis using a designed traceless organosilicon template as the directing group. [23] This remote meta-C–H functionalization of phenols represents the first example employing Rh(III) as the transition metal catalyst (Scheme 43). Thorough screening of the reaction conditions proved [RhCp*Cl2]2 to be the catalyst of choice in combination with Cu(CO2CF3)2⋅xH2O and V2O5 in DCE as the solvent of choice. Phenols bearing electron-donating and electronwithdrawing groups reacted smoothly with ethyl acrylate to afford 73b–i in good yields with excellent meta-selectivities. The scope of alkenes was also investigated and under the standard reaction conditions majority of investigated alkenes reacted well with the selected phenols giving rise to the desired olefinated products in moderate to good yields (73j–o, 50–63%). O R1
T
O [RhCp*Cl2]2 (5 mol%) Cu(CO2CF3)2 xH2O (1 equiv.) 2 V2O5 (1 equiv.) R
+
O
Et
Et
N T=
R2
A) 2-Phenylphenols R1
R2
O
DMF, 90-120 oC, 24 or 48 h
74
O
R2 75
R1 R1
O O
O O
O
Me
O
O O
O
O R2
R2 75n; R2=Me; 94% 75o; R2=tBu; 87% 75p; R2=NMe2; 73% 75q; R2=OMe; 92% 75r; R2=F; 81% 75s; R2=CF3; 88%
Si(iPr)2
73
B) 2-Heteroarylphenols
T
R1 O
R1
T
OH
CO2Et 73a; R1=H, 66% (m/others = 90:10) 73b; R1=Me, 54% (m/others = 92:8) O
R1
Rh2(OAc)4 (5 or 1 mol%) OH SPhos or PCy3 (10 or 2 mol%) CO2 (1 atm) tBuOK (4.5 equiv.)
75a; R1=H; 95% 75g; R1=F; 87% 75j; R1=Me; 66% 75k; R2=Me; 91% 75b; R1=Me; 97% 75h; R1=CF3; 89% 75l; R2=OMe; 96% 75c; R1=OMe; 94% 75i; R1=CN; 54% 75m; R2=CF3; 57% 75d; R1=F; 89% 75e; R1=Cl; 76% 75f; R1=Ph; 96%
R1
DCE, 120 oC, 36 h
72
71
T
stable CO2, as the source of CO moiety. Recently, Li et al. developed a chelation-assisted Rh(II)-catalyzed C–H carboxylation of 2-arylphenols under atmospheric pressure of CO2. [47] Remarkably, the Rh-catalyzed reaction overrides the site selectivity dictated by the well-known Kolbe-Schmitt type reaction of 2-phenylphenols and therefore occurs on the less nucleophilic aryl ring. Detailed screening of the reaction conditions justified the choice of the transition metal, ligand, base, and solvent. Rh2(OAc)4 proved superior activity in the reaction. The bridging acetate ligand in the well-defined bimetallic dimer structure of the Rh-catalyst might play an important role to facilitate the C–H cleavage. Electron-rich monodentate phosphine ligands, specifically SPhos, promoted the activity of the Rh-catalyst, which lead to the formation of the desired products in high yields. Such ligands are presumed to increase the nucleophilicity of the Rh-complex intermediate towards CO2 after C–H cleavage. Furthermore, tert-BuOK was the chosen base, as its features might help trap more CO2 and therefore increase the concentration of CO2 in the solution. Finally, the highest conversions were determined when the reaction was carried out in dimethylformamide (DMF), also a good solvent for absorbing CO2. With the optimized conditions in hand, the substrate scope for the C–H carboxylation reaction was investigated (Scheme 44). 2-Phenylphenols bearing electrondonating (75b, 75c, and 75n–q) and electron-withdrawing (75d, 75e, 75i, 75m, 75r, and 75s) groups reacted smoothly. Even sterically hindered substrates were reactive (75j, 66%). Unfortunately, halides, such as bromide, were not suitable substrates, as decomposition and dehalogenation reactions may occur. Furthermore, the scope of different 2-heteroarylphenols was tested and notably, diglyme was chosen as the optimal solvent, whereas the reaction carried out in DMF produced more side products, possibly due to a higher tendency for the heterocycles to undergo a Kolbe-Schmitt type reaction in DMF (77a–j, 71–95%).
T
R2 73j; R2=CO2CH2CF3, 56% (m/others = 88:12) 2 73k; R =CO2Me, 63% (m/others = 93:7) 73l; R2=CN, 61% (m/others = 90:10) 73m; R2=PO(OEt)2, 50% (m/others = 97:3) 73n; R2=SO 2Ph, 49% (m/others = 94:6) 73o; R2=CHO, 55% (m/others = 94:6)
Rh2(OAc)4 (1 mol%) PCy3 (2 mol%) CO2 (1 atm) tBuOK (4.5 equiv.)
R1 O
Het
R1
CO2Et
73c; R1=Me, 61% (m/others = 94:6) 73d; R1=OMe, 63% (m/others = 95:5) 73e; R1=OC(O)Me, 54% (m/others = 91:9) 73f; R1=F, 45% (m/others = 95:5) 73g; R1=Cl, 60% (m/others = 94:6) 73h; R1=CO2Me, 55% (m/others = 92:8) 73i; R1=CF3, 50% (m/others = 94:6)
Scheme 43. Rh(III)-catalyzed meta-alkenylation of phenols.
Catalytic carboxylation of non-activated C–H bonds still remains a challenge, largely due to the thermodynamic and kinetically
R1
R1
77
R1
O O
O O
O
Het
diglyme, 100 oC, 48 h
76
S
O
O O
O
N O N
77a; R1=H, 86% 77b; R1=Me, 81% 77c; R1=OMe, 83% 77d; R1=F, 71%
77e; R1=H, 95% 77f; R1=OMe, 90%
77g; R1=H, 85% 77h; R1=Me, 85% 77i; R1=F, 72%
77j; 72%
Scheme 44. A) Rh(III)-catalyzed C–H carboxylation of 2-phenylphenols. B) Rh(III)-catalyzed C–H carboxylation of 2-heteroarylphenols.
Detailed experiments were made to support a purposed catalytic cycle for this transformation (Scheme 45). First, 74b is formed
15 from 74 which coordinates with complex A with the help of t BuOK to form complex B in situ. Then, the chelation-assisted aryl C–H bond activation of complex B via proton abstraction with the assistance of tBuOK affords complex C. Nucleophilic carboxylation of C with CO2 leads to the formation of the unstable eight-membered Rh-carboxylate complex D, which is converted to complex E by ligand exchange with KOAc. Possibly, a second ligand exchange with KOAc occurs and after protonolysis of the resulting carboxylate and subsequent lactonization, the desired product 75 forms and complex A reenters the catalytic cycle. R1
BuOH tBuOK R1
t
R1
O
OK
OK O
R2
R2
R2
lactonization
75
74b
complex A
ROH + KOAc Rh2(OAc)4 + SPhos
R1
R1
ORh2(OAc)3(SPhos)
OK CO2Rh2(OAc)3(SPhos) R2
E protonolysis
B
R2 ROK
ROK
ROH + KOAc
R1
O
R2
C-H bond cleavage
Rh2(OAc)2(SPhos) R1 O
ROH + KOAc O Rh2(OAc)2(SPhos)
O D
nucleophilic addition
74
KOAc
CO2
R2
C
Scheme 45. Proposed mechanism for Rh(III)-catalyzed C–H carboxylation of 2-phenylphenols.
The same group published a similar rhodium-catalyzed protocol on C–H bond carboxylation on heteroarenes with CO2. [47,48] The difference in their previously established protocol is the use of bidentate phosphine ligands (dppm or dpppe) oppose to monodentate (SPhos or PCy3), which proved to be vital importance for this reaction. The scope of this C–H carboxylation of substituted 2-(imidazo[1,2-a]pyridine-2-yl)phenols with CO2 showed good generality towards different substituents (Scheme 46). Both electron-withdrawing (78b–d, 78i) and electrondonating (78e–h, 78j) groups were tolerated, with the latter resulting in slightly higher yields of products. Substrates with different substituents on the phenolic ring also reacted smoothly, giving the desired products in good yields (79k–n). Comparably the reactions were also carried out without the addition of Rh2(OAc)2 and the corresponding ligand (yields in parenthesis are 1H NMR yields), therefore indicating the importance of the present Rh/phosphine catalytic system on the reaction yields. R2
N R1
OH
N
N
Rh2(OAc)4 (1-5 mol%) dppm or dpppe (2-10 mol%) CO2 (1 atm) tBuOK (4.5 equiv.)
Ar(Het)
[RhCl(cod)]2 (5-10 mol%) ligand (20-40 mol%) B2(pin)2 (2 or 3 equiv.)
O N
toluene, 100-160
80
N
Ph2P O
N 79
R1
oC,
n
PPh2
dppm: n=1 dpppe: n=5
O
81a; 89% (A)
O Ar(Het) B O
15 h
81
conditions A: PCy3, 100ºC conditions B: IMesMe, 100ºC conditions C: IMXyMe, 160ºC B(pin)
B(pin)
81b; R1=OPiv, 72% (A), 0% (B) 81c; R1=OCONMe2, 66% (A), 0% (B) 81d; R1=NMe2, 68 (B)
R2
R1 81e; R1=tBu, 77% (B) 81i; R1=OCF3, 62% (B) 1 81j; R1=F, 70% (B) 81f; R =Ph, 80% (B) 81g; R1=OMe, 68% (B) 81k; R1=CF3, 61% (B) 81h; R1=OPh, 71% (B) B(pin)
B(pin)
B(pin)
S
N
R1
N
N
O
N R1
X X=Me: IMesMe X=OMe: IMXyMe
R2
R1
N
X
B(pin)
DMF, 90-100 oC, 24 or 48 h
78
A rhodium-catalyzed reaction of aryl 2-pyridyl ethers with a diboron reagent for the formation of arylboronic acids via activation of the C(aryl)–O bond was developed by Chatani and co-workers. [49] The 2-pyridylodxy (OPy) group is a frequently used motif for ortho directed metal-catalyzed C–H functionalization and the standard method to remove the pyridine ring in 2-OPy involves a N-methylation step followed by a cleavage of the C(pyridinium)–O bond by NaOMe to give the corresponding phenol. Hence, the reported method by Chanati involves the conversion of the OPy group by substituting the OPy group with a synthetically useful boryl group in a single step and in a catalytic manner. The methodology consists of three different sets of reaction conditions (conditions A, B, and C), whereas the choice of the latter depends on the nature of the substrate. The main difference between the established reaction conditions is the ligand and reaction temperature (Scheme 40). At first, conditions A, as the mildest, were developed for the desired transformation (having PCy3 as the chosen ligand and temperature at 100 ºC). Unfortunately, conditions A were ineffective for several less reactive substrates. For this reason, reinvestigation of the reaction conditions was needed which lead to the development of conditions B (IMesMe, 130 ºC). The scope showed broader tolerance for pyridyl ethers containing a range of functional groups such as simple ethers (80g, 80h), fluorinated substituents (80i–k) and amines (80d). However, conditions B proved to be unsuitable for substrates containing carbonyl functionalities (80b, 80c). Moreover, this borylation reaction was found to be relatively sensitive toward steric effects, as ortho substituted substrates gave the desired products in lower yields (81l, 41%; 81m, 50%). The decrease in the yields is presumed to be due to the formation of a reductive cleavage product, which indicates that an ortho substituent does not significantly inhibit the C(aryl)–O activation process but rather slows down the subsequent oxidative addition step. For accelerating the transmetalation step, a new NHC ligand was designed which would serve as a stronger σ-donor. As a result, a methoxysubstituted analogue of IMesMe was prepared (conditions C; IMXyMe, 160 ºC). Satisfyingly, the yields of products 81l and 81m were increased to 63% and 70%. In addition, heteroaromatic substrates also underwent the borylation reaction smoothly, giving products in good yields (81n–p, 60–82%).
O
79a; R1=H, 81% (30%) 79b; R1=F, 57% (12%) 79c; R1=Cl, 55% (8%) 79d; R1CF3, 66% (5%) 79e; R1=Me, 78% (43%) 79f; R1=Et, 95% (65%) 79g; R1=Ph, 75% (11%) 79h; R1=p-tol, 73% (43%)
O
N O
79i; R1=CF3, 62% (15%) 79j; R1=Me, 86% (34%)
N
R1
O
O 79k; R2=Br, 47% (12%) 79l; R2=Me, 84% (45%) 79m; R2=Et, 89% (55%) 79n; R2=Ph, 70% (39%)
Scheme 46. C–H carboxylation of 2-(imidazo[1,2-a]pyridine-2-yl)phenols with CO2.
81l; R1=Me, 63% (C), 42% (B) 81m; R1=Ph, 70% (C), 50% (B)
Me
N 81n; 82% (B)
N Me 81o; 60% (B)
Me 81p; 65% (B)
Scheme 47. Rh-catalyzed borylation of (hetero)aryl pyridyl ethers with B2(pin)2.
4. Ru-Catalyzed C–H Bond Functionalization In 2012, Ackermann and co-workers reported a Ru-catalyzed C– H bond arylation of 2-pyridyl-substituted phenol derivatives, the
16
Tetrahedron
first example of a ruthenium-catalyzed direct arylation via sixmembered ruthenacycle. [50] The arylation reaction was catalyzed by an in-situ formed ruthenium(II)-carboxylate complex. Under optimal conditions, 2-pyridyl-substituted phenol derivatives 82 were arylated with 4-bromoanisole in the presence of 2.5 mol % [RuCl2(p-cymene)]2, MesCO2H and K2CO3 as the base to give the corresponding monoarylated product 83 (Scheme 48). The reaction with the 2-Me substituted substrate gave the corresponding arylated pyridyl phenol 83a in a decent 44% isolated yield. Electron-withdrawing groups such as CF3 and F did not influence the reaction performance deriving the corresponding arylated products 83b, 83c, and 83d in good to excellent yields (42%, 71%, and 99%; Scheme 25). The Rucatalyzed C–H bond arylation protocol was also applicable by using less expensive and reactive aryl chlorides (X=Cl) in reaction with a set of different O-pyridyl fluorophenols 82 affording the final products in good to excellent yields (83e–r, 52–99%). [RuCl2(p-cymene)]2 (2.5 mol% or 5 mol%)
R2
O
+
R1
N
ArX X = Br, Cl
82
N
Me
MesCO2H (30 mol%) toluene, K2CO3, 120 oC, 20 h
N
CF3 O
N
O
F
83a; (X=Br), 44%
N
N
F O F
F
OMe 83b; (X=Br), 42%
Ar 83
O
F OMe
R2
O R1
OMe
OMe
83c; (X=Br), 71%
83d; (X=Br), 99% Me
N
F
N
F O
N
F
O
O R3
R3 83e; R3=OMe, (X=Cl), 98% 83f; R3=COMe, (X=Cl), 88%
83g; R3=OMe, (X=Cl), 77% 83h; R3=COPh, (X=Cl), 63%
Me Me N
F
Me N
F
N
F
O
O
R3 83i; R3=OMe, (X=Cl), 95% 3 83j; R =COMe, (X=Cl), 94% 83k; R3=CO2Me, (X=Cl), 71%
O
R3
R3 R3
83l; R3=OMe, (X=Cl), 75% 83m; R3=COMe, (X=Cl), 52%
83n; R3=OMe, (X=Cl), 99% 83o; R3=COMe, (X=Cl), 94% 83p; R3=CO2Et, (X=Cl), 61%
(85j), and esters (85k–m). Unfortunately, the desired products were not obtained when alkyl chlorides were employed as the coupling partner. O R1
+
N 84
O R1
N 85
benzene, 120 oC, 24 h
R2
R3
R4
OPy
OPy
OPy
OPy
OPy MeO
R1
85a; R1=H, 73% 85b; R1=4-Cl, 38% 85c; R1=4-OMe, 81% 85d; R1=4-NO2, n.r. 85e; R1=2-Me, 51% 85f; R1=5-Me, n.r.
MeO
MeO
MeO
Cl
R2 85g; R2=nPr, 62% 2 i 85h; R = Pr, 63%
O 85i; 58%
MeO2C
R2
85k; R2=Me, 36% 85l; R2=nHep, 34% 85m; R2=iPr, 37%
85j; 37%
Scheme 49. Ruthenium-catalyzed meta-C–H phenoxypiridines with isopropyl bromide.
alkylation
of
2-
A series of designed experiments were conducted to support the proposed mechanism shown in Scheme 50. First, 2-(2,6dimethylphenoxy)pyridine, bearing two methyl substituents on the ortho positions of the phenyl ring, failed to react with alkyl bromide, supporting the importance of the ortho-CAr–H metalation in the process. Second, an active six-membered ruthenacycle was prepared from a chosen phenol and [Ru(pcymene)Cl2]2, which was submitted under the standard reaction C–H functionalization conditions providing the desired metaalkylated product and therefore indicating that the ruthenacycle might be the active catalyst in the reaction. Finally, the desired product was not obtained when radical scavengers were added to the reaction system, suggesting that the alkylation reaction might involve a radical process. On the basis of the above mentioned results a plausible mechanism involves an active six-membered ruthenacycle A, which is subjected to an electrophilic attack at the meta-position of the directing group through a strong ortho/para-directing effect of the Ru–CAr σ-bond. The alkyl radical originates from a ruthenium-mediated single-electrontransfer process. Finally, the deprotonation of species B with the assistance of Ru(III) and the base forms a stable complex C, which undergoes ligand exchange with 2-phenoxypyridine and releases the desired meta-alkylated product, whereas the active species re-enters the catalytic cycle.
83q; R3=OMe, (X=Cl), 59% 83r; R3=COMe, (X=Cl), 57%
O R1
Scheme 48. Ru-catalyzed C–H bond arylation of 2-pyridyl-substituted phenol derivatives.
The first example of the synthesis of meta-alkylphenols via ruthenium-catalyzed C–H functionalization of phenol derivatives with sec/tert-alkyl bromides was reported by the Wang group. [51] A number of 2-phenoxypyridines bearing substituents at different positions of the phenyl ring were examined as coupling partners (Scheme 49). Substituents at the para (84b, 84c) or ortho (84e) positions of the 2-pyridyloxy group did not influence the reaction outcome. However, the corresponding product 85f was not formed with the methyl group at the meta position, which is presumed to be difficult to react due to steric hindrance. The electronic properties of the substituents also drastically influenced the final outcome of the reaction, as electron-donating substituents favored the formation of the meta-alkylated product 85c oppose to those bearing electron-withdrawing groups where no reaction was observed (85d). Furthermore, several alkyl bromides were tested as coupling partners with 2-(4methoxyphenoxy)pyridine under the established reaction conditions. Both sec-alkyl and tert-alkyl bromides favored the meta-alkylation process as well as simple ethers (85i), halogens
[Ru(p-cymene)Cl2]2 (5 mol%) 1-AdCOOH (30 mol%) K2CO3 (2 equiv.)
R2 R3 R4 (3 equiv.)
Br
84
O
N R1
85 O -
R2
N Ru L C
O
Ru(II) + KHCO3
R3
N Ru L
N
R4
84, K2CO3 1-AdCOOH
[Ru(p-cymene)Cl2]2
A
Ru(III) + K2CO3 O -
N Ru L
[Ru(III)X]
[Ru(II)]
Br
B
Scheme 50. Purposed mechanism for ruthenium-catalyzed meta-C–H alkylation of 2-phenoxypiridines with isopropyl bromide.
A novel catechol synthesis through Ru(II)-catalyzed regio- and chemo-selective C–H hydroxylation reaction was developed. [52] The protocol was initially tested on a set of different protected phenols (esters, carbonates, and carbamates), among which phenyl dimethylcarbamate gave the best result. Condition screening showed [Ru(p-cymene)Cl2]2 to be the most effective
17 catalyst in combination with K2S2O8 as the oxidant in a 1:1 solvent mixture of TFA/TFAA (Scheme 43). Pleasingly, no double-hydroxylation products were observed in all examples. Moreover, the reaction could be carried out at room temperature, although at a much slower rate. The typical reaction temperature for achieving satisfying yields was determined to be 70–90 ºC. A survey of the reaction scope showed to be very broad, including ortho-, meta-, and para-substituted carbamates, as well as those with electron-donating (86b–d) and electron-withdrawing (86e– h) groups were well tolerated. Even, acetyl and aldehyde groups were compatible with the reaction conditions, yielding products 87i and 87q in 40% and 67%, respectively. Gratifyingly, all meta-substituted carbamates only gave one regioisomeric product (87k–r), due to steric hindrance. Interestingly, when reacting carbamates bearing ester or ketone substituents, the carbamate group showed to be superior in terms of directing ability (87i, 87j, and 87r). It must be noted, that a chosen set of phenol carbamates was also converted to the desired catechols effectively by palladium catalysis (5 mol% of Pd(OAc)2) at ambient temperature, although in lower yields. NMe2
O R1 86
O
87a; R1=Me, 79% 87b; R1=OMe, 58% 87c; R1=tBu, 61% 87d; R1=Ph, 53% 87e; R1=F, 70%
O R1
TFA/TFAA, 70-90 oC, 2-3 h 87 O
R1
[Ru(p-cymene)Cl2]2 (2.5 mol%) K2S2O8 (2 equiv.)
NMe2
R1
O OH 87f; R1=Cl, 70% 87g; R1=Br, 74% 87h; R1=NO2, 70% 87i; R1=COMe, 40% 87j; R1=CO2Me, 62%
O
NMe2
O OH
NMe2
O OH 87k; R1=Me, 77% 87l; R1=CF3, 76% 87m; R1=F, 75% 87n; R1=Cl, 77%
87o; R1=Br, 73% 87p; R1=I, 81% 87q; R1=CHO, 67% 87r; R1=CO2Me, 71%
O [Ru(p-cymene)Cl2]2 (5 mol%) + Ar S Cl xylene, 120 oC, 24 h O
O N R1
88
Me p-Tosyl
O
R1
R1 89
Cl
N
O
O
N Cl
1 89a; R1=H, 83% 89c; R =OMe, 86% 89b; R1=Me, 78% 89d; R1=NO2, n.r.
O
O
p-Tosyl
p-Tosyl
Cl
O S
Ar
N Cl Me 89f; trace
N
89e; 76% F
R2
F O
F O
F F
N
Cl 89g; R2=H, 82% 89k; R2=NO2, 60% 2 t 89h; R = Bu, 78% 89l; R2=F, 75% 89i; R2=Ph, 72% 89m; R2=Cl, 80% 89j; R2=OMe, 81%
Cl
N
89n; 75%
Scheme 52. Ru-catalyzed ortho-C–H chlorination and meta-C–H sulfonation of 2-phenoxypiridines.
Similar experiments as described above in Scheme 50 were also conducted to support this Ru-catalyzed dual C–H bond functionalization mechanism indicating (1) the necessity of ortho-CAr–H metalation in the reaction process, (2) the sixmembered ruthenacycle being a plausible key active intermediate, and (3) suggestion that the reaction involves a radical process. A plausible catalytic cycle was therefore proposed (Scheme 53). Initially, the key six-membered ruthenacycle A is formed and then attacked by an arylsulfonyl chloride at the para position on the Ru–CAr σ-bond after which an oxidative addition of the arylsulfonyl chloride in followed. Finally, reductive elimination of complex B yields the final product 89.
Scheme 51. Ruthenium-catalyzed C–H hydroxylation of phenyl carbamates. O
The first example of transition-metal-catalyzed ortho/metaselective dual C–H functionalization of 2-phenoxypyridines in one reaction was described by Yang and co-workers. [53] The transformation includes an ortho-C–H chlorination and meta-C– H sulfonation of the corresponding substrates which was achieved in the presence of 5 mol% [Ru(p-cymene)Cl2]2 in xylene as the chosen solvent. The selected arylsulfonyl chloride plays an extremely important role in the reaction, as it represents both, the sulfonation and chlorination reagent, and more importantly, also the oxidant in the developed process. As the scope of the substrates was examined, the methyl group on the ortho- and para-position of the 2-pyridyloxy directing group did not affect the reaction (89b; 78%, 89e; 76%), whereas only traces of the desired product 89f were obtained for substrate bearing the Me group on the meta-position (Scheme 52). Interestingly, strong electronic effects were observed in the reaction where electrondonating substituents showed to be favorable for the reaction (89c; 86%) in contrast to electron-withdrawing groups which deactivated the reaction (89d; no reaction). Moreover, the scope of the arylsulfonyl chlorides was also examined and according to the obtained results, alkyl (89h), aryl (89i), electron-donating (89j), electron-withdrawing (89k) groups, and halides (89l, 89m, and 89n) were compatible with the applied reaction conditions.
N Cl
Cl Ru SO2Ar
O S O
89
Me
i-Pr
C-H cleavage 2
reductive elimination
O S Ar
O
O N Cl Cl Ru SO2Ar O
B
H i-Pr
O O Ar S Cl O oxidative O S addition Ar O
N Ru Cl A
88 [Ru(p-cymene)2Cl2] i-Pr
O Ar S Cl meta-C-H O functionalization
N Ru Cl i-Pr
Scheme 53. Proposed catalytic cycle for Ru-catalyzed dual C–H bond functionalization of 2-phenoxypyrydynes.
5. Ir-Catalyzed C–H Bond Functionalization In 2008, Hartwig and co-workers reported a one-pot strategy for silyl-directed Ir-catalyzed ortho-C–H borylation of phenols. [54] The approach employs a diethyl silyl directing group to affect C– H borylation at the ortho position of the phenol derivative. Phenols 90 were treated with diethylsilane (Et2SiH2) in the presence of 0.5 mol% of [Ir(cod)Cl]2 as the catalyst to give silyl ether 91 (Scheme 54). After evaporation of the solvent and redissolution of the residue in THF, bis(pinacolato)diboron (B2pin2), pinacolborane (HBpin), [Ir(cod)Cl]2, and 4,4’-di-tbutyl-2,2’-dipyridyl (dtbpy), were added. Consequently, orthoborylated silyl ethers 92 were obtained. The treatment of this borylation product with potassium hydrogen fluoride (KHF2) formed stable trifluoroborate salts 93. The one-pot silylation/C–H borylation sequence was carried out on various substituted phenols. Electron-rich phenols derived the corresponding trifluoroborylated phenols (2-Me 93a, 2-OMe 93b, and 3-tert-Bu 93d) in good yields. Additionally, the presence of halogen atom on the phenol moiety was well tolerated under the established
18
Tetrahedron
reaction conditions since the product 93c was isolated in quantitative yield. OH R1
OH 1. Et2SiH2, [Ir(cod)Cl]2 (0.5 mol%), C6H6
R1
2. B2Pin2, HBpin (5 mol%), [Ir(cod)Cl]2 (1 mol%), dtbpy (2 mol%), THF, 80 oC 3. 4 M KHF2 , THF
90 EtSiH2 [Ir]
OSiEt2H R1
KHF2 H2O OSiEt2H
B2Pin2, HBpin
R1 Bpin
[Ir], dtbpy
91
BF3K
93
92
R1 OH
tBu
BF3K
O
93e; 94%
tBu
O
B B O
BF3K
BF3K 93d; 82%
93a; R=Me, 96% 93b; R=OMe, 89% 93c; R=Cl, quant.
O
OH
OH
tBu
thermodynamically favorable oxidative addition of a C–H bond to the iridium complex occurs if the phenantroline ligand contains both methyl groups on the exactly specified positions as oppose to such ligands which lack one or both Me-groups on the 2 and 9 positions. And secondly, the reaction also exhibits H2 as a byproduct, which was found to inhibit the activity of the iridium complex and therefore slow down the reaction rate. Consequently, a flow of nitrogen was applied to the reaction mixture to remove hydrogen from the system achieving high yields of the desired products. The silylation reaction of 1,3dimethoxybenzene (94a) occurred with >10:1 selectivity on the meta C–H bond over the ortho C–H bonds (Scheme 56). In the case of 2,6-dimethylanisole (94b) and 1,2,3-trimethoxybenzene (94c) the electron-rich para C–H bond to the methoxy groups were successfully silylated forming products 95b and 95c in high 83% and 84% yields, respectively. Unfortunately, the reaction of 3,4-dimethoxytoluene afforded 95d in a very low yield even at a higher catalyst loading (4 mol%) and longer reaction time (48 h).
B H
O
O
B2pin2
N N dtbpy
HBpin
Scheme 54. Silyl-directed Ir-catalyzed ortho-C–H borylation of phenols.
OMe
[Ir(cod)(OMe)]2 (1 mol%) 2,9-Me2Phen (2 mol%) N2
OMe R1
R1 Si
dioxane, 100 ºC, 20 h
TMSO 95
94
Two sets of experiments were conducted to confirm that the ortho-functionalization results from temporary formation of an Ir–Si bond, rather than formation of a silylborane. Furthermore, H/D exchange studies indicated that the ortho-substituted product results from selective C–H activation at the ortho-position directed by the hydrosilyl group, rather than selective functionalization of ortho-C–H bond cleavage by the silylborane moiety. The plausible mechanism is proposed to proceed through a trisboryl complex A as the key intermediate (Scheme 55). Furthermore, the ortho-borylation occurs by the generation of tha bisboryl monosilyl complex C, followed by selective ortho-C–H activation and functionalization to yield complex D. Thus, coordination between Si and B gives rise to bisboryl complex. Finally, the addition of B2pin2 would release the ortho-borylated phenol 93 with regeneration of the trisboryl complex intermediate B. OSiEt2H R
R O SiMe2
N H
91
Ir Bpin
N Bpin
tBu
C
N
Bpin
N
Bpin
N
Ir N tBu
Bpin Ir Bpin
Bpin
Bpin
A
B
Bpin R O SiMe2
N Ir OSiEt2H R Bpin
H
N Bpin D
93
Scheme 55. Proposed mechanism for the Ir-catalyzed silyl-directed orthoborylation of phenols.
Recently, a new procedure for the silylation of aryl C–H bonds employing a carefully designed catalytic system has been described. [55] The high efficiency, functional group tolerance, and regioselectivity of developed methodology in based on the combination of iridium complex [Ir(cod)(OMe)]2 with a sterically hindered phenantroline ligand, 2,9-Me2-phenantroline (2,9Me2Phen). Thorough condition screening revealed two crucial features for the reaction to proceed efficiently. First, the high activity of the catalyst is evident in the appropriately chosen ligand, which turned out to be a phenantroline containing methyl groups on the 2 and 9 positions. Apparently, a more
OTMS Me
N
Me 2,9-Me2Phen
R1
OMe
OMe
R2 MeO
Si TMSO 95a; 74%
OTMS Me
R1
N
Me
OMe Si TMSO
OTMS Me
95b; R1=Me, R2=OMe, 83% 95c; R1=R2=OMe, 84%
Me
OTMS Si TMSO Me 95d; 4%
Scheme 56. Ir-catalyzed C–H silylation of anisoles.
6. Au-Catalyzed C–H Bond Functionalization An important contribution was made by Russell et al., as they managed to develop a gold-catalyzed direct arylation reaction for the construction of biaryls which proceeds at ambient temperature. [56] The key developments of the method is the use of Ph3PAuOTs as the precatalyst, conducting the reaction at room temperature in the presence of a low concentration of methanol as a co-solvent, and forming the active oxidant in situ from iodobenzene diacetate (PhI(OAc)2) and camphorsulforic acid (CSA). Two sets of reaction conditions were established, depending on the degree of functionality of the substrate. Heavily functionalized or valuable arenes were reacted in a ratio of 1:1 with the coupling partner (conditions A), whereas simple or cheap arenes were submitted with the coupling reagent in a 2:1 stoichiometry and the precatalyst loading was reduced from 2 to 1 mol% (conditions B). Most reactions were carried out within 20–40 h at ambient temperature (97a–c, 97e–g). However, sterically hindered (97m and 97n) or electron-rich (97d and 97h) required longer reaction times (up to 80 h) and higher reaction temperatures (up to 65 ºC). Diverse functionality on the arylsilanes was well tolerated under the established reaction conditions, as halogens (97n–p), sulfonates (97q), aldehydes (97r), and pivaloyl esters (97s) gave the desired biaryls in good to excellent yields (99–99%) without oxidation or transesterifications, respectively (Scheme 57).
19 R2 OR1
SiMe3
+ R3
R2 96
Ph3PAuOTs(1 or 2 mol%) PhI(OAc)2 (1.3 equiv.) CSA (1.5 equiv.)
Conditions A:
F
R3
CHCl3/CH3OH = 50:1 r.t. or 65 ºC
(1 or 2 equiv.)
OMe
O
R2
Br
OR1
97
R1
MeO
Me Br
F
F
97m; 74% 97i; R1=OH, 82% 97a; R2=Cl, 85% 97j; R1=OMs, 71% 97b; R2=Br, 92% OMe 1 i 2 97k; R =OCON Pr2 , 69% 97c; R =I, 88% 97l; R1=NPhth, 83% 97d; R2=OMs, 81% Br 97e; R2=CO2Me, 92% R3 97f; R2=NMePiv, 94% 97g; R2=NPhth, 88% 97n; R3=2-F, 92% 97q; R3=4-OTf, 72% 97o; R3=4-Cl, 97% 97r; R3=3-CHO, 77% 97h; R2=CON(Me)CH2CH2NMe2, 65% 97p; R3=3-Br, 72% 97s; R3=4-OPiv, 80%
Conditions B: Me
MeO
Me
OMe
Me F
F
97t; 68%
F
97u; 63%
97v; 46%
Scheme 57. Au-catalyzed C–H arylation of phenol derivatives for the formation of biaryl systems.
Zhang and co-workers reported the first example of a goldcatalyzed intermolecular site-selective C–H bond functionalization of unprotected phenols by using diazo compounds as the coupling partner in the presence of a tris(2,4di-tert-butylphenyl) phosphite derived gold complex under mild conditions. [57,58] The reaction proceeded in a highly chemoselective manner furnishing the desired para C–H bond functionalization products 100 (Scheme 58). The crucial element for making the reaction regioselective was the addition of the sterically hindered phosphine ligand ((2,4-tBu2C6H3O)3P)), which solely lead to the formation of para C–H functionalized products, as no ortho and meta C–H functionalization or O–H insertion products were detected. Varying the scope of different diazo compounds 99 had no effect on the selectivity and yield of the reaction (100a–g). Moreover, different substituted phenols reacted smoothly, affording the corresponding C–H functionalization products in good to excellent yields (100h–l; 83–98%). Interestingly, phenol substrate bearing an ortho-allyl substituent only gave the para C–H functionalization product 100m without the formation of any product via cyclopropanation or O–H insertion. Furthermore, when meta-methylphenol 98n and meta-methoxyphenol 98o were employed, ortho C–H functionalization products could also be detected and isolated in decent yields indicating, that the methyl and methoxy group can also act as directing groups. Surprisingly, sterically hindered phenol still gave the desired para C–H functionalization product 100p in a good 75% yield rather than the less hindered O–H insertion product. OH OH
A highly chemo- and stereoselective gold catalyzed para-C–H bond functionalization of phenols with haloalkynes was recently developed. [59] Reaction conditions screening revealed that bulkier ligands, such as IPr, improved the yield but not the (E:Z)ratio of the reaction. However, by changing the counterion to BARF– in combination with IPrAuCl not only enhanced the yield but also achieved perfect diastereoselectivity at room temperature. With the optimal reaction conditions in hand, the scope of chlorophenyl acetylene with various phenol derivatives was explored (Scheme 59). Ortho-substituted phenols all delivered exclusively para-functionalized products in good to excellent yields (102a–e; 68–93%). However, in the cases of meta-substituted phenols, a mixture of ortho- and para-addition products was obtained with good overall yields of the corresponding products (102f and 102f’; 102g and 102g’). However, the reactions involving phenols substituted on the para-position always yielded ortho-substituted products in good to excellent yields (102h–j; 73–80%). The scope with respects to the chloroalkynes was also investigated. Overall, the substituents on the phenyl ring had only a slight effect on the selectivity and yields of the reaction. For example, electron-deficient chloroalkynes showed better reactivity (102n–q) than electronrich chloroalkynes (102k–m). Furthermore, it should be mentioned that chloroalkynes showed better reactivity than bromoalkynes (102r), possibly due to the higher electronegativity, whereas the corresponding iodoalkynes did not react at all. Cl OH
OH R2 R1 +
Cl
IPrAuCl (2 mol%) NaBARF (3 mol%) DCE, r.t., 3-6 h
101 OH
OH
Ph
102f; 51% OH
R2
102h; R1=Me, 73% Ph 102i; R1=OMe, 80% 102j; R1=Ph, 77% R1
Me
Me Cl
Ph
102
R2
Cl OH
102a; R1=Me, 84% 102b; R1=tBu, 86% 102c; R1=OMe, 93% 102d; R1=CH2-CH=CH2, 68% Cl 102e; R1=Ph, 77% R1
Ph
R1
OMe
OH
OH Cl
102f’; 35% R2=Me,
Ph
OMe Cl
102g; 32%
102k; 61% 102l; R2=tBu, 74% 102m; R2=OMe, 54% 102n; R2=F, 82% Cl 102o; R2=Cl, 85% 102p; R2=Br, 92% 102q; R2=CF3, 68%
OH Cl
Ph
102g’; 59% OH
Br 102r; 49%
Scheme 59. Au-catalyzed C–H functionalization of unprotected phenols with chlorophenyl acetylenes.
R1 N2 R1
+
CO2R2
Ar
98
LAuCl (5 mol%) AgSbF6 (30 mol%)
L = (2,4-tBu2C6H3O)3P Ar
DCM, r.t.
99
2
CO2R 100
OH OH
OH
OH R1
R3
Scheme 58. Au-catalyzed C–H functionalization of unprotected phenols with diazo compounds.
Me
CO2R2 Ph
CO2R2
Ph
100a; R3=H, R2=Et, 99% 100h; R1=Me, R2=Me, 98% 100b; R3=4-Cl, R2=Me, 99% 100i; R1=F, R2=Et, 85% 100j; R1=Cl, R2=Me, 83% 100c; R3=4-Br, R2=Et, 99% 100d; R3=4-Me, R2=Me, 98% 100k; R1=Br, R2=Me, 86% 3 2 100e; R =2-Cl, R =Me, 91% 100l; R1=I, R2=Me, 92% 100f; R3=3-OMe, R2=Me, 70% 100g; R3=3-CF3, R2=Me, 63%
CO2Me
100m; 68%
Me Ph
CO2Me
100p; 75% R1
OH
R1
OH
Ph CO2Me Ph CO2Me R1=Me: 100n; 57% R1=Me: 100n’; 39% 1 1 R =OMe: 100o; 34% R =OMe: 100o’; 57%
The preliminary competitive kinetic study showed no kinetic isotope effect and therefore revealing that the C–H bond cleavage of phenol is not involved in the rate-determining step. Hence, C– H activation of phenol by gold is unlikely and so the reaction should proceed via nucleophilic addition of phenol onto the πactivated alkyne (Scheme 60). A series of experiments with deuterated starting materials and solvents proved that no direct transfer of the proton released from the Wheland intermediate takes place. Instead, exchange processes with either the acidic phenol group or traces of water in the reaction media occurs. Based on the results the authors propose a mechanism in which Au coordinates to the chloro-substituted alkyne carbon which leads to a more stable π-activated alkyne A/vinyl cation B. The
20
Tetrahedron
phenol then attacks the highly electrophilic alkyne after which the final product 102 in formed. LAu+
Cl OH
phenol (anisole) gave the aminated product preferably at the para position of the methoxy group (106a), whereas in the cases of other disubstituted phenols the amination reaction proceeded rather at the ortho position to the methoxy functionality (106b–f).
R1 Ar
OMe
Cl
102
OMe
R1
+ 105
HO H
Carbocationic nature LAu+ Ar Cl
Cl [Au]
R1
Ar
NH3
MsO OTf (1.5-4 equiv.)
OMe Cl AuL
B
NH2 106a; 65% (o/m/p = 4/1/14.3) 101
Scheme 60. Proposed reaction mechanism for Au-catalyzed C–H functionalization of phenols with haloalkynes
106 NH2
OMe NH2
m
p
Ar OH
R1
MeCN/H2O, 16 h, r.t.
o
Ar
A
FeSO4 (5 mol%)
R1 106b; R1=Br, 78% 106c; R1=NH2, 70% 106d; R1=CO2Me, 64% 106e; R1=CN, CN% 106f; R1=Me, 53% (o/m = 4.8/1)
Scheme 62. Iron-catalyzed direct C–H amination of phenols.
7. Fe-Catalyzed C–H Bond Functionalization A chemoselective iron-catalyzed oxidative cross-coupling reaction, also known as cross-dehydrogenative coupling (CDC) was developed by Pappo and co-workers. [60] Such methods represent a practical and sustainable strategy in the formation of new C–C bonds as they are achieved directly from two C–H bonds without the need of prefunctionalization of the coupling partners. Iron complexes with high oxidations states are generated following the oxygen–oxygen bond scission of organic peroxides or molecular oxygen. Hence, these high-valent iron species are capable of inducing a single electron transfer (SET) process, which generates an active radical cation species that reacts with a nucleophile. The general system for such transformations usually relies on the use on Fe(III) salts, a terminal oxidant, and 1,2-dichloroethane (DCE) or toluene as the solvent. Furthermore, prolong reactions times and heating is required to initiate the oxidation process and to ensure satisfying results. Unfortunately, such harsh conditions result in the formation of side-products, typically homocoupling processes take place. The protocol developed by Pappo is based on an ironcatalyzed oxidative coupling of phenols carried out in fluorinated solvents, which significantly reduces the oxidative potential of the phenols and thereby facilitates the coupling reactions under mild conditions, avoiding the formation of homocoupled byproducts. Among the tested fluorinated solvents, 1,1,1,3,3,3hexafluoropropan-2-ol (HFIP) and 2,2,2-trifluoroethanol (TFE) were chosen as the optimal solvents as non-symmetrical biaryl products 104a–e were formed in good to excellent yields at room temperature (Scheme 61). OMe FeCl3 (5-15 mol%) tBuOOtBu (1.5-2 equiv.) Ar OH 103
+
MeO OMe (1-3 equiv.)
HFIP or TFE, r.t.
OMe HO Ar MeO
OH OMe
MeO
OMe 104a; R1=H, 79% 104b; R1=CO2Me, 93% 104c; R1=Br, 77%
MeO MeO
OMe
9. References
OH
OH OMe
OMe 104d; 37%
In this review our aim was to summarize the transition-metal catalysts applied for the C–H bond functionalization of phenol derivatives. In surveying the literature on the transition-metal C– H bond functionalization of phenol derivatives, we have recognized achievements and developments that have been realized by using transition metals such as Pd, Rh, Ru, Ir, Au, and Fe. A great number of C–H bond functionalization reactions have been possible using Pd as the chosen catalyst being capable of overcoming continuous challenges of selectivity. Thus, acylation, arylation, hydroxylation, bromination and olefination have been achieved via Pd-catalyzed C–H functionalization. Other metals such as Ir and Ru have been demonstrated to be effective especially in borylation and arylation reactions respectively. Additionally, C–H bond arylation and olefination have also been achieved using Rh catalysis. Metal-catalyzed C–H insertions of the discussed systems, being directed by increasingly complex templates, have given rise to selective meta- and para-functionalization, however, they are still remaining a challenging area for future development. Regarding the discussed methodologies, only some of them meet the criteria of green and environmentally benign synthetic strategies. Thus, those catalyzed transformations possessing relatively large directing groups hardly meet the definition. Consequently, the future developments should be directed towards a greener approach. Finally, known mechanistic insights for reactions catalyzed by Pd, Rh, Ru, Ir, and Au are summarized and in general involve metalacyclic intermediates forming more stable five-membered cyclometalated complexes or even less typical the corresponding six-membered metalacycles.
104
OMe
R1
8. Conclusion
MeO MeO
OMe OMe
1.
OMe 104e; 51%
Scheme 61. Iron-catalyzed oxidative cross-coupling of phenols with arenes.
Direct C–H amination of phenol derivatives without relying on a directing group is reported. [61] An inexpensive iron precatalyst, FeSO4, showed superior activity over other metals (MnSO4, Cu(MeCN)4PF6). Furthermore, the use of a newly developed amination reagent (MsO–NH3+ –OTf) afforded the desired aminated phenols in satisfying yields (Scheme 62). Unsubstituted
2.
Weber, M.; Kleine-Boymann, M. Phenol. In Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, Germany, 2000, pp. 503– 519; (b) Tyman, J. H. P. Synthetic and Natural Phenols; Studies in Organic Chemistry, Vol. 52, Elsevier, Amsterdam, 2014; (c) Z. Rappoport, The 1. Chemistry of Phenols, Ed. John Wiley & Sons, Chichester, UK, 2003. Chen, C.-T.; Martin-Martinez, F. J.; Jung, G. S.; Buehler, M. J. Chem. Sci. 2017, 8, 1631–1641; (b) Finkbeiner, H.; Hay, A. S.; Blanchard, H. S.; Endres, G. F. J. Org. Chem. 1996, 31, 549–555; (c) W. Hesse,W.; Lang, J. Phenolic Resins. In Ullmann’s
21 3.
4.
5.
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, Germany, 2000, pp. 583–600. (a) Top. Organomet. Chem.: Directed Metallation, Vol. 24 (Ed.: N. Chatani), Springer, Heidelberg/New York, 2007. (b) Top. Organomet. Chem.: C–H Activation, Vol. 292 (Ed.: J.-Q. Yu and Z. Shi), Springer, Heidelberg/Dordrecht/London/New York, 2010. (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879–2932; (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802; (c) Colby, D. A.; Tsai, A. S.; Bergman, R.G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814–825; (d) Giri, R.; Shi, N.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242–3272; (e) Liu W.; Ackermann, L. ACS Catal. 2016, 6, 3743– 3752; (f) He, J.; Wasa, M.; Chan, K. S. L.; Shao,Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754–8786. (a) Omae, I. Coord. Chem. Rev. 2004, 248, 995– 1023; (b) Al Mamari, H. H.; Al Awaimri, N.; Al Lawati, Y. Molbank, 2019, 2019(3), M1075; (c) Al Mamari, H. H.; Al Lawati, Y. Molbank 2020, 2020, M1099.
6.
7.
8.
9. 10. 11. 12. 13. 14.
15. 16. 17.
(a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155; (b) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965–3972; (c) Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657–3659. (a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743; (b) Aihara, Y.; Chatani, N. Chem. Sci. 2013, 4, 664–670; (c) Rouquet, G.; Chatani, N. Chem. Sci. 2013, 4, 2201–2208; (d) Ano. Y.; Tobisu, M.; Chatani, N. Org. Lett. 2012, 14, 354–359. (a) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726–11743; (b) Al Mamari, H. H.; Diers, E.; Ackermann, L. Chem. Eur. J. 2014, 20, 9739–9743; (c) Gu, Q.; Al Mamari, H.H.; Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem. Int. Ed. 2014, 53, 3868–3871. Angew. Chem. 2014, 126, 3949-3952. Huang, Z.; Lumb, J.-P. ACS Catal. 2019, 9, 521– 555. Hennings, D. D.; Iwasa, S.; Rawal,V. H. J. Org. Chem. 1997, 62, 2–3. Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844–10845. Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468–469. Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837–5844. (a) Jia, C.; Piao, D.: Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992–1995, (b) Jia, C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252–7263. Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem., Int. Ed. 1997, 36, 1740–1741. Gu, S.; Chen, C.; Chen, W. J. Org. Chem. 2009, 74,7203–7206. Wan, L.; Dastbaravardeh, N.; Li, G.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 18056–18059.
18. (a) Moreno-Manas, M.; Pleixats, R. Acc. Chem. Res. 2003, 36, 638–643, (b) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. J. Am. Chem. Soc. 2013, 135, 86–89. 19. Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. D.; Yu, J.-Q. J. Am. Chem. Soc. 2016, 138, 9269–9276. 20. Liu, L.-Y.; Qiao, J. X.; Yeung, K.-S.; Ewing,W. R.; Yu, J.-Q. J. Am. Chem. Soc. 2019, 141, 14870– 14877. 21. Luo, J.; Preciado,S.; Larossa, I. J. Am. Chem. Soc. 2014, 136, 4109–4112. 22. Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406–12409. 23. Mi, R.-J.; Sun, J.; Kühn, E.; Zhou, M.-D.; Xu, Z. Chem. Commun. 2017, 53, 13209–13212. 24. Patra, T.; Bag, S.; Kancherla, R.; Mondal, A.; Dey, A.; Pimparkar, S.; Agasti, S.; Modak, A.; Maiti, D. Angew. Chem. Int. Ed. 2016, 55, 7751–7755. 25. Maity, S.; Hoque, E.; Dhawa, U.; Maiti, D. Chem. Commun. 2016, 52, 14003–14006. 26. Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 7567–7571. 27. Wang, P.; Verma, P.; Xia, G.; Shi, J.; Qiao, J. X.; Tao, S.; Cheng, P. T. W.; Poss, M. A.; Farmer, M. E.; Yeung, K.-S.; Yu, J.-Q. Nature 2017, 551, 489– 494. 28. Xu, J.; Chen, J.; Gao, F.; Xie, S.; Xu, X.; Jin, Z.; Yu, J.-Q. J. Am. Chem. Soc. 2019, 141, 1903–1907. 29. Dou, Y.; Kenry; Liu, J.; Jiang, J.; Zhu, Q. Chem. Eur. J. 2019, 25, 6896–6901. 30. Sharma, U.; Naveen, T.; Maji, A.; Manna, S.; Maiti, D. Angew. Chem. Int. Ed. 2013, 52, 12669–12673. 31. 1 For selected examples see: (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C.; J. Nat. Prod. 2000, 64,134–135, (b) Bowyer, P. W.;Tate, E. W.; Leatherbarrow, R. J.; Holder, A. A.; Smith, D. F.; Brown, K. A. ChemMedChem 2008, 3, 402–408, c) De Luca, L.; Nieddu, G.; Porcheddu, A.; Giacomelli, G. Curr. Med. Chem. 2009, 16, 1–20, d) Day, S.-H.; Chiu, N.-Y.; Tsao, L.-T.; Wang, J.-P.; Lin, C.-N. J. Nat. Prod. 2000, 63, 1560–1562. 32. Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012, 14, 1760–1763. 33. Luo, S.; Luo, F.-X.; Zhang, X.-S.; Shi, Z.-J. Angew. Chem. Int. Ed. 2013, 2, 10598–10601. 34. Kim, M.; Sharma, S.; Park, J.; Kim, M.; Choi, Y.; Jeon, Y.; Kwak, J. H.; Kim, I. S. Tetrahedron 2013, 69, 6552–6559. 35. Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.F.; Xu, J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 9250–9253. 36. Huang, C.; Chavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 17630– 17633. 37. Duan, S.; Xu, Y.; Zhang, X.; Fan, X. Chem. Commun. 2016, 52, 10529–10532. 38. Lou, S.-J.; Chen, Q.; Wang, Y.-F.; Xu, D.-Q.; Du, X.-H.;. He, J.-Q.; Mao, Y.-j.; Xu, Z.-Y. ACS Catal. 2015, 5, 2846–2849.
22
Tetrahedron 39. Gao, C.; Li, H.; Liu, M.; Ding, J.; Huang, X.; Wu, H.; Gao, W.; Wu, G. RSC Adv. 2017, 7, 46636– 46643. 40. Sun, X.; Sun, Y.; Zhang, C.; Rao, Y. Chem. Commun. 2014, 50, 1262–1264. 41. John, A.; Nicholas, K. M. J. Org. Chem. 2017, 72, 5600–5605. 42. Bedford, B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew. Chem. Int. Ed. 2003, 42, 112–114. 43. Bedford, R. B.; Limmert, M. E. J. Org. Chem. 2003, 68, 8669–8682. 44. Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F. Org. Lett. 2011, 13, 3235–3237. 45. Finkbeiner, P.; Kloeckner, U.; Nachtsheim, B. J. Angew. Chem. Int. Ed. 2015, 54, 4949–4952. 46. Mi, R.-J.; Sun, Y.-Z.; Wang, J.-Y.; Sun, J.; Xu, Z.; Zhou, M.-D. Org. Lett. 2018, 20, 5126–5129. 47. Fu, L.; Li, S.; Cai, Z.; Ding, Y.; Guo, X.-Q.; Zhou, L.-P.; Yuan, D.; Sun, Q.-F.; Li, G. Nat. Catal. 2018, 1, 469–478. 48. Huang, R.; Li, S.; Fu, L.; Li, G. Asian J. Org. Chem. 2018, 7, 1376–1379. 49. Kinuta, H.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015, 137, 1593–1600. 50. Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012, 14, 1154–1157. 51. Li, G.; Gao, P.; Qu, C.; Yan, Q.; Wang, Y.; Yang, S.; Wang, J. Org. Lett. 2017, 19, 2682–2685. 52. Yang, X.; Sun, Y.; Chen, Z.; Rao, Y. Adv. Synth. Catal. 2014, 356, 1625–1630. 53. Li, G.; Zhu, B.; Ma, X.; Jia, C.; Lv, X.; Wang, J.; Zhao, F.; Lv,Y.; Yang, S. Org. Lett. 2017, 19, 5166– 5169. 54. Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534–7535. 55. Karmel, C.; Chen, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2019, 141, 7063–7072. 56. Ball, L. T.; Lloyd-Jones, G. C.; Russell, C. A. Science 2012, 337, 1644–1648. 57. Yu, Z.; Ma, B.; Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136, 6904–6907. 58. Liu, Y.; Yu, Z.; Zhang, J. Z.; Liu, L.; Xia, F.; Zhang, J. Chem Sci. 2016, 7, 1988–1995. 59. Adak, T.; Schulmeister, J.; Dietl, M. C.; Rudolph, M.; Rominger, F.; Hashmi,A. S. K. Eur. J. Org. Chem. 2019, 3867–3876. 60. Gaster, E.; Vainer, Y.; Regev, A.; Narute, S.; Sudheendran, K.; Werbeloff, A.; Shalit, H.; Pappo, D. Angew. Chem. Int. Ed. 2015, 54, 4198–4202. 61. Legnani, L.; Cerai, G. P.; Morandi, B. ACS Catal. 2016, 6, 8162–8165.
Review Highlights: The review covers advances, and developments in the topic of metal-catalyzed C-H bond functionalization of phenol derivatives with the chelation assistance using directing groups. The review provides information and latest developments in C-H bond functionalization of phenol derivatives as catalyzed by various transition metals: • • • • • •
Pd-Catalyzed C–H Bond Functionalization Rh-Catalyzed C–H Bond Functionalization Ru-Catalyzed C–H Bond Functionalization Ir-Catalyzed C–H Bond Functionalization Au-Catalyzed C–H Bond Functionalization Fe-Catalyzed C–H Bond Functionalization
Hamad Al Mamari obtained his DPhil (PhD) degree (2006) at the University of Oxford under the supervision of Professor David Hodgson. Upon completion of his PhD, he returned to his home institution, Sultan Qaboos University, Muscat, Oman to hold the rank of an Assistant Professor. In 2012/2013 he spent oneyear sabbatical at Georg-August University, Göttingen, Germany. In that period, he worked in the field of C-H bond functionalization in the research group of Professor Lutz Ackermann. Later, he spent short-term visits at the Department of Chemistry, School of Science, University of Tokyo in the group of Professor Eiichi Nakamura (2015 & 2017), the Institut für Anorganische Chemie, JuliusMaximilians-Universität, Würzburg, Germany in the group Professor Todd Marder (2016), and at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia in the group of Professor Dr. Bogdan Štefane. His research interests are themed in organic synthesis with emphasis in developments of methods and reactions in the field of C-H bond functionalization and their applications in natural product synthesis.
Bogdan Štefane received his PhD in chemistry in 2000 at the University of Ljubljana under the supervision of Professor S. Polanc. From 2002 to 2004 he was a Marie Curie postdoctoral fellow at the University of Oxford, working with Professor D. M. Hodgson. In 2009 he continued his post-doctoral education as a Fulbright Fellow at the University of Maryland in the research group of Professor H. O. Sintim. In 2017 he spent 4 months as a visiting Professor at Sultan Qaboos University in Oman. In 2004 he became an Assistant Professor and 2011 received the position of an Associate Professor at the University of Ljubljana, where he is currently the head of the Department of Organic Chemistry. His research interests are the development of novel synthetic methods for the synthesis of heterocyclic compounds, transition metal catalysis and design of catalysts, activation of inert chemical bonds, and photochemistry.
Helena Brodnik Žugelj received her PhD at the Faculty of Chemistry and Chemical Technology, University of Ljubljana in 2017 under the supervision of Professor Bogdan Štefane. During her PhD studies she was a visiting scholar at the University of Toronto (Ontario, Canada) in the research group of prof. Mark Lautens. After completing her studies, she became a teaching assistant at the Department of Organic Chemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana. Her main research interests are developing novel and efficient synthetic methods for the activation of inert C–H bonds by employing various transition-metal complexes for the synthesis of structurally complex heterocyclic compounds of biological value and also studying the mechanistic background such transformations.
Declaration of Interest Statement
The authors declare no conflict of interest
Dr. Hamad Al Mamari Corresponding author