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Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds
Article
Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds Tao Yang, Xianxiao Chen, Weidong Rao, Ming Joo Koh [email protected]
HIGHLIGHTS A Ni-catalyzed protocol for dicarbofunctionalization of alkenes is described Stable organohalides are used as substrates under mild reductive conditions Aryl-alkylation, alkenyl-alkylation, and dialkylation reactions can be achieved The method is applicable to the concise synthesis of bioactive molecules
An inexpensive Ni-based catalyst, in combination with a readily recyclable 8aminoquinoline directing group, promotes efficient and regioselective addition of two different organohalides across alkenyl carbonyl compounds under mild reductive conditions. The method has broad functional group tolerance and is applicable to aryl-alkylation, alkenyl-alkylation, and dialkylation transformations. Utility of the strategy is highlighted through concise synthesis of bioactive molecules that are difficult to access by alternative procedures. Kinetic studies revealed insights into the mechanism of the multicomponent reaction.
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Article
Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds Tao Yang,1 Xianxiao Chen,1,2 Weidong Rao,2 and Ming Joo Koh1,3,*
SUMMARY
The Bigger Picture
Catalytic alkene difuntionalization is a convenient platform for introducing complexity in molecules and has wide applications in organic synthesis. Yet a compelling challenge that remains to be solved is the regioselective insertion of two highly functionalized carbon-based moieties, derived from stable and readily available organohalide electrophiles without the need for pre-synthesized organometallic reagents, across C=C bonds in unactivated alkylsubstituted alkenes. Here, we show that catalytic amounts of an inexpensive Ni-based catalyst, in combination with a readily recyclable 8-aminoquinoline directing group, promotes efficient and site-selective addition of two different organohalides (iodides and bromides) across aliphatic alkenes under mild reductive conditions. Compared to previous studies, this protocol exhibits broad and complementary functional group tolerance that extends to aryl-alkylation, alkenyl-alkylation, and dialkylation transformations. The utility of the strategy is demonstrated through concise synthesis of biologically active molecules. Kinetic studies and other control experiments shed further light on the mechanistic underpinnings of the multicomponent reaction.
Access to multifunctional compounds from stable and easily accessible substrates is a coveted goal in chemical synthesis. Alkene difunctionalization provides a powerful way to expeditiously generate molecular complexity, but existing methods either rely on the use of pre-prepared and sensitive organometallic reagents or have limited functional group compatibility that restricts utility. A catalytic manifold that enables the direct union of aliphatic alkenes with different classes of stable and readily available organohalides represents a more practical alternative and expands the toolbox available to construct molecules. As reported here, a catalytic reductive alkene difunctionalization protocol that addresses the aforementioned issues has been devised. This disclosure could find broad applicability in organic synthesis and inspire chemists to develop multicomponent catalytic systems that promote the assembly of high-value building blocks from simple starting materials.
INTRODUCTION Alkenes belong to one of the most abundant and extensively utilized classes of feedstock chemicals in chemical synthesis.1 The ability to install two different motifs, with high efficiency and exquisite control of regioselectivity, through vicinal addition across unsaturated hydrocarbons2 provides a convenient and direct avenue of assembling multifunctional molecules en route to countless biologically active compounds. An important variant of these transformations is the intermolecular 1,2-insertion of two carbon-based groups across alkenes. Previous catalytic studies are largely focused on the union of activated p-systems (e.g., styrenes and Michael acceptors) with an organometallic nucleophile and an organohalide or redox-active electrophile3–10 (see Supplemental Information for extended bibliography). In contrast, reactions with less activated alkyl-substituted alkenes present a formidable challenge because of the lack of sufficient substrate bias, consequently giving rise to poor catalytic efficiency and/or regioisomeric product mixtures. These issues could be addressed by appending the aliphatic alkene to a coordinating moiety that serves as an auxiliary to direct regioselective additions of organozinc (alkyl/aryl) reagents11–15 or aryl/alkenylboronates16–18 with organohalides (Scheme 1A). However, critical shortcomings pertaining to functional group compatibility exist. A number of moieties (e.g., carboxylic acids, alcohols, and secondary amides) that are prevalent in nature and widely used in chemistry are susceptible to side reactions especially when organozinc species19 are involved
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Scheme 1. Catalytic Approaches to Directed Regioselective Di-Carbofunctionalization of Unactivated Alkenes
(Scheme 1A, box). On the other hand, alkene additions with the less-reactive alkylboron reagents are yet to be reported. A related complementary set of reactions that were recently demonstrated to achieve site-selective difunctionalization of activated and unactivated alkenes employ two different organohalide electrophiles in the presence of an inexpensive stoichiometric reductant (Scheme 1B).20–25 These versatile reductive coupling26–35 transformations typically preclude the use of pre-prepared organometallic reagents, potentially enabling a greater diversity of functionalities derived from the relatively more stable and readily accessible carbon-based electrophiles to be incorporated. Despite the associated advantages, development in this area is still in its infancy, and reported methods suffer from distinct drawbacks: (1) multicomponent transformations are restricted to aryl-alkylation/acyl-alkylation between aryl iodides or acyl
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1Department
of Chemistry, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore
2Jiangsu Key Laboratory of Biomass-Based Green
Fuels and Chemicals, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China 3Lead
Contact
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Scheme 2. Proposed Pathway to Achieve Regioselective Reductive Di-Carbofunctionalization of Unactivated Alkenes and the Associated Challenges
chlorides with perfluoroalkyl or tertiary alkyl iodides (primary and secondary alkyl variants are ineffective substrates), (2) reactions with internal C=C bonds are plagued by poor efficiency and/or regioselectivities, and (3) reported examples furnish products that incorporate alkyl units at the terminal olefinic position. Access to the opposite regioisomer is yet to be conceived. A recent disclosure involving reductive aryl-alkylation allows unactivated alkenes devoid of directing groups to be utilized, although only tertiary alkyl units can be installed site-selectively.24 Therefore, there is compelling demand for a general and practical protocol, using inexpensive Ni-based catalysts in conjunction with an easily recyclable directing auxiliary, that merge aliphatic alkenes with a functionalized alkyl halide and another organohalide of various electronic and steric properties (e.g., aryl-, heteroaryl-, alkenyl-, and alkylsubstituted) (Scheme 1C). Furthermore, the method to be developed must be compatible with a wide range of functionalities, including those that are sensitive toward organometallic nucleophiles (cf. Scheme 1A, box). Successful implementation of this strategy is expected to complement existing approaches, enhance our ability to access a larger assortment of important molecules, and offer a straightforward entry to structurally complex analogs that are difficult to obtain otherwise. The challenge remains whether an effective auxiliary can be identified to deliver sufficient regiochemical control, especially for alkenes with longer carbon chain lengths that can hamper reactivity and erode site selectivity36 (see below for further discussion).
RESULTS AND DISCUSSION Reaction Design Based on previous reports involving directed alkene difunctionalizations11–18 and reductive cross coupling,37 we envisioned a possible catalytic sequence as illustrated in
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Table 1. Evaluation of Reaction Conditions
Entry
DG
Ni Complex
Reductant
Solvent
Yield (%)a
1
A
Ni(cod)2
Mn
DMF
60
2
A
Ni(cod)2
Zn
DMF
trace
3
A
Ni(cod)2
TDAE
DMF
67
4
A
NiI2
Mn
DMF
81
5
A
NiCl2(PPh3)2
Mn
DMF
51
6
A
NiCl2(py)4
Mn
DMF
31
7
A
NiBr2,glyme
Mn
DMF
78
8
A
Ni(acac)2
Mn
DMF
72
9b
A
NiI2
Mn
DMF
41
10
B
NiI2
Mn
DMF
28
11
C
NiI2
Mn
DMF
38
12
D
NiI2
Mn
DMF
ND
13
E
NiI2
Mn
DMF
ND
14
F
NiI2
Mn
DMF
25
15
A
NiI2
Mn
DMA
72
16
A
NiI2
Mn
NMP
64
17
A
NiI2
Mn
THF
trace
18
A
NiI2
Mn
Toluene
trace
Abbreviations: DG, directing group; TDAE, tetrakis(dimethylamino)ethylene; DMA, N, N-dimethylacetamide; DMF, N, N-dimethylformamide; NMP, N-methyl-2pyrrolidone; THF, tetrahydrofuran; cod, 1,5-cyclooctadiene; py, pyridine; acac, acetylacetonate; ND, not detected. a Yields are for isolated and purified products. b Reaction was conducted at room temperature.
Scheme 2. A putative Ni(0) complex I that associates with an alkene tethered to a directing unit (e.g., 8-aminoquinoline) can undergo direct oxidative addition (or halogen atom abstraction followed by radical recombination) with one organohalide (XG1) followed by a site-selective 1,2-migratory insertion across the C=C bond in 1 to afford a stabilized quinoline-chelated Ni(II) intermediate II. At this stage, single-electron reduction of the Ni center with an appropriate reducing agent could occur to form a reactive Ni(I) species III that engages with the second organohalide (XG2) to afford a penta-coordinate Ni(III) complex IV. The ensuing reductive elimination then generates a Ni(I) species V with concomitant release of the desired product 2. After a final single-electron reduction, I is regenerated to turn over the catalytic cycle. Whereas catalytic alkene difunctionalizations that employ an organometallic nucleophile and an electrophile typically proceed through initial reaction with the electrophile, alkene migratory insertion and transmetallation with the nucleophile (or the reverse order) in a chemoselective fashion,3–18 systems that involve two organohalide electrophiles can potentially lead to a myriad of products arising from
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Scheme 3. Catalytic Reductive Aryl-Alkylation of b,g-Unsaturated Amides Unless otherwise stated, all Ni-catalyzed reactions were conducted under the optimized conditions with alkyl iodides (XG 2 : I–alkyl). Yields are for isolated and purified products (single regioisomers). For the synthesis of 2aa–2ai, alkyl bromides (XG 2 : Br-alkyl) were used.
competitive addition of substituents (G1 or G2) across the alkene as well as crosselectrophile coupling26–35,37 (cf. Scheme 2, dashed box), particularly if XG1 and XG2 are similarly reactive. Adding to these complications is the need to identify parameters that tolerate a wide variety of sensitive functional groups. We sought to address these challenges by developing an efficient catalytic manifold that relies on chemoselective additions of two different organohalides to deliver high site selectivity. Optimization Studies We commenced our investigations by examining conditions for the operationally simple union of b,g-unsaturated amides with commercially available iodobenzene and 1-iodobutane (Table 1). In the presence of 10 mol % of Ni(cod)2 and the bidentate 8-aminoquinoline directing auxiliary (A)38 in DMF (dimethylformamide) at 40 C, a survey of different reducing agents (entries 1–3) revealed that both manganese and TDAE were effective in promoting reductive difunctionalization, furnishing the desired product as a single regioisomer in 60% and 67% yield, respectively, with 20%–30% unreacted alkene. The sense of regioselectivity was determined to be identical to that derived from transformations involving organozinc reagents11 (aryl group inserted at terminal position; see below for further discussion). Intriguingly, only trace amounts of undesired diarylation or dialkylation side products were detected. We opted to continue our optimization studies using the relatively less-expensive manganese as reductant and evaluated the performance of various Ni-based salts (entries 4–8). A further boost in efficiency was observed with 10 mol % of NiI2 (entry 4), giving the product in 81% yield. Conducting the reaction at ambient temperature led to incomplete conversion of the starting alkene (50% recovered) and a reduced yield (41% yield; entry 9). When the directing unit was switched to other bidentate and monodentate groups (BF), a drastic diminution in efficiency was found (entries 10–14), underscoring the unique ability of A in stabilizing the Ni-based intermediates (cf. Scheme 2) for efficient turnover. The effect of the solvent was also probed, and we discovered that less-polar media (e.g., THF [tetrahydrofuran] and toluene in entries 17 and 18) were more detrimental to the catalytic system (alkene largely unreacted) than the more polar variants such as DMF, DMA (dimethylacetamide), and NMP (N-methyl-2-pyrrolidone) in entries 4, 15, and 16, respectively, with DMF emerging as optimal. Scope of the Method We proceeded to test the generality of our developed conditions by examining a variety of functionalized electrophiles in reductive aryl-alkylation transformations of 8-aminoquinoline-tethered b,g-unsaturated amides (Scheme 3). Aryl iodides and bromides containing electron-donating or electron-deficient substituents on the ortho-, meta-, or para-positions of the aromatic ring served as effective substrates, delivering 2a2t in 48%–84% yield. It merits mention that previously reported three-component reductive di-carbofunctionalizations that focused on aryl iodides as the corresponding bromide substrates were less efficient.20,24 Reactions are compatible with a nitrile (2q), carbonyl compounds (2i and 2r), carboxylic acid derivatives (2s and 2t), as well as carbamates with acidic NH units (2j) that could be problematic with basic organozinc reagents.19 Molecules with halogen (2c and 2d) and boronate (2k) groups that are amenable to further derivatization could be secured.
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Scheme 4. Extension to Reductive Alkenyl-Alkylation and Dialkylation of b,g-Unsaturated Amides, Internal Alkenes as well as Reductive ArylAlkylation of g,d-Unsaturated Amides Unless otherwise stated, all Ni-catalyzed reactions were conducted under the optimized conditions. Yields are for isolated and purified products (single regioisomers). Products 2ao–2at were obtained in 89:11 to >98:2 diastereomeric ratios.
Heterocyclic moieties (2o and 2p) were also tolerated in the catalytic system without the need for N-protection (2p). The scope of the aliphatic cross-partner was assessed using a wide assortment of primary alkyl halides. Across the board, reactions proceeded smoothly in the presence of a silyl ether (2w), a Lewis basic phthalimide (2y), a functionalizable organohalide or organoboronate (2z and 2ac, respectively), an acetal (2aa), or protic units (2x, 2ab, and 2ae–2ai) to afford the expected products in 33%–87% yield. Access to 2x, 2ab, and 2ae–2ai by alternative procedures (cf. Scheme 1A) would not be feasible, because the required alkylmetal nucleophile is unstable toward acidic groups.19 Synthesis of alkene-appended 2ad substantiates the role of the directing auxiliary in promoting chemoselective reductive aryl-alkylation on the b,g-unsaturated amide. Transformations with secondary alkyl halides, however, gave poor regioselectivities as a consequence of competitive reaction with the Ni species (cf. Scheme 2; see Supplemental Information for details). The reductive difunctionalization conditions are also applicable to alkenyl-alkylation and dialkylation by switching to alkenyl or aliphatic halides (Scheme 4). Acyclic
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Scheme 5. Demonstration of Functional Group Compatibility and Application to Concise Synthesis of Biologically Active Compounds Unless otherwise stated, all Ni-catalyzed reactions were conducted under the optimized conditions. Yields are for isolated and purified products (single regioisomers).
alkenes 2aj and 2ak could be generated in 42% and 55% yield, respectively, without isomerization of the olefin geometry. Reactions that employ two alkyl iodides (one primary and one secondary) consistently afforded products resulting from the secondary alkyl motif installed selectively at the terminal olefinic end (2al–2an). Transformations with 1,2-disubstituted alkenes (E- or Z-) were less efficient but proceeded with high stereospecificity, delivering the products 2ao–2at in 41%–88% yield and up to >98:2 diastereomeric ratio. Dialkylation of internal alkenes with two different alkyl halides was also stereospecific but comparatively less efficient (see Supplemental Information for details). The observed stereochemical outcome arises from a syn b-migratory insertion process across the C=C bond (cf. I / II in Scheme 2) and is similar to results from the analogous alkene difunctionalizations involving organometallic nucleophiles.11,36 Extending the alkene carbon chain length to effect g,d-difunctionalization was possible, and the corresponding products 2au–2ay could be obtained in 59%–75% yield, underscoring the ability of the directing group in stabilizing six-membered nickelacycles36 (cf. II, III, and IV in Scheme 2). However, further extensions to the carbon skeleton of the alkene proved deleterious to reaction efficiency and site selectivity. Application to Complex Molecule Synthesis The feasibility of employing the reductive difunctionalization protocol in a late-stage setting was corroborated when we subjected a number of aryl iodides derived from biologically active molecules that bear multiple sensitive Lewis basic and Brønsted acidic centers to our standard reaction conditions (Scheme 5, top). The desired aryl-alkylation products 2az–2aab were secured in 54%–80% yield, showcasing the exceptional functional group compatibility of the method. Our developed catalytic approach offered the opportunity to devise new synthesis routes for a number of biologically active molecules (Scheme 5, bottom, AC). The first instance involves reductive aryl-alkylation to generate 2aac in 63% yield, which was followed by alkaline hydrolysis and reduction to give alcohol 5 in 85% yield (8-aminoquinoline recovered in 90% yield). A final Mitsunobu reaction with 4-hydroxybenzaldehyde then afforded 6, a precursor to sphingosine-1-phosphate receptor modulator 7,39 in 92% yield. In another formal synthesis, reductive aryl-alkylation to give 2aad could be accomplished in 41% yield, which was subsequently subjected to Ni-catalyzed methanolic cleavage to furnish 8, an intermediate used in the preparation of anti-cancer drug candidate 9.40 It merits mention that generation of the corresponding Brønsted acidic secondary amide-containing alkylzinc reagent that is required to access 2aad through previously established aryl-alkylation protocols11 would be difficult.19 The third application relates to the synthesis of 10, a precursor to vitronectin receptor antagonist 11.41 10 was derived from 2aae by methanolysis, which itself could be assembled in 76% yield from catalytic union of alkene 1a, (2-iodoethyl)benzene, and 4-iodophenol without protection of the acidic phenol motif, highlighting the robustness of our reductive di-carbofunctionalization method. Overall, the synthesis sequences presented in Scheme 5 are shorter and compare favorably to the alternative procedures described in previous reports.39–41
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Scheme 6. Control Experiments to Elucidate Mechanistic Nuances Unless otherwise stated, all reactions were conducted under the optimized conditions. Yields are determined by GC analysis with n-tridecane as internal standard, except for the mixture of 2aaf/2aaf 0 (isolated).
Mechanistic Investigations To gain a preliminary understanding of the mechanistic pathways through which the present reductive di-carbofunctionalization operates, we performed a series of control experiments as shown in Scheme 6. Stoichiometric reaction of 1a with a known Ni(0) complex, Ni(cod)2, at 40 C in DMF followed by treatment with three equivalents of iodobenzene for 5 h led to a reaction mixture that furnished 12 (phenyl unit inserted at terminal position) upon alcoholic quenching and analysis by GCMS (Scheme 6A). In a separate vessel, the same reaction mixture that was subjected to 1-iodobutane in the presence of manganese at 40 C for 8 h successfully afforded the expected aryl-alkylation product 2a in 55% yield. In contrast, 2a was not detected when the reductant was omitted in the reaction mixture. These results demonstrate that (1) selective reaction with the aryl electrophile and subsequent alkene insertion occurs prior to engagement with the second alkyl electrophile to deliver the observed regiochemical outcome and (2) a stoichiometric reducing agent is necessary to facilitate reaction with the alkyl electrophile for product formation, possibly through the steps as depicted in Scheme 2.
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Figure 1. Kinetic Studies on the Catalytic Reductive Di-Carbofunctionalization System (A) Plot of k in versus 1-iodobutane concentrations. (B) Plot of k in versus 4-iodotoluene concentrations. (C) Plot of k in versus alkene 1a concentrations. (D) Plot of k in versus NiI 2 concentrations.
The radical clock experiment using (bromomethyl)cyclopropane as an electrophile provided a 41:59 mixture of 2aaf and the ring-opened product 2aaf’ in 56% yield, implying that (bromomethyl)cyclopropane likely reacts with the Ni(I) complex (cf. III / IV in Scheme 2) through a bromine abstraction followed by a radical recombination36 process via a cyclopropylmethyl radical intermediate that is prone to ring rupture (Scheme 6B). Preliminary kinetic studies were carried out to shed light on the roles of each component (aryl iodide, alkyl iodide, alkene 1a, and NiI2 catalyst) on the rate of reductive dicarbofunctionalization. Control experiments revealed a lack of dependence on the manganese reductant, which is congruent with previous observations in reductive cross-electrophile coupling.29 Measurements of the initial rates (kin) for the catalytic union of 1a, 4-iodotoluene, and 1-iodobutane at varying concentrations of each component were conducted (Figures 1A–1D). Results showed that the reductive di-carbofunctionalization exhibits a first order rate dependence on 1-iodobutane and the catalyst (Figures 1A and 1D, respectively), but no appreciable deviation in rate was detected by changing the concentration of 1a (Figure 1C). Intriguingly, although kin was initially found to have a positive dependence on 4-iodotoluene concentration (%0.3 M; undesired alkene dialkylation is competitive), the rate of product formation visibly slows down as the concentration is raised further (Figure 1B). The observed reliance of reaction rate upon the concentrations of the alkyl iodide
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and NiI2 suggest that the reaction of III with alkyl iodide to give IV (cf. Scheme 2) might be rate-limiting.7 The apparent inverse rate dependence on aryl iodide concentration at >0.3 M could be rationalized by the onset of competitive coordination (possibly through p-complexation;29 <1% alkene diarylation or dialkylation side products detected) to the intermediate organonickel species III that consequently diminishes reaction rate by depleting ligation sites for the incoming alkyl iodide to undergo halogen atom abstraction (cf. III / IV, Scheme 2). Further efforts to elucidate the mechanism through extensive investigations and DFT calculations are ongoing. Conclusions Catalytic quantities of a Ni-based complex in conjunction with a versatile directing auxiliary42–45 and manganese as a reducing agent enabled 1,2-vicinal additions of two different organohalides across unactivated alkenes with high efficiency and complete site selectivity. A wide array of acidic and basic functional groups that are otherwise susceptible to side reactions in the presence of organometallic compounds, can be tolerated under the reductive di-carbofunctionalization conditions. The present method is amenable to late-stage synthetic manipulations and can be readily employed in concise scalable preparation of multifunctional biologically active molecules. Given the recent renewed interest in base metal-catalyzed CC bond-forming transformations,46 we expect our studies to find broad utility in chemistry and facilitate current endeavors in designing practical multicomponent reactions that assemble high-value building blocks from stable and readily available starting materials.
EXPERIMENTAL PROCEDURES Detailed experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION Supplemental Information can be found online at https://doi.org/10.1016/j.chempr. 2019.12.026.
ACKNOWLEDGMENTS This research was supported by the National University of Singapore President’s Assistant Professorship start-up grants R-143-000-A50-133 and R-143-000-A50-750 (M.J.K.). X.C. acknowledges funding support from the National First-class Disciplines (PNFD).
AUTHOR CONTRIBUTIONS T.Y. and X.C. performed the experiments. M.J.K. directed the investigations with assistance from W.R. M.J.K. wrote the manuscript with revisions provided by the other authors.
DECLARATION OF INTERESTS The authors declare no competing interests. Received: September 20, 2019 Revised: November 9, 2019 Accepted: December 20, 2019 Published: January 16, 2020
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Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds Tao Yang, Xianxiao Chen, Weidong Rao, Ming Joo Koh [email protected]
HIGHLIGHTS A Ni-catalyzed protocol for dicarbofunctionalization of alkenes is described Stable organohalides are used as substrates under mild reductive conditions Aryl-alkylation, alkenyl-alkylation, and dialkylation reactions can be achieved The method is applicable to the concise synthesis of bioactive molecules
An inexpensive Ni-based catalyst, in combination with a readily recyclable 8aminoquinoline directing group, promotes efficient and regioselective addition of two different organohalides across alkenyl carbonyl compounds under mild reductive conditions. The method has broad functional group tolerance and is applicable to aryl-alkylation, alkenyl-alkylation, and dialkylation transformations. Utility of the strategy is highlighted through concise synthesis of bioactive molecules that are difficult to access by alternative procedures. Kinetic studies revealed insights into the mechanism of the multicomponent reaction.
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Article
Broadly Applicable Directed Catalytic Reductive Difunctionalization of Alkenyl Carbonyl Compounds Tao Yang,1 Xianxiao Chen,1,2 Weidong Rao,2 and Ming Joo Koh1,3,*
SUMMARY
The Bigger Picture
Catalytic alkene difuntionalization is a convenient platform for introducing complexity in molecules and has wide applications in organic synthesis. Yet a compelling challenge that remains to be solved is the regioselective insertion of two highly functionalized carbon-based moieties, derived from stable and readily available organohalide electrophiles without the need for pre-synthesized organometallic reagents, across C=C bonds in unactivated alkylsubstituted alkenes. Here, we show that catalytic amounts of an inexpensive Ni-based catalyst, in combination with a readily recyclable 8-aminoquinoline directing group, promotes efficient and site-selective addition of two different organohalides (iodides and bromides) across aliphatic alkenes under mild reductive conditions. Compared to previous studies, this protocol exhibits broad and complementary functional group tolerance that extends to aryl-alkylation, alkenyl-alkylation, and dialkylation transformations. The utility of the strategy is demonstrated through concise synthesis of biologically active molecules. Kinetic studies and other control experiments shed further light on the mechanistic underpinnings of the multicomponent reaction.
Access to multifunctional compounds from stable and easily accessible substrates is a coveted goal in chemical synthesis. Alkene difunctionalization provides a powerful way to expeditiously generate molecular complexity, but existing methods either rely on the use of pre-prepared and sensitive organometallic reagents or have limited functional group compatibility that restricts utility. A catalytic manifold that enables the direct union of aliphatic alkenes with different classes of stable and readily available organohalides represents a more practical alternative and expands the toolbox available to construct molecules. As reported here, a catalytic reductive alkene difunctionalization protocol that addresses the aforementioned issues has been devised. This disclosure could find broad applicability in organic synthesis and inspire chemists to develop multicomponent catalytic systems that promote the assembly of high-value building blocks from simple starting materials.
INTRODUCTION Alkenes belong to one of the most abundant and extensively utilized classes of feedstock chemicals in chemical synthesis.1 The ability to install two different motifs, with high efficiency and exquisite control of regioselectivity, through vicinal addition across unsaturated hydrocarbons2 provides a convenient and direct avenue of assembling multifunctional molecules en route to countless biologically active compounds. An important variant of these transformations is the intermolecular 1,2-insertion of two carbon-based groups across alkenes. Previous catalytic studies are largely focused on the union of activated p-systems (e.g., styrenes and Michael acceptors) with an organometallic nucleophile and an organohalide or redox-active electrophile3–10 (see Supplemental Information for extended bibliography). In contrast, reactions with less activated alkyl-substituted alkenes present a formidable challenge because of the lack of sufficient substrate bias, consequently giving rise to poor catalytic efficiency and/or regioisomeric product mixtures. These issues could be addressed by appending the aliphatic alkene to a coordinating moiety that serves as an auxiliary to direct regioselective additions of organozinc (alkyl/aryl) reagents11–15 or aryl/alkenylboronates16–18 with organohalides (Scheme 1A). However, critical shortcomings pertaining to functional group compatibility exist. A number of moieties (e.g., carboxylic acids, alcohols, and secondary amides) that are prevalent in nature and widely used in chemistry are susceptible to side reactions especially when organozinc species19 are involved
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Scheme 1. Catalytic Approaches to Directed Regioselective Di-Carbofunctionalization of Unactivated Alkenes
(Scheme 1A, box). On the other hand, alkene additions with the less-reactive alkylboron reagents are yet to be reported. A related complementary set of reactions that were recently demonstrated to achieve site-selective difunctionalization of activated and unactivated alkenes employ two different organohalide electrophiles in the presence of an inexpensive stoichiometric reductant (Scheme 1B).20–25 These versatile reductive coupling26–35 transformations typically preclude the use of pre-prepared organometallic reagents, potentially enabling a greater diversity of functionalities derived from the relatively more stable and readily accessible carbon-based electrophiles to be incorporated. Despite the associated advantages, development in this area is still in its infancy, and reported methods suffer from distinct drawbacks: (1) multicomponent transformations are restricted to aryl-alkylation/acyl-alkylation between aryl iodides or acyl
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1Department
of Chemistry, National University of Singapore, 12 Science Drive 2, Singapore 117549, Singapore
2Jiangsu Key Laboratory of Biomass-Based Green
Fuels and Chemicals, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China 3Lead
Contact
*Correspondence: [email protected] https://doi.org/10.1016/j.chempr.2019.12.026
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Scheme 2. Proposed Pathway to Achieve Regioselective Reductive Di-Carbofunctionalization of Unactivated Alkenes and the Associated Challenges
chlorides with perfluoroalkyl or tertiary alkyl iodides (primary and secondary alkyl variants are ineffective substrates), (2) reactions with internal C=C bonds are plagued by poor efficiency and/or regioselectivities, and (3) reported examples furnish products that incorporate alkyl units at the terminal olefinic position. Access to the opposite regioisomer is yet to be conceived. A recent disclosure involving reductive aryl-alkylation allows unactivated alkenes devoid of directing groups to be utilized, although only tertiary alkyl units can be installed site-selectively.24 Therefore, there is compelling demand for a general and practical protocol, using inexpensive Ni-based catalysts in conjunction with an easily recyclable directing auxiliary, that merge aliphatic alkenes with a functionalized alkyl halide and another organohalide of various electronic and steric properties (e.g., aryl-, heteroaryl-, alkenyl-, and alkylsubstituted) (Scheme 1C). Furthermore, the method to be developed must be compatible with a wide range of functionalities, including those that are sensitive toward organometallic nucleophiles (cf. Scheme 1A, box). Successful implementation of this strategy is expected to complement existing approaches, enhance our ability to access a larger assortment of important molecules, and offer a straightforward entry to structurally complex analogs that are difficult to obtain otherwise. The challenge remains whether an effective auxiliary can be identified to deliver sufficient regiochemical control, especially for alkenes with longer carbon chain lengths that can hamper reactivity and erode site selectivity36 (see below for further discussion).
RESULTS AND DISCUSSION Reaction Design Based on previous reports involving directed alkene difunctionalizations11–18 and reductive cross coupling,37 we envisioned a possible catalytic sequence as illustrated in
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Table 1. Evaluation of Reaction Conditions
Entry
DG
Ni Complex
Reductant
Solvent
Yield (%)a
1
A
Ni(cod)2
Mn
DMF
60
2
A
Ni(cod)2
Zn
DMF
trace
3
A
Ni(cod)2
TDAE
DMF
67
4
A
NiI2
Mn
DMF
81
5
A
NiCl2(PPh3)2
Mn
DMF
51
6
A
NiCl2(py)4
Mn
DMF
31
7
A
NiBr2,glyme
Mn
DMF
78
8
A
Ni(acac)2
Mn
DMF
72
9b
A
NiI2
Mn
DMF
41
10
B
NiI2
Mn
DMF
28
11
C
NiI2
Mn
DMF
38
12
D
NiI2
Mn
DMF
ND
13
E
NiI2
Mn
DMF
ND
14
F
NiI2
Mn
DMF
25
15
A
NiI2
Mn
DMA
72
16
A
NiI2
Mn
NMP
64
17
A
NiI2
Mn
THF
trace
18
A
NiI2
Mn
Toluene
trace
Abbreviations: DG, directing group; TDAE, tetrakis(dimethylamino)ethylene; DMA, N, N-dimethylacetamide; DMF, N, N-dimethylformamide; NMP, N-methyl-2pyrrolidone; THF, tetrahydrofuran; cod, 1,5-cyclooctadiene; py, pyridine; acac, acetylacetonate; ND, not detected. a Yields are for isolated and purified products. b Reaction was conducted at room temperature.
Scheme 2. A putative Ni(0) complex I that associates with an alkene tethered to a directing unit (e.g., 8-aminoquinoline) can undergo direct oxidative addition (or halogen atom abstraction followed by radical recombination) with one organohalide (XG1) followed by a site-selective 1,2-migratory insertion across the C=C bond in 1 to afford a stabilized quinoline-chelated Ni(II) intermediate II. At this stage, single-electron reduction of the Ni center with an appropriate reducing agent could occur to form a reactive Ni(I) species III that engages with the second organohalide (XG2) to afford a penta-coordinate Ni(III) complex IV. The ensuing reductive elimination then generates a Ni(I) species V with concomitant release of the desired product 2. After a final single-electron reduction, I is regenerated to turn over the catalytic cycle. Whereas catalytic alkene difunctionalizations that employ an organometallic nucleophile and an electrophile typically proceed through initial reaction with the electrophile, alkene migratory insertion and transmetallation with the nucleophile (or the reverse order) in a chemoselective fashion,3–18 systems that involve two organohalide electrophiles can potentially lead to a myriad of products arising from
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Scheme 3. Catalytic Reductive Aryl-Alkylation of b,g-Unsaturated Amides Unless otherwise stated, all Ni-catalyzed reactions were conducted under the optimized conditions with alkyl iodides (XG 2 : I–alkyl). Yields are for isolated and purified products (single regioisomers). For the synthesis of 2aa–2ai, alkyl bromides (XG 2 : Br-alkyl) were used.
competitive addition of substituents (G1 or G2) across the alkene as well as crosselectrophile coupling26–35,37 (cf. Scheme 2, dashed box), particularly if XG1 and XG2 are similarly reactive. Adding to these complications is the need to identify parameters that tolerate a wide variety of sensitive functional groups. We sought to address these challenges by developing an efficient catalytic manifold that relies on chemoselective additions of two different organohalides to deliver high site selectivity. Optimization Studies We commenced our investigations by examining conditions for the operationally simple union of b,g-unsaturated amides with commercially available iodobenzene and 1-iodobutane (Table 1). In the presence of 10 mol % of Ni(cod)2 and the bidentate 8-aminoquinoline directing auxiliary (A)38 in DMF (dimethylformamide) at 40 C, a survey of different reducing agents (entries 1–3) revealed that both manganese and TDAE were effective in promoting reductive difunctionalization, furnishing the desired product as a single regioisomer in 60% and 67% yield, respectively, with 20%–30% unreacted alkene. The sense of regioselectivity was determined to be identical to that derived from transformations involving organozinc reagents11 (aryl group inserted at terminal position; see below for further discussion). Intriguingly, only trace amounts of undesired diarylation or dialkylation side products were detected. We opted to continue our optimization studies using the relatively less-expensive manganese as reductant and evaluated the performance of various Ni-based salts (entries 4–8). A further boost in efficiency was observed with 10 mol % of NiI2 (entry 4), giving the product in 81% yield. Conducting the reaction at ambient temperature led to incomplete conversion of the starting alkene (50% recovered) and a reduced yield (41% yield; entry 9). When the directing unit was switched to other bidentate and monodentate groups (BF), a drastic diminution in efficiency was found (entries 10–14), underscoring the unique ability of A in stabilizing the Ni-based intermediates (cf. Scheme 2) for efficient turnover. The effect of the solvent was also probed, and we discovered that less-polar media (e.g., THF [tetrahydrofuran] and toluene in entries 17 and 18) were more detrimental to the catalytic system (alkene largely unreacted) than the more polar variants such as DMF, DMA (dimethylacetamide), and NMP (N-methyl-2-pyrrolidone) in entries 4, 15, and 16, respectively, with DMF emerging as optimal. Scope of the Method We proceeded to test the generality of our developed conditions by examining a variety of functionalized electrophiles in reductive aryl-alkylation transformations of 8-aminoquinoline-tethered b,g-unsaturated amides (Scheme 3). Aryl iodides and bromides containing electron-donating or electron-deficient substituents on the ortho-, meta-, or para-positions of the aromatic ring served as effective substrates, delivering 2a2t in 48%–84% yield. It merits mention that previously reported three-component reductive di-carbofunctionalizations that focused on aryl iodides as the corresponding bromide substrates were less efficient.20,24 Reactions are compatible with a nitrile (2q), carbonyl compounds (2i and 2r), carboxylic acid derivatives (2s and 2t), as well as carbamates with acidic NH units (2j) that could be problematic with basic organozinc reagents.19 Molecules with halogen (2c and 2d) and boronate (2k) groups that are amenable to further derivatization could be secured.
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Scheme 4. Extension to Reductive Alkenyl-Alkylation and Dialkylation of b,g-Unsaturated Amides, Internal Alkenes as well as Reductive ArylAlkylation of g,d-Unsaturated Amides Unless otherwise stated, all Ni-catalyzed reactions were conducted under the optimized conditions. Yields are for isolated and purified products (single regioisomers). Products 2ao–2at were obtained in 89:11 to >98:2 diastereomeric ratios.
Heterocyclic moieties (2o and 2p) were also tolerated in the catalytic system without the need for N-protection (2p). The scope of the aliphatic cross-partner was assessed using a wide assortment of primary alkyl halides. Across the board, reactions proceeded smoothly in the presence of a silyl ether (2w), a Lewis basic phthalimide (2y), a functionalizable organohalide or organoboronate (2z and 2ac, respectively), an acetal (2aa), or protic units (2x, 2ab, and 2ae–2ai) to afford the expected products in 33%–87% yield. Access to 2x, 2ab, and 2ae–2ai by alternative procedures (cf. Scheme 1A) would not be feasible, because the required alkylmetal nucleophile is unstable toward acidic groups.19 Synthesis of alkene-appended 2ad substantiates the role of the directing auxiliary in promoting chemoselective reductive aryl-alkylation on the b,g-unsaturated amide. Transformations with secondary alkyl halides, however, gave poor regioselectivities as a consequence of competitive reaction with the Ni species (cf. Scheme 2; see Supplemental Information for details). The reductive difunctionalization conditions are also applicable to alkenyl-alkylation and dialkylation by switching to alkenyl or aliphatic halides (Scheme 4). Acyclic
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Scheme 5. Demonstration of Functional Group Compatibility and Application to Concise Synthesis of Biologically Active Compounds Unless otherwise stated, all Ni-catalyzed reactions were conducted under the optimized conditions. Yields are for isolated and purified products (single regioisomers).
alkenes 2aj and 2ak could be generated in 42% and 55% yield, respectively, without isomerization of the olefin geometry. Reactions that employ two alkyl iodides (one primary and one secondary) consistently afforded products resulting from the secondary alkyl motif installed selectively at the terminal olefinic end (2al–2an). Transformations with 1,2-disubstituted alkenes (E- or Z-) were less efficient but proceeded with high stereospecificity, delivering the products 2ao–2at in 41%–88% yield and up to >98:2 diastereomeric ratio. Dialkylation of internal alkenes with two different alkyl halides was also stereospecific but comparatively less efficient (see Supplemental Information for details). The observed stereochemical outcome arises from a syn b-migratory insertion process across the C=C bond (cf. I / II in Scheme 2) and is similar to results from the analogous alkene difunctionalizations involving organometallic nucleophiles.11,36 Extending the alkene carbon chain length to effect g,d-difunctionalization was possible, and the corresponding products 2au–2ay could be obtained in 59%–75% yield, underscoring the ability of the directing group in stabilizing six-membered nickelacycles36 (cf. II, III, and IV in Scheme 2). However, further extensions to the carbon skeleton of the alkene proved deleterious to reaction efficiency and site selectivity. Application to Complex Molecule Synthesis The feasibility of employing the reductive difunctionalization protocol in a late-stage setting was corroborated when we subjected a number of aryl iodides derived from biologically active molecules that bear multiple sensitive Lewis basic and Brønsted acidic centers to our standard reaction conditions (Scheme 5, top). The desired aryl-alkylation products 2az–2aab were secured in 54%–80% yield, showcasing the exceptional functional group compatibility of the method. Our developed catalytic approach offered the opportunity to devise new synthesis routes for a number of biologically active molecules (Scheme 5, bottom, AC). The first instance involves reductive aryl-alkylation to generate 2aac in 63% yield, which was followed by alkaline hydrolysis and reduction to give alcohol 5 in 85% yield (8-aminoquinoline recovered in 90% yield). A final Mitsunobu reaction with 4-hydroxybenzaldehyde then afforded 6, a precursor to sphingosine-1-phosphate receptor modulator 7,39 in 92% yield. In another formal synthesis, reductive aryl-alkylation to give 2aad could be accomplished in 41% yield, which was subsequently subjected to Ni-catalyzed methanolic cleavage to furnish 8, an intermediate used in the preparation of anti-cancer drug candidate 9.40 It merits mention that generation of the corresponding Brønsted acidic secondary amide-containing alkylzinc reagent that is required to access 2aad through previously established aryl-alkylation protocols11 would be difficult.19 The third application relates to the synthesis of 10, a precursor to vitronectin receptor antagonist 11.41 10 was derived from 2aae by methanolysis, which itself could be assembled in 76% yield from catalytic union of alkene 1a, (2-iodoethyl)benzene, and 4-iodophenol without protection of the acidic phenol motif, highlighting the robustness of our reductive di-carbofunctionalization method. Overall, the synthesis sequences presented in Scheme 5 are shorter and compare favorably to the alternative procedures described in previous reports.39–41
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Scheme 6. Control Experiments to Elucidate Mechanistic Nuances Unless otherwise stated, all reactions were conducted under the optimized conditions. Yields are determined by GC analysis with n-tridecane as internal standard, except for the mixture of 2aaf/2aaf 0 (isolated).
Mechanistic Investigations To gain a preliminary understanding of the mechanistic pathways through which the present reductive di-carbofunctionalization operates, we performed a series of control experiments as shown in Scheme 6. Stoichiometric reaction of 1a with a known Ni(0) complex, Ni(cod)2, at 40 C in DMF followed by treatment with three equivalents of iodobenzene for 5 h led to a reaction mixture that furnished 12 (phenyl unit inserted at terminal position) upon alcoholic quenching and analysis by GCMS (Scheme 6A). In a separate vessel, the same reaction mixture that was subjected to 1-iodobutane in the presence of manganese at 40 C for 8 h successfully afforded the expected aryl-alkylation product 2a in 55% yield. In contrast, 2a was not detected when the reductant was omitted in the reaction mixture. These results demonstrate that (1) selective reaction with the aryl electrophile and subsequent alkene insertion occurs prior to engagement with the second alkyl electrophile to deliver the observed regiochemical outcome and (2) a stoichiometric reducing agent is necessary to facilitate reaction with the alkyl electrophile for product formation, possibly through the steps as depicted in Scheme 2.
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Figure 1. Kinetic Studies on the Catalytic Reductive Di-Carbofunctionalization System (A) Plot of k in versus 1-iodobutane concentrations. (B) Plot of k in versus 4-iodotoluene concentrations. (C) Plot of k in versus alkene 1a concentrations. (D) Plot of k in versus NiI 2 concentrations.
The radical clock experiment using (bromomethyl)cyclopropane as an electrophile provided a 41:59 mixture of 2aaf and the ring-opened product 2aaf’ in 56% yield, implying that (bromomethyl)cyclopropane likely reacts with the Ni(I) complex (cf. III / IV in Scheme 2) through a bromine abstraction followed by a radical recombination36 process via a cyclopropylmethyl radical intermediate that is prone to ring rupture (Scheme 6B). Preliminary kinetic studies were carried out to shed light on the roles of each component (aryl iodide, alkyl iodide, alkene 1a, and NiI2 catalyst) on the rate of reductive dicarbofunctionalization. Control experiments revealed a lack of dependence on the manganese reductant, which is congruent with previous observations in reductive cross-electrophile coupling.29 Measurements of the initial rates (kin) for the catalytic union of 1a, 4-iodotoluene, and 1-iodobutane at varying concentrations of each component were conducted (Figures 1A–1D). Results showed that the reductive di-carbofunctionalization exhibits a first order rate dependence on 1-iodobutane and the catalyst (Figures 1A and 1D, respectively), but no appreciable deviation in rate was detected by changing the concentration of 1a (Figure 1C). Intriguingly, although kin was initially found to have a positive dependence on 4-iodotoluene concentration (%0.3 M; undesired alkene dialkylation is competitive), the rate of product formation visibly slows down as the concentration is raised further (Figure 1B). The observed reliance of reaction rate upon the concentrations of the alkyl iodide
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and NiI2 suggest that the reaction of III with alkyl iodide to give IV (cf. Scheme 2) might be rate-limiting.7 The apparent inverse rate dependence on aryl iodide concentration at >0.3 M could be rationalized by the onset of competitive coordination (possibly through p-complexation;29 <1% alkene diarylation or dialkylation side products detected) to the intermediate organonickel species III that consequently diminishes reaction rate by depleting ligation sites for the incoming alkyl iodide to undergo halogen atom abstraction (cf. III / IV, Scheme 2). Further efforts to elucidate the mechanism through extensive investigations and DFT calculations are ongoing. Conclusions Catalytic quantities of a Ni-based complex in conjunction with a versatile directing auxiliary42–45 and manganese as a reducing agent enabled 1,2-vicinal additions of two different organohalides across unactivated alkenes with high efficiency and complete site selectivity. A wide array of acidic and basic functional groups that are otherwise susceptible to side reactions in the presence of organometallic compounds, can be tolerated under the reductive di-carbofunctionalization conditions. The present method is amenable to late-stage synthetic manipulations and can be readily employed in concise scalable preparation of multifunctional biologically active molecules. Given the recent renewed interest in base metal-catalyzed CC bond-forming transformations,46 we expect our studies to find broad utility in chemistry and facilitate current endeavors in designing practical multicomponent reactions that assemble high-value building blocks from stable and readily available starting materials.
EXPERIMENTAL PROCEDURES Detailed experimental procedures are provided in the Supplemental Information.
SUPPLEMENTAL INFORMATION Supplemental Information can be found online at https://doi.org/10.1016/j.chempr. 2019.12.026.
ACKNOWLEDGMENTS This research was supported by the National University of Singapore President’s Assistant Professorship start-up grants R-143-000-A50-133 and R-143-000-A50-750 (M.J.K.). X.C. acknowledges funding support from the National First-class Disciplines (PNFD).
AUTHOR CONTRIBUTIONS T.Y. and X.C. performed the experiments. M.J.K. directed the investigations with assistance from W.R. M.J.K. wrote the manuscript with revisions provided by the other authors.
DECLARATION OF INTERESTS The authors declare no competing interests. Received: September 20, 2019 Revised: November 9, 2019 Accepted: December 20, 2019 Published: January 16, 2020
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