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Synlett 2021; 32(15): 1479-1483
DOI: 10.1055/a-1478-2280
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Nickel-Catalyzed Electronically Reversed Enantioselective Hydrocarbofunctionalizations of Acrylamides

Lou Shi
,
Wei Shu  ∗

This work was supported by the NSFC (21971101 and 21801126), Guangdong Basic and Applied Basic Research Foundation (2019A1515011976), The Pearl River Talent Recruitment Program (2019QN01Y261), Guangdong Provincial Key Laboratory of Catalysis (No. 2020B121201002), and the Thousand Talents Program for Young Scholars.
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Dedicated to the 10th anniversary of the Chemistry Department at SUSTech.

Abstract

Asymmetric hydrocarbofunctionalization of alkenes has emerged as an efficient strategy for synthesizing optically active molecules through a carbon–carbon bond-forming process from readily available alkenes and carboelectrophiles. Here, we present a summary of our efforts to control the regio- and enantioselectivity of hydrocarbofunctionalizations of electron-deficient alkenes with a nickel catalyst and a chiral bisoxazolidine ligand. The reaction permits electron-reversed hydrocarbofunctionalizations of acrylamides with excellent enantioselectivity. This operationally simple protocol permits the asymmetric hydroalkylation, hydrobenzylation, or hydropropargylation of acrylamides. This reaction is useful for preparing a wide range of α-branched chiral amides with broad functional-group tolerance.


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Key words

hydroalkylations - hydrobenzylations - hydropropargylations - hydrofunctionalizations - asymmetric catalysis - cross-couplings

Introduction

Due to their abundance and versatile reactivity, alkenes are among the most widely employed synthetic blocks in organic synthesis.[1] Among the numerous transformations of alkenes, hydrocarbofunctionalizations have evolved into one of the most important as they permit the transformation of alkenes into alkanes by carbon–carbon bond formation.[2] In particular, the formation of saturated carbon–carbon bonds (alkyl–alkyl bonds formation) by hydrofunctionalization represents a compelling alternative approach to diversely substituted saturated molecular scaffolds from simple and easily available starting materials.[2] [3]

Nickel-catalyzed cross-coupling of racemic alkyl electrophiles with alkyl organometallic reagents to construct alkyl–alkyl bonds has become well established over the recent decades.[4] Breakthroughs have been achieved in the asymmetric cross-coupling of racemic alkyl electrophiles with racemic alkyl organometallic reagents.[5] As a potential alternative to the conventional alkyl nucleophile–alkyl electrophile cross-coupling strategy, asymmetric hydrocarbofunctionalization of alkenes with saturated electrophiles is highly desirable.[6]

Fu and co-workers reported a seminal Ni-catalyzed enantioconvergent hydroalkylation of alkenes with racemic secondary and more sterically congested tertiary α-bromocarbonyl compounds, forging a stereogenic center adjacent to a carbonyl group (Scheme [1a]).[7] In 2020, a Ni-catalyzed enantioconvergent hydroalkylation of alkenes with α-bromo phosphorus or sulfur oxides was reported that delivered a stereogenic center adjacent to a heteroatom (phosphorus or sulfur) by constructing alkyl–alkyl bonds (Scheme [1b]).[8] During the review of the present work, the Hu group reported a Ni-catalyzed enantioselective hydroalkylation of vinyl boronates with nonactivated alkyl iodides to afford enantioenriched α-branched alkyl boronates (Scheme [1c]).[9] These examples prove that it is possible to construct a stereogenic carbon center within a newly formed carbon–carbon bond (Schemes 1a–c). We wondered whether it would be possible to construct a stereogenic carbon center next to a newly formed alkyl–alkyl bond. We applied a nickel hydride-mediated process to α-substituted acrylamides with nonactivated electrophiles to afford enantioenriched α-branched amides in good yields with excellent enantioselectivities by forging a stereogenic carbon center adjacent to the newly formed alkyl–alkyl bond (Scheme [1d]). The conditions could be applied to enantioselective hydroalkylation, hydrobenzylation, or hydropropargylation of acrylamides to afford diversely substituted amides bearing an α-tertiary stereogenic carbon center.[10]

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Scheme 1 Strategies for hydrocarbofunctionalizations of alkenes

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Reaction Development

We started our investigation by using N-phenylmethacrylamide (1a) and 3-phenyl-1-bromopropane (2a) as the prototype substrates to evaluate the reaction conditions. After extensive preliminary evaluation of the reaction parameters, we found that the reaction proceeded smoothly to afford the electronically reversed hydroalkylated product 3a with NiBr2·glyme (10 mol%) as the catalyst precursor, a bidentate nitrogen-coordinating ligand L as the ligand (12 mol%), trimethoxysilane (3 equiv) as the hydride source, potassium phosphate monohydrate (3 equiv) as the base, and TBAI (2 equiv) and t-butanol (4 equiv) as additives in diethyl ether at –10 °C (Scheme [2]).

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Scheme 2 Ligand optimization of the reaction. Reagents and conditions: 1a (0.1 mmol), 2a (0.2 mmol), TBAI (2 equiv), (MeO)3SiH (3 equiv), K3PO­4·H2O (3 equiv), t-BuOH (4 equiv), Et2O (0.05 M), –10 °C, 40 h. Isolated­ yields after flash chromatography are reported. The ee was determined­ by HPLC on a chiral stationary phase. a 3-Phenyl-1-iodopropane (2b) was used instead of 2a and in the absence of TBAI.

Next, we turned to evaluate the ligand effect on the reaction with an emphasis on bisoxazolidine-based ligands (Scheme [2]). The use of the indanyl-substituted bisoxazolidine ligand L1 or the cyclopropyl BOX Ligand L2 gave only a trace of the desired product 3a. The tetrabenzyl-substituted BOX ligand L3 catalyzed the reaction to deliver 3a in 45% yield with 30% ee. The use of trans-diphenyl-substituted BOX ligands with various substituents L4 and L5 dramatically improved the coupling efficiency, giving 3a in yields of 65 and 47% and with 87% and 77% ee, respectively. Notably, the BOX ligand L6 with a cyclopentyl group at the position α to the oxygen of the bisoxazolidine ring substantially increased the enantiomeric excess of 3a to 90%, suggesting the significance of a steric effect at this position. After examining BOX ligands L7–L12 with various substituents in the position α to the oxygen of the bisoxazolidine ring, we obtained 3a in 64% yield with 92% ee by using L12. Further optimization revealed that the use of 3-phenyl-1-iodopropane (2b) instead of 2a, in the absence of TBAI, furnished chiral amide 3a in 75% yield and 93% ee.

With the optimized reaction conditions in hand, we tested a wide variety of acrylamides and saturated carbon electrophiles (Scheme [3]). The reaction tolerates a wide variety of functional groups and substitution patterns for both the acrylamide and the electrophile. N-Arylacrylamides with electron-withdrawing or electron-donating groups were well tolerated in the reaction, affording the corresponding hydroalkylated chiral amides in good yields with excellent enantioselectivities. Next, acrylamides with various substitution patterns at the α- and β-positions were examined. Alkyl chains with various lengths and functional groups were compatible with the reaction, furnishing the corresponding α-branched chiral amides in good yields with excellent enantioselectivities (Scheme [3a]). Moreover, a wide range of primary alkyl halides (including iodides and bromides) were tolerated under the reaction conditions, delivering a number of enantioenriched amides with good efficiency and excellent enantioselectivity (Scheme [3b]). Secondary alkyl halides were also reactive under the optimized conditions, giving the desired amides in moderate yields and with excellent enantioselectivities.

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Scheme 3 Selected substrate scope for enantioselective hydrocarbofunctionalizations of acylamides. Reagents and conditions: acrylamide (0.2 mmol), electrophile (0.4 mmol), NiBr2·glyme (0.02 mmol), L12 (0.024 mmol), K3PO4·H2O (0.6 mmol), t-BuOH (0.8 mmol), Et2O (0.05 M), –10 °C, 40 h. Isolated yields after flash chromatography are reported. The enantiomeric excess was determined by HPLC on a chiral stationary phase.

Next, propargyl bromides were tested. Propargyl bromides are challenging in nickel hydride chemistry because both the alkynyl moiety and the corresponding coupling products are reactive toward nickel hydride. Notably, alkyl-, aryl-, and silyl-substituted propargyl bromides were all suitable substrates for this reaction, undergoing enantioselective hydropropargylation with exclusive chemoselectivity to furnish the α-propargylated amides in good yields and with excellent enantioselectivities (Scheme [3c]). Furthermore, various benzylic bromides reacted to give electronically reversed enantioselective hydrobenzylation products of acrylamide (Scheme [3d]). To the best of our knowledge, these are the first examples of enantioselective hydropropargylation and hydrobenzylation of alkenes.[11] To further demonstrate the synthetic potential of this catalytic protocol, the reaction conditions were successfully applied to late-stage functionalization of complex molecules, including natural products and drug molecules (Scheme [3e]). Different absolute configurations of the chiral ligand L12 delivered the corresponding configurations of the newly formed carbon center, regardless of the existing stereochemistry in the complex molecules.


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Mechanistic Investigation

To gain insight into the mechanism of this reaction, several investigations were conducted (Scheme [4]). First, substrate 5, containing both acrylamide and acrylate moieties, and 3-phenyl-1-iodopropane (2b) were subjected to standard conditions. Interestingly, 6 was obtained in 57% yield with 94% ee (Scheme [4a]). Site-selective enantioselective hydroalkylation occurred with the acrylamide moiety of 5. No hydroalkylation reaction was observed for 2-methylacrylate moiety, which was reduced to isobutyrate without further alkyl–alkyl bond formation. This result suggested that the presence of an amide group is essential for the Ni-catalyzed C(sp3)–C(sp3) bond-forming step. Next, the reaction was conducted by using a deuterated silane (Ph2SiD2)[12] under otherwise standard conditions (Scheme [4b]). The desired hydroalkylation product 7 was obtained in 43% yield with 91% ee, along with the hydrogenation product 8 in 55% yield. Deuterium incorporation (>98% D) was observed at the α-position of amide 7. No deuterium incorporation was detected in the methyl group of 7. These results indicate that the Ni–H insertion step onto the alkene to form an alkyl–Ni species is irreversible and enantiodetermining.

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Scheme 4 Mechanistic investigations of the reaction

A mechanistic hypothesis consistent with our findings is presented in Scheme [5] based on the mechanistic results and precedents from the literature.[7] [8] [9] [10] , [12] [13] First, the nickel(II) bromide precursor is reduced in the presence of a silane and a base to generate the nickel(I) intermediate M1 and then the nickel(I) hydride species M2.[14] M2 undergoes an electronically reversed enantioselective hydrometalation onto the acrylamide to give the alkylnickel(I) intermediate M3, with the formation of a tertiary stereogenic carbon center. This nickel(I) intermediate undergoes oxidative addition with a carboelectrophile R–X, facilitated by the amide directing group, to form the Ni(III) intermediate M4. This undergoes reductive elimination to form a C(sp3)–C(sp3) bond with the release of the final product and regeneration of the nickel(I) species M1.

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Scheme 5 Tentative mechanism for the reaction

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Conclusion and Future Outlook

We have developed the first general protocol for Ni-catalyzed intermolecular electronically reversed and enantioselective hydrocarbofunctionalizations of acrylamides. Facilitated by a newly developed BOX ligand, this anti-Markovnikov­ process can be applied to enantioselective hydroalkylations, hydropropargylations, and hydrobenzylations of acrylamides to construct a stereogenic center adjacent to the newly formed carbon–carbon bond in good yields and with excellent enantioselectivities, representing the first examples of catalytic asymmetric hydrobenzylation and hydropropargylation of alkenes. The mild conditions provide direct and practical access to enantioenriched amides containing an α-tertiary stereogenic carbon center that readily racemizes. We expect that this reaction might provide insight and inspiration for the development of asymmetric nickel-mediated reactions of alkenes with diverse bond formation and selectivity control.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We acknowledge the assistance of SUSTech Core Research Facilities. We thank Dr. Xiaoyong Chang (SUSTech) for X-ray crystallographic analysis of 3k,[15] and Dr. Yi-Zhou Zhan (SUSTech) and Peng-Fei Yang (SUSTech) for reproducing the results.


Corresponding Author

Wei Shu
Shenzhen Grubbs Institute, Department of Chemistry, and Guangdong Provincial Key Laboratory of Catalysis Southern University of Science and Technology
Shenzhen 518055, Guangdong
P. R. of China   

Publication History

Received: 01 April 2021

Accepted after revision: 08 April 2021

Accepted Manuscript online:
08 April 2021

Article published online:
03 May 2021

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Zoom Image
Scheme 1 Strategies for hydrocarbofunctionalizations of alkenes
Zoom Image
Scheme 2 Ligand optimization of the reaction. Reagents and conditions: 1a (0.1 mmol), 2a (0.2 mmol), TBAI (2 equiv), (MeO)3SiH (3 equiv), K3PO­4·H2O (3 equiv), t-BuOH (4 equiv), Et2O (0.05 M), –10 °C, 40 h. Isolated­ yields after flash chromatography are reported. The ee was determined­ by HPLC on a chiral stationary phase. a 3-Phenyl-1-iodopropane (2b) was used instead of 2a and in the absence of TBAI.
Zoom Image
Scheme 3 Selected substrate scope for enantioselective hydrocarbofunctionalizations of acylamides. Reagents and conditions: acrylamide (0.2 mmol), electrophile (0.4 mmol), NiBr2·glyme (0.02 mmol), L12 (0.024 mmol), K3PO4·H2O (0.6 mmol), t-BuOH (0.8 mmol), Et2O (0.05 M), –10 °C, 40 h. Isolated yields after flash chromatography are reported. The enantiomeric excess was determined by HPLC on a chiral stationary phase.
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Scheme 4 Mechanistic investigations of the reaction
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Scheme 5 Tentative mechanism for the reaction