Nickel-catalyzed reductive coupling of homoenolates and their higher homologues with unactivated alkyl bromides

Tingzhi Lin,Pengcheng Qian,Jianyou Mao,Yuanyun Gu,Patrick J Walsh,Haixing Guan

doi:10.1038/s41467-020-19194-x

Tingzhi Lin, Pengcheng Qian + Show 4 more

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https://doi.org/10.1038/s41467-020-19194-x

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Abstract

The catalytic generation of homoenolates and their higher homologues has been a long-standing challenge. Like the generation of transition metal enolates, which have been used to great affect in synthesis and medicinal chemistries, homoenolates and their higher homologues have much potential, albeit largely unrealized. Herein, a nickel-catalyzed generation of homoenolates, and their higher homologues, via decarbonylation of readily available cyclic anhydrides has been developed. The utility of nickel-bound homoenolates and their higher homologues is demonstrated by cross-coupling with unactivated alkyl bromides, generating a diverse array of aliphatic acids. A broad range of functional groups is tolerated. Preliminary mechanistic studies demonstrate that: (1) oxidative addition of anhydrides by the catalyst is faster than oxidative addition of alkyl bromides; (2) nickel bound metallocycles are involved in this transformation and (3) the catalyst undergoes a single electron transfer (SET) process with the alkyl bromide.

Highlights

The catalytic generation of homoenolates and their higher homologues has been a longstanding challenge
Ni(COD)[2] and bipy were used as catalyst precursors in dimethylacetamide (DMA) at 80 °C for 12 h
After 12 h under these conditions, the desired decarbonylative product 3aa was obtained in 63% assay yield (AY) (Table 1, entry 1, AY, determined by GC analysis of the unpurified reaction mixture with dodecane as internal standard)

Summary

Introduction

The catalytic generation of homoenolates and their higher homologues has been a longstanding challenge. Preliminary mechanistic studies demonstrate that: (1) oxidative addition of anhydrides by the catalyst is faster than oxidative addition of alkyl bromides; (2) nickel bound metallocycles are involved in this transformation and (3) the catalyst undergoes a single electron transfer (SET) process with the alkyl bromide Homoenolates and their higher homologs represent important synthetic intermediates that have found broad applications in natural product synthesis and pharmaceutical sciences[1,2,3]. In addition to ring opening of cyclopropanols, directing groupassisted palladium-catalyzed β-C–H activations are an alternative strategy to generate and functionalize palladium-homoenolates of carboxylic acid derivatives[33,34,35,36]. This is likely due to the relatively slow oxidative addition of alkyl electrophiles and facile β-hydride elimination of the resulting intermediates[41,42,43,44]

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