Asymmetric benzylic C(sp3)\u2212H acylation via dual nickel and photoredox catalysis

Leitao Huan,De Zhong,Weisai Zu,Haohua Huo,Xiaomin Shu

doi:10.1038/s41467-021-23887-2

Abstract

Asymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C−H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C−H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C−H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.

Highlights

Asymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis
Nickel and photoredox dual catalysis have emerged as a powerful tool for the direct C(sp3)−H functionalization of feedstock hydrocarbons by leveraging photoredoxmediated C−H activation and nickel’s unique ability in alkyl cross-couplings[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] (Fig. 1b)
We report an enantioselective benzylic C−H acylation of alkylarenes with in situ-activated carboxylic acids enabled by nickel and photoredox dual catalysis (Fig. 1c, top)

Summary

Introduction

Asymmetric C(sp3)−H functionalization is a persistent challenge in organic synthesis. Nickel and photoredox dual catalysis have emerged as a powerful tool for the direct C(sp3)−H functionalization of feedstock hydrocarbons by leveraging photoredoxmediated C−H activation and nickel’s unique ability in alkyl cross-couplings[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33] (Fig. 1b) This strategy allows the use of mild and robust conditions to perform C−H cleavage via a hydrogen atom transfer (HAT) or single-electron transfer (SET) pathway.

Methods

Results

Conclusion