Carbene-catalysed reductive coupling of nitrobenzyl bromides and activated ketones or imines via single-electron-transfer process.

Bao-Sheng Li,Song Yang,Richard D Webster,Rupert S J Proctor,Yuexia Zhang,Baoan Song,Yonggui Robin Chi,Yuhuang Wang

doi:10.1038/ncomms12933

Abstract

Benzyl bromides and related molecules are among the most common substrates in organic synthesis. They are typically used as electrophiles in nucleophilic substitution reactions. These molecules can also be activated via single-electron-transfer (SET) process for radical reactions. Representative recent progress includes α-carbon benzylation of ketones and aldehydes via photoredox catalysis. Here we disclose the generation of (nitro)benzyl radicals via N-heterocyclic carbene (NHC) catalysis under reductive conditions. The radical intermediates generated via NHC catalysis undergo formal 1,2-addition with ketones to eventually afford tertiary alcohol products. The overall process constitutes a formal polarity-inversion of benzyl bromide, allowing a direct coupling of two initially electrophilic carbons. Our study provides a new carbene-catalysed reaction mode that should enable unconventional transformation of (nitro)benzyl bromides under mild organocatalytic conditions.

Highlights

Benzyl bromides and related molecules are among the most common substrates in organic synthesis
In our recent efforts in developing N-heterocyclic carbene (NHC)-enabled radical reactions, we have found that the presence of a nitro group is important to initiate a SET process under NHC catalysis
We report that benzyl bromides, bearing a nitro substituent on the benzene ring, can undergo an NHC-mediated SET process using an aldehyde as a formal reductant (Fig. 1a)

Summary

Introduction

Benzyl bromides and related molecules are among the most common substrates in organic synthesis They are typically used as electrophiles in nucleophilic substitution reactions. MacMillan has pioneered the use of ruthenium photoredox catalysts to enable single-electron-transfer (SET) processes under light to form radicals that can react with enamines catalytically generated from aldehydes and amine catalysts[7,8]. In our recent efforts in developing NHC-enabled radical reactions, we have found that the presence of a nitro group (in either substrates[15] or reagents16) is important to initiate a SET process under NHC catalysis. We report that benzyl bromides, bearing a nitro substituent on the benzene ring, can undergo an NHC-mediated SET process using an aldehyde as a formal reductant (Fig. 1a).

Methods

Results

Conclusion