Catalytic enantioselective reductive domino alkyl arylation of acrylates via nickel/photoredox catalysis

Yan-En Wang,Dan Xiong,Haixing Guan,Fan Zhang,Pengcheng Qian,Patrick J. Walsh,Qianqian Lu,Jianyou Mao

doi:10.1038/s41467-021-26794-8

Abstract

Nonsteroidal anti-inflammatory drug derivatives (NSAIDs) are an important class of medications. Here we show a visible-light-promoted photoredox/nickel catalyzed approach to construct enantioenriched NSAIDs via a three-component alkyl arylation of acrylates. This reductive cross-electrophile coupling avoids preformed organometallic reagents and replaces stoichiometric metal reductants by an organic reductant (Hantzsch ester). A broad range of functional groups are well-tolerated under mild conditions with high enantioselectivities (up to 93% ee) and good yields (up to 90%). A study of the reaction mechanism, as well as literature precedence, enabled a working reaction mechanism to be presented. Key steps include a reduction of the alkyl bromide to the radical, Giese addition of the alkyl radical to the acrylate and capture of the α-carbonyl radical by the enantioenriched nickel catalyst. Reductive elimination from the proposed Ni(III) intermediate generates the product and forms Ni(I).

Highlights

Nonsteroidal anti-inflammatory drug derivatives (NSAIDs) are an important class of medications
Enantioenriched α-aryl propionic acids are an important class of nonsteroidal anti-inflammatory medications (NSAIDs)[1,2] and are key building blocks for further elaboration
Motivated by a desire to broaden the scope of coupling partners while avoiding moistureand air-sensitive organometallic reagents, Reisman[12,13,14,15,16], Doyle[17], Weix[18], and their groups developed nickel catalyzed asymmetric reductive cross-electrophile coupling reactions using stoichiometric metal reductants (Zn or Mn)

Summary

Introduction

Nonsteroidal anti-inflammatory drug derivatives (NSAIDs) are an important class of medications. Inspired by their elegant studies, we disclosed an example of highly enantioselective nickel-photoredox catalyzed reductive cross-coupling of racemic α-chloro esters with aryl iodides (Fig. 1c) to construct enantioenriched NSAID derivatives[19]. After a systematic study of reaction conditions (see Table S1 in the Supporting Information for details), we were please to find that employing 4CzIPN (10 mol%), NiBr2 (10 mol%), L6 (11 mol%), Cy2NMe (3.0 equiv.) and HEH (3.0 equiv.) in N,N-dimethylacetamide (DMA, 0.33 M) under blue LED irradiation at room temperature for 24 h furnished the α-aryl ester (4a) in 82% assay yield (AY, determined by GC integration of the unpurified reaction mixture against an internal standard).

Results

Conclusion