Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis

Abstract

The formation of carbon–carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)­aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy toleratesamong othersacidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

Asymmetric synthesis of aryl/vinyl alkyl carbinol estersviaNi-catalyzed reductive arylation/vinylation of 1-chloro-1-alkanol esters

“…Of note was the competency of 1-chloropropyl isobutyrate that delivered 14 in high yield and ee, indicating that an alkanoyl ester is also suitable under the reaction conditions. The alkyl chains containing different terminal groups such as iPr (15), Ph (16), OBz (18,19), an ester group (20), MeS (21), Ts ( 22) and a cholic acid derivative (23) were all compatible in this method, but a large b group such as tBu signicantly affects the yield (17).…”

“…The Glorius group has demonstrated that a Ni-catalyzed reductive coupling of 1-bromo-1-alkanol ester intermediates with aryl bromides could furnish racemic aryl alkyl carbinols. 18 Herein, we report a strategy of Ni-catalyzed reductive coupling of a diverse set of racemic 1-chloro-1-alkanol esters with aryl and vinyl halides/triflates using a chiral bisimidazoline (BiIm) ligand, affording a facile access to enantioenriched aryl/vinyl alkyl carbinols ( Scheme 1C ). This method displays a broad substrate scope and excellent functional group compatibility for the efficient preparation of chiral aryl/vinyl alkyl carbinols.…”

“…In line with the rapid growth of Ni-catalyzed enantioselective cross-electrophile coupling reactions over the past decade, 16,17 we wondered the feasibility of the preparation of chiral secondary alcohols via Ni-catalyzed asymmetric cross-coupling of the readily available 1-halo-1-alkanol esters 13,18 with C(sp 2 )-electrophiles. The Glorius group has demonstrated that a Ni-catalyzed reductive coupling of 1-bromo-1-alkanol ester intermediates with aryl bromides could furnish racemic aryl alkyl carbinols.…”

Radical umpolung chemistry enabled by dual catalysis: concept and recent advances

“…More recently, Glorius and co-workers developed radical carbonyl umpolung arylation enabled by dual nickel/ photoredox catalysis (Scheme 13). 57 Due to the high reduction potential, aldehydes and ketones are always difficult to reduce to the corresponding ketyl radicals. Dual Lewis acid/photoredox catalysis strategy has already become a useful approach to generate ketyl radical from aromatic aldehyde and ketones.…”

“…56 Scheme 13 Radical carbonyl umpolung arylation enabled by dual catalysis (Glorius). 57 synthetic tool in radical umpolung chemistry that was firstly utilized by Rovis and co-workers (Scheme 14). 68 They successfully achieved enantioselective α-acylation of tertiary amines with aldehydes enabled by dual NHC catalysis and photoredox catalysis.…”