Asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene enabled by chiral Brønsted base catalysts

Abstract

Benzylic functionalisation of unactivated alkylarenes remains as a significant challenge in asymmetric catalysis due to their less reactive nature. Here, we show development of catalytic asymmetric C(sp3)–H functionalization of unactivated alkylarenes such as toluene with imines. The reactions proceeded smoothly under proton-transfer conditions using a chiral, strong Brønsted base catalyst system. A chiral Brønsted base prepared from an alkylpotassium and a chiral amine ligand was found to effectively form a promising asymmetric environment around a benzyl anion. Optimization of the reaction conditions revealed that the use of the alkaline metal amide, potassium hexamethyldisilazide (KHMDS), as an additive was most effective, and enantioselective and atom economical carbon–carbon bond-forming reactions at the benzylic positions of unactivated alkylarenes was achieved without using any transition-metal catalyst. Benzylic functionalisation of unactivated toluenes remains a challenge in asymmetric catalysis. Here a chiral Brønsted base catalyses the enantioselective C(sp3)-H functionalization of unactivated alkylarenes, enabling carbon-carbon bond formation at benzylic positions of toluene derivatives.