Site-Selective C−H Arylation of Diverse Arenes Ortho to Small Alkyl Groups

Abstract

Catalytic systems for direct C−H activation of arenes commonly show preference for electronically activated and sterically exposed C−H sites. Here we show that a range of functionally rich and pharmaceutically relevant arene classes can undergo site-selective C−H arylation ortho to small alkyl substituents, preferably endocyclic methylene groups. The C−H activation is experimentally supported as being the selectivity-determining step, while computational studies of the transition state models indicate the relevance of non-covalent interactions between the catalyst and the methylene group of the substrate. Our results suggest that preference for C(sp2)−H activation next to alkyl groups could be a general selectivity mode, distinct from common steric and electronic factors.