Recent advances in benzylic and heterobenzylic lithiation

Aryl and heteroaryl rings are omnipresent in small molecule drugs, and examples bearing multiple substitutions at benzylic positions are ubiquitous across a range of pharmaceutical families. The comparative acidity of α-aryl protons makes organolithium mediated deprotonation-substitution protocols an attractive strategy for effecting substitutions at benzylic positions. In this review, we survey recent advances in benzylic lithiation chemistry, including 1) lithiations facilitated by heteroatom-appended directing groups, 2) lateral lithiations enabled by directing groups attached in the aryl ortho-position, as well as 3) examples remote from any Lewis basic group. Recent 4) heterobenzylic and 5) stereoselective benzylic lithiations are also summarized.