Asymmetric Hydrogenation of Exocyclic α,β-Unsaturated Nitriles: An Access to Chiral 2-Benzocyclic Acetonitriles and Ramelteon

A highly efficient and enantioselective hydrogenation of exocyclic alpha,beta-unsaturated nitriles catalyzed by the Rh-JosiPhos complex for synthesis of the chiral 2-benzocyclic acetonitriles has been developed. Both (Z)- and (E)-isomers of exocyclic alpha,beta-unsaturated nitriles with various benzocyclic structures, including heterocyclic (chroman and tetrahydroquinoline) scaffolds, were hydrogenated successfully, achieving excellent enantioselectivities (up to 97% ee) and high turnover numbers (TON up to 4000). Furthermore, this methodology provides an efficient, concise, and practical synthetic route to the sleep agent (S)-Ramelteon.