Asymmetric Hydrogenation of Cyclic Imines and Enamines: Access to 1,5-Benzodiazepine Pharmacophores

Abstract

A new strategy towards the pharmacologically relevant class of dihydro-1,5-benzodiazepines was developed by applying a rhodium-catalyzed asymmetric hydrogenation. The approach represents an efficient protocol providing access to the optically active products in excellent yields (up to 99%) and with high enantioselectivities (up to 92% ee). The versatility of the methodology was demonstrated by a broad substrate scope including alkyl, aryl, and heteroaryl substituents as well as halides. Furthermore, investigations regarding the reaction mechanism were performed and unraveled a preferred reaction of the tautomeric enamine in the rhodium-catalyzed asymmetric hydrogenation.

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

“…Previously, the same group provided an operationally simple route to other biologically relevant heterocyclic compounds, such as dihydrobenzodiazepines, by AH. 116 The enantioselective synthesis of seven-membered Ncontaining heterocycles has attracted considerable attention during recent decades, as they are versatile pharmacophores in medicinal chemistry. In 2012, Fan and co-workers reported that two Ru/diamine catalysts were highly efficient in the AH of benzodiazepines S16 (Scheme 11).…”

“…A wide range of valuable disubstituted and spirocyclic 2-aryl indolines P15b were prepared in excellent results, albeit at elevated H 2 pressure. Previously, the same group provided an operationally simple route to other biologically relevant heterocyclic compounds, such as dihydrobenzodiazepines, by AH …”