Accessing NH-Pyrrolidines from 1,4-Dicarbonyl Compounds via Catalytic Dioxime Cyclization

The increasing role of polysubstituted pyrrolidines in pharmaceutical design necessitates the development of efficient and stereoselective methods for their synthesis. Double reductive amination of 1,4-dicarbonyl compounds is a common route to build the pyrrolidine ring, yet its catalytic version is challenging due to the competing reduction of C═O groups, formation of pyrroles through the Paal-Knorr reaction, and the difficulty of involving ammonia in the process. Here, we propose a solution to these fundamental issues through a two-step sequence involving smooth conversion of 1,4-diketones to dioximes followed by their reductive cyclization to NH-pyrrolidines on a heterogeneous nickel catalyst. The cyclization process is diastereoselective, high-yielding, scalable, and enables one-pot reductive amination and α-deuteration of the resulting NH-pyrrolidines. The method was applied to develop a practical synthesis of useful pyrrolidines from platform chemicals. Studies of the mechanism enabled the characterization of almost all organic intermediates in the reductive cyclization of 1,4-dioximes.