Ring expansion of 2-chloromethyl pyrrolidine or azetidine: Compared theoretical investigation

DFT calculation were performed in order to simulate the ring enlargement of N-isopropyl-2-chloromethyl pyrrolidine and azetidine into the corresponding 3-chloro piperidine and 3-chloro pyrrolidine, respectively. These ring enlargements are prototypes of reactions that have found growing applications in the synthesis of nitrogen heterocycles. Both calculations were conducted in gas phase and in DMSO, using a polarizable continuum model. In gas phase, these ring enlargements were found to be synchronous reactions, with a single transition state, but in DMSO, significant decrease of energy barrier is observed, and the two reactions differ now to a large extent, since the azetidine rearranges through a strained 1-azonia-bicyclo[2.1.0]pentane intermediate 5′, while the pyrrolidine still rearranges in a single step process.