Synthesis of Bis(β-Oximinoalkyl)malonates and Their Catalytic Reductive Cyclization to Piperidines

Hitherto unknown bis(beta-oximinoalkyl)malonates were demonstrated to be convenient platforms for the synthesis of saturated N-heterocycles. Upon heterogeneous catalytic hydrogenation, these dioximes undergo reductive cyclization to give substituted piperidine-4,4'-dicarboxylates, which are valuable building blocks in medicinal chemistry. By using dioximes bearing an additional ester group in the side chain, tandem piperidine/pyrrolidinone ring closure leading to indolizidinone framework was showcased in this work. A modular synthesis of initial bis(beta-oximinoalkyl)malonates (both symmetrically and unsymmetrically substituted) was accomplished via a sequential Michael addition of two nitrosoalkene molecules to malonic ester. The mechanism of the reductive cyclization of dioximes to piperidines was investigated by isotope scrambling experiments and isolation of intermediates.

Automated summary

This study demonstrated that bis(beta-oximinoalkyl)malonates are convenient platforms for synthesizing saturated N-heterocycles. Heterogeneous catalytic hydrogenation of these compounds leads to reductive cyclization and the formation of substituted piperidine-4,4'-dicarboxylates, which are important building blocks in medicinal chemistry. The synthesis of initial bis(beta-oximinoalkyl)malonates was achieved through the sequential Michael addition of nitrosoalkene molecules to malonic ester. The mechanism of the reductive cyclization of dioximes to piperidines was investigated using isotope scrambling experiments and intermediates were isolated.