Spotting the unforeseen in the preparation of N-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives

Abstract

Azetidine derivatives are a popular class of heterocycles in pharmacologically active molecules due to their rigidity, smaller size, and lower lipophilicity compared to pyrrolidines and piperidines, while maintaining similar basicity. However, azetidines exhibit unique reactivity dependent on stereoelectronic factors and reaction conditions, leading to potential instabilities and rearrangements during synthesis. In our attempt to prepare Abrocitinib analogues by replacing the cis-cyclobutane-1,3-diamine scaffold with azetidin-3-amine, we discovered an unforeseen rearrangement of the N-(azetidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine substructure to the tricyclic (2,3-dihydro-1H-imidazo[1,2-c]pyrrolo[3,2-e]pyrimidin-2-yl)methanamine. These findings highlight the need for careful characterization of azetidine-containing compounds when based on N-(azetidin-3-yl)pyrimidin-4-amine substructures and suggest potential methods for preparation of new tricyclic scaffolds.