Development of a sustainable continuous flow synthesis of functionalized azetines and azetidines

Although historically less studied than its higher homologues belonging to the class of N-containing heterocycles, the azetidine nucleus is present in various biologically active compounds of both natural and synthetic derivation. Sufficient robustness and strong molecular rigidity are the main features that encourage the introduction of this motif in compounds for applications in medicinal chemistry. Moreover, beneficial effects on the pharmacokinetic profile of pharmaceutically relevant structures connected with the introduction of this small and strained ring have been reported. In this contribution, we attempted to merge our long-lasting interests in azetidine lithiation and flow microreactor technology by reporting the generation of two different lithiated four-membered azaheterocycles under continuous flow conditions. N-1-Boc-3-iodoazetidine acts as a platform to prepare both C3-lithiated azetidine and C2-lithiated azetine by simply selecting the lithiating agent. In this work, we highlighted how the flow approach enables to manage the lithiated intermediates at higher temperatures with respect to batch. This, in combination with the use of the ecofriendly cyclopentyl methyl ether (CPME) as the solvent, allows the development of sustainable processes. Moreover, further manipulation of 2-substituted azetines will be described.