Skeletal Rearrangement of Pyridine Derivatives via a Light-Induced Ring Expansion

Dedication

Dedicated to our friend, Professor Paul Knochel, on the occasion of his 70^th birthday.

Abstract

We report an efficient synthetic route to access 1,2-diazepines from readily available pyridines through dearomative ring expansion. By initially using previously established methods to obtain the pyridinium ylide intermediate on multigram scale, the diazepine was obtained through a 6π electrocyclic ring opening upon irradiation with 370 nm light. 1,2-Diazepines are among the least common nitrogen heterocycles present in FDA-approved drugs, likely due to the lack of synthetic pathways that enable access to these scaffolds rather than a lack of biological significance. While pyridine expansions are generally multistep procedures, our work has shown promise for a one-pot route to this expansion product. Taken together, this work provides access to synthetically difficult drug cores, while also introducing synthetic handles for further derivatization.

Keywords

Skeletal editing - Pyridines - Diazepines - Ring expansion - Pyridinium ylides

National Institute of General Medical Sciences

GM125206

Japan Society for the Promotion of Science

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

NIH Office of the Director

S10OD026749

We thank the National Institute of General Medical Sciences (NIGMS, GM125206) for support. M.C.R. thanks NIGMS for supplement funding. T.K. thanks the Japan Society for the Promotion of Science and T.S. thanks the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung for postdoctoral fellowship support. Research reported pertaining to cryoprobe NMR data in this publication was supported by the NIH Office of the Director under Award Number S10OD026749.

Publication History

Received: 31 March 2025

Accepted after revision: 29 April 2025

Article published online:
18 August 2025

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