Metal Catalyzed Coupling/Carbonylative Cyclizations for Accessing Dibenzodiazepinones: An expedient route to Clozapine and other drugs

Submitting author affiliation:
Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

Beilstein Arch. 2023, 202351.

Published 22 Nov 2023

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A sequential strategy to access 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones (DBDAPs) is disclosed in this article through Palladium and Copper catalyzed amination (Buchwald-Hartwig (B-H) or Chan-Lam (C-L))  followed by palladium catalyzed carbonylative cyclization with Mo(CO)6 as CO surrogate (to avoid toxic CO handling) of readily available o-pheneylenediamine and either 1,2-dibromobenzene or 2-bromobenzeneboronic acid. 10,11-Dihydro-5H-dibenzo[b,e][1,4]diazepinone could be synthezised in good yield using a sequential catalytic procedure, using both C-L and B-H approaches. Gratifingly, the use of the C-L reaction was more impressive, and afforded the dibenzodiazepinones in good yields (up to 45%; 2 steps) and much milder conditions using copper as the catalyst. The synthetic utility of this novel strategy was showcased by demonstrating a formal synthesis for the anti-psychotic drug clozapine and to an anti-cancer triazole-DBDAP hybrid.

Keywords: Chan-Lam; Buchwald-Hartwig; one-pot; nitrogen heterocycle; carbonylative cyclization

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Moutayakine, A.; Burke, A. J. Beilstein Arch. 2023, 202351. doi:10.3762/bxiv.2023.51.v1

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