Benzodiazepines are a class of biologically active heterocycles that are used as active pharmaceutical ingredients. Method developments that expand the accessible fluorinated benzodiazepine library provide potential improvements to drug metabolic stability and may mitigate unsolicited side effects associated with their use. The installation of a fluorine atom on the C-3 carbon of the 1,5-3H-benzodiazepine framework has been achieved via novel synthesis. Microwave-assisted reaction of bifunctional electrophilic synthons, 2-fluoroalk-3-yn-1-ones with o-phenylenediamines, yields 3-fluoro-1,5-3H-benzodiazepines. Spectral characterization of (E)-3-amino-2-fluoro-2-alkenone intermediate confirmed the chemoselectivity of amine nucleophile towards the alkyne function and supports the proposed mechanism of benzodiazepine formation. This methodology accesses the 1,5-3H-benzodiazepine scaffold with a specifically positioned fluorine atom at the C-3 carbon, expanding both the library of drug candidates and synthetic avenues.

Synthesis of fluorinated 1,5-3H-benzodiazepines from substituted o-phenylenediamines and 2-fluoroalk-3-yn-1-ones

2019 Fall National Meeting

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