Synthesis of Benzothiazinones from Benzoyl Thiocarbamates: Application to Clinical Candidates for Tuberculosis Treatment

Benzothiazinones are a structural motif found in biologically active compounds, such as the clinical candidates BTZ‐043 and Macozinone for the treatment of tuberculosis. We describe a robust, two‐step method to synthesize 2‐amino‐substituted benzothiazinones from benzoyl thiocarbamates, which were prepared in a one‐pot procedure from benzoyl chlorides. The intramolecular cyclization and ethoxy displacement steps were also amenable to adoption in continuous flow as exemplified by select substrates. We report a strategy for the synthesis of amino‐substituted benzothiazinones using an intramolecular cyclization and ethoxy displacement approach. This resulted in a two‐step synthesis of the anti‐tuberculosis clinical candidates BTZ‐043 and Macozinone without the use of toxic carbon disulfide.