Thioarylation of anilines using dual catalysis: two-step synthesis of phenothiazines.

Amy C Dodds, Sabrina Puddu, Andrew Sutherland

Organic & biomolecular chemistry 2022 Jul 20

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A two-step synthesis of phenothiazines has been developed using a dual-catalytic ortho-thioarylation reaction of anilines as the key step. Activation of N-(2-bromophenylthio)succinimide was achieved using the super Lewis acid, iron(III) triflimide and the Lewis base, diphenyl selenide, resulting in an accelerated and efficient ortho-thioarylation reaction of various protected aniline derivatives and less reactive, unprotected analogues. The thioarylated adducts were then cyclised to the desired phenothiazines using either an Ullmann-Goldberg or Buchwald-Hartwig coupling reaction. The dual catalytic thioarylation and copper(I)-catalysed cyclisation approach was used for the four-step synthesis of methopromazine, a neuroleptic agent with antipsychotic activity.

Citation

Amy C Dodds, Sabrina Puddu, Andrew Sutherland. Thioarylation of anilines using dual catalysis: two-step synthesis of phenothiazines. Organic & biomolecular chemistry. 2022 Jul 20;20(28):5602-5614