Synthesis of phenoxathiins using an iron-catalysed C-H thioarylation.

Phenoxathiins are an important class of sulfur-containing heterocycle, found as the core component in numerous pharmaceutically active agents and materials. Despite this importance, there are relatively few methods for the synthesis of these heterocycles that avoid complex starting materials, harsh conditions or precious transition metals. We report a two-step synthesis of phenoxathiins from phenols using iron and copper-mediated reactions. The first step involves the accelerated ortho-thioarylation of phenols using N-(2-bromophenylthio)succinimide, catalysed by the Lewis acid, iron(III) triflimide and the Lewis base, bis(4-methoxyphenyl)sulfane. In the second step, the thioarylated products were converted to a series of phenoxathiins using a copper-mediated, Ullmann-type, C-O bond forming cyclisation reaction. The synthetic utility of this two-step approach for the preparation of biologically relevant phenoxathiins was demonstrated using natural product-based phenols.

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

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.

Regioselective C-H Thioarylation of Electron-Rich Arenes by Iron(III) Triflimide Catalysis.

A mild and regioselective method for the preparation of unsymmetrical biaryl sulfides using iron(III) catalysis is described. Activation of N-(arylthio)succinimides using the powerful Lewis acid iron(III) triflimide allowed the efficient thiolation of a range of arenes, including anisoles, phenols, acetanilides, and N-heterocycles. The method was applicable for the late-stage thiolation of tyrosine and tryptophan derivatives and was used as the key step for the synthesis of pharmaceutically relevant biaryl sulfur-containing compounds such as the antibiotic dapsone and the antidepressant vortioxetine. Kinetic studies revealed that while N-(arylthio)succinimides bearing electron-deficient arenes underwent thioarylation catalyzed entirely by iron(III) triflimide, N-(arylthio)succinimides with electron-rich arenes displayed an autocatalytic mechanism promoted by the Lewis basic product.

Synthesis of Thiazoloindole α-Amino Acids: Chromophores Amenable to One- and Two-Photon Induced Fluorescence.

Thiazoloindole α-amino acids have been synthesized in four steps from tryptophan using a dual-catalytic thiolation reaction and a copper-mediated intramolecular N-arylation process. Late-stage diversification of the thiazoloindole core with electron-deficient aryl substituents produced chromophores that on one-photon excitation displayed blue-green emission, mega-Stokes shifts, and high quantum yields. The thiazoloindole amino acids could also be excited via two-photon absorption in the near-infrared, demonstrating their potential for biomedical imaging applications.