Synthesis of diaryl thioethers from aryl halides and potassium thiocyanate

A method for the preparation of thioethers using a Palladium catalyst without poisoning.

This is one of those papers that upon reading you feel it has potential. Hajipour et al. (Isfahan University, Iran) has published a method for the synthesis of diaryl thioethers (that is, Ar-S-Ar) by using a new Palladium catalyst. Some other groups (Hartwig, for example) have contributed also to this transformation, which is trickier that it seems. Some sulfur sources poison the metal-based catalyst so a replacement must be used, like potassium thiocyanate and thioacetamide. Other protocols use an aryl thiol as starting material, but aryl thiols are notoriously stinky. One recent example of drug with an aryl thioether motif is Vortioxetine.

What the group of Hajipour has done is to prepare a new Palladium catalyst (don’t worry, the preparation is described in the paper, just two steps starting from (-)-nicotine), which is not poisoned by the sulfur source. In a typical reaction, they mix 2 eq. of aryl halide, potassium thiocyanate, the catalyst ([DBNT][PdCl4]) and KOH in DMSO. The protocol is applied mostly to aryl halides, but four examples with halopyridines are included.

Diaryl Thioethers Synthesis

But once again, the experimental design could be better. As usual the authors follow the normal ‘optimization’ protocol, the OFAT approach. So they run 30 reactions changing the base, the solvent, etc… and once they have ‘optimized’ the yield for the model substrate, they go with the examples: no surprises there, most of them are 4-substituted, just in case… At least they have run some experiments checking selectivity of aryl dihalides (for example 4-bromoiodobenzene), which they have. Remarkably, the reaction works also with chlorides. And I wonder if they have tried the synthesis of asymmetric thioethers.

Appl. Organometal. Chem. 201428, pp 879-883.
See: 10.1002/aoc.3230