While this route effectively provided initial quantities of 3, the use of NaSMe, even as the more convenient aqueous solution, was not desirable due to its potent stench, which proved difficult to eliminate even with the most rigorous containment procedures.
A “stench-free” protocol was subsequently explored in which NaSMe was replaced with thiourea and iodomethane. Thus, heating chloride 6 with thiourea in EtOH at 65 °C resulted in an SNAr reaction to give the thiouronium salt 8 in 95% yield (Scheme 3). Conveniently, the thiouronium salt was isolated simply by direct filtration of the cooled reaction mixture. Treatment of a water solution of 8 with aqueous NaOH and MeI resulted in hydrolysis of the thiouronium salt to the 2-mercaptopyridine sodium salt and urea, with subsequent S-methylation to give the sulfide 7. Again, 7 was not isolated but was directly oxidized by AcOOH to give sulfone 3 in 70% yield after crystallization. This process avoided the stench associated with the NaSMe process, as thiourea and the thiouronium salt 8 were odorless solids.It doesn't surprise me that they designed a route to avoid the use of NaSMe, but I am surprised to learn that they couldn't keep the smell contained, even with "the most rigorous containment procedures." Neat that they were able to use thiourea in its place, though. I'll bet the plant/kilo lab operators (and their friends and their families) were pleased with this new route.
1. Reeves, J.T.; Tan, Z.; Reeves, D.C.; Song, J.J.; Han, Z.S.; Xu, Y.; Tang, W.; Yang, B.-S.; Razavi, H.; Harcken, C.; Kuzmich, D.; Mahaney, P.E.; Lee, H.; Busacca, C.A.; Senanayake, C.H. "Development of an Enantioselective Hydrogenation Route to (S)‑1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine." Org. Process Res. Dev. ASAP DOI: dx.doi.org/10.1021/op5001513