Methanesulfonyl chloride, reaction with aniline

Almotnptan (5, LAS-31416) was discovered and developed by Almirall in Spain. The U.S. marketing rights were licensed to Pharmacia and then to Janssen. The synthesis commenced with the reaction of (p-nitrophenyl)-methanesulfonyl chloride (57) with pyrrolidine, followed by hydrogenation of the nitro group to give aniline 58 (Scheme 21). The hydrazine 59 was prepared by diazotization of 58 followed by reduction of the resulting diazonium salt with stannous chloride. Hydrazine 59 was treated with 4-chlorobutanal diethyl acetal in aqueous HCl and hydrazone 60 precipitated and was... 

A mechanically stirred solution of aniline (139.7 g, 1.5 mole) in pyridine (2 L), under N2 is cooled in an ice bath. Methanesulfonyl chloride (171.8 g, 1.5 mole) is added dropwise to this solution while the temperature is maintained at 15°-20°C, which results in a red-orange color change in the reaction mixture. After the addition is complete the ice bath is removed and the reaction is allowed to continue at room temperature. The reaction is complete after 2.5 h. The reaction mixture is concentrated in vacuo and the residue is combined with 700 ml of water which results in crystallization of a dark red material. 

A complication in this study was the observation of mixed second- and third-order kinetics with water or aniline as the trap (in 1,2-dimethoxyethane, DME). Deuterium labelling showed that both the second- and third-order reactions proceeded by way of the sulfene. More recent observations show that the third-order term is more pronounced in benzene (being seen with 2-propanol as the sulfene trap), and becomes less marked as the solvent polarity increases to DME and methylene chloride43. The original kinetic study42 also presented a case for an ElcB-like E2 process for the reactions of phenyl methanesulfonyl chloride with tertiary amines, and provided evidence that the sulfene is not formed via the sulfonylammonium salt, RS02NR3, i.e. by nucleophilic catalysis. 

---