Design of new reaction conditions for the Sugasawa reaction based on mechanistic insights

A process to prepare 2-propionyl-4-bromoaniline by ortho acylation of 4-bromoaniline under Sugasawa conditions was developed. Upon scale-up in a pilot plant, the process gave lower yields than in the laboratory in four out of five plant runs. Analysis of the pilot-plant data, in conjunction with reaction calorimetric experiments, showed that expulsion of HCl from the reaction medium was key for obtaining high product yields. New reaction conditions were subsequently developed for carrying out ortho acylation of 4-bromoaniline (1). The reaction mixture containing aniline/BCl3/AlCl3/C2H5CN was added to a refluxing solution of toluene to allow for substantial HCl expulsion and thus obtain the optimum yield of the desired product. Aniline hydrochlorides were also shown to be suitable starting materials under these conditions. Mechanistic implications of these findings are discussed. The new reaction conditions significantly increased the yield.