Prototype Pictet-Spengler reactions catalyzed by superacids. Involvement of dicationic superelectrophiles

The Pictet-Spengler reaction, an acid-catalyzed intramolecular cyclization of intermediate imines of 2-arylethylamine to give 1,2,3,4-tetrahydroisoqui nolines, has long been limited to active substrates which bear strongly ele ctron-donating groups such as a methoxy or a hydroxy group on the cyclizing benzene ring. in this paper, we present superacid-catalyzed Pictet-Spengle r reactions of imines of a-phenethylamine, including the prototype Pictet-S pengler reaction of N-methylene-2-phenethylamine, to give the parent and 1- substituted 1,2,3,4-tetrahydroisoquinolines in moderate to high yields. The yields are dependent on the acidity of the media. A linear relationship wa s found between the rate of the cyclization and the acidity of the reaction media in kinetic studies of N-methylene-2-phenethylamine and related imine s, strongly supporting the intervention of an additional protonative activa tion of the N-protonated imines, that is, the involvement of dicationic sup erelectrophiles, N,N-diprotonated imines (ammonium-carbenium dications). We further found that the prototype cyclization of the parent N-methylene-2-p henethylamine is also catalyzed by TFA to give 1,2,3,4-tetrahydroisoquinoli ne in good yield, although the cyclization is significantly slower than tha t catalyzed by superacids. The prototype Pictet-Spengler cyclization of N-m ethylene-2-phenethylamine can thus take place both through the monocation ( the N-monoprotonated imine) and the dication (the N,N-diprotonated imine), the latter reaction being predominant in superacids.