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-tetrahydroisoquinolines, has long been limited to active substrates which bear strongly electron-donating groups such as a methoxy or a hydroxy group on the cyclizing benzene ring. In this paper, we present superacid-catalyzed Pictet−Spengler reactions of imines of 2-phenethylamine, including the prototype Pictet−Spengler 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 was found between the rate of the cyclization and the acidity of the reaction media in kinetic studies of N-methylene-2-phenethylamine and related imines, strongly supporting the intervention of an additional protonative activation of the N-protonated imines, that is, the involvement of dicationic superelectrophiles, N,N-diprotonated imines (ammonium−carbenium dications). We further found that the prototype cyclization of the parent N-methylene-2-phenethylamine is also catalyzed by TFA to give 1,2,3,4-tetrahydroisoquinoline in good yield, although the cyclization is significantly slower than that catalyzed by superacids. The prototype Pictet−Spengler cyclization of N-methylene-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.