Bronsted acid-catalyzed facile synthesis of α-substituted N-arylaminoacetals and their downstream conversions to functionalized pyrroles

alpha-Substituted N-arylaminoacetals are important building blocks for organic synthesis, which can be synthesized via Mannich reaction by using glyoxal dimethyl acetal as a key precursor. As the acetal fragment was known to be susceptible to acid, in literature methods, the Mannich reaction was performed under either neutral or gently acidic conditions. As a result, only a few kinds of alpha-substituted N-arylaminoacetals have been synthesized via Mannich reaction until now. We found surprisingly that Mannich adducts of glyoxal dimethyl acetal, arylamines and ketones are quite stable toward strong Bronsted acid. This led us to use successfully p-toluenesulfonic acid as the acid catalyst to synthesize a broad range of alpha-substituted N-arylaminoacetals. The Mannich adducts could be obtained in good to excellent yields. Particularly, these products were demonstrated to be able to react with 1,3-dicarbonyl compounds in the presence of Sc(OTf)(3) catalyst. A special class of multi-substituted pyrroles were thus synthesized, which can be converted to some important heterocyclic compounds including indoles and 2-formyl-N-arrylpyrroles. Dimethyl acetals of quinoline-2-carbaldehydes were also synthesized via one-pot three-component reactions of glyoxal dimethyl acetal, electron-rich anilines, and acetone.