Acid-catalyzed [2 + 2 + 2] cycloaddition of two cyanamides and one ynamide: highly regioselective synthesis of 2,4,6-triaminopyrimidines
Alexey Yu. Dubovtsev, Valeria Vladislavovna Zvereva, Nikolay V. Shcherbakov, Dmitry Dar’in, Alexander S. Novikov, Vadim Yu. Kukushkin
Abstract
Triflic acid (10 mol%) catalyzes the highly regioselective [2 + 2 + 2] cycloaddition between two cyanamides and one ynamide to grant the 2,4,6-triaminopyrimidine core. The developed synthetic method is effective for the preparation of a family of the diversely substituted heterocyclic products (30 examples; yields up to 94%). The synthesis can be easily scaled up and conducted in gram quantities. As demonstrated by the post-functionalizations involving the amino-substituents, the obtained heterocycles represent a useful platform for the construction of miscellaneous pyrimidine-based frameworks. The performed density functional theory calculations verified a particular role of H+, functioning as an electrophilic activator, in the regioselectivity of the cycloaddition.