Journal of Organic Chemistry 2012-10-05

Evaluation of electrophilic heteroaromatic substitution: synthesis of heteroaromatic-fused pyrimidine derivatives via sequential three-component heterocyclization.

Fung Fuh Wong, Yu-Ying Huang, Chun-Hsi Chang

Index: J. Org. Chem. 77(19) , 8492-500, (2012)

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Abstract

A new sequential three-component heterocyclization was developed by reacting aromatic and heterocyclic substrates, including aminobenzenes, 1-aminonaphthalene, 2-aminopyrazines, 5-aminopyrazoles, 3-aminopyridine, 5-aminopyrimidine, 5-aminoquinoline, and 8-aminoquinoline, with formamide in the presence of PBr(3). The reaction gave the corresponding pyrazolo[3,4-d]pyrimidines in good yields (59-96%), except for aminobenzenes and 3-aminopyridine. A plausible reaction mechanism involving amidination, electrophilic substitution imination, and oxidative cyclization in three steps was proposed to account for the heterocyclization. The reactivity of the reaction was found proportional to the electrophilicity of the aromatic or heterocyclic substrate.