Synthesis of imidazo[1,5‐<i>c</i>]pyrimidine derivatives

Abstract

Abstract Two complementary procedures, each starting from 6‐aminomethyluracil ( 2 ), have been used to prepare imidazo[1,5‐ c ]pyrimidines with a variety of substituents at positions 3, 5, 6, and 7. The starting material, 2 , can be readily prepared from commercially available 6‐chloromethyluracil by reaction with anhydrous ammonia. In the first procedure, 2 is acylated and then cyclodehydrated by reaction with phosphorus oxychloride to give a separable mixture of a 3‐substituted 5,7‐dichloroimidazo[1,5‐ c ]pyrimidine and a 3‐substituted 7‐chloroimidazo[1,5‐ c ]pyrimidin‐5(6 H )‐one. The relative product distribution is subject to some control by the choice of the acyl substituent on the starting uracil. The resulting dichloro compounds were derivatized by reaction at the 5‐position with various nucleophiles, although the 7‐chloro substituent is unreactive. An alternative synthetic method proceeds from 2 in six efficient steps (protection as the phthalimide, chlorination, nucleophilic substitution, deprotection, acylation, and cyclodehydration) to 3‐substituted‐5,7‐bis(methylthio)imidazo[1,5‐ c ]pyrimidines. These compounds may also be derivatized by nucleophilic substitution at the 5‐position.