Unusual Nucleophilic Addition of Grignard Reagents in the Synthesis of 4‑Amino-pyrimidines

Pyrimidines have
always received considerable attention because
of their importance in synthesis and elucidation of biochemical
roles, in particular that of vitamin B1. Herein, we describe a reaction
pathway in a Grignard reagent-based synthesis of substituted pyrimidines.
A general synthesis of α-keto-2-methyl-4-amino pyrimidines and
their C6-substituted analogues from 4-amino-5-cyano-2-methylpyrimidine
is reported. The presence of the nitrile substituent in the starting
material also results in an unusual reaction pathway leading to C6-substituted
1,2-dihydropyrimidines. Grignard reagents that give normal pyrimidine
products under standard reaction conditions can be switched to give
dihydropyrimidines by holding the reaction at 0 °C before quenching.