Regioselective synthesis of 1,2,4-trisubstituted imidazole from a mechanistic and synthetic prospective

Abstract

The highly substituted 1,2,4-trisubtituted imidazole was regioselectively synthesized via base mediated domino reaction of amidine scaffold with phenacyl bromide followed by in situ N-alkylation of imidazole. The reaction conditions were optimized in order to access three phenomenon (neutralization, condensation, and N-alkylation) in a single pot. A mechanism for the formation of N–H imidazole and its subsequent N-alkylation is depicted by isolation of reaction of intermediates. Electron donating group facilitate N-alkylation, whereas no N-alkylation was observed in the presence of electron withdrawing (NO2) group. The synthesized compounds and reaction intermediate were characterized using NMR, FTIR, and HRMS. Exact orientation of various aromatic rings in regioselective N-alkylated product was confirmed using single crystal X-ray analysis.