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.

Graphical Abstract

Keywords:

• Domino reaction
• imidazole
• pseudo-multicomponent
• regioselectivity

Acknowledgments

Authors are highly thankful to DST-PURSE (SR/PURSE Phase 2/40(G)), New Delhi and Dr. APJ Abdul Kalam CIL, GJUS&T, Hisar.