Highly substituted imidazoles are privileged scaffolds in medicinal and synthetic chemistry; however, general and modular access to densely substituted variants remains limited. Although Ugi-derived imidazole formation has been reported in isolated cases, its broader applicability has not been systematically explored. Herein, we present a comprehensive expansion and optimization of an Ugi-based one-pot synthesis enabling the preparation of tetrasubstituted imidazoles from readily accessible glyoxal derivatives. In contrast to earlier studies largely restricted to aryl glyoxals, this protocol demonstrates broad compatibility with aliphatic and aromatic glyoxals, as well as diverse amines, carboxylic acids, and isocyanides, providing full substitution control over all four positions of the imidazole ring. Key parameters governing chemoselectivity and ammonium-induced cyclization were identified, affording the target imidazoles in moderate to excellent yields. This study establishes the Ugi–imidazole transformation as a robust and diversity-oriented synthetic platform suitable for the rapid generation of medicinally relevant imidazole scaffolds.
Straat et al. (Fri,) studied this question.