Work

Systematic Expansion of an Ugi-Based Multicomponent Synthesis of Tetrasubstituted Imidazoles

Year: 2026

Type: article

Abstract: 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.

Source: ACS Omega

DOI: 10.1021/acsomega.5c13353

Authors: Robin van der Straat, Justyna Kalinowska-Tluscik, Katarzyna Kurpiewska, Alexander Dömling

Institutions: University of Groningen, Jagiellonian University, University Hospital Olomouc, Institute of Molecular and Translational Medicine, Palacký University Olomouc

Language: English

Topic: Multicomponent Synthesis of Heterocycles

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: gold

Estimated APC paid: $1,935

Funders: KWF Kankerbestrijding, HORIZON EUROPE Widening participation and spreading excellence, HORIZON EUROPE European Research Council, NextGenerationEU