Multicomponent coupling reactions (MCRs) are highly atom-efficient, one-pot reactions that combine three or more starting materials to produce several new bonds. The use of MCRs shortens the number of linear steps in synthetic routes to complex, biologically-active molecules for pharmaceutical development and drug discovery efforts. To identify and refine a drug candidate, libraries of related molecules are often prepared and structure activity relationships (SARs) are examined; when MCRs are included in the synthetic plan, they provide built-in component variation opportunities for diversification.

The Ugi-Smiles reaction is a four-component coupling (4CC) that utilizes an amine, isocyanide, phenol, and aldehyde in a one-pot process. It was recently discovered that utilizing a conjugated aldehyde and an alcohol solvent in this reaction resulted in a five-component coupling, which can formally be described as an oxy-Michael Ugi-Smiles process. The observed coupling occurs in competition with the expected Ugi-Smiles reaction. This work describes efforts focused on modifying reaction temperature, alcohol and isocyanide components, and exploring the reaction pathway to discover when the alcoholic solvent participates in the reaction and adds to the Ugi-Smiles scaffold.