Strong Hydrogen Bond Donating Solvents Accelerate the Passerini Three-Component Reaction

We report enhanced reaction rates of the Passerini reaction (P-3CR) using 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as a cosolvent. Although alcoholic solvents typically increase the energy barrier of the rate-determining step for the P-3CR, we observed significant rate enhancements even when employing strong hydrogen bond donating (HBD) alcohols as cosolvents. This rate enhancement was observed for most aprotic organic solvents, with the exception of strong hydrogen bond accepting (HBA) solvents such as DMF. Experimental kinetic studies and DFT calculations provided a mechanistic rationale for our observations. An investigation of the substrate scope showed that this rate enhancement generally resulted in a (slight) increase of the overall yield in the P-3CR.