Mechanistic Study of Dienamine Catalysis for the Proline-Catalyzed Cyclohexadienal Formation from α,β-Unsaturated Aldehydes in Methanol

Organocatalyzed Diels-Alder cycloadditions via dienamine intermediates provide stereoselective access to synthetically valuable cyclohexadienals. We employed electrospray (ESI) mass spectrometry and quantum-chemical methods to investigate the proline-catalyzed self condensation of α,β-unsaturated aldehydes in methanol. Key steps in the catalytic cycle include dienamine formation, cycloaddition, and elimination of the proline catalyst. The last step is rate-determining. Combining the results of our experiments and density functional theory (DFT) calculations, we found no evidence to support the involvement of a second catalyst molecule, which had previously been postulated to enhance the crucial elimination step. Detected ions were mass-selected and probed by collision-induced dissociation using both the original and a charge-tagged catalyst. Their reactivity is consistent with the proposed intermediate position in the catalytic cycle. The presence of methanol results in a second productive pathway via hemiacetal formation without the need for dual activation, revising previous mechanistic assumptions about proline-catalyzed dienamine reactions.