Chemoselective Intermolecular Cross-Benzoin Reactions Via Pyridinium-Zwitterion Intermediates

Abstract Despite considerable advances in the well-established benzoin reaction, cross-benzoin reactions remain challenging often due to limited substrate scope, generation of undesired products, and engineered catalysts. Here we outline an entirely new entry path into this useful reaction by demonstrating that readily generated hydroxycarbenes (R–C̅–OH) can serve as alternative synthons for benzoin reactions. We do so by trapping the hydroxycarbene intermediates to avoid their rapid quantum-mechanical tunneling [1,2]H-shifts to the corresponding aldehydes. By extending the pyridine probe technique, nascent hydroxycarbenes are intercepted to form persistent zwitterionic intermediates. These intermediates subsequently react with a variety of aldehydes, enabling cross-benzoin reactions in high yields and chemoselectivities. We provide the first characterization of hydroxycarbene-derived zwitterionic intermediates, using mass spectrometric analyses and support their formation and reactivity with computational studies. Our findings establish nucleophilic trapping as a practical tool for taming hydroxycarbene reactivity and expanding their synthetic utility.