Aryne-arylamine-aldehyde three-component reaction for the synthesis of drug-like 2-aminobenzyl ethers

Kobayashi's fluoride-mediated approach to aryne generation remains the dominant strategy in aryne chemistry and has been widely applied in aryne-capture reactions involving both nucleophiles and electrophiles. However, many electrophile-trapping variants are limited by the presence of acidic protons, which compete with the desired electrophilic quench. Accordingly, considerable effort has been devoted to the development of anhydrous fluoride sources to enable efficient interception of the aryne intermediate. In this context, we recently reported a CsF/diglyme system that outperformed commonly used methods. Here, we describe the application of this CsF/diglyme protocol in an aryne-arylamine-aldehyde three-component reaction that efficiently furnishes 2-aminobenzyl ether products through a tandem aryne capture, electrophile quench, and Smiles-type rearrangement cascade. Importantly, these conditions enable the efficient use of aliphatic aldehydes, providing access to amino analogues of biologically active molecules.