Phosphonium Ion-Tethered Secondary Amines for Chemospecific 5-Enolexo Aldol Condensations of 6-Ketoaldehydes

A novel and highly selective 5-enolexo-exo-trig aldol condensation of 6-ketoaldehydes is presented using a proline-based alkylphosphonium ion catalyst. Bulky and oxophilic phosphonium ion plays a vital role in facilitating kinetic aldenamine formation and activating keto groups for aldol addition. This innovative approach exclusively targets five-membered carbo- and heterocyclic aldehydes, involving unusual aldehydes as donors and ketones as acceptors. Especially, enolizable aryl keto aldehydes and heteroatom-embedded ketoaldehydes exclusively produced cyclized products with our new catalyst, while other catalysts provided predominantly self-aldol or decomposed products. The scope and diversity of the method demonstrated by synthesizing different carboxaldehydes, including cyclopentene, indene, dihydrofuran, benzofuran, dihydropyrrole, indole, thiofuran, dihydrothiofuran, and benzothiofurans.