The widespread presence of butenolide motifs in pharmaceuticals, natural products, and small-molecule biological probes has continuously motivated the development of efficient synthetic strategies. Herein, we describe a practical and broadly applicable strategy for the construction of highly functionalized butenolides through an HFIP-mediated three-component cascade hydroaminoalkylation-aza-Prins reaction under metal-free conditions. The structural and functional diversity of the readily accessible secondary amines, keto acids, and allenes offers a versatile and flexible platform for the rapid construction of valuable butenolides. The versatility of the developed protocol is underscored by its successful application to the late-stage functionalization of medicinally relevant complex molecules and natural products.
Huang et al. (2026) studied this question.