A Systematic Study and Mechanistic Insights into the Alkynyl-Prins Cyclization–Rearrangement Cascade of 2-(Alkynol)benzoates: Controlled Synthesis of 3-(Furan-3-ylidene) and 3-(Pyran-3-ylidene)phthalides

Abstract

We report a controlled and systematic approach for the divergent synthesis of 3-(furan-3-ylidene)- and 3-(pyran-3-ylidene)phthalides via an alkynyl-Prins cyclization of (2-alkynol)benzoates. In contrast to our previous work for the synthesis of [n,5]-oxaspirophthalides (n = 5–7), this study demonstrates that the ylidenyl-phthalide frameworks can be selectively constructed as the primary products by modifying reaction conditions, such as the addition of NaI. Given that these motifs are prevalent in various bioactive natural products and medicinal compounds, we have established a structurally diverse library of these previously difficult-to-access frameworks. Furthermore, detailed reactivity studies of these compounds (both E- and Z-) provided critical mechanistic insights for the formation of earlier reported [n,5]-oxaspirophthalides. These studies confirm that the E-ylidenyl-phthalides are the true intermediates, which undergo the rearrangement cascade to [n,5]-oxaspirophthalides, while the Z-isomer remains unreactive.