One-pot regio-selective synthesis of 3,5-disubstituted isoxazoles via CuI catalyzed consecutive acyl Sonogashira coupling and intramolecular cyclization

Abstract

This study presents a novel approach for synthesizing various regio-selective 3,5-disubstituted isoxazoles using inexpensive CuI catalysis. Moderate to good yields of the target compounds were achieved through this method. Based on the experimental results and literature insights, a plausible mechanism involving two consecutive Cu-catalytic cycles, Sonogashira coupling, and intramolecular cyclization was proposed. Notably, opposite regio-selectivity was observed between products obtained from uncatalyzed and CuI-catalyzed reactions. The outcomes of this CuI-catalyzed one-pot protocol represent an improvement over previous methods, offering a promising avenue for diverse isoxazole derivative synthesis. The proposed process involves homogeneous CuI-promoted one-pot three-component regio-selective synthesis of 3,5-disubstituted isoxazoles, with key in situ α,β-unsaturated ynone intermediates crucial for subsequent reactions. This approach streamlines synthesis, allowing simultaneous assembly of multiple chemical components in a single reaction vessel, while minimizing the need for complex steps and costly reagents. Overall, this strategy holds promise for rapid and economical production of diverse 3,5-disubstituted isoxazoles, with potential applications in medicinal chemistry and materials science.

Graphical abstract