Green and Metal-free Strategies for Isoxazole Synthesis: A Review of Sonochemical and Organocatalytic Approaches.

The isoxazole ring is a common moiety in heterocyclic compounds due to its distinctive structural features. Isoxazole is a promising scaffold with diverse biological activities such as anticancer, antibacterial, and anti-inflammatory. Green chemistry synthetic routes aim to reduce hazardous by-products and enhance the applications of isoxazole derivatives in pharmaceutical chemistry. This review covers recent green and metal-free approaches to isoxazole synthesis, emphasizing key methodologies such as sonochemistry, organocatalysis, and other green chemistry strategies. These techniques, notably sonochemistry and organocatalysis, offer operational simplicity, superior atom economy, reduced waste, and improved adherence to green chemistry principles. Additionally, the review assesses limitations seen in metal-catalyzed synthesis-such as high costs, toxicity, limited supply, excessive waste, and difficult separation from products. To address these challenges, current research focuses on developing green, metal-free alternatives that are clean, safe, costeffective, and sustainable. The key benefits of green, metal-free isoxazole synthesis include solventfree reactions, reduced waste, eco-friendliness, cost-effectiveness, rapid reaction times, and high chemo- and regioselectivity under mild conditions. The evolving role of isoxazole in pharmaceutical chemistry underscores its continued importance in drug discovery and development.