The synthesis of heterocycles has constituted a proliferating and growing area in chemistry. Among these, isoxazole motifs are commonly found in many drug candidates, novel materials, and versatile intermediates used to synthesize complex natural products.
Isoxazoles are typically synthesized through a 1,3-dipolar cycloaddition between nitrile oxides (NOs) and terminal alkynes. However, this type of cycloaddition often results in low regioselectivity, forming complex mixtures of 3,5-isoxazoles and 3,4-isoxazoles. To improve regioselectivity, Cu-catalysts have been shown to enhance selectivity for the 3,5-isoxazoles, while Ru(II)-catalysts favour the formation of 3,4-isoxazoles. However, these solution-based protocols suffer significant drawbacks, such as long reaction times, low atom economy, and low energy efficiency. 
A more promising alternative is mechanochemistry, which offers unprecedented modes of reactivity and selectivity with a lower environmental impact. Despite the diverse application of isoxazoles, very few reports have utilized mechanochemistry to synthesize these heterocycles. Herein, we discuss the impact of mechanochemistry in combination with catalysis in the regiospecific synthesis of 3,5-isoxazoles and 3,4-isoxazoles from terminal alkynes and NOs. Furthermore, we will highlight the applicability of the developed mechanocatalytic conditions in the synthesis of trisubstituted isoxazoles from internal alkynes and NOs. 
Additionally, we explored the impact of mechanochemistry in desymmetrizations by cycloaddition-type reactions, specifically, in the desymmetrization of unbiased bis- and tris-alkynes to access unprecedented 3,5-isoxazoles-alkyne adducts selectively. This approach allows for the modular synthesis of unsymmetrical bis-3,5-isoxazoles.