Achieving Regioselective Control for Mechanochemical Reactions: A Planetary Ball-Milling, Ru-Catalyzed Synthesis of 3,4- and 3,4,5-Isoxazoles

Abstract

A mechanochemical-enabled Ru-catalyzed regioselective synthesis of 3,4-isoxazoles and 3,4,5-isoxazoles from terminal and internal alkynes and hydroxyimidoyl chlorides is reported. This solid-state and solvent-free approach carefully examines the impact of the milling conditions on regiocontrol in 1,3-dipolar cycloadditions using mechanochemical means. The study reveals that milling frequency, jar material, and the choice of liquid additive for liquid-assisted grinding (LAG) significantly influence the catalytic activity of the Ru catalyst. Transmission electron microscope (TEM) analysis confirms the crucial role of coordinating liquid additives such as acetone and cyclopentyl methyl ether (CPME) in stabilizing and reducing the size of the in-situ formed Ru nanoparticles, which is essential for catalytic activity. The applicability of this protocol is further demonstrated through the synthesis of a library of 3,4- and 3,4,5-isoxazoles from a wide range of terminal and internal alkynes with varying physical states and electronic properties that highlights the potential of this method for the synthesis of more complex target molecules.