Mechanochemical Desymmetrization of Unbiased Bis‐ and Tris‐alkynes to Access 3,5‐Isoxazoles‐Alkyne Adducts and Unsymmetrical Bis‐3,5‐isoxazoles**

Abstract

A mechanochemical desymmetrization of symmetrical bis‐ and tris‐alkynes by a controlled 1,3‐dipolar cycloaddition reaction using nitrile oxide dipoles (NOs). This operationally simple protocol allows access to 3,5‐isoxazole‐alkyne adducts from easily prepared or commercially available symmetrical bis‐ and tris‐alkynes in moderate to excellent yields. In addition, we have highlighted the synthetic utility of 3,5‐isoxazole‐alkyne by developing a route to access, for the first time, β‐ketoenamine‐alkyne derivatives, and unsymmetrical bis‐3,5‐isoxazoles.

Synthesis of Molsidomine and Mesocarb Analog via Mechanochemistry

“…[17] For the synthesis of N6-functionalized ImSyds, depending on which nucleophile reacts first with CDI, there are two possible strategies by desymmetrization of CDI. [18] Few years ago, an access to ImSyd-based prodrugs was developed thanks to carbonylimidazolium activation (Scheme 1a). [4] This CDI-based strategy gave access to a large number of N-carbonyl derivatives of ImSyds but required the activation of the imidazole moiety through a methylation extrastep, lacking of sustainability with the use of toxic and hazardous reagent (MeI) and solvents (DMF, acetonitrile or dichloromethane).…”