Mechanochemical synthesis of 3,5-isoxazoles and its synthetic applications in the desymmetrization of unbiased poly(alkyne) systems Rafael A. Hernandez R., a Pat Forgione a,b a Department of Chemistry and Biochemistry, Concordia University, Canada, b Centre for Green Chemistry and Catalysis, McGill University, Canada The synthesis of heterocycles has constituted a proliferate and growing area in organic chemistry. Heterocycles are found in novel molecules with unprecedented pharmacological activity and in novel material with interesting electronic and photoelectronic properties. 1 Specifically, isoxazole motifs are among the most frequently encountered heterocycle in many drug candidates and a versatile intermediate in synthesizing natural products. 2,3 Among the possible di-substitution patterns of isoxazoles, 3,5-isoxazoles ( 1 ) have been regularly encountered because of their synthetic accessibility. 3 However, significant drawbacks are commonly encountered for the solution-based protocols, such as the long reaction times, low atom economy, and low energy efficiency. Alternatively, mechanochemical synthesis has been utilized in synthesizing complex organic molecules, demonstrating unprecedented modes of reactivity and selectivity with a lower environmental impact. 4 Although the 3,5-isoxazole motif ( 1 ) has found application in diverse areas, only a limited number of reports have applied mechanochemistry, and have shown the impact of isoxazole in the synthesis of more intricate molecules. 5 Herein, we would like to discuss the impact of mechanochemistry in synthesizing 3,5-isoxazoles ( 1 ) from terminal alkynes ( 2 ) and hydroxyimidoyl chlorides ( 3 ) via a 1,3-dipolar cycloaddition catalyzed by a recyclable Cu(II) nanocomposite ( Figure 1a ). Additionally, we would like to deliberate further the impact of mechanochemistry in cycloaddition type reactions in the desymmetrization of unbiased poly(alkyne) ( 4 ) systems to selectively access unprecedented 3,5-isoxazoles-alkyne adducts, which allows for the modular synthesis of non-symmetrical bis(3,5- isoxazoles) systems ( 6 ) ( Figure 1b ).
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