Yield (11a) 9a:11a We evaluated the effect of the optimized conditions on different bis-and tris-alkynes (Scheme 1). The aromatic bis-alkynes (7a-f) displayed a selectivity towards hydroxyimidoyl chlorides of opposing electronic nature. Bis-alkyne systems on an aromatic electron-neutral ring (ENR) (7a-b) and electron-deficient ring (EDR) (7e) best reacted with hydroxyimidoyl chloride bearing an electron donating group (EDG) (8e) where the corresponding 3,5isoxazole-alkyne adducts (9e), (9h), and (9n) were obtained in excellent yields. When ENR bis-alkyne (7a) was reacted with an hydroxyimidoyl chloride bearing electron-neutral groups (ENG) (8d), 3,5-isoxazole-alkyne adduct (9d) was desymmetrize with an excellent yield, where desymmetrization of bis-alkyne (7a) previously was reported to require at least 10 equivalents of bisalkyne substrate to achieve selectivity for the formation of the 3,5isoxazole-alkyne adduct. In contrast, when ENR bis-alkynes (7a-b) reacted with hydroxyimidoyl chlorides bearing an electronwithdrawing groups (EWG) (8a-c), 3,5-isoxazole-alkyne adducts (9a-c), (9g), and (9m) were obtained in low yields. The opposite trend was observed for bis-alkynes on electron-rich rings (ERR) (7d) which showed higher reactivity for hydroxyimidoyl chlorides bearing EWG (8a). This led to the formation of 3,5-isoxazolealkyne adduct (9j) in higher yields than (9k) from a hydroxyimidoyl chloride (8e) with an EDG. The electronic discrimination of bisalkyne systems for hydroxyimidoyl chlorides of opposite electronic nature can be explained by an increase in polarizability for the resulting 3,5-isoxazole-alkyne adduct. The physical state of the bis-alkyne influenced the performance of the reaction. Liquid aromatic bis-alkynes were more reactive than solid substrates. This may be due to the limited mass transfer of the solid reagents in contrast to the liquid reagents. This difference was observed when comparing the reactivity of solid ENR bis-alkyne (7a) and liquid bis-alkyne (7b) when reacted with hydroxyimidoyl chloride (8e) bearing an EDG. Synthesis of the 3,5-isoxazole-alkyne adduct (9h) resulted in higher yields than that obtained for (9e). A similar trend in reactivity was observed for liquid thiophene bis-alkyne (7f). Liquid thiophene bis-alkyne (7f) showed equal reactivity for hydroxyimidoyl chlorides bearing an EWG (8a) or an EDG (8e) to form 3,5-isoxazole-alkyne adducts (9o) and (9p), respectively, with excellent yields without any clear electronic discrimination. Alkyl poly-alkyne have been investigated in the context of CuAAC due to the possibility of autocatalysis. The presence of alkylalkyne moieties with a high degree of rotation can stabilize Cu(I) catalysts and accelerate the cycloaddition reaction. Consequently, we investigated the desymmetrization of alkyl bisand tris-alkynes to form 3,5-isoxazole-alkyne adducts (7g-i). The proposed conditions were demonstrated to be effective for desymmetrizing alkyl bis-and tris-alkynes, and no trend in the electronic properties of the hydroxyimidoyl chlorides was observed. Desymmetrization of liquid tris-alkyne (7g) and bisalkyne (7i) demonstrated improved yields by removing the mesitylene liquid additive, producing the corresponding 3,5isoxazoles-alkyne adducts (9r-u) in excellent yields. This effect was also observed in the desymmetrization of the aromatic trisalkyne (7c), where the yield improves in the absence of liquid additive, with 3,5-isoxazole-alkyne (9i) obtained in excellent yields. Synthesis of (9i) by solution-based protocols required an excess of tris-alkyne (7c) and long reaction times to comparable yields and selectivity. The scalability of the reaction was investigated for the solid bis-alkyne (7a) and liquid bis-alkyne (7i). The 1.0 g scale mechanochemical synthesis of 3,5-isoxazolealkyne adduct (9e) from solid aromatic bis-alkyne (7a) showed a modest decrease in yield. In contrast, the 1.0 g scale synthesis of 3,5-isoxazole-alkyne adduct (9t) from liquid bis-alkyne (7i) showed no decrease in yield.