Desymmetrization is a modification that results in the loss of symmetry elements within a molecule, such as a mirror plane, an axis of rotation, or a center of inversion. Desymmetrization strategies are frequently employed in the synthesis of natural products, biologically active substances, and novel organic materials. Desymmetrization of symmetrical bis-and trisalkyne via a controlled 1,3-dipolar cycloaddition with nitrile oxide dipoles (NOs) to form 3,5-isoxazole-alkyne adducts has not been thoroughly investigated, and only a few examples have been reported. To date, desymmetrization of bis-and tris-alkyne focused on CuAAC (Copper Azide Alkyne Cycloaddition) to form 1,4-triazole-alkyne adducts. Current desymmetrization strategies to synthesize 3,5-isoxazole-alkyne or azide-alkyne adducts require protecting groups, specific dipoles, and an excess amount of the bis-or tris-alkyne. The reported approaches suffer from poor atom efficiency due to an excess amount of starting material, the formation of undesired symmetrical by-products, the use of toxic solvents, and laborious methodologies. Therefore, developing sustainable and efficient methodologies to improve atom economy and access novel chemical space is highly desired. Mechanochemical desymmetrization represents a concrete extension to previously developed desymmetrization methodologies. For example, Štrukil et al. exploited a mechanochemical click desymmetrization of aromatic diamines (1) to form mono-and bis-(thioureas) (2) in quantitative yields (Scheme 1a). Similarly, Lanzillotto et al. demonstrated a mechanochemical desymmetrization of CDI (1,1'carbonyldiimidazole) (3) to form carbamates (4) (Scheme 1b). Seo et al. reported a step-wise arylation of symmetrical dibromoarenes (5) by a mechanochemical Suzuki-Miyaura crosscoupling to obtain unsymmetrical arylated systems (6) (Scheme 1c). Mechanochemical 1,3-dipolar cycloaddition reactions between NOs generated by dehydrohalogenation of hydroxyimidoyl chloride to desymmetrize symmetrical bis-or trisalkynes (7) remain unstudied (Scheme 1d). Herein, we report a selective, scalable, quick, and atom-efficient mechanochemical desymmetrization of bis-and tris-alkynes (7) to access 3,5isoxazole-alkyne adducts (9). This protocol demonstrates compatibility for diverse bis-and tris-alkynes (7) and does not require protecting groups or excess poly-alkyne substrate. Additionally, we demonstrate the utility of this methodology in the modular synthesis of unsymmetrical bis-3,5-isoxazoles derivatives (10) (Scheme 1d). Our investigations began by optimizing the desymmetrization of the symmetrical solid aromatic bis-alkyne (7a) with ester hydroxyimidoil chloride (8a) to form the 3,5-isoxazole-alkyne adduct (9a) (Table ). All reactions were performed in a Pulverisette 7 mill, with reactants contained in a stainless-steel (SS) jar along with eight SS balls (32 g) of 1 cm diameter for 60 min at 60 Hz (Table , entry 1). The desired product (9a) can be obtained selectively without the need to use an excess of either the aromatic bis-alkyne (7a) or ester hydroxyimidoyl chloride (8a, Table , entries 2-4). We attempted to improve the performance of the reaction by screening different additives with Lewis acid character (entry 5-9, Table ). These additives accelerate cycloaddition via πcomplexation with the alkyne moiety. Using 1.0 equivalent of Cu(NO3)2•2.5H2O improves the selectivity favoring the formation of the desired 3,5-isoxazole-alkyne adduct (9a) over the undesired symmetrical bis-3,5-isoxazole (11a) (entry 7, Table ). Other nanocomposites and metal additives such as Cu/Al2O3, ZnCl2, and IrCl3•xH2O were detrimental to the desymmetrization and promoted the formation of symmetrical bis-3,5-isoxazole (11a) or the dimerization of the NOs to obtain undesired furoxans (entry 6-9). In addition to the plausible complexation between Cu(II) and the alkyne moiety, Cu(NO3)2•2.5H2O may serve as a solid-state diluting agent that homogenizes the mixture, thus promoting the desymmetrization and the formation of 3,5isoxazole-alkyne adduct (9a). Increasing substrate dilution by using grinding auxiliary agents (GAAs) such as NaCl, KCl, or Al2O3 in combination with Cu(NO3)2•2.5H2O were ineffective and the 3,5-isoxazole-alkyne adduct (9a) was obtained in lower yields (entry 10-12). We also investigated the effect of liquid-assisted grinding (LAG) in terms of the η parameter (defined as the ratio of the volume of liquid additive µL to the total mass of reactants in mg). LAG has been demonstrated to accelerate mechanochemical reactions by facilitating bulk-mass transfer and was shown to modify and enhance reaction selectivity. An increase in the reaction yield and selectivity for 3,5-isoxazole-alkyne adduct (9a) was achieved when using aromatic liquid additives (entry 1,15-16), where mesitylene was found to be the most effective additive (entry 1). Only 0.25 µL/mg of mesitylene was required and increasing the amount beyond this did not improve the yield and selectivity for the desired adduct (9a), while polar and protic liquid additives did not improve the yield or selectivity (9a) (entry 13-14). These observations suggest that mesitylene has the suitable polarity to accelerate the dehydrohalogenation of the hydroxyimidoyl chloride to form the corresponding NO. The low polarity of the liquid additive accelerates cycloadditions by polarizing the NO and stabilizing the transition state . Additionally, π-π stacking between the mesitylene additive and bis-alkyne (7a) could promote the activation of the dipolarophile, making it more reactive toward NOs. Several reports utilized copper(I) catalysis to accelerate 1,3dipolarcycloaddition reactions. In our case, in situ formation of Cu(I) by reduction of Cu(II) salts with sodium ascorbate or addition of Cu(I) complexes in sub-stoichiometric amounts were ineffective and lower selectivity and/or yields for the desired 3,5isoxazole-alkyne (9a) were obtained (see supporting information for details). Optimizations demonstrated that using equimolar amounts of bisalkyne (7a) and hydroxyimidoyl chloride (8a) in combination with 2.0 equivalents of Na2CO3, 1.0 equivalent Cu(NO3)2•2.5H2O and using mesitylene as a liquid additive were the optimal conditions to desymmetrize aromatic bis-alkyne.