Solvent-free synthesis of 3,5-isoxazoles via 1,3-dipolar cycloaddition of terminal alkynes and hydroxyimidoyl chlorides over Cu/Al2O3 surface under ball-milling conditions

Scalable, solvent-free synthesis of 3,5-isoxazoles under ball-milling conditions has been developed. The proposed methodology allows the synthesis of 3,5-isoxazoles in moderate to excellent yields from terminal alkynes and hydroxyimidoyl chlorides, using a recyclable Cu/Al2O3 nanocomposite catalyst. Furthermore, the proposed conditions are reproducible to a 1.0-gram scale without further milling time variations.

We began our investigation by performing an optimisation of the 1,3-dipolar cycloaddition reaction between alkyne 2a and hydroxyimidoyl chlorides 3a by milling the selected substrates in a stainless-steel (SS) jar in the planetary ball-mill to obtain 3,5-isoxazole 1a (Table 1). During the optimization, the effect of milling time, amount of milling media, base, and equivalents of hydroxyimidoyl chlorides were studied to obtain the highest yield of 3,5-isoxazole 1a (Table 1). Optimization revealed the combination of 1.0 equivalent of alkyne 2a, 1.5 equivalents of hydroxyimidoyl chlorides 3a, and 2.0 equivalents of Na 2 CO 3 while milling for 20 minutes with 8 SS balls provided the most effective conditions (Table 1, entry 1). Our rst control experiments focused on optimizing the milling time (Table 1, entries 2-5). Milling the reagents for less than 20 minutes affords lower product yields (Table 1, entries 2 and 3). Conversely, milling the reagents longer than 20 minutes leads to a decrease in yield to about 60% (Table 1, entries 4 and 5). The strong abrasion of the SS milling media for extended periods could lead to a ringopening by a reduction of the N-O to yield b-keto-enamine. 36,37 Having optimized the milling time, we next attempted to improve the yield by varying the equivalents of hydroxyimidoyl chlorides 3a since reaction stoichiometry has been shown to impact the product formed during mechanochemical reactions. 38,39 3,5-isoxazole 1a was obtained in lower yields when using equimolar amounts alkyne 2a to hydroxyimidoyl chlorides 3a (entry 6, Table 1). Because nitrile oxides rapidly dimerize to form furoxans by a competing 1,3-dipolar cycloaddition. [40][41][42][43][44][45] Likewise, increasing the equivalents of 18a from 1.0 to 2.0 equivalents lowered the yield of the reaction (entry 7, Table 1). We obtained the highest yield with 1.5 equivalents of the hydroxyimidoyl chlorides of 3a, and these conditions were used for further experiments (entry 1, Table 1). We next studied the effect of diverse carbonated bases in the reaction. We observed that changing the base did not improve the yield of the reaction, and Ag 2 CO 3 was most detrimental to the reaction as it   Milling for 10 min, 7 SS balls 59 3 Milling for 15 min 7 SS balls 64 4 Milling for 30 min 58 5 Milling for 40 min 60 6 Using 1.0 equiv. of 3a 65 7 Using 2.0 equiv. of 3a 57 8 Using K 2 CO 3 71 9 Using Cs 2 CO 3 71 10 Using CaCO 3 44 11 Using Ag 2 CO 3 18 12 Using NEt 3 N.R. promoted furoxan formation (entries 8-11, Table 1). 46,47 Using triethylamine (NEt 3 ) proved impractical as the addition of NEt 3 to hydroxyimidoyl chlorides was highly exothermic in the absence of solvent (entry 12, Table 1). During the screening, we observed that milling time inuences the reaction yield. 35,48 Therefore, a milling time optimization for other alkyne and hydroxyimidoyl chloride combinations revealed that the most optimal milling time was determined to be between 10 and 30 minutes (see ESI † for milling time optimizations).
As shown in Fig. 4, stannanyl isoxazole 1a and 1b, silyl isoxazole 1c, and phenyl isoxazole 1d were synthesized with satisfactory yields under the proposed conditions. To explain these results, we suggest an electronic argument. The electronwithdrawing character of the metal substituents, stannyl or silyl of alkyne 2a and 2b, respectively, accelerates the reaction by deactivating the alkyne moiety. [49][50][51] It is observed that alkyne 2a bearing the alkylstannane substituent has a more pronounced effect than the alkyne with the silyl substituent (2b). Therefore, alkyne 2a was the most reactive as it reacted with hydroxyimidoyl chlorides 3a and 3b to synthesize 3,5-isoxazole 1a and 1b respectively, in short times and excellent yields (Fig. 4). On the other hand, ethynyltrimethylsilane (2b) was less reactive as it could only react with a more labile hydroxyimidoyl chlorides 3b to form 3,5-isoxazole 1c (Fig. 4). Comparably, we suggest that the phenyl substituent of alkyne 1c increases the polarizability of the molecule, resulting in deactivating the alkyne moiety. As a result, phenylacetylene (1c) reacted in excellent yields with hydroxyimidoyl chlorides 1b. 42 In addition, we observed that the electronic nature of the hydroxyimidoyl chloride substituent affects the reactivity of the nitrile oxide dipole. Hydroxyimidoyl chlorides 3a containing an aromatic substituent with strong electron-withdrawing groups decreased the reactivity of the nitrile oxide. 52,53 Consequently, the nitrile oxide synthesized in situ from hydroxyimidoyl chlorides 3a could only react with tributyl(ethynyl)stannane (2a). On the other hand, hydroxyimidoyl chlorides 3b was the most reactive due to the bearing of a weaker electron-withdrawing group such as the ester functional group. 43,52 Unfortunately, other alkynes containing substituents such as esters, pyridines, or substituted arenes were not tolerated under these conditions. Previous reports demonstrated the effect of copper catalyst or copper additives to accelerate the reaction and obtain the 3,5-isoxazoles in a regioselective manner. 15,53-59 Therefore, we aimed to investigate the effect of copper additives or catalysts on this reaction.
The practicality of the proposed methodology allows the recovery of Cu/Al 2 O 3 nanocomposite catalyst directly aer the milling of the reagents. In addition, the catalyst recovery allowed investigating the reusability of the recovered catalyst. The Cu/Al 2 O 3 was reused on four occasions, and it was observed that 3,5-isoxazole 1f was obtained successfully with only a minimal drop in yield with each subsequent use for the rst two recycling cycles (Fig. 7). The decrease in yield is explained by the decrease in the concentration of active Cu species in the Cu/ Al 2 O 3 nanocomposite (see ESI †). ICP-MS analysis demonstrates that the Cu concentration of the rst recycling represents a decrease of 1.24-fold (with respect to the fresh catalyst); thus, similar yields are obtained compared to the fresh catalyst (Fig. 7). However, the decrease in Cu concentration becomes more substantial for the second and third reuse with a decrease of 2.42 and 6.48-fold, respectively. Therefore, a considerable decrease in the yield of isoxazole 1f is observed. Furthermore, a change in the oxidation state and the bonding of the supported Cu(II) ions. X-ray Photoelectron Spectroscopy (XPS) analysis of the rst and second recycled catalyst reveals that the characteristic satellite signals of Cu(II) found at about 942.8 eV are weak while the satellite signal at 963.2 eV is absent. Additionally, the 2p 3/2 signal at about 933-934 eV is wider than in the fresh sample (see ESI for XPS spectra of the fresh, Fig. S3 for rst recycling and Fig. S4 † for second recycling). These observations suggest that the supported Cu(II) is reduced to Cu(0) and CuO is formed with each subsequent recycling. [65][66][67] Lastly, we evaluated the sustainability of the proposed mechanochemical 1,3-dipolar cycloaddition conditions by comparing E-factor for the synthesis of 3,5 isoxazoles 1d and 1f to previously reported solution-based conditions (Fig. 8). 54,68 Using E-factor, the values calculated for the planetary ball milling conditions (pathway a and c, Fig. 8) demonstrate the sustainability of this methodology compared to solution-based reactions (pathway b and d) (see ESI † for calculations). With our conditions, the absence of organic solvent is the most signicant factor contributing to lowering the E-factor. 69 Time differences were also another factor of comparison with previously reported solution-based conditions. Our mechanochemical conditions did not surpass 60 minutes, contrary to the reported  solution-based conditions that require at least two hours to synthesize the desired 3,5-isoxazoles. Furthermore, our conditions did not show any sensitivity to oxygen or moisture present in the air as all reactions were performed in an open atmosphere.

Conclusions
In conclusion, we have developed a scalable, solvent-free, and efficient mechanochemical synthesis of 3,5-isoxazoles via 1,3dipolar cycloaddition from terminal alkynes and hydroxyimidoyl chlorides. We presented two methodologies; a catalystfree methodology which scopes extended to dipolarophiles bearing alkyl stannane substituent. Under catalyst-free conditions, ethynyltrimethylsilane (2c) and phenylacetylene (2d) reacted satisfactorily with (E,Z)-2-chloro-2-(hydroxyimino) acetate (3b). Additionally, a Cu/Al 2 O 3 mediated methodology allowed to react a broader range of dipolarophiles bearing electron-donating or electron-withdrawing substituents with any hydroxyimidoyl chloride. The reported methodology was scalable to a 1.0-gram scale without additional milling time variations. The Cu/Al 2 O 3 catalyst was demonstrated to easily be recycled and reused three times with only a slight reduction in yield. The reported conditions require shorter reaction times, they had a lower E-factor, and no prevention was taken to air or moisture, making these methodologies less environmentally harmful and more practical than previously reported solutionbased methodologies.

Conflicts of interest
There are no conicts to declare.