[3 + 2] Cycloaddition reactions of nitrile oxides generated in situ from aldoximes with alkenes and alkynes under ball-milling conditions

ABSTRACT A convenient and efficient [3 + 2] cycloaddition reaction of alkenes and alkynes with the in situ generated nitrile oxides from aldoximes in the presence of NaCl, Oxone and Na2CO3 has been developed to afford a series of isoxazoles and isoxazolines at room temperature in yields up to 85% and 86%, respectively. The current methodology exhibits a wide substrate scope, (hetero)aromatic and aliphatic aldoximes, alkenes including acrylate esters, acrylonitrile, chalcone, styrene, N-methylmaleimide and [60]fullerene, phenylacetylene, and alkynes containing CH2OH, SiMe3, COCH3 or CO2CH3 group can be employed. The present protocol features good functional group tolerance, short reaction time, mild reaction conditions and high atom economy, providing an efficient and environmentally friendly access to isoxazoles and isoxazolines. GRAPHICAL ABSTRACT


Introduction
As a consequence of the huge potential applications in environmental protection and waste reduction, mechanochemistry has continued to capture the interest of chemists worldwide (1)(2)(3)(4)(5)(6)(7)(8). The ball-milling technique as an attractive and efficient mechanochemical methodology has advantages in increasing reaction yields, shortening reaction time and improving reaction selectivity. In addition, the mechanochemical protocols are suitable for substrates with poor solubility and can even alter the chemical selectivity, providing products which are difficult or impossible to access in the liquid-phase reactions (9)(10)(11)(12)(13)(14). Therefore, the ball-milling technique has been extensively utilized in organic synthesis (15)(16)(17)(18)(19).
Isoxazoles and isoxazolines are important structures in organic chemistry and pharmaceutical chemistry, which widely exist in various natural compounds and synthetic drugs (20)(21)(22). They often display versatile pharmacological activities, such as anti-cancer and anti-tumor activities (23)(24), antibacterial activities (25), analgesic and antiinflammatory activities (26), and so on (27)(28). On the other hand, they are also important intermediates in organic synthesis and important precursors for the synthesis of β-hydroxyl ketones, β-amino acids and γ-amino alcohols (29)(30)(31)(32)(33)(34). Given the widespread utility of isoxazoles and isoxazolines, it is not surprising that a variety of methods have been developed for their synthesis. The [3 + 2] cycloaddition of nitrile oxides with various alkenes and alkynes is an important strategy to synthesize isoxazoles and isoxazolines. The formation of nitrile oxides relies heavily on oxidation of aldoximes. In the past decades, quite a number of oxidants have been reported (35)(36)(37)(38)(39)(40)(41)(42). However, most oxidants either require complex preparation or produce toxic byproducts. Therefore, the development of convenient and green strategies toward isoxazoles and isoxazolines is highly desirable.
Oxone (2KHSO 5 ·KHSO 4 ·K 2 SO 4 ) is a stable, environmentally friendly, non-toxic oxidant, which has been used in mechanochemical reactions (43)(44)(45)(46)(47). In our previous work, we reported that the dimerization of nitrile oxides generated in situ from aldoximes in the presence of Oxone, NaCl and base under ball-milling conditions could afford furoxans in high yields (Scheme 1a) (47). Inspired by this result, we envisioned that the addition of alkenes and alkynes to the in situ generated nitrile oxides may compete with the dimerization process and lead to isoxazoles and isoxazolines. Herein, we report the details for the mechanosynthesis of these [3 + 2] cycloaddition products under ball-milling conditions (Scheme 1b). We have found that various (hetero)aromatic and aliphatic aldoximes, diverse alkenes such as acrylate esters, acrylonitrile, chalcone, styrene, N-methylmaleimide and [60]fullerene, different alkynes including simple phenylacetylene and those containing functional group CH 2 OH, SiMe 3 , COCH 3 or CO 2 CH 3 can be utilized to generate the [3 + 2] cycloadducts in good yields.

Results and discussion
Initially, we chose (E)-4-methylbenzaldehyde oxime (1a) and methyl acrylate (2a) as the model substrates to screen the optimal reaction conditions. At first, a mixture of 1a (0.1 mmol), 2a (0.1 mmol), NaCl (0.1 mmol), Oxone (0.1 mmol) and NEt 3 (0.1 mmol) together with four stainless-steel balls (5 mm in diameter) was introduced into a stainless-steel jar (5 mL) and milled vigorously (30 Hz) in a Retsch MM400 mixer mill (Retsch GmbH, Haan, Germany) at room temperature for 30 min. As a result, the desired product, i.e. methyl 3-(p-tolyl)-4,5-dihydroisoxazole-5-carboxylate 3aa, was obtained in 28% yield along with the undesired furoxan product in 33% yield (Table 1, entry 1). Encouraged by this initial result, we tried to replace the base NEt 3 . To our delight, when Na 2 CO 3 was employed, 3aa could be obtained in 54% yield along with the minor byproduct furoxan in 7% yield (Table 1, entry 2), indicating that Na 2 CO 3 was more productive for this [3 + 2] cycloaddition reaction than NEt 3 . Increasing the amount of 2a from 1.0 to 1.2 equiv. resulted in a slightly higher yield of 59%, yet further increasing to 1.5 equiv. could not give a better product yield although the byproduct furoxan was formed in a trace amount (Table 1, entries 3 and 4). Similarly, when the amount of Na 2 CO 3 was increased from 1.0 to 1.2 equiv. and 1.5 equiv., 3aa was obtained in 62% and 69% yields, respectively, whereas further increasing to 2.0 equiv. could not provide a higher yield (Table 1, entries 5−7). The amount of NaCl and Oxone was subsequently optimized, and it was found that when the dosage of both NaCl and Oxone was increased from 1.0 to 1.1 equiv., the yield could be increased to 75% (Table 1, entries 8−11). Then, the reaction time was investigated. As the reaction time was extended from 30 min to 60 min, product 3aa was isolated in 85% yield (Table 1, entry 12). Further extending the reaction time to 90 min led to a slightly decreased yield of 84% (Table 1, entry 13). The liquidassisted grinding (LAG) protocol has acted as a power tool to promote mechanochemical reactions (48)(49)(50)(51). Accordingly, several liquids such as ethyl alcohol (EtOH), dichloromethane (DCM), ethyl acetate (EtOAc) and acetonitrile (CH 3 CN) were added to the reaction mixture. However, it was found that the addition of LAG was detrimental to this reaction ( Table 1, entries 14−17). Therefore, the optimized reaction conditions of the [3 + 2] cycloaddition reaction were established as follows: 0.1 mmol 1a, 1.2 equiv. 2a, 1.1 equiv. NaCl, 1.1 equiv. Oxone and 1.5 equiv. Na 2 CO 3 at 30 Hz for 60 min (Table 1, entry 12).
Having established the optimal reaction conditions, the substrate scope of alkenes and alkynes were investigated, and the results are shown in Scheme 2. Firstly, tert-butyl acrylate, acrylonitrile and chalcone, of which alkenes bearing electron-withdrawing groups, reacted smoothly with 1a to provide products 3ab, 3ac and 3ad in 82%, 72% and 66% yields, respectively. It should be pointed out that 3ad consisted of two regioisomers 3ad' and 3ad'' with isolated yields of 37% and 29%, respectively. Styrene 2e also worked well in this reaction system, and afforded the corresponding product 3ae in 67% yield. To our satisfaction, N-methylmaleimide 2f was also compatible under the standard reaction conditions, and the desired product 3af was isolated in 77% yield. What is more, the cycloaddition reaction could also be expanded to alkynes and provide the corresponding isoxazoles in moderate to good yields. Phenylacetylene 2g gave the corresponding product 3ag in 83% yield. Alkynes bearing CH 2 OH and SiMe 3 groups 2h and 2i proceeded efficiently to provide products 3ah and 3ai in 65% and 70% yields, respectively. The keto-substituted alkyne 2j could be used to give 3aj in 78% yield. The diester-substituted alkyne 2k proved to be feasible for this procedure and afforded product 3ak in 79% yield. Gratifyingly, [60]fullerene (C 60 ), which behaves as an electron-deficient polyolefin, could also be employed and provided 3al in 36% yield (the yield based on consumed C 60 was 45%). The structures of products were unambiguously confirmed by single-crystal X-ray diffraction analysis with 3aa as an example (see the Supplementary Materials for details).
To further investigate the substrate generality, we explored the substrate scope of aldoximes. As shown in Scheme 3, different kinds of aldoximes were well tolerated under the optimal reaction conditions. For instance, when aldoxime 1b with the para-substituted electron-donating methoxy group was used, product 3ba was obtained in 76% yield. The substrates 1c and 1d with para-substituted electron-withdrawing groups (Br, CO 2 Me) gave the corresponding products 3ca and 3da in 80% and 83% yields, respectively. Similarly, 1naphthaldehyde oxime also proved to be feasible for this procedure and provided product 3ea in 76% yield. Satisfactorily, 3-phenylpropanal oxime 1f and conjugate aldoxime 1g were also suitable substrates for this transformation, affording the corresponding products 3fa and 3ga in 82% and 69% yields. Moreover, the heteroaromatic aldoximes 3h−j could be used under our oxidation conditions for the [3 + 2] cycloaddition. Nicotinaldehyde oxime 1h, thiophene-2-carbaldehyde oxime 1i and benzofuran-2-carbaldehyde oxime 1j afforded products 3ha, 3ia and 3ja in 75%, 70% and 86% yields, respectively.
To further evaluate the practicability of the present mechanochemical protocol, a scale-up reaction of aldoxime 1a (6 mmol) with 2a (7.2 mmol) was carried out under the optimal reaction conditions (Scheme 4). To our delight, product 3aa was obtained in a satisfactory yield of 74% (0.97 g), which indicated that the present method could be easily adopted for a larger-scale preparation.
In order to assess the greenness of this mechanochemical process, complete and simple environmental factors (cEF and sEF), atom economy (AE) and reaction mass efficiency (RME) for the mechanochemical synthesis of 3aa were quantified, showing advantages in greenness compared with the liquid-phase counterpart (see the Supplementary Materials for details).

Conclusions
In summary, we have successfully developed the mechanochemical solvent-free reactions of alkenes and alkynes with the in situ generated nitrile oxides from aldoximes NaCl, Oxone and Na 2 CO 3 , affording isoxazoles and isoxazolines at room temperature in yields up to 85% and 86%, respectively. In the current protocol, (hetero)aromatic and aliphatic aldoximes, alkenes including acrylate esters, acrylonitrile, chalcone, styrene, N-methylmaleimide and [60]fullerene, phenylacetylene, and alkynes containing CH 2 OH, SiMe 3 , COCH 3 or CO 2 CH 3 group can be utilized. This process provides an efficient and environmentally friendly access to a variety of isoxazole and isoxazoline derivatives with remarkable functional group compatibility, short reaction time and good yields. We expect that this efficient method will be of great interest to organic and drug synthesis.

General information
All reagents were obtained from commercial sources and used without further purification. NMR spectra were recorded on a Bruker Advance III HD 400 NMR spectrometer (Bruker BioSpin AG, Fällanden, Switzerland; 400 MHz for 1 H NMR; 101 MHz for 13 C NMR) and a Bruker Advance III HD 500 NMR spectrometer (Bruker BioSpin AG, Fällanden, Switzerland; 500 MHz for 1 H NMR; 126 MHz for 13 C NMR). 1 H NMR chemical shifts were determined relative to TMS at 0.00 ppm or CDCl 3 at δ 7.26 ppm. 13 C NMR chemical shifts were determined relative to TMS at 0.00 ppm or CDCl 3 at δ 77.08 ppm. Data for 1 H NMR and 13 C NMR are reported as follows: chemical shift (δ, ppm), multiplicity (s = Scheme 2. Reaction scope of alkenes and alkynes 2a-l. a,b a Unless otherwise stated, the reactions were performed in a stainless-steel jar (5 mL) with 1a (0.1 mmol), NaCl (0.11 mmol), Oxone (0.11 mmol), Na 2 CO 3 (0.15 mmol) and 2a-l (0.12 mmol) together with 4 stainless-steel balls (5 mm in diameter) by using a Retsch MM400 mixer mill at 30 Hz for 60 min. b Isolated yields based on 1a. c 1a (0.1 mmol), NaCl (0.11 mmol), Oxone (0.11 mmol), Na 2 CO 3 (0.15 mmol), 2l (0.05 mmol) and isolated yield based on C 60 . d Isolated yield based on consumed C 60 . singlet, d = doublet, t = triplet, m = multiplet). High-resolution mass spectra (HRMS) were taken on a Waters Acquity UPLC-Xevo G2 QTof mass spectrometer (Waters, Milford, MA, USA) with FTMS-ESI in positive mode. Ball-milling reactions were performed in a MM400 mixer mill (Retsch GmbH, Haan, Germany), using a 5 mL stainless-steel jar with four 5 mm diameter stainless-steel balls and were milled at a frequency of 1800 rounds per minute (30 Hz) at room temperature.
Aldoximes 1 were prepared according to the reported protocol (52).

Mechanochemical synthesis and characterization of products 3aa-al and 3ba-ja
A mixture of aldoximes 1a-l (0.1 mmol), NaCl (0.11 mmol), Oxone (0.11 mmol), Na 2 CO 3 (0.15 mmol) and alkenes or alkynes (0.12 mmol) together with four stainless-steel balls (5 mm in diameter) was introduced into a stainless-steel jar (5 mL). The reaction vessel along with another identical vessel was closed and fixed on the vibration arms of a Retsch MM400 mixer mill, and was vibrated at a rate of 1800 rounds per minute (30 Hz) at room temperature for 60 min. After completion of the reaction, the resulting mixtures from the two runs were combined by washing with ethyl acetate. Then, the reaction mixture was filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in a vacuum. The residue was separated by flash column chromatography on silica gel with ethyl acetate/petroleum ether as the eluent to afford products 3aa-al and 3ba-ja.

Mechanochemical gram-scale synthesis of 3aa
A mixture of 1a (0.41 g, 3 mmol), NaCl (0.19 g, 3.3 mmol), Oxone (2.03 g, 3.3 mmol), Na 2 CO 3 (0.48 g, 4.5 mmol) and 2a (0.33 mL, 3.6 mmol) together with four stainless-steel balls (7.5 mm in diameter) was introduced into a stainless-steel jar (10 mL). The reaction vessel along with another identical vessel was closed and fixed on the vibration arms of a Retsch MM400 mixer mill, and was vibrated at a rate of 1800 rounds per minute (30 Hz) at room temperature for 60 min. After completion of the reaction, the resulting mixtures from the two runs were combined by washing with ethyl acetate. Then, the reaction mixture was filtered through a silica gel plug with ethyl acetate as the eluent and evaporated in a vacuum. The residue was separated by flash column chromatography on silica gel with ethyl acetate/petroleum ether as the eluent to afford products 3aa (0.97 g, 74%).

Synthesis of 3aa in liquid phase
To a stirred solution of 1a (27.4 mg, 0.2 mmol) in CH 3 CN (2 mL) were added NaCl (13.9 mg, 0.22 mmol), Oxone (138.9 mg, 0.22 mmol), Na 2 CO 3 (32.3 mg, 0.3 mmol) and 2a (22 µL, 0.24 mmol). The reaction mixture was allowed to stir at room temperature for 2 h. Then, the reaction mixture was filtered through a silica gel plug with ethyl acetate as the eluent, the solvent was subsequently removed under reduced pressure. The residue was purified by flash chromatography on silica gel with petroleum ether/ethyl acetate as eluent to give product 3aa (8.4 mg, 19% yield).

Disclosure statement
No potential conflict of interest was reported by the author(s).