**2. Results and Discussion**

#### *2.1. Optimization of the Reaction Conditions*

First, we compared the effects of different acids and solvents. The reaction of benzoylnitromethane **1a** with allylbenzene **2a** to form isoxazoline **3a** was performed and the results were summarized in Table 1. It is noted that the reaction without acid did not proceed. In the presence of various acids, i.e., HCl, HNO3, H2SO4, TFA, H3PO4, fluoroboric acid, MsOH, and *p*-TsOH, the yield was significantly improved. It appears that oxidative acids produced similar good yield (Table 1, entries 3 and 4), but reagents used there are expensive, toxic, and dangerous. It was found that MsOH in *i*-PrOH at 80 ◦C effectively promoted the formation desired isooxazoline. However, the yield of **3a** was slightly lower than that of *p*-TsOH (LD50: 1410 mg/kg) (Table 1, entries 8 and 9), and MsOH (LD50: 200 mg/kg) is highly toxic. Therefore, *p*-TsOH, which is non-oxidizing, corrosive, and low toxic was selected to participate in the synthesis of isoxazoline with a yield of 67%. While among the five tested solvents (ACN, *i*-PrOH, DMF, DMSO, and H2O), it was found that the yield reduced significantly with the relative polarity of the solvent (Table 1, entries 9–13) and can obviously is the best solvent.

The reaction temperature and amount of *p*-TsOH were further optimized. The results were shown in Figure 2. Then, the optimal condition was regarded acanACN as solvent, 4 equiv of *p*-TsOH was involved in the reaction at 80 ◦C for 22 h, in which a good yield of 90% could be obtained.


**Table 1.** Reaction condition optimization a.

<sup>a</sup> General conditions: **1a** (0.125 mmol), **2a** (0.625 mmol), solvent (0.2 mL) at 80 ◦C for 22 h. <sup>b</sup> Data from PubChem 25 ◦C. <sup>c</sup> Isolated yield.

**Figure 2.** Optimization of the reaction conditions. (**a**) The effect of various equivalence of *p*-TsOH; (**b**) The effect of various temperature. The amount of *p*-TsOH was 0.5 mmol. General conditions: **1a** (0.125 mmol), **2a** (0.625 mmol), ACN (0.2 mL) at 80 ◦C or indicated temperature for 22 h.
