**1. Introduction**

Heterocycles are important structural elements, which are present in natural products from all classes and in many biologically active synthetic compounds [1]. Heterocyclic compounds perform an important role in chemical industry, e.g., food fragrance and dyes. Amongst these, isoxazole and its derivatives represent a group of five-element heterocyclic compounds containing oxygen and nitrogen atoms of a valuable class [2]. Additionally, they have performed a vital role in the theoretical development of heterocyclic chemistry and are also extensively used in organic synthesis [3]. Isoxazoles have attracted an increasing research interest, and are widely used and studied in the modern drug discoveries as non-classical amide or ester bioisosteres, and potential pharmacophores endowed, and most isoxazoles have strong biological activity [4,5].

Isoxazolines are partially saturated analogs of isoxazoles as important intermediates for synthesis of varieties of fascinating organic molecules applicable to both basic organic synthesis and life sciences [6]. Isoxazolines can be converted into various synthetic units, such as hydroxy ketones [7], amino alcohols [8], β-hydroxynitrile [9], and masked aldols [10], and be used as synthetic equivalent of 1,3-dicarbonyl structure [11]. Isoxazolines can exhibit a variety of bioactivities, such as anti-inflammatory [12], anticancer [13], hypoglycemic [14], antibacterial [15], anti-HIV [16], anti-Alzheimer's [17], antifungal [18], antimalarial [19], antioxidant [20], anti-tuberculosis [21], and antinociceptive [22] activities (Figure 1). Isoxazolines can also be good herbicides [23] and insecticides [24]. Therefore, the development of new methods for more efficient synthesis has been always an attractive task.

Based on the characteristics and wide application of isoxazolines derivatives, the research progress of isoxazolines derivatives have progressed rapidly in recent years, and a large number of synthetic methods for isoxazole derivatives are reported in the literature every year. These approaches can be summarized as the following four major types: (1) 1,3-dipolar cycloaddition between nitrile oxide and unsaturated hydrocarbon [25–29], (2) intramolecular addition cyclization reaction of unsaturated hydroxime [30–33], (3) condensation reactions of 1,3-dicarbonyl derivatives [34], and (4) cycloisomerization [35]. In the past decades, the 1,3-dipole cycloaddition reaction of alkenes with nitrile oxide is the most direct and extensive

**Citation:** Yang, C.; Hu, S.; Pan, X.; Yang, K.; Zhang, K.; Liu, Q.; Xin, X.; Li, J.; Wang, J.; Yang, X. Novel Synthesis of Dihydroisoxazoles by *p*-TsOH-Participated 1,3-Dipolar Cycloaddition of Dipolarophiles withα-Nitroketones. *Molecules* **2023**, *28*, 2565. https://doi.org/10.3390/ molecules28062565

Academic Editors: Alison Rinderspacher, Mircea Darabantu and Gloria Proni

Received: 1 February 2023 Revised: 6 March 2023 Accepted: 6 March 2023 Published: 11 March 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

method for the construction of isoxazoline skeletons [36]. Nitrile oxides are usually derived from aldoximes and nitro compounds [37,38], but the common use of transition metal catalysts, such as Cu(I), Cu(II), and Ru(II), in the reaction makes the products residual metal and cytotoxic [39–41], which limits its application in biology and drug development (Scheme 1). Therefore, the development of practical, simple, and cost-effective new methods for synthesis 2-oxazolines would complement current methods.

**Figure 1.** Structures of isooxazolines with bioactivity.

In the previous study, we first used the alkaline catalyst chloramine-T to catalyze the reaction of α-nitroketone and alkene to synthesize isoxazoline with a yield of 77% [42]. In the present work, we report a novel synthesis of dihydroisoxazoles by *p*-TsOH (anhydrous) participated 1,3-dipolar cycloaddition of isoxazoline with *α*-nitroketones. On one hand, compared with the strong acid (H2SO4)-catalyzed synthesis of isoxazole [43], *p*-TsOH gives a milder reaction condition that avoids carbonization of organic substance, and it is low in toxicity and is inexpensive. On the other hand, Natarajan Arumugam and coworkers [44] reported a good, facile, and efficient method for the rapid synthesis of fused pyrrolidine and indolizinoindole heterocycles through 1,3-dipolar cycloaddition in the

presence of *p*-TsOH. Additionally, Zhenghui Guan and co-workers [45] also demonstrated a *p*-TsOH mediated 1,3-dipolar cycloaddition approach of nitroolefins and sodium azide for the synthesis of 4-aryl-NH-1,2,3-triazoles, and a slightly higher yield (93%) was isolated. It is an efficient *p*-TsOH-mediated 1,3-dipole cycloaddition reaction that can tolerate a wide range of functional groups, and quickly and easily obtain the target product under mild conditions. *p*-TsOH was discovered as a vital additive in this type of 1,3-dipolar cycloaddition. Herein, isoxazolines, given the importance of preparing biologically active molecules, are chosen for validation of the accessibility, operational simplicity, and atom economy of our method.

$$\begin{array}{ccccc} \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} \\ \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} \\ \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} \\ \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} & \mathbf{\hat{R}}\_{\text{v}} \\ \end{array}$$

**Scheme 1.** Overview of the 1,3-dipolar cycloaddition of hydrocarbons and α-nitro ketones [36,39].
