3-Benzoylisoxazolines by 1,3-Dipolar Cycloaddition: Chloramine-T-Catalyzed Condensation of α-Nitroketones with Dipolarophiles

In this study, 3-benzoylisoxazolines were synthesized by reacting alkenes with various α-nitroketones using chloramine-T as the base. The scope of α-nitroketones and alkenes is extensive, including different alkenes and alkynes to form various isoxazolines and isoxazoles. The use of chloramine-T, as the low-cost, easily handled, moderate base for 1,3-dipolar cycloaddition is attractive.

Moderate to good reaction efficiency can be obtained by utilizing these acidic or basic catalytic systems. The majority of the reactions undergo 1,3-dipolar cycloadditions with different α-nitroketones to obtain various isoxazoles. However, it is reported that 1,3-dipolar cycloadditions that start from nitroalkanes bearing a carbonyl group do not proceed smoothly and thus, generate the desired products in low yields. Tsubaki et al. [22] recently developed nitrile oxide cycloaddition reactions between nitrile oxides derived from Oalkyloxime-substituted nitroalkanes and various alkenes to construct 2-isoxazolines with electron-withdrawing groups. Although this method proceeds smoothly with nitroalkanes and various alkenes, it requires the preparation of O-alkyloxime-substituted nitroalkanes as precursors. To simplify this reaction, we tested several other bases and identified chloramine-T a commercially available agent, to give superior results [23]. We found that chloramine salts showed highly attractive practical characteristics: easy and amenable preparation at large scales, nontoxic by-products, excellent reactivity and high stability to air and heat. In this study, we successfully developed a chloramine-T catalytic system for 1,3-dipolar cycloaddition of dipolarophiles with α-nitroketones. To the best of our knowledge, it is the first time that chloramine-T has been used in 1,3-dipolar cycloaddition reactions to obtain isoxazolines from α-nitroketones.    Previous studies described various methods for synthesizing isoxazolines, namely, the 1,3-dipolar cycloaddition of dipolarophiles [13] (alkynes, alkenes) with nitrile oxides from aldoximes [14] or α-nitroketones. In the case of α-nitroketones, nitrile oxides are prepared by dehydration with an acid (such as sulfuric acid [15], p-toluenesulfonic acid [16,17] or polyphosphoric acid-silica (PPA/SiO2) [18]) or a base (such as N-methylimidazole [19], 1,4-diazabicyclo [2.2.2] octane [20] and copper (II) acetate/N-methylpiperidine [21]) as the catalytic systems.
Moderate to good reaction efficiency can be obtained by utilizing these acidic or basic catalytic systems. The majority of the reactions undergo 1,3-dipolar cycloadditions with different α-nitroketones to obtain various isoxazoles. However, it is reported that 1,3-dipolar cycloadditions that start from nitroalkanes bearing a carbonyl group do not proceed smoothly and thus, generate the desired products in low yields. Tsubaki et al. [22] recently developed nitrile oxide cycloaddition reactions between nitrile oxides derived from Oalkyloxime-substituted nitroalkanes and various alkenes to construct 2-isoxazolines with electron-withdrawing groups. Although this method proceeds smoothly with nitroalkanes and various alkenes, it requires the preparation of O-alkyloxime-substituted nitroalkanes as precursors. To simplify this reaction, we tested several other bases and identified chloramine-T a commercially available agent, to give superior results [23]. We found that chloramine salts showed highly attractive practical characteristics: easy and amenable preparation at large scales, nontoxic by-products, excellent reactivity and high stability to air and heat. In this study, we successfully developed a chloramine-T catalytic system for 1,3-dipolar cycloaddition of dipolarophiles with α-nitroketones. To the best of our knowledge, it is the first time that chloramine-T has been used in 1,3-dipolar cycloaddition reactions to obtain isoxazolines from α-nitroketones.

Results and Discussion
Benzoylnitromethane 1a (1 equiv) was reacted with allylbenzene 2a (5 equiv) in the presence of various bases in acetonitrile at 80 • C. The results are summarized in Table 1 (entries 1-6). No reaction occurred in the base-free system. Chloramine-T was the best among the bases tested herein. It is conceivable that 0.5 equivalents of chloramine-T can provide a better yield (Table 1, entries 6-9). According to the results, a few solvents were screened for optimization. Cycloaddition was found to be reliant on the solvent. Although H 2 O inhibited the cycloaddition, the reaction worked in DMSO and DMF, while CH 3 CN as the solvent provided the best results (Table 1, entries 10-13), producing 3a with a yield of 77%. Increasing the temperature to 90 • C or lowering it to 60 • C resulted in a lesser yield ( Table 1, entries 14 and 15). Thus, the reaction in optimal conditions was conducted at 80 • C for 18 h with 0.5 equiv of chloramine-T in the presence of acetonitrile as the solvent; and 3a was obtained with a yield of 77%. screened for optimization. Cycloaddition was found to be reliant on the solvent. Although H2O inhibited the cycloaddition, the reaction worked in DMSO and DMF, while CH3CN as the solvent provided the best results (Table 1, entries 10-13), producing 3a with a yield of 77%. Increasing the temperature to 90 °C or lowering it to 60 °C resulted in a lesser yield ( Table 1, entries 14 and 15). Thus, the reaction in optimal conditions was conducted at 80 °C for 18 h with 0.5 equiv of chloramine-T in the presence of acetonitrile as the solvent; and 3a was obtained with a yield of 77%. Under the optimized reaction conditions, various substrates were subjected to 1,3dipolar cycloaddition (Scheme 1). Several electronically varied α-nitroketones were subjected to cycloaddition. Efficiency was considered as the sensitivity of cycloaddition to electronic substituents. Electron-deficient α-nitroketones (3b-3d, Scheme 1) provided products in slightly better yields related to electron-rich α-nitroketones (3e and 3f, Scheme 1). Phenacyl nitro derivatives incorporating tert-butyl and phenyl at the para-position were also successful in the cycloaddition (3g and 3h, Scheme 1). Simple nitroketones were efficiently coupled with allylbenzene (3i, Scheme 1). Chloramine-T 0.5 77 7
Next, we investigated the scope of the alkenes in Scheme 2. Alkene alternative with contrasting and electronically varied substituents reacted with benzoylnitromethane 1a smoothly under the standard conditions to obtain the desired products in excellent yields. Moreover, the electron-rich allylbenzenes and allylalkanes produced the product in good yields (5a-5e, Scheme 2). Similarly, the electron-deficient ones, such as allyl chloride, produced the product in excellent yields (5f, Scheme 2). Good yields were also obtained in the cycloaddition of cyclohexene (5g, Scheme 2). Next, we investigated the scope of the alkenes in Scheme 2. Alkene alternative with contrasting and electronically varied substituents reacted with benzoylnitromethane 1a smoothly under the standard conditions to obtain the desired products in excellent yields. Moreover, the electron-rich allylbenzenes and allylalkanes produced the product in good yields (5a-5e, Scheme 2). Similarly, the electron-deficient ones, such as allyl chloride, produced the product in excellent yields (5f, Scheme 2). Good yields were also obtained in the cycloaddition of cyclohexene (5g, Scheme 2).  Finally, 1a was reacted with 1-hexyne in the presence of chloramine-T in acetonitrile at 70 • C for 18 h. Isoxazoles 7a and 7b were obtained with a yield of 68% and 64% (Scheme 3). This result demonstrated that this reaction is also suitable for cycloadditions to form isoxazoles.

Scheme 2. Scope of alkenes.
Finally, 1a was reacted with 1-hexyne in the presence of chloramine-T in acetonitrile at 70 °C for 18 h. Isoxazoles 7a and 7b were obtained with a yield of 68% and 64% (Scheme 3). This result demonstrated that this reaction is also suitable for cycloadditions to form isoxazoles. A possible mechanism for the reaction is shown in Scheme 4. In acetonitrile, the ion pair 9, which is formed between nitronate 1 and the protonated base 8, undergoes cycloaddition with dipolarophile 2 to obtain intermediate 10. Subsequently, the ion pair intermediate adduct 10 releases chloramine-T 8 to produce the 2-hydroxyoxazolidine 11, which is then dehydrated to give the product 3. Finally, another nitronate 1 reacts with chloramine-T 8 to obtain the new ion pair intermediate 9.

General Experimental Methods
The structures of produced compounds were firmly confirmed by 13 C NMR and 1 H NMR spectra and supported by HRMS, IR data (see the Supplementary Materials). 1 H NMR (400 MHz) and 13 C NMR (101 MHz) were recorded at room temperature by using a DRX-400 spectrometer (Bruker, Germany) in CDCl3. Chemical shifts were given in parts per million (ppm) on the delta (δ) scale. The solvent peak was used as a reference

General Experimental Methods
The structures of produced compounds were firmly confirmed by 13 C NMR and 1 H NMR spectra and supported by HRMS, IR data (see the Supplementary Materials). 1 H NMR (400 MHz) and 13 C NMR (101 MHz) were recorded at room temperature by using a DRX-400 spectrometer (Bruker, Germany) in CDCl 3 . Chemical shifts were given in parts per million (ppm) on the delta (δ) scale. The solvent peak was used as a reference value, for 1 H NMR: CDCl 3 δ 7.26; for 13 C NMR: CDCl 3 at 77.16 ppm. IR spectra were recorded using an Avatar 360 FT-IR ESP spectrometer Nicolet (Waltham, MA, USA) at room temperature. HR-ESI-MS spectra were acquired using an Agilent 6210 ESI/TOF mass spectrometer (Agilent Technologies, Santa Clara, CA, USA). Analytical TLC was run on silica gel plates (GF254, Yantai Institute of Chemical Technology, Yantai, China). Spots on the plates were observed under UV light. Column chromatography was performed on silica gels (200~300 mesh and 300-400 mesh; Qingdao Marine Chemical Factory, Qingdao, China). Super-dry solvent CH 3 CN, DMSO and DMF were purchased from Aldrich and used as supplied. The α-nitroketones were synthesized using the same method as reported in the literature [16].

Conclusions
Isoxazolines and isoxazoles are biologically active molecules. The development and improvement of syntheses directed towards isoxazolines and isoxazoles is a continuing pursuit. Herein, we have developed an effective cycloaddition of various α-nitroketones with alkenes or alkynes by using the cheap base chloramine-T. The low cost and ease of handling of this moderate base are its outstanding properties. The cycloaddition described in this study is an integrated approach for synthesizing isoxazolines and isoxazoles. We are currently investigating other ways to integrate isoxazolines.
Supplementary Materials: The following are available online. The Supplementary Materials contain experimental protocols, analytical data for products and NMR spectra.