Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes

The intramolecular oxidative cycloaddition reaction of alkyne- or alkene-tethered aldoximes was catalyzed efficiently by hypervalent iodine(III) species to afford the corresponding polycyclic isoxazole derivatives in up to a 94% yield. The structure of the prepared products was confirmed by various methods, including X-ray crystallography. Mechanistic study demonstrated the crucial role of hydroxy(aryl)iodonium tosylate as a precatalyst, which is generated from 2-iodobenzoic acid and m-chloroperoxybenzoic acid in the presence of a catalytic amount of p-toluenesulfonic acid.


Introduction
Heterocycles play a key role in modern drug discovery and agrochemistry [1][2][3][4][5][6]. Heterocyclic fragments can be found in the structure of many marketed small molecules. Currently, approximately 60% of approved US FDA drugs are derivatives of nitrogen heterocycles [7,8]. Isoxazole fragment is among the most popular heterocyclic fragments of drugs. These heterocycles have two connected heteroatoms in the structure. As a result, isoxazoles can form specific interactions with various protein targets via hydrogen bonds, as well as stacking and hydrophilic interactions. All these structural advantages have made them very popular in drug discovery. Their derivatives exhibit a broad range of bioactivities, such as being anticancer, antibacterial, antifungal, antimicrobial, antiviral, and antituberculosis [9][10][11][12][13][14][15].
This study is devoted to the investigation of synthetic approaches to isoxazole-or isoxazoline-fused heterocycles via the catalytic intramolecular cycloaddition of alkyne-or alkene-tethered aldoximes using hypervalent hydroxy(aryl)iodonium species generated in the reaction system (Figure 1c), as well as the study of the reaction mechanism. Hypervalent iodine compounds are known as low-toxic, environmentally benign reagents that have been

Results and Discussion
In order to find the optimal conditions for intramolecular cycloaddition, alkyne-tethered aldoxime 1a was treated with a catalytic amount of iodine reagent 2, p-toluenesulfonic acid and m-CPBA in various solvents at room temperature (Table 1). After the screening of solvents for this reaction (entries 1-8), dichloromethane was found to be the best solvent and the target compound 3a was obtained in a 94% yield (entry 1). However, decreasing the amount of p-toluenesulfonic acid or using trifluoromethanesulfonic acid instead of p-toluenesulfonic acid resulted in lower yields of the desired product 3a (entries 9-11). These results indicated that the addition of p-toluenesulfonic acid was necessary for the intramolecular cycloaddition of aldoxime 1a. In addition, when the reaction time was shortened, the yield of the desired product 3a was decreased (entry 12). Moreover, we observed a decline of the yield of the target product when 5 mol% and 1 mol% of 2-iodobenzoic acid 2a were used (entries [13][14]. Thus, 10 mol% of 2-iodobenzoic acid 2a is the most suitable for the reaction. Other iodine reagents 2 were found less efficient (entries 1, 15-18).

Results and Discussion
In order to find the optimal conditions for intramolecular cycloaddition, alkyne-tethered aldoxime 1a was treated with a catalytic amount of iodine reagent 2, p-toluenesulfonic acid and m-CPBA in various solvents at room temperature (Table 1). After the screening of solvents for this reaction (entries 1-8), dichloromethane was found to be the best solvent and the target compound 3a was obtained in a 94% yield (entry 1). However, decreasing the amount of p-toluenesulfonic acid or using trifluoromethanesulfonic acid instead of p-toluenesulfonic acid resulted in lower yields of the desired product 3a (entries 9-11). These results indicated that the addition of p-toluenesulfonic acid was necessary for the intramolecular cycloaddition of aldoxime 1a. In addition, when the reaction time was shortened, the yield of the desired product 3a was decreased (entry 12). Moreover, we observed a decline of the yield of the target product when 5 mol% and 1 mol% of 2iodobenzoic acid 2a were used (entries [13][14]. Thus, 10 mol% of 2-iodobenzoic acid 2a is the most suitable for the reaction. Other iodine reagents 2 were found less efficient (entries 1, [15][16][17][18]. Having in hand optimal reaction conditions, we performed the catalytic intramolecular cycloaddition of various alkyne-or alkene-tethered aldoximes 1 under optimized conditions ( Figure 2). It should be pointed out that all starting compounds can be prepared very efficiently from the corresponding salicylaldehydes. It was found that the reaction is very general both for alkene and acetylene-derived starting materials to form the corresponding condensed heterocycles 3a-j. The structure of product 3c was established by X-ray crystallography. The intramolecular cycloaddition of aldoximes 1a-j containing electron-donating or electron-withdrawing groups in the molecule afforded the desired products 3a-j in up to a 91% yield. Furthermore, this catalytic system was also effective in the reaction of alkene-tethered aldoximes 1k-s, and the desired isoxazoline-fused cyclic products 3k-s were obtained in up to a 90% yield. In comparison with other approaches [37,40,70] to the synthesis of fused isoxazoles and isoxazolines, our method is robust, affords comparable or higher yields of desired products, is easy to perfrom and does not require the use of excess oxidant or heating for the generation of intermediate-nitrile oxides. In addition, especially interesting is the possibility to perform the reaction with internal alkyne 1t or alkenes 1u,v. The respective products 3t-v were isolated in 40-90% yields.  Having in hand optimal reaction conditions, we performed the catalytic intramolecular cycloaddition of various alkyne-or alkene-tethered aldoximes 1 under optimized conditions ( Figure 2). It should be pointed out that all starting compounds can be prepared very efficiently from the corresponding salicylaldehydes. It was found that the reaction is very general both for alkene and acetylene-derived starting materials to form the a Reaction conditions: Aldoxime 1a (0.20 mmol, 1 equiv.), iodine reagent 2 (10 mol%) and p-toluenesulfonic acid (0-20 mol%) with m-CPBA (0.30 mmol, 1.5 equiv.) stirred in solvent (2 mL) at room temperature for 12-24 h. b Yield of product 3a determined from 1 H NMR spectra of the reaction mixture (using as 1,2-dibromoethane as an internal standard) are shown (numbers in parentheses show an isolated yield of 3a). c Aldoxime 1a was detected from the reaction mixture. d TfOH was used instead of p-TsOH·H 2 O. e Reaction time was 12 h. f 5 mol% were used. g 1 mol% were used.
To explore the mechanism of this reaction, several control experiments have been performed ( Figure 3, and see the Supporting Information for details: Scheme S1, Figures S1 and S2).
The key point of the reaction is the generation of the active hypervalent iodine species, which mediates an intermediate formation. The treatment of 2a and m-CPBA in the presence of p-toluenesulfonic acid produced hydroxy(aryl)iodonium tosylate [71], the formation of which was confirmed by ESI mass spectrometry and 1 H NMR spectroscopy (see Supporting Information for details: Scheme S1, Figure S1). Although the similar hydroxy(aryl)iodonium species is instantaneously formed from m-CPBA and 2a in the absence of p-toluenesulfonic acid, this species is immediately converted to 2-iodosylbenzoic acid (IBA 4), which cannot be applied for the intramolecular cycloaddition of aldoxime 1a (Table 1, entry 10 and Figure 3, reaction (a)). Therefore, it was expected that p-toluenesulfonic acid would play a very significant role in the generation and supply of the active species. Actually, the reaction of 1a with 4 in the presence of a catalytic amount of p-toluenesulfonic acid produced the desired compound 3a in a 79% yield (reaction (b)). At the same time, we suggested that the active species can be formed with the 3-chlorobenzoic acid, which is produced during the oxidation of 2-iodobenzoic acid by m-CPBA. The addition of 3-chlorobenzoic acid instead of p-toluenesulfonic acid has not yielded 3a, and 1a was recovered from the reaction mixture (reaction (c)). These results indicate that the presence of a catalytic amount of p-toluenesulfonic acid in this reaction is sufficient to work in the reaction systems as well as contribute significantly to the formation of the active species. The reaction proceeds only in the case of the stronger acid p-TsOH (pK a = −2.8), but not 3-chlorobenzoic acid (pK a = 3.8). Additionally, we have found that the reaction of protected oxime 5 under optimized conditions did not yield the desired product 3a (reaction (d)), and the starting compound 5 was recovered from the reaction mixture. This experiment confirms a ligand exchange of hypervalent iodine species with aldoxime and subsequent nitrile oxide formation [62].
corresponding condensed heterocycles 3a-j. The structure of product 3c was established by X-ray crystallography. The intramolecular cycloaddition of aldoximes 1a-j containing electron-donating or electron-withdrawing groups in the molecule afforded the desired products 3a-j in up to a 91% yield. Furthermore, this catalytic system was also effective in the reaction of alkene-tethered aldoximes 1k-s, and the desired isoxazoline-fused cyclic products 3k-s were obtained in up to a 90% yield. In comparison with other approaches [37,40,70] to the synthesis of fused isoxazoles and isoxazolines, our method is robust, affords comparable or higher yields of desired products, is easy to perfrom and does not require the use of excess oxidant or heating for the generation of intermediate-nitrile oxides. In addition, especially interesting is the possibility to perform the reaction with internal alkyne 1t or alkenes 1u,v. The respective products 3t-v were isolated in 40-90% yields.  the reaction systems as well as contribute significantly to the formation of the active species. The reaction proceeds only in the case of the stronger acid p-TsOH (pKa = −2.8), but not 3-chlorobenzoic acid (pKa = 3.8). Additionally, we have found that the reaction of protected oxime 5 under optimized conditions did not yield the desired product 3a (reaction (d)), and the starting compound 5 was recovered from the reaction mixture. This experiment confirms a ligand exchange of hypervalent iodine species with aldoxime and subsequent nitrile oxide formation [62].  Based on these control experiments and the related reactions of hypervalent iodine(III) compounds [37,59,69,70,72,73], we proposed the reaction mechanism ( Figure 4). Hydroxy(aryl)iodonium tosylate 6 plays the role of the active species. It is produced by the reaction of p-toluenesulfonic acid with 4, which is generated from m-CPBA and 2a.

General Experimental Remarks
All commercial reagents were ACS grade reagents and used without further purification from freshly opened containers. All solvents were distilled prior to use. Melting points were determined in an open capillary tube with Buchi M-580 melting point apparatus. Infrared spectra were recorded as ATR on a P Agilent Cary 630 FT-IR spectrophotometer. NMR spectra were recorded on a Bruker BioSpin NMR spectrometer at 400 or 600 MHz (( 1 H NMR), 101 or 150 MHz ( 13 C NMR), 376 MHz ( 19 F NMR)). Chemical shifts are reported in parts per million (ppm). High-resolution mass spectrometry measurements were performed using a Shimadzu LCMS-9030 Q-TOF mass spectrometer, coupled with LC-30 UHPLC system. X-ray crystal analysis was performed by Rigaku XtaLAB Syn-

General Experimental Remarks
All commercial reagents were ACS grade reagents and used without further purification from freshly opened containers. All solvents were distilled prior to use. Melting points were determined in an open capillary tube with Buchi M-580 melting point apparatus. Infrared spectra were recorded as ATR on a P Agilent Cary 630 FT-IR spectrophotometer. NMR spectra were recorded on a Bruker BioSpin NMR spectrometer at 400 or 600 MHz (( 1 H NMR), 101 or 150 MHz ( 13 C NMR), 376 MHz ( 19 F NMR)). Chemical shifts are reported in parts per million (ppm). High-resolution mass spectrometry measurements were performed using a Shimadzu LCMS-9030 Q-TOF mass spectrometer, coupled with LC-30 UHPLC system. X-ray crystal analysis was performed by Rigaku XtaLAB Synergy, single source at home/near, HyPix using CuKα radiation (λ = 1.54184 Å) at 105 K. Please see the supporting information or the cif file for more detailed crystallography information. The (E)-2-(Prop-2-yn-1-yloxy)benzaldehyde O-methyl oxime 5 was prepared according to the reported procedure [74].

Conclusions
We have developed a reliable and efficient method for the synthesis of diverse fused isoxazoles and isoxazolines via catalytic intramolecular oxidative cycloaddition of aldoximes with the use of hypervalent iodine species. The reaction mechanism was studied in detail by various spectroscopic methods and control experiments. It was found that the key intermediate is hydroxy(aryl)iodonium tosylate. This hypervalent iodine derivative is generated in situ from 2-iodobenzoic acid and m-CPBA in the presence of p-toluenesulfonic acid.
Author Contributions: A.Y., M.S.Y. and A.S. supervised the project; I.A.M. and A.Y. analyzed data, discussed with P.S.P. and V.G.N. and wrote the manuscript; I.A.M. did the experiments and characterized the X-ray structure of 3c. All authors contributed to the revision. All authors have read and agreed to the published version of the manuscript.