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Article

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

by
Irina A. Mironova
1,
Valentine G. Nenajdenko
2,
Pavel S. Postnikov
1,
Akio Saito
3,
Mekhman S. Yusubov
1,* and
Akira Yoshimura
4,*
1
Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
2
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russia
3
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan
4
Faculty of Pharmaceutical Sciences, Aomori University, 2-3-1 Kobata, Aomori 030-0943, Japan
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(12), 3860; https://doi.org/10.3390/molecules27123860
Submission received: 30 May 2022 / Revised: 13 June 2022 / Accepted: 14 June 2022 / Published: 16 June 2022
(This article belongs to the Special Issue Recent Advances in the Use of Azoles in Medicinal Chemistry)
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Abstract

:
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.

1. 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].
The 1,3-dipole cycloaddition reaction is one of the most powerful methods to construct five-membered heterocycles [16,17,18,19,20,21,22,23,24,25,26]. The cycloaddition of nitrile oxides with alkenes and acetylenes is often used in the synthesis of isoxazoles and isoxazolines [27,28,29,30,31,32,33,34,35,36,37]. However, nitrile oxides are unstable species usually generated in situ from aldoximes under appropriate conditions [38,39,40]. The intramolecular version of the cycloaddition of nitrile oxides with alkenes and acetylenes is less investigated. On the other hand, this approach can provide an efficient approach to condensed heterocyclic systems containing isoxazole or isoxazoline rings.
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 applied to various organic synthetic reactions [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. In recent years, several examples of the oxidative cycloaddition of aldoximes with alkenes or alkynes were demonstrated using hypervalent iodine(III) species as oxidants (Figure 1a,b) [65,66,67,68,69]. However, the intramolecular version of the catalytic oxidative cycloaddition of aldoximes is unknown so far. In the present work, we have developed an efficient synthesis of fused isoxazole derivatives using this approach.

2. 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).
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.
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 1H 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 (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. The intermediate 6 reacts with aldoxime 1 via the ligand exchange reaction to produce iodonium intermediate 7. Next, nitrile oxide 8 is formed by the elimination of 2a and p-toluenesulfonic acid. Subsequent intramolecular cycloaddition results in the desired isoxazole derivatives 3. Finally, the regenerated 2a reacts with m-CPBA to continue the next catalytic reaction cycle.

3. Materials and Methods

3.1. 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 ((1H NMR), 101 or 150 MHz (13C NMR), 376 MHz (19F 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].

3.2. General Cyclization Procedure of 2-Alkoxyaldoximes 1

The 2-Iodobenzoic acid 2a (5.0 mg, 0.020 mmol), m-CPBA (52 mg, 0.30 mmol) and p-TsOH•H2O (7.6 mg, 0.040 mmol) were added to 2-alkoxybenzaldehyde oximes 1 (0.20 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 24 h. After the completion reaction, saturated NaHCO3 (15 mL), water (5 mL) and then dichloromethane (3 mL) were added, and the mixture was extracted with dichloromethane. The organic layer was dried with MgSO4 and concentrated under reduced pressure. Purification by column chromatography (hexane-CH2Cl2 = 3:1) afforded the pure product 3.
4H-Chromeno [4,3-c]isoxazole (3a) [37]: Reaction of (E)-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1a (34 mg, 0.20 mmol) according to the general procedure afforded 32 mg (94%) of product 3a, isolated as yellowish oil; IR (ATR) cm−1: 3118, 3059, 2921, 2866, 1614, 1470, 1360, 1213, 1109, 765, 743; 1H NMR (400 MHz, CDCl3): δ 8.21 (t, J = 1.2 Hz, 1H), 7.88 (dd, J = 7.6, 1.6 Hz, 1H), 7.40–7.32 (m, 1H), 7.10–7.05 (m, 1H), 7.02 (dd, J = 8.2, 1.0 Hz, 1H), 5.24 (d, J = 1.2 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 155.0, 153.8, 150.8, 132.3, 124.7, 122.6, 118.0, 114.1, 111.3, 61.5; HRMS (ESI-positive mode): calcd for C10H8NO2 [M + H]+, 174.0550, found, 174.0550.
Large scale reaction for preparation of 4H-Chromeno [4,3-c]isoxazole (3a) [37]: Reaction of (E)-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1a (1000 mg, 5.71 mmol) according to the general procedure afforded 951 mg (96%) of product 3a, isolated as yellowish oil.
8-Fluoro-4H-chromeno [4,3-c]isoxazole (3b): Reaction of (E)-5-fluoro-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1b (38 mg, 0.20 mmol) according to the general procedure afforded 32 mg (84%) of product 3b, isolated as colorless solid: mp 103.0–104.2 °C; IR (ATR) cm−1: 3126, 3074, 2933, 1624, 1478, 1243, 1172, 1107, 783, 740; 1H NMR (400 MHz, CDCl3): δ 8.24 (t, J = 1.1 Hz, 1H), 7.56 (dd, J = 8.0, 2.8 Hz, 1H), 7.11–7.03 (m, 1H), 6.99 (dd, J = 9.0, 4.6 Hz, 1H), 5.23 (d, J = 1.1 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 157.9 (d, 1JCF = 242.3 Hz), 153.6 (d, 4JCF = 2.5 Hz), 151.1, 151.1 (d, 4JCF = 2.4 Hz), 119.4 (d, 3JCF = 8.1 Hz), 119.2 (d, 2JCF = 23.8 Hz), 114.9 (d, 3JCF = 9.2 Hz), 111.3, 110.9 (d, 2JCF = 24.8 Hz), 61.6; 19F NMR (376 MHz, CDCl3): δ -120.1; HRMS (ESI-positive mode): calcd for C10H7FNO2 [M + H]+, 192.0455; found, 192.0456.
8-Chloro-4H-chromeno [4,3-c]isoxazole (3c) [75]: Reaction of (E)-5-chloro-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1c (41 mg, 0.20 mmol) according to the general procedure afforded 29 mg (71%) of product 3c, isolated as colorless solid: mp 127.1–128.7 °C (lit. [75]; 122.0 °C); IR (ATR) cm−1: 3116, 3072, 2920, 1611, 1469, 1355, 1212, 1127, 1083, 766, 742; 1H NMR (400 MHz, CDCl3): δ 8.24 (t, J = 1.2 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 8.8, 2.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.25 (d, J = 1.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3): δ 153.4, 153.1, 151.2, 132.1, 127.6, 124.4, 119.5, 115.3, 111.1, 61.7; HRMS (ESI-positive mode): calcd for C10H735ClNO2 [M + H]+, 208.0160; found, 208.0160.
8-Bromo-4H-chromeno [4,3-c]isoxazole (3d) [76]: Reaction of (E)-5-bromo-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1d (50 mg, 0.20 mmol) according to the general procedure afforded 37 mg (74%) of product 3d, isolated as yellowish solid: mp 120.2–120.9 °C (lit. [76], 118.0–119.0 °C); IR (ATR) cm−1: 3112, 3067, 2922, 1607, 1464, 1353, 1210, 1128, 758; 1H NMR (400 MHz, CDCl3): δ 8.24 (t, J = 1.0 Hz, 1H), 8.00 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 8.8, 2.6 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 5.25 (d, J = 1.0 Hz, 2H).; 13C NMR (101 MHz, CDCl3): δ 153.9, 152.9, 151.2, 135.0, 127.3, 119.9, 115.7, 114.8, 111.0, 61.6; HRMS (ESI-positive mode): calcd for C10H779BrNO2 [M + H]+, 251.9655; found, 251.9650.
6,8-Dibromo-4H-chromeno [4,3-c]isoxazole (3e): Reaction of (E)-3,5-dibromo-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1e (66 mg, 0.20 mmol) according to the general procedure afforded 53 mg (80%) of product 3e, isolated as yellowish solid: mp 149.0–150.0 °C; IR (ATR) cm−1: 3138, 3123, 3065, 2919, 1597, 1450, 1375, 1217, 1117, 787, 749.; 1H NMR (400 MHz, CDCl3): δ 8.28 (t, J = 1.2 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 5.37 (d, J = 1.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3): δ 152.6, 151.6, 150.8, 137.7, 126.5, 116.6, 114.8, 113.0, 110.8, 62.5.; HRMS (ESI-positive mode): calcd for C10H679Br2NO2 [M + H]+, 329.8760; found, 329.8755.
8-Nitro-4H-chromeno [4,3-c]isoxazole (3f): Reaction of (E)-5-nitro-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1f (44 mg, 0.20 mmol) according to the general procedure afforded 40 mg (91%) of product 3f, isolated as colorless solid: mp 221.7–222.1 °C; IR (ATR) cm−1: 3090, 2948, 1620, 1582, 1528, 1507, 1475, 1340, 1226, 1129, 749.; 1H NMR (400 MHz, CDCl3): δ 8.81 (d, J = 2.6 Hz, 1H), 8.41–8.27 (m, 1H), 8.24 (dd, J = 9.2, 2.6 Hz, 1H), 7.13 (d, J = 9.2 Hz, 1H), 5.43 (d, J = 1.2 Hz, 1H).; 13C NMR (101 MHz, CDCl3): δ 159.5, 152.2, 151.9, 142.6, 127.5, 120.9, 118.8, 113.9, 110.2, 62.6.; HRMS (ESI-positive mode): calcd for C10H7N2O4 [M + H]+, 219.0400; found, 219.0399.
8-Methyl-4H-chromeno [4,3-c]isoxazole (3g) [39]: Reaction of (E)-5-methyl-2-(prop-2-yn-1-yloxy)benzaldehyde oxime 1g (37 mg, 0.20 mmol) according to the general procedure afforded 30 mg (81%) of product 3g, isolated as yellowish solid: mp 103.6–105.2 °C (lit. [39]; 103.0–104.0 °C); IR (ATR) cm−1: 3101, 3060, 2920, 1620, 1577, 1487, 1460, 1359, 1212, 1130, 783, 745; 1H NMR (400 MHz, CDCl3): δ 8.19 (t, J = 1.2 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.2, 2.0 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 5.21 (d, J = 1.2 Hz, 2H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 154.0, 152.9, 150.7, 133.0, 132.1, 124.8, 117.7, 113.8, 111.5, 61.4, 20.8.; HRMS (ESI-positive mode): calcd for C11H10NO2 [M + H]+, 188.0706; found, 188.0708.
4H-Benzo [5,6]chromeno [4,3-c]isoxazole (3h) [77]: Reaction of (E)-2-(prop-2-yn-1-yloxy)-1-naphthaldehyde oxime 1h (45 mg, 0.20 mmol) according to the general procedure afforded 30 mg (67%) of product 3h, isolated as yellowish solid: mp 175.0–176.0 °C (lit. [77]; 180.0–181.0 °C); IR (ATR) cm−1: 3107, 2924, 2870, 1591, 1519, 1443, 1357, 1221, 1119, 770, 748; 1H NMR (400 MHz, CDCl3): δ 9.05 (d, J = 8.0 Hz, 1H), 8.27 (t, J = 1.2 Hz, 1H), 7.87–7.83 (m, 1H), 7.83–7.79 (m, 1H), 7.68–7.62 (m, 1H), 7.49–7.43 (m, 1H), 7.20 (d, J = 8.8 Hz, 1H), 5.33 (d, J = 1.2 Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 154.9, 154.6, 149.7, 133.0, 130.2, 129.8, 128.5, 128.5, 126.5, 125.0, 118.7, 111.9, 108.0, 61.5.; HRMS (ESI-positive mode): calcd for C14H10NO2 [M + H]+, 224.0706; found, 224.0704.
9-Chloro-4H-chromeno [4,3-c]isoxazole (3i): Reaction of (E)-2-chloro-6-(prop-2-yn-1-yloxy)benzaldehyde oxime 1i (42 mg, 0.20 mmol) according to the general procedure afforded 37 mg (88%) of product 3i, isolated as colorless solid: mp 100.5–101.0 °C; IR (ATR) cm−1: 3100, 2926, 1600, 1454, 1406, 1364, 1219, 1151, 1099, 780, 742; 1H NMR (400 MHz, CDCl3): δ 8.30 (t, J = 1.2 Hz, 1H), 7.30–7.24 (m, 1H), 7.17 (dd, J = 8.0, 1.2 Hz, 1H), 6.98 (dd, J = 8.0, 1.2 Hz, 1H), 5.21 (d, J = 1.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3): δ 156.4, 152.9, 150.6, 132.5, 131.8, 124.6, 116.7, 114.4, 112.2, 61.3; HRMS (ESI-positive mode): calcd for C10H735ClNO2 [M + H]+, 208.0160; found, 208.0164.
6-Chloro-4H-chromeno [4,3-c]isoxazole (3j): Reaction of (E)-3-chloro-6-(prop-2-yn-1-yloxy)benzaldehyde oxime 1j (42 mg, 0.20 mmol) according to the general procedure afforded 36 mg (86%) of product 3j, isolated as colorless solid: mp 112.3–113.3 °C; IR (ATR) cm−1: 3119, 2923, 1605, 1467, 1433, 1355, 1222, 1145, 1085, 786, 734; 1H NMR (400 MHz, CDCl3): δ 8.27 (t, J = 1.2 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.44 (dd, J = 8.0, 1.6 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 5.37 (d, J = 1.2 Hz, 2H).; 13C NMR (101 MHz, CDCl3): δ 153.4, 151.2, 150.7, 132.7, 123.1, 122.8, 115.6, 111.0, 62.3; HRMS (ESI-positive mode): calcd for C10H735ClNO2 [M + H]+, 208.0160; found, 208.0161.
3a,4-Dihydro-3H-chromeno [4,3-c]isoxazole (3k) [37]: Reaction of (E)-2-(allyloxy)benzaldehyde oxime 1k (35 mg, 0.20 mmol) according to the general procedure afforded 28 mg (80%) of product 3k, isolated as pale solid: mp 59.7–61.0 °C (lit. [37] 60–61 °C); IR (ATR) cm−1: 3075, 2995, 2933, 2880, 1607, 1467, 1458, 1228, 1155, 760; 1H NMR (400 MHz, CDCl3): δ 7.79 (dd, J = 8.0, 1.6 Hz, 1H), 7.39–7.30 (m, 1H), 7.03–6.97 (m, 2H), 6.95 (dd, J = 8.4, 1.2 Hz, 1H), 4.75–4.64 (m, 2H), 4.14–4.04 (m, 1H), 4.01–3.86 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 155.7, 152.9, 132.6, 125.8, 122.0, 117.5, 113.1, 70.7, 69.4, 46.0; HRMS (ESI-positive mode): calcd for C10H10NO2 [M + H]+, 176.0706; found, 176.0710.
8-Fluoro-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3l): Reaction of (E)-2-(allyloxy)-5-fluorobenzaldehyde oxime 1l (39 mg, 0.20 mmol) according to the general procedure afforded 33 mg (85%) of product 3l, isolated as colorless solid: mp 145.3–146.4 °C; IR (ATR) cm−1: 3063, 2932, 2884, 1614, 1481, 1459, 1301, 1235, 1171, 1121, 741; 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J = 8.2, 3.0 Hz, 1H), 7.08–7.00 (m, 1H), 6.91 (dd, J = 9.0, 4.6 Hz, 1H), 4.74–4.63 (m, 2H), 4.10–4.01 (m, 1H), 3.98–3.85 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 157.3 (d, 1JCF = 242.1 Hz), 152.5 (d, 4JCF = 2.4 Hz), 151.9 (d, 4JCF = 1.9 Hz), 119.9 (d, 2JCF = 24.1 Hz), 118.9 (d, 3JCF = 8.1 Hz), 113.7 (d, 3JCF = 8.8 Hz), 111.2 (d, 2JCF = 24.4 Hz), 71.0, 69.4, 45.6; 19F NMR (376 MHz, CDCl3) δ -121.0.; HRMS (ESI-positive mode): calcd for C10H9FNO2 [M + H]+, 194.0612; found, 194.0605.
8-Chloro-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3m) [37]: Reaction of (E)-2-(allyloxy)-5-chlorobenzaldehyde oxime 1m (42 mg, 0.20 mmol) according to the general procedure afforded 34 mg (81%) of product 3m, isolated as colorless solid: mp 129.7–130.1 °C (lit. [37] 129–130 °C); IR (ATR) cm−1: 3038, 2923, 2873, 1610, 1474, 1443, 1226, 1132, 734; 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 2.6 Hz, 1H), 7.28 (dd, J = 9.1, 2.6 Hz, 1H), 6.90 (d, J = 9.1 Hz, 1H), 4.75–4.65 (m, 2H), 4.11–4.02 (m, 1H), 3.98–3.85 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 154.1, 152.0, 132.4, 127.0, 125.1, 119.0, 114.3, 71.0, 69.4, 45.5; HRMS (ESI-positive mode): calcd for C10H935ClNO2 [M + H]+, 210.0316; found, 210.0319.
8-Bromo-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3n) [37]: Reaction of (E)-2-(allyloxy)-5-bromobenzaldehyde oxime 1n (51 mg, 0.20 mmol) according to the general procedure afforded 41 mg (80%) of product 3n, isolated as colorless solid: mp 126.7–127.8 °C (lit. [37] 125.0–127 °C); IR (ATR) cm−1: 2985, 2924, 2870, 1603, 1474, 1436, 1206, 1131, 728; 1H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.8, 2.4 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.77–4.66 (m, 2H), 4.11–4.03 (m, 1H), 3.98–3.85 (m, 2H).; 13C NMR (101 MHz, CDCl3): δ 154.6, 151.9, 135.3, 128.2, 119.4, 114.9, 114.3, 71.0, 69.4, 45.5; HRMS (ESI-positive mode): calcd for C10H979BrNO2 [M + H]+, 253.9811; found, 253.9812.
8-Nitro-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3o) [37]: Reaction of (E)-2-(allyloxy)-5-nitrobenzaldehyde oxime 1o (44 mg, 0.20 mmol) according to the general procedure afforded 35 mg (80%) of product 3o, isolated as colorless solid: 220.0–221.0 °C (lit. [37] 215.0–217.0 °C); IR (ATR) cm−1: 3071, 3022, 2923, 1608, 1576, 1513, 1454, 1342, 1232, 1127, 839, 745; 1H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.2, 2.8 Hz, 1H), 7.08 (d, J = 9.2 Hz, 1H), 4.87–4.76 (m, 2H), 4.22–4.14 (m, 1H), 4.05–3.94 (m, 2H).; 13C NMR (101 MHz, CDCl3): δ 159.8, 151.1, 142.4, 127.4, 122.1, 118.5, 113.5, 71.3, 70.0, 45.0.; HRMS (ESI-positive mode): calcd for C10H9N2O4 [M + H]+, 221.0557; found, 221.0553.
8-Methyl-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3p) [70]: Reaction of (E)-2-(allyloxy)-5-methylbenzaldehyde oxime 1p (38 mg, 0.20 mmol) according to the general procedure afforded 31 mg (82%) of product 3p, isolated as yellowish solid: 140.7–141.8 °C (lit. [70] 142 °C); IR (ATR) cm−1: 3058, 2995, 2915, 2875, 1606, 1484, 1229, 1133, 744; 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.4, 2.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.76–4.62 (m, 2H), 4.11–4.01 (m, 1H), 3.99–3.84 (m, 2H), 2.30 (s, 3H).; 13C NMR (101 MHz, CDCl3): δ 153.7, 153.1, 133.6, 131.4, 125.6, 117.3, 112.7, 70.7, 69.4, 46.1, 20.6; HRMS (ESI-positive mode): calcd for C11H12NO2 [M + H]+, 190.0863; found, 190.0869.
3a,4-Dihydro-3H-benzo [5,6]chromeno [4,3-c]isoxazole (3q) [37]: Reaction of (E)-2-(allyloxy)-1-naphthaldehyde oxime 1q (45 mg, 0.20 mmol) according to the general procedure afforded 28 mg (62%) of product 3q, isolated as yellowish solid: 75.0–75.8 °C (lit. [37] 78–80 °C); IR (ATR) cm−1: 3052, 2999, 2935, 2879, 1621, 1578, 1512, 1440, 1227, 1123, 747; 1H NMR (400 MHz, CDCl3): δ 9.03 (dd, J = 8.8, 1.0 Hz, 1H), 7.85–7.75 (m, 2H), 7.65–7.57 (m, 1H), 7.48–7.39 (m, 1H), 7.11 (d, J = 9.2 Hz, 1H), 4.82–4.75 (m, 1H), 4.75–4.68 (m, 1H), 4.25 (dd, J = 8.8, 1.0 Hz, 1H), 4.17–4.05 (m, 1H), 3.94 (dd, J = 12.7, 8.0 Hz, 1H).; 13C NMR (101 MHz, CDCl3): δ 155.8, 153.3, 133.6, 130.6, 129.4, 128.7, 128.5, 126.7, 124.9, 118.3, 106.2, 69.6, 69.3, 47.1; HRMS (ESI-positive mode): calcd for C14H12NO2 [M + H]+, 226.0863; found, 226.0862.
9-Chloro-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3r): Reaction of 2-(allyloxy)-6-chlorobenzaldehyde 1r (42 mg, 0.20 mmol) according to the general procedure afforded 35 mg (83%) of product 3r, isolated as colorless solid: 145.2–145.8 °C; IR (ATR) cm−1: 3091, 2986, 2932, 2871, 1588, 1482, 1442, 1228, 1178, 1149, 726; 1H NMR (400 MHz, CDCl3): δ 7.25–7.19 (m, 1H), 7.08 (dd, J = 7.8, 1.1 Hz, 1H), 6.88 (dd, J = 8.4, 1.1 Hz, 1H), 4.72–4.64 (m, 2H), 4.14–4.04 (m, 1H), 4.01–3.88 (m, 2H); 13C NMR (101 MHz, CDCl3): δ 156.7, 151.3, 133.2, 131.8, 123.9, 116.1, 112.7, 69.9, 69.0, 46.4; HRMS (ESI-positive mode): calcd for C10H935ClNO2 [M + H]+, 210.0316; found, 210.0320.
6-Chloro-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3s): Reaction of 2-(allyloxy)-3-chlorobenzaldehyde 1s (42 mg, 0.20 mmol) according to the general procedure afforded 36 mg (86%) of product 3s, isolated as colorless solid: mp 104.7–105.5 °C; IR (ATR) cm−1: 3073, 2988, 2929, 2867, 1600, 1468, 1438, 1230, 1145, 1079, 727; 1H NMR (400 MHz, CDCl3): δ 7.72 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 6.98–6.92 (m, 1H), 4.89–4.81 (m, 1H), 4.81–4.69 (m, 1H), 4.23–4.10 (m, 1H), 4.04–3.90 (m, 2H).; 13C NMR (101 MHz, CDCl3): δ 152.3, 151.3, 132.8, 124.3, 122.6, 122.2, 114.8, 71.0, 70.0, 45.6; HRMS (ESI-positive mode): calcd for C10H935ClNO2 [M + H]+, 210.0316; found, 210.0313.
3-Phenyl-4H-chromeno [4,3-c]isoxazole (3t): Reaction of (E)-2-((3-phenylprop-2-yn-1-yl)oxy)benzaldehyde oxime 1t (50 mg, 0.20 mmol) according to the general procedure afforded 45 mg (90%) of product 3t, isolated as colorless solid: mp 156.0–157.0 °C; IR (ATR) cm−1: 3059, 2924, 2875, 1612, 1577, 1474, 1446, 1420, 1375, 1299, 1221, 1101, 756, 744; 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 7.8, 1.6 Hz, 1H), 7.65–7.59 (m, 2H), 7.54–7.43 (m, 3H), 7.39–7.33 (m, 1H), 7.11–7.05 (m, 1H), 7.03 (dd, J = 8.2, 1.0 Hz, 1H), 5.45 (s, 2H).; 13C NMR (101 MHz, CDCl3) δ 161.7, 155.1, 154.7, 132.2, 130.3, 129.3, 127.4, 126.3, 124.5, 122.4, 117.8, 114.2, 106.7, 62.6; HRMS (ESI-positive mode): calcd for C16H12NO2 [M + H]+, 250.0863; found, 250.0863.
3-Phenyl-3a,4-dihydro-3H-chromeno [4,3-c]isoxazole (3u) [37]: Reaction of (E)-2-(cinnamyloxy)benzaldehyde oxime 1u (51 mg, 0.20 mmol) according to the general procedure afforded 20 mg (40%) of product 3u, isolated as colorless solid: mp 151.9–152.9 °C (lit. [37] 156–158 °C); IR (ATR) cm−1: 3037, 2999, 2927, 2884, 1600, 1467, 1454, 1233, 1218, 1119, 1032, 999, 754; 1H NMR (400 MHz, CDCl3): δ 7.77 (dd, J = 7.6, 1.6 Hz, 1H), 7.42–7.31 (m, 5H), 7.30–7.24 (m, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 5.18 (d, J = 12.6 Hz, 1H), 4.58 (dd, J = 10.4, 2.0 Hz, 1H), 4.17 (dd, J = 12.4, 10.4 Hz, 1H), 3.89–3.78 (m, 1H). 13C NMR (101 MHz, CDCl3): δ 154.5, 152.3, 136.2, 131.6, 127.9, 125.6, 124.5, 120.9, 116.4, 112.1, 84.7, 68.0, 51.9; HRMS (ESI-positive mode): calcd for C16H14NO2 [M + H]+, 252.1019; found, 252.1020.
2a,2a1,3,4,5,5a-Hexahydroxantheno [9,1-cd]isoxazole (3v) [37]: Reaction of (E)-2-(cyclohex-2-en-1-yloxy)benzaldehyde oxime 1v (42 mg, 0.20 mmol) according to the general procedure afforded 30 mg (70%) of product 3v, isolated as colorless solid: mp 104.7–105.5 °C (lit. [37] 103–104 °C); IR (ATR) cm−1: 2492, 2924, 2862, 1600. 1573, 1493,1458, 1380, 1344, 1319, 1292, 1264, 1227, 1207, 1158, 1113, 1029, 999, 901, 868, 840, 812, 754, 710, 649, 516, 450; 1H NMR (600 MHz, CDCl3) δ 7.86 (dd, J = 7.8, 1.8 Hz, 1H), 7.37–7.30 (m, 1H), 7.00–6.96 (m, 1H), 6.94 (dd, J = 8.1, 0.9 Hz, 1H), 4.93 (m, 1H), 4.74 (m, 1H), 3.82 (m, 1H), 2.06–1.96 (m, 2H), 1.66–1.59 (m, 1H), 1.44–1.35 (m, 1H), 1.35–1.24 (m, 1H), 1.11–1.01 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 153.9, 153.6, 132.8, 125.4, 121.5, 118.1, 112.8, 80.3, 74.8, 47.4, 27.8, 27.2, 17.3; HRMS (ESI-positive mode): calcd for C13H13NO2 [M + H]+ calcd for C13H14NO2+, 216.1025; found, 216.1021.

4. 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.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27123860/s1. Scheme S1: ESI-Mass study of the generation of active species for intramolecular oxidative cycloaddition of aldoximes; Figure S1: ESI-Mass study of the generation of active species for intramolecular oxidative cycloaddition of aldoximes; Figure S2. 1H NMR spectroscopy study of the generation of active species for intramolecular oxidative cycloaddition of aldoximes; General procedure for the synthesis of 1 and its spectral data; X-ray single crystal data of compound 3c; NMR spectra of 1, 3 and 5. References [39,74,75,76,77,78,79,80,81,82,83,84,85] are cited in the supplementary materials.

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.

Funding

This research was funded by the Russian Science Foundation (RSF-21-73-20031 and RSF-16-13-10081-P) and the JSPS Fund for the Promotion of Joint International Research (grant no. 16KK0199) and JST CREST (no. JRMJCR19R2).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We also thank the Center for Chemical Analysis and Materials Research of Research Park of St. Petersburg State University for their assistance with HRMS and X-ray data analysis.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are available from the authors.

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Molecules 27 03860 g001 550
Figure 1. Reactions of aldoximes using catalytic hypervalent iodine(III) species.
Figure 1. Reactions of aldoximes using catalytic hypervalent iodine(III) species.
Molecules 27 03860 g001
Molecules 27 03860 g002 550
Figure 2. Catalytic intramolecular cycloaddition of aldoximes 1 a,b. a Reaction conditions: Aldoxime 1 (0.20 mmol, 1 equiv.), 2a (10 mol%) and p-toluenesulfonic acid (20 mol%) with m-CPBA (0.30 mmol, 1.5 equiv.) stirred in dichloromethane (2 mL) at room temperature for 24 h. b Isolated yields of 3. c The yield of 3a is given for 1 g scale reaction.
Figure 2. Catalytic intramolecular cycloaddition of aldoximes 1 a,b. a Reaction conditions: Aldoxime 1 (0.20 mmol, 1 equiv.), 2a (10 mol%) and p-toluenesulfonic acid (20 mol%) with m-CPBA (0.30 mmol, 1.5 equiv.) stirred in dichloromethane (2 mL) at room temperature for 24 h. b Isolated yields of 3. c The yield of 3a is given for 1 g scale reaction.
Molecules 27 03860 g002
Molecules 27 03860 g003 550
Figure 3. Control experiments.
Figure 3. Control experiments.
Molecules 27 03860 g003
Molecules 27 03860 g004 550
Figure 4. Proposed reaction mechanism.
Figure 4. Proposed reaction mechanism.
Molecules 27 03860 g004
Table
Table 1. Optimization of the catalytic intramolecular cycloaddition of aldoxime 1a a.
Table 1. Optimization of the catalytic intramolecular cycloaddition of aldoxime 1a a.
Molecules 27 03860 i001
EntrySolventIodine Reagent 2p-TsOH·H2O (mol%)3a Yield (%) b
1CH2Cl22-IC6H4CO2H 2a2094 (94)
2CHCl32-IC6H4CO2H 2a2052 (50) c
3Et2O2-IC6H4CO2H 2a2032 (31) c
4MeCN2-IC6H4CO2H 2a2081 (80) c
5Hexane2-IC6H4CO2H 2a2056 (52) c
6PhH2-IC6H4CO2H 2a2073 (73) c
7THF2-IC6H4CO2H 2a2081 (81) c
8MeOH2-IC6H4CO2H 2a2070 (70) c
9CH2Cl22-IC6H4CO2H 2a1061 (61) c
10CH2Cl22-IC6H4CO2H 2anone36 (35) c
11CH2Cl22-IC6H4CO2H 2a– d86 (81)
12 eCH2Cl22-IC6H4CO2H 2a2073 (72) c
13CH2Cl22-IC6H4CO2H 2a f2081
14CH2Cl22-IC6H4CO2H 2a g2062
15CH2Cl2PhI 2b2073 (54) c
16CH2Cl2TBAI 2c2020 (20) c
17CH2Cl2I2 2d2015 c
18CH2Cl2none209 c
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 1H 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·H2O. e Reaction time was 12 h. f 5 mol% were used. g 1 mol% were used.
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Mironova, I.A.; Nenajdenko, V.G.; Postnikov, P.S.; Saito, A.; Yusubov, M.S.; Yoshimura, A. Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes. Molecules 2022, 27, 3860. https://doi.org/10.3390/molecules27123860

AMA Style

Mironova IA, Nenajdenko VG, Postnikov PS, Saito A, Yusubov MS, Yoshimura A. Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes. Molecules. 2022; 27(12):3860. https://doi.org/10.3390/molecules27123860

Chicago/Turabian Style

Mironova, Irina A., Valentine G. Nenajdenko, Pavel S. Postnikov, Akio Saito, Mekhman S. Yusubov, and Akira Yoshimura. 2022. "Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes" Molecules 27, no. 12: 3860. https://doi.org/10.3390/molecules27123860

APA Style

Mironova, I. A., Nenajdenko, V. G., Postnikov, P. S., Saito, A., Yusubov, M. S., & Yoshimura, A. (2022). Efficient Catalytic Synthesis of Condensed Isoxazole Derivatives via Intramolecular Oxidative Cycloaddition of Aldoximes. Molecules, 27(12), 3860. https://doi.org/10.3390/molecules27123860

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