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Article

Clean and Efficient Synthesis of Isoxazole Derivatives in Aqueous Media

by
Guolan Dou
1,*,
Pan Xu
2,
Qiang Li
3,
Yukun Xi
2,
Zhibin Huang
2 and
Daqing Shi
2,*
1
School of Safety Engineering, China University of Mining & Technology, Xuzhou 221116, China
2
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
3
Hainan Chuntch Pharmaceutical Company Limited, Hainan Province Seaport Bonded Area 6th Workshop, Haikou 570216, China
*
Authors to whom correspondence should be addressed.
Molecules 2013, 18(11), 13645-13653; https://doi.org/10.3390/molecules181113645
Submission received: 5 August 2013 / Revised: 22 October 2013 / Accepted: 31 October 2013 / Published: 5 November 2013
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
A series of 5-arylisoxazole derivatives were synthesized via the reaction of 3-(dimethyl-amino)-1-arylprop-2-en-1-ones with hydroxylamine hydrochloride in aqueous media without using any catalyst. This method has the advantages of easier work-up, mild reaction conditions, high yields, and an environmentally benign procedure.

1. Introduction

The need to reduce the amount of toxic waste and byproducts arising from chemical processes requires increasing emphasis on the use of less toxic and environmentally compatible materials in the design of new synthetic methods [1]. One of the most promising approaches is the use of water as the reaction medium [2]. Compared to organic solvents the aqueous medium is less expensive, less dangerous, and more environmentally friendly. In recent years, there has been increasing recognition that water is an attractive medium for many organic reactions [3,4,5]. Many important types of heterocycles, such as furans, pyridines, quinolines, indoles, triazines, acridines, pyrazines, and pyrimidines have been synthesized in aqueous media [6,7,8,9,10,11,12,13,14,15]. The synthesis of new and other important type of heterocyclic compounds in water continues to attract wide attention among synthetic chemists.
Nitrogen-containing heterocyclic building blocks are of great importance to both medical and organic chemists, and their synthesis continues to represent a challenge from both academic and industrial perspectives [16]. Isoxazole derivatives are an important class of heterocyclic pharmaceuticals and bioactive natural products because of their significant and wide spectrum of biological activities, including potent and selective antagonism of the NMDA receptor [17] and anti-HIV activity [18]. Many syntheses of isoxazoles have been developed [19,20]. However, these syntheses are usually carried out in organic solvents. As part of our current studies on the development of new routes to heterocyclic systems in aqueous media [21,22,23,24,25,26,27,28], we now report an efficient and clean synthetic route to isoxazole derivatives via the reaction of 3-(dimethylamino)-1-arylprop-2-en-1-ones with hydroxylamine hydrochloride in aqueous media.

2. Results and Discussion

When an equivalent mixture of an 3-(dimethylamino)-1-arylprop-2-en-1-one derivative 1 and hydroxylamine hydrochloride (2) was stirred at 50 °C in aqueous media, 5-arylisoxazole derivatives 3 were obtained in good yields (Scheme 1). The results are summarized in Table 1.
Molecules 18 13645 g001 550
Scheme 1. The synthesis of 5-arylisoxazole derivatives in aqueous media.
Scheme 1. The synthesis of 5-arylisoxazole derivatives in aqueous media.
Molecules 18 13645 g001
Table
Table 1. The synthetic results of 5-arylisoxazole derivatives in aqueous media.
Table 1. The synthetic results of 5-arylisoxazole derivatives in aqueous media.
EntryProductArRIsolated Yield (%)
13a4-ClC6H4H88
23b4-CH3OC6H4H93
33c4-BrC6H4H89
43dNaphthen-2-ylH84
53eC6H5CH388
63f4-CH3OC6H4CH392
73g4-CH3C6H4CH389
83h4-BrC6H4CH390
93i4-ClC6H4CH386
103j4-CH3OCOC6H4CH384
113k4-BocNHC6H4CH386
123lThiophen-2-ylCH393
As shown in Table 1, this protocol could be applied to the 3-(dimethylamino)-1-arylprop-2-en-1-ones with both electron-withdrawing groups (such as halide groups) and electron-donating groups (such as methyl or methoxyl groups). Polysubstituted 3-(dimethylamino)-1-arylprop-2-en-1-ones could also be used in this synthesis. We concluded that the electronic nature of the substituent on the aromatic ring of 3-(dimethylamino)-1-arylprop-2-en-1-ones had no significant effect on this reaction. This synthesis was confirmed to follow the group-assisted-purification chemistry process [29,30,31], which can avoid traditional chromatography and recrystallization purification, that is, all the pure products can be obtained only by suction filtration without further purification. All the products 3 were identified from their IR, 1H-NMR, and HRMS spectra.
Although the detailed mechanism of this reaction remains to be fully clarified, the formation of 5-arylisoxazoles 3 could be explained by the reaction sequence presented in Scheme 2. First, the Michael addition of 3-(dimethylamino)-1-arylprop-2-en-1-ones 1 and hydroxylamine 2 gives the intermediate A, which then eliminates one molecule of dimethylamine to give the intermediate B, which upon intramolecular cyclization and dehydration gives rise to the final product 3.
Molecules 18 13645 g002 550
Scheme 2. The proposed mechanism for the synthesis of 5-arylisoxazoles.
Scheme 2. The proposed mechanism for the synthesis of 5-arylisoxazoles.
Molecules 18 13645 g002

3. Experimental

All reagents were purchased from commercial suppliers and used without further purification. Melting points are uncorrected. IR spectra were recorded on Varian F-1000 spectrometer in KBr with absorptions in cm−1. 1H-NMR and 13C-NMR spectra were recorded on a Varian Inova-300 MHz or Varian Inova-400 MHz in CDCl3 solution. J Values are in Hertz. Chemical shifts are expressed in parts per million downfield from internal standard TMS. High-resolution mass spectra (HRMS) were obtained using Bruker microTOF-Q instrument.

3.1. General Procedure for the Synthesis of 3-(Dimethylamino)-1-arylprop-2-en-1-ones 1a–l

A solution of substituted acetophenone (2 nmol) in N,N-dimethylformamide dimethyl acetal or N,N-dimethylacetamide dimethyl acetal (10 mL) was refluxed for 20 h during which time some methanol was formed and removed through a reflux condenser. After cooling, the precipitate was collected by suction to give compounds 1.
1-(4-Chlorophenyl)-3-(dimethylamino)prop-2-en-1-one (1a). Mp: 84–86 °C; IR (KBr) ν: 2916, 2804, 1648, 1580, 1545, 1433, 1411, 1353, 1279, 1237, 1118, 1088, 1053, 1010, 980, 899, 837, 790, 742, 678 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.89 (s, 3H, NCH3), 3.12 (s, 3H, NCH3), 5.63 (d, J = 12.4 Hz, 1H, CH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.78 (d, J = 12.8 Hz, 1H, CH), 7.81 (d, J = 8.4 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 37.2, 45.0, 91.6, 128.2, 128.8, 136.8, 138.7, 154.4, 187.0; HRMS calcd. for C11H13ClNO [M+H]+: 210.0686; found: 210.0685.
3-(Dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one (1b). Mp: 92–94 °C; IR (KBr) ν: 2905, 2838, 1643, 1603, 1583, 1432, 1358, 1305, 1242, 1175, 1117, 1057, 1026, 901, 774 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.89 (s, 3H, NCH3), 3.05 (s, 3H, NCH3), 3.80 (s, 3H, CH3O), 5.66 (d, J = 12.4 Hz, 1H, CH), 6.86-6.88 (m, 2H, ArH), 7.74 (d, J = 12.4 Hz, 1H, CH), 7.86–7.88 (m, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 37.1, 44.8, 55.2, 91.5, 113.1, 129.3, 132.9, 153.7, 161.8, 187.2; HRMS calcd. for C12H16NO2 [M+H]+: 206.1181; found: 206.1205.
1-(4-Bromophenyl)-3-(dimethylamino)prop-2-en-1-one (1c). Mp: 81–83 °C; IR (KBr) ν: 2910, 2808, 1649, 1575, 1540, 1435, 1357, 1304, 1271, 1237, 1120, 1056, 1003, 895, 847, 808, 775, 760, 673 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.88 (s, 3H, NCH3), 3.11 (s, 3H, NCH3), 5.62 (d, J = 12.4 Hz, 1H, CH), 7.50 (d, J = 8.4 Hz, 2H, ArH), 7.73 (s, 1H, CH), 7.75–7.79 (m, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 37.3, 45.1, 91.6, 125.4, 129.1, 131.3, 139.3, 154.6, 187.2; HRMS calcd. for C11H13BrNO [M+H]+: 254.0181; found: 254.0182.
3-(Dimethylamino)-1-(naphthalen-2-yl)prop-2-en-1-one (1d). Mp: 94–95 °C; IR (KBr) ν: 2927, 2898, 2809, 1636, 1554, 1427, 1291, 1253, 1189, 1111, 1045, 909, 863, 826, 781, 759 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.91 (s, 3H, NCH3), 3.09 (s, 3H, NCH3), 5.85 (d, J = 12.4 Hz, 1H, CH), 7.46–7.53 (m, 2H, ArH), 7.82–7.87 (m, 3H, ArH), 7.92 (t, J = 6.8 Hz, 1H, CH), 8.00–8.03 (m, 1H, ArH), 8.40 (s, 1H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 37.3, 45.0, 92.4, 124.7, 126.2, 127.2, 127.7, 127.8, 129.2, 132.8, 134.7, 137.9, 154.3, 188.4; HRMS calcd. for C15H15NO [M+H]+: 226.1232; found: 226.1234.
3-(Dimethylamino)-1-phenylbut-2-en-1-one (1e). Oil; IR (KBr) ν: 2911, 1650, 1555, 1500, 1450, 1357, 1310, 1267, 1027, 1067, 1000, 900, 857, 775, 761, 673 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.64 (s, 3H, CH3), 3.03 (s, 6H, N(CH3)2), 5.69 (s, 1H, CH), 7.13 (s, 1H, ArH), 7.41 (t, J = 6.4 Hz, 2H, ArH), 7.82 (d, J = 7.6 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 19.5, 42.7, 52.4, 117.3, 128.2, 130.0, 130.5, 133.9, 151.6, 166.1, 172.3; HRMS calcd. for C12H15NO [M+H]+: 190.1232; found: 190.1245.
3-(Dimethylamino)-1-(4-methoxyphenyl)but-2-en-1-one (1f). Mp: 134–136 °C; IR (KBr) ν: 2961, 2835, 1671, 1574, 1460, 1307, 1167, 1081, 1025, 917, 865, 782, 746, 694 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.62 (s, 3H, CH3), 3.02 (s, 6H, N(CH3)2), 3.81 (s, 3H, CH3O), 5.64 (s, 1H, CH), 6.86 (d, J = 8.4 Hz, 2H, ArH), 7.84 (d, J = 8.4 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.3, 39.9, 55.2, 92.1, 113.0, 129.0, 135.5, 161.3, 163.3, 187.1; HRMS calcd. for C13H18NO2 [M+H]+: 220.1338; found: 220.1341.
3-(Dimethylamino)-1-(-4-methylphenyl)but-2-en-1-one (1g). Mp: 94–96 °C; IR (KBr) ν: 2913, 2808, 1660, 1577, 1561, 1450, 1357, 1300, 1277, 1122, 1066, 1000, 899, 847, 775, 760, 673 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.37 (s, 3H, CH3), 2.65 (s, 3H, CH3), 3.06 (s, 6H, N(CH3)2), 5.67 (s, 1H, CH), 7.18 (d, J = 7.6 Hz, 2H, ArH), 7.77 (d, J = 8.0 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.4, 21.4, 40.0, 92.6, 127.3, 128.7, 140.3, 140.5, 163.6, 188.1; HRMS calcd. for C13H17NO [M+H]+: 204.1388; found: 204.1386.
1-(4-Bromophenyl)-3-(dimethylamino)but-2-en-1-one (1h). Mp: 88–92 °C; IR (KBr) ν: 2931, 1721, 1616, 1500, 1420, 1385, 1354, 1220, 1161, 1069, 1030, 1007, 849, 769, 680, 627 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.63 (s, 3H, CH3), 3.06 (s, 6H, N(CH3)2), 5.58 (s, 1H, CH), 7.49 (d, J = 8.4 Hz, 2H, ArH), 7.70 (d, J = 8.4 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.5, 40.1, 92.0, 124.6, 128.4, 128.9, 131.1, 131.8, 141.8, 186.7; HRMS calcd. for C12H14BrNO [M+H]+: 267.0259; found: 267.0256.
1-(4-Chlorophenyl)-3-(dimethylamino)but-2-en-1-one (1i). Mp: 82–84 °C; IR (KBr) ν: 3039, 2961, 2804, 1676, 1620, 1537, 1411, 1379, 1351, 1278, 1224, 1166, 1089, 1024, 1010, 921, 862, 772, 739, 712, 678 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.62 (s, 3H, CH3), 3.04 (s, 6H, N(CH3)2), 5.57 (s, 1H, CH), 7.31 (d, J = 8.4 Hz, 2H, ArH), 7.76 (d, J = 8.4 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.4, 40.1, 92.0, 128.0, 128.6, 136.0, 141.3, 164.3, 186.5; HRMS calcd. for C12H14ClNO [M+H]+: 224.0842; found: 224.0861.
Methyl 4-(3-dimethylamino)but-2-enoyl)benzoate (1j). Mp: 103–106 °C; IR (KBr) ν: 2951, 1720, 1620,1600, 1569, 1434, 1282, 1217, 1110, 1037, 1011, 921, 868, 825, 759, 725 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.64 (s, 3H, CH3), 3.06 (s, 6H, N(CH3)2), 3.89 (s, 3H, CH3), 5.61 (s, 1H, CH), 7.85 (d, J = 8.0 Hz, 2H, ArH), 8.01 (d, J = 8 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.5, 40.1, 52.1, 92.5, 127.1, 129.3, 131.2, 147.0, 164.6, 166.7, 186.9; HRMS calcd. for C14H17NO3 [M+H]+: 248.1287; found: 248.1292.
tert-Butyl (4-(3-dimethylamino)but-2-enoyl)phenyl)carbamate (1k). Mp: 218–220 °C; IR (KBr) ν: 3242, 3087, 2963, 1721, 1615, 1482, 1361, 1310, 1269, 1245, 1152, 1085, 1050, 1022, 922, 866, 788, 690 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.50 (s, 9H, C(CH3)3), 2.62 (s, 3H, CH3), 3.04 (s, 6H, N(CH3)2), 5.65 (s, 1H, CH), 6.83 (s, 1H, NH), 7.37 (d, J = 8.4 Hz, 2H, ArH), 7.81 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.4, 28.3, 40.0, 80.6, 92.3, 117.3, 128.4, 137.4, 140.4, 152.5, 163.5, 187.2; HRMS calcd. for C17H25N2O3 [M+H]+: 305.1865; found: 305.1866.
3-(Dimethylamino)-1-(thiophen-2-yl)but-2-en-1-one (1l). Mp: 90–91 °C; IR (KBr) ν: 3078, 2919, 2815, 1694, 1622, 1543, 1422, 1380, 1345, 1228, 1170, 1085, 1064, 1028, 906, 860, 837, 771, 723 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.59 (s, 3H, CH3), 3.01 (s, 6H, N(CH3)2), 5.60 (s, 1H, CH), 6.99 (s, 1H, ArH), 7.37 (s, 1H, ArH), 7.51 (s, 1H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 16.5, 40.0, 91.6, 127.2, 127.4, 129.4, 150.0, 163.8, 180.1; HRMS calcd. for C10H14NOS [M+H]+: 196.0796; found: 196.0807.

3.2. General Procedure for the Synthesis of Isoxazole Derivatives 3a–l

3-(Dimethylamino)-1-arylprop-2-en-1-one 1 (1 nmol), hydroxylamine hydrochloride 2 (1 nmol) and water (5 mL) were added to a 25-mL round-bottom flask. The mixture was then stirred at 50 °C for 2 h. After completion of the reaction, the mixture was then cooled to room temperature. The precipitate was collected by suction filtration to give products 3 without further purification.
5-(4-Chlorophenyl)isoxazole (3a). Mp: 85–87 °C (lit. [19] 84–85 °C); IR (KBr) ν: 1601, 1447, 1264, 1128, 1109, 1088, 802 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 6.52 (d, J = 2.0 Hz, 1H, C4-H), 7.45 (d, J = 8.4 Hz, 2H, ArH), 7.73 (d, J = 8.4 Hz, 2H, ArH), 8.30 (d, J = 2.0 Hz, 1H, C3-H); 13C-NMR (75 MHz, CDCl3) δ (ppm) 98.9, 125.6, 127.0, 129.2, 136.1, 150.8, 168.1; HRMS calcd. for C9H7ClNO [M+H]+: 180.0216; found: 180.0215.
5-(4-Methoxyphenyl)isoxazole (3b). Mp: 60–62 °C (lit. [19] 64–65 °C); IR (KBr) ν: 3002, 1605, 1510, 1446, 1251, 1175, 1020, 906, 787, 675 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.86 (s, 3H, CH3O), 6.39 (d, J = 1.6 Hz, 1H, C4-H), 6.98 (d, J = 8.8 Hz, 2H, ArH), 7.73 (d, J = 8.8 Hz, 2H, ArH), 8.25 (d, J = 1.6 Hz, 1H, C3-H); 13C-NMR (75 MHz, CDCl3) δ (ppm) 55.3, 97.2, 114.3, 120.0, 127.3, 150.7, 161.0, 169.2; HRMS calcd. for C10H10NO2 [M+H]+: 176.0712; found: 176.0718.
5-(4-Bromophenyl)isoxazole (3c). Mp: 112–114 °C (lit. [19] 114–116 °C); IR (KBr) ν: 1629, 1427, 1077, 1021, 846, 775 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 6.53 (d, J = 1.6 Hz, 1H, C4-H), 7.60 (d, J = 8.4 Hz, 2H, ArH), 7.66 (d, J = 8.8 Hz, 2H, ArH), 8.30 (d, J = 1.6 Hz, 1H, C3-H); 13C-NMR (75 MHz, CDCl3) δ (ppm) 99.0, 124.5, 126.0, 127.2, 132.2, 150.9, 168.2; HRMS calcd. for C9H7BrNO [M+H]+: 223.9711; found: 223.9716.
5-(Naphthalen-1-yl)isoxazole (3d). Mp: 90–92 °C; IR (KBr) ν: 3049, 1562, 1449, 1360, 1265, 1190, 910, 808, 738 cm−1; 1H-NMR (300 MHz, CDCl3) δ (ppm) 6.63 (d, J = 1.6 Hz, 1H, C4-H), 7.53–7.56 (m, 2H, ArH), 7.84–7.93 (m, 4H, ArH), 8.30–8.34 (m, 2H, C3-H and ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 98.9, 122.8, 124.3, 125.5, 126.8, 127.2, 127.7, 128.5, 128.8, 132.9, 133.8, 150.8, 169.3; HRMS calcd. for C13H10NO [M+H]+: 196.0762; found: 196.0768.
3-Methyl-5-phenylisoxazole (3e). Mp: 67–69 °C (lit. [32] 67 °C); IR (KBr) ν: 3056, 2983, 1600, 1424, 1258, 1039, 897, 766, 683 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.36 (s, 3H, CH3), 6.37 (s, 1H, C4-H), 7.42–7.48 (m, 3H, ArH), 7.75–7.77 (m, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 100.1, 125.6, 127.4, 128.8, 129.9, 160.2, 169.5; HRMS calcd. for C10H10NO [M+H]+: 160.0762; found: 160.0770.
5-(4-Methoxyphenyl)-3-methylisoxazole (3f). Mp: 99–101 °C; IR (KBr) ν: 2936, 1612, 1510, 1430, 1253, 1174, 1022, 787, 680 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.33 (s, 3H, CH3), 3.85 (s, 3H, CH3O), 6.24 (s, 1H, C4-H), 6.96 (d, J = 8.8 Hz, 2H, ArH), 7.69 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 55.2, 98.7, 114.2, 120.3, 127.2, 160.2, 160.8, 169.5; HRMS calcd. for C11H12NO2 [M+H]+: 190.0868; found: 190.0862.
3-Methyl-5-(4-methylphenyl)isoxazole (3g). Mp: 88–90 °C (lit. [33] 92 °C); IR (KBr) ν: 3063, 2961, 1603, 1415, 1259, 1114, 1044, 956, 895, 792, 680 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.13 (s, 3H, CH3), 2.18 (s, 3H, CH3), 6.09 (s, 1H, C4-H), 7.04 (d, J = 8.4 Hz, 2H, ArH), 7.43 (d, J = 8.0 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 21.3, 99.5, 124.8, 125.6, 129.5, 140.1, 160.2, 169.7; HRMS calcd. for C11H12NO [M+H]+: 174.0919; found: 174.0914.
5-(4-Bromophenyl)-3-methylisoxazole (3h). Mp: 126–128 °C; IR (KBr) ν: 2978, 1598, 1467, 1404, 1256, 1061, C4-H), 7.41 (d, J = 8.0 Hz, 2H, ArH), 7.67 (d, J = 8.0 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 100.4, 125.9, 126.9, 129.1, 135.9, 160.4, 168.4; HRMS calcd. for C10H9ClNO [M+H]+: 194.0373; found: 194.0378.
5-(4-Chlorophenyl)-3-methylisoxazole (3i). Mp: 88–89 °C (lit. [34] 90–91 °C); IR (KBr) ν: 1600, 1451, 1400, 1249, 1092, 1053, 833cm-1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.34 (s, 3H, CH3), 6.34 (s, 1H, C4-H), 7.41 (d, J = 8.0 Hz, 2H, ArH), 7.67 (d, J = 8.0 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 100.4, 125.9, 126.9, 129.1, 135.9, 160.4, 168.4; HRMS calcd. for C10H9ClNO [M+H]+: 194.0373; found: 194.0378.
Methyl 4-(3-methylisoxazol-5-yl)benzoate (3j). Mp: 88–90 °C; IR (KBr) ν: 2945, 1720, 1601, 1419, 1274, 1182, 1105, 950, 774 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.36 (s, 3H, CH3), 3.93 (s, 3H, CH3O), 6.46 (s, 1H, C4-H), 7.81 (d, J = 8.4 Hz, 2H, ArH), 8.10 (d, J = 8.4 Hz, 2H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 52.2, 101.6, 125.5, 130.1, 131.1, 131.2, 160.4, 166.2, 168.3; HRMS calcd. for C12H12NO3 [M+Na]+: 240.0637; found: 240.0650.
tert-Butyl 4-(3-methylisoxazol-5-yl)phenylcarbamate (3k). Mp: 120–121 °C; IR (KBr) ν: 3363, 3005, 2978, 1701, 1520, 1413, 1237, 1160, 835, 772 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.48 (s, 9H, (CH3)3C), 2.25 (s, 3H, CH3), 6.71 (s, 1H, C4-H), 7.59 (d, J = 8.8 Hz, 2H, ArH), 7.71 (d, J = 8.4 Hz, 2H, ArH), 9.65 (s, 1H, NH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.5, 28.2, 80.9, 99.2, 118.3, 122.1, 126.6, 140.0, 152.4, 160.3, 169.3; HRMS calcd. for C15H19N2O3 [M+H]+: 275.1396; found: 275.1392.
3-Methyl-5-(thiophen-2-yl)isoxazole (3l). Oil; IR (KBr) ν: 2933, 1605, 1422, 1033, 899, 792, 706 cm−1; 1H-NMR (400 MHz, CDCl3) δ (ppm) 2.33 (s, 3H, CH3), 6.24 (s, 1H, C4-H), 7.11 (t, J = 4.4 Hz, 1H, ArH), 7.43 (d, J = 4.8 Hz, 1H, ArH), 7.48 (d, J = 3.6 Hz, 1H, ArH); 13C-NMR (75 MHz, CDCl3) δ (ppm) 11.4, 100.0, 126.7, 127.7, 128.0, 129.4, 160.3, 160.4; HRMS calcd. for C8H8NOS [M+H]+: 166.0327; found: 166.0322.

4. Conclusions

In conclusion, we have developed an efficient synthesis of isoxazole derivatives via the reaction of 3-(dimethylamino)-1-arylprop-2-en-1-ones with hydroxylamine hydrochloride in aqueous media without using any catalyst. This method has the advantages of an easier work-up, mild reaction conditions, high yields, and an environmentally benign procedure.

Acknowledgments

We are grateful to The Joint Funds of the National Natural Science Foundation of China and Shenhua Group Corporation Limited (No. 51134020), the National Natural Science Foundation of China Youth Science Foundation (Grant No. 51204171 and 51004105), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Amato, I. The slow birth of green chemistry. Science 1993, 259, 1538–1541. [Google Scholar] [CrossRef]
  2. Fringuell, F.; Piematti, O.; Pizzo, F.; Vaccaro, L. Recent advances in Lewis acid catalyzed Diels-Alder reactions in aqueous media. Eur. J. Org. Chem. 2001, 2001, 439–455. [Google Scholar]
  3. Breslow, R. Hydrophobic effects on simple organic reactions in water. Acc. Chem. Res. 1991, 24, 159–164. [Google Scholar] [CrossRef]
  4. Li, C.J. Organic reactions in aqueous media—with a focus on carbon-carbon bond. Chem. Rev. 1993, 93, 2023–2035. [Google Scholar] [CrossRef]
  5. Li, C.J. Organic reactions in aqueous media with a focus on carbon-carbon bond formations: A decade update. Chem. Rev. 2005, 105, 3095–3166. [Google Scholar] [CrossRef]
  6. Dandia, A.; Arya, K.; Sati, M.; Sarangi, P. Green chemical synthesis of fluorinated 1,3,5-triaryl-s-triazines in aqueous medium under microwaves as potential antifungal. J. Fluorine Chem. 2004, 125, 1273–1277. [Google Scholar] [CrossRef]
  7. Wang, X.S.; Zhang, M.M.; Zeng, Z.S.; Shi, D.Q.; Tu, S.J.; Wei, X.Y.; Zong, Z.M. A simple and clean procedure for the synthesis of polyhydroacridine and quinoline derivatives: Reaction of Schiff base with 1,3-dicarbonyl compounds in aqueous medium. Tetrahedron Lett. 2005, 46, 7169–7173. [Google Scholar] [CrossRef]
  8. Cho, C.S.; Kim, J.S.; Oh, B.H.; Kim, T.J.; Shim, S.C.; Yoon, N.S. Ruthenium-catalyzed synthesis of quinolines from anilines and allylammonium chlorides in an aqueous medium via amine exchange reaction. Tetrahedron 2000, 56, 7747–7750. [Google Scholar] [CrossRef]
  9. Khadikar, B.M.; Gaikar, V.G.; Chitnavis, A.A. Aqueous hydrotrope solution as a safer medium for microwave enhanced hantzsch dihydropyridine ester synthesis. Tetrahedron Lett. 1995, 36, 8083–8086. [Google Scholar] [CrossRef]
  10. Cho, C.S.; Kim, J.H.; Shim, S.C. Ruthenium-catalyzed synthesis of indoles from anilines and trialkanolammonium chlorides in an aqueous medium. Tetrahedron Lett. 2000, 41, 1811–1814. [Google Scholar] [CrossRef]
  11. Totlani, V.M.; Peterson, D.G. Reactivity of epicatechin in aqueous glycine and glucose maillard reaction models: Quenching of C2, C3, and C4 sugar fragments. J. Agric. Food Chem. 2005, 53, 4130–4135. [Google Scholar] [CrossRef]
  12. Wnorowski, A.; Yaylayan, V.A. Influence of pyrolytic and aqueous-phase reactions on the mechanism of formation of maillard products. J. Agric. Food Chem. 2000, 48, 3549–3554. [Google Scholar] [CrossRef]
  13. Bose, D.S.; Fatima, L.; Mereyala, H.B. Green chemistry approaches to the synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones by a three-component coupling of one-pot condensation reaction: Comparison of ethanol, water, and solvent-free conditions. J. Org. Chem. 2003, 68, 587–590. [Google Scholar] [CrossRef]
  14. Shi, D.Q.; Chen, J.; Zhuang, Q.Y.; Hu, H.W. Three-component processes for the synthesis of 4-aryl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydrocoumarin in aqueous media. J. Chem. Res. 2003, 2003, 674–675. [Google Scholar] [CrossRef]
  15. Jin, T.S.; Zhang, J.S.; Guo, T.T.; Wang, A.Q. One-pot clean synthesis of 1,8-dioxo-decahydro-acridines catalyzed by p-dodecylbenzesulfonic acid in aqueous media. Synthesis 2004, 2004, 2001–2005. [Google Scholar]
  16. Wender, P.A.; Verma, V.A.; Paxton, T.J.; Pillow, T.H. Function-oriented synthesis, step economy, and drug design. Acc. Chem. Res. 2008, 41, 40–49. [Google Scholar] [CrossRef]
  17. Conti, P.; Amici, M.D.; Grazioso, G.; Roda, G.; Pinto, A.; Hansen, K.B.; Nielsen, B.; Madsen, U.; Bräuner-Osborne, H.; Egebjerg, J.; Vestri, V.; Pellegrini-Giampietro, D.E.; Sibille, P.; Acher, F.C.; Micheli, C.D. Synthesis, binding affinity at glutamic acid receptors, neuroprtective effects, and molecular modeling investigation of novel dihydroisoxazole amino acids. J. Med. Chem. 2005, 48, 6315–6325. [Google Scholar] [CrossRef]
  18. Srirastara, S.; Bajpai, L.K.; Batra, S.; Bhaduri, A.P.; Maikhuri, J.P.; Gupta, G.; Dhar, J.D. In search of new chemical entities with spermicidal and anti-HIV activities. Bioorg. Med. Chem. 1999, 7, 2607–2613. [Google Scholar] [CrossRef]
  19. Lin, Y.; Lang, S.A. New synthesis of isoxazoles and isothiazoles. A convenient synthesis of thioenaminones from enaminones. J. Org. Chem. 1980, 45, 4857–4860. [Google Scholar] [CrossRef]
  20. Nakamura, T.; Sato, M.; Kakinuma, H.; Miyata, N.; Taniguchi, K.; Bando, K.; Koda, A.; Kameo, K. Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors. J. Med. Chem. 2003, 46, 5416–5427. [Google Scholar] [CrossRef]
  21. Shi, D.Q.; Niu, L.H.; Yao, H.; Jiang, H. An efficient synthesis of pyrimido[4,5-b]quinoline derivatives via three-component reaction ia aqueous media. J. Heterocycl. Chem. 2009, 46, 237–242. [Google Scholar] [CrossRef]
  22. Shi, D.Q.; Shi, J.W.; Rong, S.F. An efficient and clean synthesis of pyrido[2,3-d]pyrimidine-4,7-dione derivatives in aqueous media. J. Heterocycl. Chem. 2009, 46, 1331–1334. [Google Scholar] [CrossRef]
  23. Shi, D.Q.; Yao, H. Clean synthesis of furo[3,4-e]pyrazolo[3,4-b]pyridine-5-one derivatives in aqueous media. J. Heterocycl. Chem. 2009, 46, 1335–1338. [Google Scholar] [CrossRef]
  24. Li, Y.L.; Chen, H.; Shi, C.L.; Shi, D.Q.; Ji, S.J. Efficient one-pot synthesis of spirooxindole derivatives catalyzed by L-proline in aqueous media. J. Comb. Chem. 2010, 12, 231–237. [Google Scholar] [CrossRef]
  25. Chen, H.; Shi, D.Q. Efficient one-pot synthesis of novel spirooxindole derivatives via three-component reaction in aqueous medium. J. Comb. Chem. 2010, 12, 571–576. [Google Scholar] [CrossRef]
  26. Shi, D.Q.; Shi, J.W.; Rong, S.F. A facile and clean synthesis of pyrimidine derivatives via three-component reaction in aqueous media. Chin. J. Chem. 2010, 28, 791–796. [Google Scholar] [CrossRef]
  27. Dou, G.L.; Zhong, X.X.; Wang, D.M.; Shi, D.Q. An efficient synthesis of N-substituted-3-aryl-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)propanamides by four-component reaction in aqueous medium. Chin. J. Chem. 2011, 29, 2368–2372. [Google Scholar] [CrossRef]
  28. Shi, D.Q.; Li, Y.; Wang, H.Y. Synthesis of indeno[2’,1’:5,6]pyrido[2,3-d]pyrimidine derivatives andtheir recognition properties as new type anion receptors. J. Heterocycl. Chem. 2012, 49, 1086–1090. [Google Scholar] [CrossRef]
  29. Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. Asymmetric catalytic Strecker reaction of N-phosphonyl imines with Et2AlCN using amino alcohols and BINOLs as catalysts. Chem. Commun. 2010, 46, 4330–4332. [Google Scholar] [CrossRef]
  30. Kaur, P.; Pindi, S.; Wever, W.; Rajale, T.; Li, G. Asymmetric catalytic N-phosphonyl imine chemistry: The use of primary free amino acids and Et2AlCN for asymmetric catalytic Strecker reaction. J. Org. Chem. 2010, 75, 5144–5150. [Google Scholar] [CrossRef]
  31. Kaur, P.; Wever, W.; Pindi, S.; Milles, R.; Gu, P.; Shi, M.; Li, G. The GAP chemistry for chiral N-phosphonyl imine-based Strecker reaction. Green Chem. 2011, 13, 1288–1292. [Google Scholar] [CrossRef]
  32. Jyoti, S.; Vidya, D.; Santosh, T. Domino primary alcohol oxidation—Wittig reaction: Total synthesis of ABT-418 and (E)-4-oxonon-2-enoic acid. Synthesis 2004, 2004, 1859–1863. [Google Scholar] [CrossRef]
  33. Umaprasanna, B. B-Diketones in ring formation. III. J. Indian Chem. Soc. 1931, 8, 119–128. [Google Scholar]
  34. Choji, K.; Akira, K.; Yuko, Y.; Yoshimori, O. Ring transformation reaction of 1,4,6-trisubstituted 2(1H)-pyrimidinones and –thiones with hydroxylamine. Chem. Pharma. Bull. 1981, 29, 2516–2519. [Google Scholar] [CrossRef]
  • Sample Availability: Samples of the compounds 3 are available from the authors.

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MDPI and ACS Style

Dou, G.; Xu, P.; Li, Q.; Xi, Y.; Huang, Z.; Shi, D. Clean and Efficient Synthesis of Isoxazole Derivatives in Aqueous Media. Molecules 2013, 18, 13645-13653. https://doi.org/10.3390/molecules181113645

AMA Style

Dou G, Xu P, Li Q, Xi Y, Huang Z, Shi D. Clean and Efficient Synthesis of Isoxazole Derivatives in Aqueous Media. Molecules. 2013; 18(11):13645-13653. https://doi.org/10.3390/molecules181113645

Chicago/Turabian Style

Dou, Guolan, Pan Xu, Qiang Li, Yukun Xi, Zhibin Huang, and Daqing Shi. 2013. "Clean and Efficient Synthesis of Isoxazole Derivatives in Aqueous Media" Molecules 18, no. 11: 13645-13653. https://doi.org/10.3390/molecules181113645

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