Simple Synthesis of Symmetrical 4-Substituted 3,5-Dialkylisoxazoles$ Wayne M. Best,a Emilio L. Ghisalberti*b and Marianne Powellb aChemistry Centre (WA), East Perth, Western Australia, 6004, Australia bDepartment of Chemistry, University of Western Australia, Nedlands, Western Australia, 6907, Australia A number of symmetrical 4-substituted 3,5-dialkylisoxazoles have been prepared by treatment of aromatic aldehydes with nitroalkanes and aqueous sodium hydroxide. In a project aimed at determining the e€ects of various bases on the condensation of nitroethane with 4-methoxy- benzaldehyde, it was found that using butylamine, triethyl- amine, DBU or sodium hydroxide di€ering amounts of 4-(4-methoxyphenyl)-3,5-dimethylisoxazole 1 were produced.Whereas the Rrst three bases yielded only 15% of the isoxazole, use of sodium hydroxide resulted in the formation of the compound in 69% isolated yield (Scheme 1). The structure of 1 was determined from its spectral character- istics.Importantly, HMBC techniques showed that the two methyls (dC 10.7 and 11.4; dH 2.24 and 2.38) on the hetero- cyclic ring were symmetrically disposed with respect to C4 (dC 116.2). Treatment of a number of aromatic aldehydes under the same conditions yielded the corresponding 4-aryl 3,5- dimethylisoxazoles in good yields (Table 1). The only excep- tion was N,N-dimethylaminobenzaldehyde which a€orded 12% of the corresponding isoxazole, as determined by GC-MS analysis.A poor yield was also obtained with the alkyl aldehyde 2,2-dimethylpropionaldehyde. As expected, aldehydes with a-protons, e.g. butyraldehyde, or with a,b-unsaturation, cinnamaldehyde, did not survive treatment with sodium hydroxide and little or no formation of the corresponding isoxazole could be detected by GC-MS analysis of the recovered products. Reaction of nitropropane with 4-methoxybenzaldehyde a€orded the 3,5-diethyl- isoxazole 9 in 78% yield. Of the numerous methods available for the synthesis of isoxazoles, one that has been used frequently involves the condensation of doubly activated nitro compounds, nitrophenylmethane and ethyl nitroacetate, with an aromatic aldehyde.1 Since better yields of the isoxazoles can be obtained simply by treatment of the intermediate b-nitro- styrene (A, Scheme 2) with potassium hydroxide, the mechanism must also involve a retroaldol reaction of the b-nitrostyrene.Thus, reaction of 4-methoxy-b-nitrostyrene with potassium hydroxide produced 4-p-methoxyphenyl-3,5- diphenylisoxazole. Aliphatic nitroalkanes have not been generally used in this type of synthesis of isoxazoles, although the formation of 3,4,5-trimethyl- or 3,4,5-triethyl-isoxazoles on treatment of nitroethane or nitropropane with alkali-metal hydroxides has been known for a long time.1 To our know- ledge, the only other example available refers to the conden- sation of 6-bromo-3,4-methylenedioxybenzaldehyde with nitroethane, butylamine and sodium carbonate.Instead of the expected b-nitrostyrene, a low yield (3%) of the 4-aryl-3,5-dimethylisoxazole was obtained, the structure of which was determined by 13C NMR methods.2 Under our conditions, use of sodium hydroxide, 3,4-methylenedioxy- J. Chem. Research (S), 1998, 388�}389$ Scheme 1 Table 1 Products from the reaction of nitroethane and nitropropane with various aldehydes Aldehyde Product Yield (%) 4-Methoxybenzaldehyde 4-(4-methoxyphenyl)-3,5-dimethylisoxazole (1) 69 2-Methoxybenzaldehyde 4-(2-methoxyphenyl)-3,5-dimethylisoxazole (2) 70 Benzaldehyde 3,5-dimethyl-4-phenylisoxazole (3) 73 3,4-Methylenedioxybenzaldehyde 4-(3,4-methylenedioxyphenyl)-3,5-dimethylisoxazole (4) 85 4-Chlorobenzaldehyde 4-(4-chlorophenyl)-3,5-dimethylisoxazole (5) 92 4-Nitrobenzaldehyde 3,5-dimethyl-4-(4-nitrophenyl)isoxazole (6) 71 Furfuraldehyde 4-(2-furyl)-3,5-dimethylisoxazole (7) 96 2,2-Dimethylpropionaldehyde 3,5-dimethyl-4-(1,1-dimethylethyl)isoxazole (8) 6 4-Methoxybenzaldehyde 4-(4-methoxyphenyl)-3,5-diethylisoxazole (9) 78 Scheme 2 benzaldehyde and nitroethane a€orded 85% of the isoxazole (Table 1).Of some interest is the reaction of nitroethane with 4-nitrobenzaldehyde. The unstable isoxazole produced gave $This is a Short Paper as deRned in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M).*To receive any correspondence. 388 J. CHEM. RESEARCH (S), 1998spectroscopic properties consistent with a 4-aryl-3,5-dimethyl substitution. It is interesting that the reaction ofnitrophenylmethane with 2-nitrobenzaldehyde has beenreported3 to produce the 5-aryl-3,4-diphenylisoxazole. Thiscould arise from Michael addition at the b-carbon of thestyrene directed by the electron-withdrawing nitro group inthe aromatic ring (Scheme 3).Experimental1H and 13C NMR spectra (Table 2) were measured for CDCl3solutions at either 200 (Varian Gemini 200) or 300 MHz (BruckerAM-300). Melting points were determined with a Koer block.GC-MS data were obtained with a Hewlett-Packard instrumentequipped with an HP1 column (10 m).The GC temperature wasprogrammed from 70 to 310 8C at 20 8Cmin£¾1.General Procedure for the Synthesis of Isoxazoles.A mixture ofnitroethane or nitropropane (9.3 mmol), aldehyde (4.41 mmol)and ethanol (7 ml) was stirred rapidly at room temperature (r.t.).A solution of NaOH (6.4 M, 2 ml) was added dropwise and themixture heated under reux for 5 to 18 h.The cooled reactionmixture was extracted with diethyl ether and the ether fractionwashed with brine and dried over MgSO4. The residue remainingafter evaporation of the ether was puried either by columnchromatography (silica) or by distillation. Since nitroethane andnitropropane were used in excess, trimethyl- and triethyl-isoxazolewere also produced. These could be removed by column chromatog-raphy, or, given their volatility, under vacuum.4-(4-Methoxyphenyl)-3,5-dimethylisoxazole 1.Crystalline, mp37¡Ó38 8C (lit.,4 65.6¡Ó67.5 8C); GC 7.52 min (Found: C, 70.8; H, 6.4;N, 7.0.Calc. for C12H13NO2: C, 70.9; H, 6.5; N, 6.9%); H 2.24(2 H, s, C5 methyl), 2.38 (3 H, s, C3 methyl), 3.84 (3 H, s, OCH3),6.90¡Ó7.20 (4 H, AA'BB' pattern, aromatic hydrogens); m/z 203(M) (96), 188 (5), 160 (18), 134 (92), 119 (100), 91 (49), 43 (40%).4-(2-Methoxyphenyl)-3,5-dimethylisoxazole 2.Oil; bp 106¡Ó109 8C(block temp.)/3 Torr; GC 7.39 min (Found: C, 71.0; H, 6.5; N, 7.0.C12H13NO2 requires C, 70.9; H, 6.5; N, 6.9%); H (200 MHz) 2.17(3 H, s, C5 methyl), 2.27 (3 H, s, C3 methyl), 3.78 (3 H, s, OCH3),6.90¡Ó7.20 (4 H, m, aromatic hydrogens); m/z 203 (M) (56), 160(25), 147 (19), 131 (18), 119 (30), 91 (100), 43 (61%).3,5-Dimethyl-4-phenylisoxazole 3.Needles; mp 40¡Ó42 8C (lit.,4oil); GC 6.34 min (Found: C, 76.3; H, 6.4.Calc.for C11H11NO:C, 76.3; H, 6.4%); H (200 MHz) 2.27 (3 H, s, C5 methyl), 2.43(3 H, s, C3 methyl), 7.22¡Ó7.48 (5 H, m, aromatic hydrogens); m/z173 (M) (98), 158 (30), 130 (45), 104 (100), 89 (69), 78 (68), 63(43), 43 (49%).4-(3,4-Methylenedioxyphenyl)-3,5-dimethylisoxazole 4.Plates; mp50¡Ó52 8C; GC 8.12 min (Found: C, 66.5; H, 5.3; N, 6.4. C12H11NO3requires C, 66.4; H, 5.1; N, 6.5%); H (200 MHz) 2.28 (3 H, s, C5methyl), 2.38 (3 H, s, C3 methyl), 6.04 (2 H, s, methylenedioxy),6.75¡Ó6.92 (3 H, m, aromatic protons); m/z 217 (M) (100), 202 (9),174 (24), 148 (62), 147 (95), 133 (26), 89 (23), 75 (35), 43 (42%).4-(4-Chlorophenyl)-3,5-dimethylisoxazole 5.Oil; bp 98¡Ó100 8C(block temp.)/0.2 Torr; GC 7.10 min (Found: N, 6.9, C11H10ClNOrequires N, 6.8%); H (200 MHz) 2.22 (3 H, s, C5 methyl), 2.36(3 H, s, C3 methyl), 7.12¡Ó7.42 (4 H, m, aromatic protons); m/z209/207 (M) (70/23), 194 (16), 166 (27), 140 (85), 125 (41), 133(100), 63 (25), 43 (95%).3,5-Dimethyl-4-(4-nitrophenyl)isoxazole 6.Rosettes, mp 85¡Ó87 8C;GC 8.54 min (Found: N, 13.2.C11H10N2O3 requires: N, 12.8%);H (200 MHz) 2.28 (3 H, s, C5 methyl), 2.45 (3 H, s, C3 methyl),7.45¡Ó8.32 (3 H, AA'BB', aromatic protons); m/z 218 (M) (29), 203(10), 130 (12), 103 (22), 91 (15), 77 (32), 6316), 51 (13), 43 (100%).4-(2-Furyl)-3,5-dimethylisoxazole 7.Needles; mp 42¡Ó44 8C; GC4.98 min (Found: C, 66.3; H, 5.6. C9H9NO2 requires C, 66.3;H, 5.6%); H 2.38 (3 H, s, C5 methyl), 2.55 (3 H, s, C3 methyl),6.32 (1 H, dd, J 9, 2, H-3'), 6.46 (1 H, dd, J 9, 7, H-4'), 7.47 (1 H,dd, J 7, 2 Hz, H-5'); m/z 163 (M) (19), 148 (8), 121 (10), 107 (20),94 (21), 79 (22), 66 (67), 51 (46), 43 (100%).3,5-Dimethyl-4-(1,1-dimethylethyl)isoxazole 8.Oil; GC 4.14 min;H (200 MHz) 1.32 (9 H, s, tert-butyl protons), 2.34 (3 H, s, C5methyl), 2.42 (3 H, s, C3 methyl), 7.45¡Ó8.32 (3 H, AA'BB', aromaticprotons); m/z 153 (M, C9H15NO) (17), 139 (12), 138 (100), 96 (61),80 (61), 80 (10), 53 (11), 43 (88%).3,5-Diethyl-4-(4-methoxyphenyl)isoxazole 9.Oil; GC 8.13 min(Found: N, 6.0.C14H17NO2 requires N, 6.1%); H (200 MHz) 1.18(3 H, t, J 6.4, C5 methylene), 1.23 (3 H, t, J, 6.4, C3 methylene),2.64 (2 H, q, J 6.4), 2.72 (2 H, d, J 6.4 Hz), 3.88 (3 H, s, OCH3),6.88¡Ó7.22 (4 H, AA'BB', aromatic protons); m/z 232 (M) (63), 216(100), 202 (15), 174 (10), 148 (12), 134 (18), 119 (14), 105 (10), 91(11%).Received, 19th February 1998; Accepted, 27th March 1998Paper E/8/01428KReferences1 P.Gru nanger and P. Vita-Finzi, The Chemistry of HeterocyclicCompounds, Wiley, New York, 1991, vol. 49.2 G. M. Buchan and A. B. Turner, J. Chem. Soc., Perkin Trans. 1,1975, 2115.3 P. Rubbli and B. Hegedu s, Helv. Chim. Acta, 1939, 22, 405.4 S. Labadie, Synth. Commun., 1994, 24, 2604.Table 2 13C NMR data of 4-substituted 3,5-dialkylisoxazoles, determined in CDCl3 at 75 MHzCompound C3 C4 C5 C3-Alkyl C5-Alkyl Others1 164.8 116.2 158.8 11.3 10.7 122.6 (C1'), 130.2 (C2', 6'), (C2', 6'), 114.2 (C3', 5');159.0 (C4'), 55.3 (OMe)2 165.5 113.0 157.0 11.3 10.4 118.7 (C1'), 159.5 (C2'), 110.8 (C3'), 129.3 (C4'), 120.4(C5'), 131.2 (C6'), 55.0 (OMe)3 165.1 116.4 158.7 11.5 10.7 130.4 (C1'), 129.0 (C2', 6'), 128.7 (C3', 5'), 127.5 (C4')4 164.7 116.3 158.7 11.4 10.7 123.9 (C1'), 109.4 (C2'), 147.0 (C3'), 147.9 (C4'), 122.6(C5'), 108.6 (C6'), 101.2 (OCH2O)5 165.3 115.6 158.4 12.4 11.5 133.5 (C1'), 130.3 (C2', 6'), 129.0 (C3', 5'), 128.8 (C4')6 166.3 115.1 158.1 11.8 10.9 137.5 (C1'), 124.2 (C2', 6'), 130.0 (C2', 5'), 147.1 (C4')7 165.4 108.2 157.7 12.4 11.5 145.6 (C2'), 106.6 (C3'), 111.1 (C4'), 141.8 (C5')8 163.0 120.6 159.1 14.0 13.6 28.9 (C1'), 29.9 (C1' methyl carbons)9 162.8 114.9 159.0 18.9 18.9 122.7 (C1'), 130.5 (C2', 6'), 114.5 (C3', 5'), 163.6 (C4'),12.1, 12.2 (methyl carbons), 55.2 (OMe)Scheme 3J. CHEM. RESEARCH (S), 1998 389