Simple Synthesis of Symmetrical 4-Substituted 3,5-Dialkylisoxazoles

Article abstract of DOI:10.1039/a801428k

A number of symmetrical 4-substituted 3,5-dialkylrsoxazoles have been prepared by treatment of aromatic aldehydes with nitroalkanes and aqueous sodium hydroxide.

Full text of DOI:10.1039/a801428k

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388 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 388±389$
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 ®rst 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).
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.
Scheme 1
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.
Scheme 2
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-
Of the numerous methods available for the synthesis
of isoxazoles, one that has been used frequently involves
Table 1 Products from the reaction of nitroethane and nitropropane with various aldehydes
Aldehyde
Product
Yield (%)
4-Methoxybenzaldehyde
2-Methoxybenzaldehyde
Benzaldehyde
3,4-Methylenedioxybenzaldehyde
4-Chlorobenzaldehyde
4-Nitrobenzaldehyde
Furfuraldehyde
2,2-Dimethylpropionaldehyde
4-Methoxybenzaldehyde
4-(4-methoxyphenyl)-3,5-dimethylisoxazole (1)
4-(2-methoxyphenyl)-3,5-dimethylisoxazole (2)
3,5-dimethyl-4-phenylisoxazole (3)
4-(3,4-methylenedioxyphenyl)-3,5-dimethylisoxazole (4)
4-(4-chlorophenyl)-3,5-dimethylisoxazole (5)
3,5-dimethyl-4-(4-nitrophenyl)isoxazole (6)
4-(2-furyl)-3,5-dimethylisoxazole (7)
69
70
73
85
92
71
96
6
3,5-dimethyl-4-(1,1-dimethylethyl)isoxazole (8)
4-(4-methoxyphenyl)-3,5-diethylisoxazole (9)
78
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
*To receive any correspondence.
$This is a Short Paper as de®ned 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).

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J. CHEM. RESEARCH (S), 1998 389
Table 2 13C NMR data of 4-substituted 3,5-dialkylisoxazoles, determined in CDCl3 at 75 MHz
Compound
C3
C4
C5
C3-Alkyl
11.3
C5-Alkyl
10.7
Others
1
164.8
116.2
158.8
122.6 (C1'), 130.2 (C2', 6'), (C2', 6'), 114.2 (C3', 5');
159.0 (C4'), 55.3 (OMe)
118.7 (C1'), 159.5 (C2'), 110.8 (C3'), 129.3 (C4'), 120.4
(C5'), 131.2 (C6'), 55.0 (OMe)
2
165.5
113.0
157.0
11.3
10.4
3
4
165.1
164.7
116.4
116.3
158.7
158.7
11.5
11.4
10.7
10.7
130.4 (C1'), 129.0 (C2', 6'), 128.7 (C3', 5'), 127.5 (C4')
123.9 (C1'), 109.4 (C2'), 147.0 (C3'), 147.9 (C4'), 122.6
(C5'), 108.6 (C6'), 101.2 (OCH2O)
5
6
7
8
9
165.3
166.3
165.4
163.0
162.8
115.6
115.1
108.2
120.6
114.9
158.4
158.1
157.7
159.1
159.0
12.4
11.8
12.4
14.0
18.9
11.5
10.9
11.5
13.6
18.9
133.5 (C1'), 130.3 (C2', 6'), 129.0 (C3', 5'), 128.8 (C4')
137.5 (C1'), 124.2 (C2', 6'), 130.0 (C2', 5'), 147.1 (C4')
145.6 (C2'), 106.6 (C3'), 111.1 (C4'), 141.8 (C5')
28.9 (C1'), 29.9 (C1' methyl carbons)
122.7 (C1'), 130.5 (C2', 6'), 114.5 (C3', 5'), 163.6 (C4'),
12.1, 12.2 (methyl carbons), 55.2 (OMe)
3,5-Dimethyl-4-phenylisoxazole 3.ÐNeedles; mp 40±42 8C (lit.,4
spectroscopic properties consistent with
a
4-aryl-3,5-
oil); 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±7.48 (5 H, m, aromatic hydrogens); m/z
173 (M ) (98), 158 (30), 130 (45), 104 (100), 89 (69), 78 (68), 63
(43), 43 (49%).
dimethyl substitution. It is interesting that the reaction of
nitrophenylmethane with 2-nitrobenzaldehyde has been
reported3 to produce the 5-aryl-3,4-diphenylisoxazole. This
could arise from Michael addition at the b-carbon of the
styrene directed by the electron-withdrawing nitro group in
the aromatic ring (Scheme 3).
‡
4-(3,4-Methylenedioxyphenyl)-3,5-dimethylisoxazole 4.ÐPlates; mp
50±52 8C; GC 8.12 min (Found: C, 66.5; H, 5.3; N, 6.4. C12H11NO3
requires C, 66.4; H, 5.1; N, 6.5%); ꢀH (200 MHz) 2.28 (3 H, s, C5
methyl), 2.38 (3 H, s, C3 methyl), 6.04 (2 H, s, methylenedioxy),
‡
6.75±6.92 (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.ÐOil; bp 98±100 8C
(block temp.)/0.2 Torr; GC 7.10 min (Found: N, 6.9, C11H10ClNO
requires N, 6.8%); ꢀH (200 MHz) 2.22 (3 H, s, C5 methyl), 2.36
(3 H, s, C3 methyl), 7.12±7.42 (4 H, m, aromatic protons); m/z
‡
209/207 (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.ÐRosettes, mp 85±87 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),
Scheme 3
‡
7.45±8.32 (3 H, AA'BB', aromatic protons); m/z 218 (M ) (29), 203
Experimental
(10), 130 (12), 103 (22), 91 (15), 77 (32), 63 (16), 51 (13), 43 (100%).
4-(2-Furyl)-3,5-dimethylisoxazole 7.ÐNeedles; mp 42±44 8C; GC
4.98 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,
1H and 13C NMR spectra (Table 2) were measured for CDCl3
solutions at either 200 (Varian Gemini 200) or 300 MHz (Brucker
AM-300). Melting points were determined with a Ko¯er block.
GC-MS data were obtained with a Hewlett-Packard instrument
equipped with an HP1 column (10 m). The GC temperature was
programmed from 70 to 310 8C at 20 8C min
‡
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%).
1
.
General Procedure for the Synthesis of Isoxazoles.ÐA mixture of
nitroethane 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 the
mixture heated under re¯ux for 5 to 18 h. The cooled reaction
mixture was extracted with diethyl ether and the ether fraction
washed with brine and dried over MgSO4. The residue remaining
after evaporation of the ether was puri®ed either by column
chromatography (silica) or by distillation. Since nitroethane and
nitropropane were used in excess, trimethyl- and triethyl-isoxazole
were also produced. These could be removed by column chromatog-
raphy, or, given their volatility, under vacuum.
3,5-Dimethyl-4-(1,1-dimethylethyl)isoxazole 8.ÐOil; GC 4.14 min;
ꢀH (200 MHz) 1.32 (9 H, s, tert-butyl protons), 2.34 (3 H, s, C5
methyl), 2.42 (3 H, s, C3 methyl), 7.45±8.32 (3 H, AA'BB', aromatic
protons); 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.ÐOil; 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±7.22 (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%).
4-(4-Methoxyphenyl)-3,5-dimethylisoxazole 1.ÐCrystalline, mp
37±38 8C (lit.,4 65.6±67.5 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±7.20 (4 H, AA'BB' pattern, aromatic hydrogens); m/z 203
Received, 19th February 1998; Accepted, 27th March 1998
Paper E/8/01428K
‡
References
(M ) (96), 188 (5), 160 (18), 134 (92), 119 (100), 91 (49), 43 (40%).
4-(2-Methoxyphenyl)-3,5-dimethylisoxazole 2.ÐOil; bp 106±109 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±7.20 (4 H, m, aromatic hydrogens); m/z 203 (M ) (56), 160
(25), 147 (19), 131 (18), 119 (30), 91 (100), 43 (61%).
1 P. Grunanger and P. Vita-Finzi, The Chemistry of Heterocyclic
Compounds, 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. Hegedus, Helv. Chim. Acta, 1939, 22, 405.
4 S. Labadie, Synth. Commun., 1994, 24, 2604.
‡