The regiospecific synthesis of some new 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1002/jccs.200800198

The compounds with isoxazolemoiety havemany pharmacological, biological and industrial applications, specifically their antiviral activity. In this research work, seven new compounds of 3,5-disubstituted isoxazoles were synthesized. Propargyl alcohol (1)

Full text of DOI:10.1002/jccs.200800198

1322
Journal of the Chinese Chemical Society, 2008, 55, 1322-1325
The Regiospecific Synthesis of Some New 3,5-Disubstituted Isoxazoles
Ladan Edjlali
Laboratory of Organic Chemistry Research, Department of Applied Chemistry, Islamic Azad University,
Tabriz Branch, P. O. Box 1655, Tabriz, Iran
The compounds with isoxazole moiety have many pharmacological, biological and industrial applica-
tions, specifically their antiviral activity. In this research work, seven new compounds of 3,5-disubstituted
isoxazoles were synthesized. Propargyl alcohol (1) reacted with benzoyl chloride to give propargylphen-
ylcarboxylate (2). Then, the aldehydes (3a-3g) were converted to the related oximes (4a-4g) and nitrile-
oxides in situ by NaOCl, consequently. Reaction of compound 2 with nitrileoxides in a [3+2] cycloaddi-
tion reaction gave regiospecifically isoxazoles (5a-5g). 1H NMR, 13C NMR, FT-IR, and elemental analy-
ses confirmed the structure of the synthesized compounds.
Keywords: Isoxazoles; Propargyl alcohol; [3+2] cycloaddition.
INTRODUCTION
Isoxazoles are a large group of compounds, a number
the isoxazole ring was obtained regiospecifically (Scheme
V). Therefore, for the synthesis of the isoxazole ring, pro-
pargyl alcohol was protected by benzoyl chloride as a suit-
able protecting group to produce propargylphenyl carbox-
ylate (2) in high yield (Scheme II).8, 9 If the hydroxyl group
of propargyl alcohol is not protected, it will oxidize in the
next step. Then, the aldehydes (3a-3g) are converted to the
oximes (4a-4g) in high yield by NH2OH.HCl in pyridine as
a solvent (Scheme III). The obtained data of oximes are
listed in Table 1.
of which display interesting medicinal or agricultural activ-
ity or have some other industrial utility.1 Various pharma-
cologically important isoxazoles with antibacterial, antivi-
ral, antiinflammatory, antidiabetic, antifungal, antiparkin-
son, antihypertensive and antitumor activity have already
been reported.2 Isoxazoles are unique in their chemical be-
havior, not only among heterocyclic compounds in general,
but also among related azoles. This is because isoxazoles
possess the typical properties of the aromatic system, which
are in fact rather pronounced in these derivatives, together
with high lability of the ring under certain conditions, par-
ticularly at the nitrogen-oxygen bond.2 They were first syn-
thesized in 1903.3 The preparation of several isoxazoles
with antipicornavirus activity has also been achieved by G.
D. Diana et al.4,5 Recently, we synthesized new analogues
of isoxazoles and studied their electrochemical behav-
iours.6,7 This work describes the synthesis of some new
members of the isoxazole family with a structure which has
two substitutions in the 3 and 5 positions.
In the next step, the obtained oximes (4a-4g) were
converted to the related nitrileloxids in situ with NaOCl.
Then, reaction of nitrileoxides with propargylphenyl car-
boxylate (2) by a [3+2] cycloaddition reaction gave the re-
lated isoxazoles (5a-5g) in high yields (Scheme IV).10 The
Scheme I
Ar
N
CH2OCOPh
O
RESULTS AND DISCUSSION
Several methods exist for the synthesis of isoxazole
rings. The most important and the most used method is the
[3+2] cycloaddition reaction. In this approach, the isoxazole
ring was obtained by using an alkyne and a nitriloxide,
which are produced by oxidation of oximes. In this method,
Scheme II
PhCOCl
HC
CCH2OH
HC
CCH2OCOPh
2
Et3N
1
* Corresponding author. E-mail: ladan_ejlali@yahoo.com

Synthesis of New Isoxazoles
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1323
Table 1. Characterization of synthesized Ar-CH = NOH
Yield
(%)
m.p.
FT-IR
(cm-1)
Entry
Ar
(°C)
3600-3000, 2950, 1650, 1550, 1280, 1200, 1100, 950, 865-
810, 700
4b
4c
4d
4e
4f
4-methylphenyl
phenyl
87
80
74
liquid 3500-2500, 1600, 1575, 1490, 1410, 1270, 1170, 1150, 920
3500-3200, 1615-1530, 1345, 1300, 1100, 935, 835, 800, 750,
3-nitrophenyl
4-nitrophenyl
3-bromophenyl
2-phenylethyl
90
122
700.
96
130
80
3500-3200, 1600, 1530, 1345, 1100, 840, 745
3100-2300, 1620, 1585, 1535, 1475, 1415, 1310, 1200, 106,
970, 900.
91.5
89
4g
74
3400-2400, 1600, 1490, 1420, 1300, 1065, 900, 750, 690.
Scheme III
Scheme IV
Ar
NH2OH.HCl
NaOCl
ArCHO
3a-3g
ArCH
4a-4g
NOH
2 + [4a-4g]
N
Py
CH2OCOPh
CH2Cl2
O
5a-5g
Scheme V
a - Ar =
OCH3
CH3
e - Ar =
NO2
HC
CCH2OCOPh
4a-4g
5a-5g
Br
_
b - Ar =
c - Ar =
+
ArC
N
O
f - Ar =
chased from Merck and used without further purification.
Preparation of propargylphenylcarboxilate (2)
To a mixture of propargyl alcohol (1) (9.97 g, 0.18
mol), Et3N (20.6 g, 0.20 mol) and benzene (50 mL) was
-CH -CH
g - Ar =
2
2
NO2
o
slowly added PhCOCl (25.0 g, 0.18 mol) at 0-5 C. The
d - Ar =
mixture was stirred at room temperature for 2 h, filtered
and evaporated. The residue was distilled at reduced pres-
sure (12 mmHg/37 oC) to give 25.5 g (94%) of 2 as color-
less oil. FT-IR (neat, cm-1) 3450, 3300, 3100, 2950, 1730
(C=O), 1600, 1450, 1260, 1100.
synthesized isoxazoles were purified by preprative T.L.C.
and characterized by FT-IR, 1H NMR, 13C NMR and ele-
mental analyses.
Preparation of 4-methoxybenzaldoxime (4a)11
EXPERIMENTAL
A solution of 4-methoxy benzaldehyde (11.15 g, 0.08
mol), hydroxylamine hydrochloride (25.25 g, 0.36 mol),
and pyridine (25 mL) was refluxed for 2 h and the solvent
evaporated. The reaction mixture was dissolved in water
and the aqueous layer extracted with ethylacetate (EtOAc)
2 times. The organic layer was dried with Na2SO4, filtered
and evaporated. Recrystallization of solid residue from
EtOAc and petroleum ether gave 8.93 g (80%) of 4a. m.p.
60 oC; FT-IR (KBr, cm-1) 3200, 1610, 1570, 960, 1H NMR
Instruments and materials
Melting points were determined using an Electrother-
mal 9100 apparatus. 1H NMR and 13C NMR spectra were
recorded on a Bruker (400 MHz) in CDCl3. FT-IR spectra
were recorded on a Shimadzu IR-408 spectrophotometer.
Elemental analyses were performed by a Heraus CHN-O-
RAPID instrument.
All chemicals were regeant grade materials pur-

1324 J. Chin. Chem. Soc., Vol. 55, No. 6, 2008
Edjlali
(CDCl3, ppm) 3.65 (s, 3H, CH3), 6.7 (d, J = 11 Hz, 2H,
Ar-H), 7.35 (d, J = 11 Hz, 2H, Ar-H), 8.0 (s, 1H, CH), 9.0
(s, 1H, OH).
Preparation of 3-(3-nitrophenyl)-5-[methyl(phenylcar-
boxylate)]isoxazole (5d)
This compound was prepared with the described
method for 4a, Yield 75%, m.p. 71 oC; FT-IR (KBr, cm-1)
3050, 2090, 1720, 1610, 1525, 1445, 1345, 1260, 1100,
800, 700. 1H NMR (CDCl3, ppm) 5.6 (s, 2H, CH2), 6.81 (s,
1H, isoxazole-H), 7.45-8.55 (m, 9H, Ar-H); 13C NMR
(CDCl3, ppm) 57.2, 102.5, 105, 122.3, 125.1, 128.9, 129.2,
130, 130.3, 132.9, 134, 150, 155, 160, 169; Anal. Calc. for
C17H12N2O5: C, 62.96; H, 3.73; N, 8.64; Found: C, 62.52;
H, 3.58; N, 8.60.
Preparation of compounds (4b-4g)
These compounds were prepared with the described
method for 4a and data are listed in Table 1.
Preparation of 3-(4-methoxyphenyl)-5-[methyl(phenyl-
carboxylate)]isoxazole (5a)
To a mixture of 4-methoxybenzaldoxime (4a) (11.36
g, 0.08 mol) and 2 (8.24 g, 0.11 mol) in CH2Cl2 (125 mL)
was added dropwise NaOCl (150 mL, 20%) and stirred at
room temperature for 48 h. The organic phase was sepa-
rated, dried and the solvent removed in vacuum. The resi-
due was purified by column chromatography on silica gel
100 (eluent CH2Cl2 - petroleum ether 4:1 (v/v); Rf = 0.5) to
Preparation of 3-(4-nitrophenyl)-5-[methyl(phenylcar-
boxylate)]isoxazole (5e)
This compound was prepared with the described
method for 4a, Yield 63%, m.p. 136 oC; FT-IR (KBr, cm-1):
3100, 2950, 1725, 1590, 1510, 1425, 1345, 1310, 1260,
1100, 850, 700; 1H NMR (CDCl3, ppm) 5.55 (s, 2H, CH2),
6.8 (s, 1H, isoxazole-H), 7.3-8.4 (m, 9H, Ar-H); 13C NMR
(CDCl3, ppm) 57.4, 102.8, 114, 124.6, 127.1, 128.9, 130.2,
134, 135, 145, 157.5, 163, 167; Anal. Calc. for C17H12N2O5:
C, 62.9; H, 2.73; N, 8.64; Found: C, 62.54; H, 3.61; N,
8.86.
o
give 5a (78%) as a white solid. m.p. 109 C; FT-IR (KBr
cm-1): 3100, 3000, 2900, 1720 (C=O), 1605, 1525, 1420,
1300, 1250, 1160, 1085, 1020, 900, 810, 700; 1H NMR
(CDCl3, ppm) 3.9 (s, 3H, CH3), 5.5 (s, 2H, CH2), 6.7 (s, 1H,
isoxazole-H), 7-8.1 (m, 9H, Ar-H); 13C NMR (CDCl3,
ppm) 55.7, 57.3, 104.5, 114.7, 121.6, 128, 128.6, 128.9,
129.2, 130.3, 133.9, 163.1, 166, 167.4; Anal. Calc. for
C18H15NO4: C, 69.89; H, 4.89; N, 4.53; Found: C, 69.59; H,
4.85; N, 4.37.
Preparation of 3-(3-bromophenyl)-5-[methyl(phenyl-
carboxylate)]isoxazole (5f)
This compound was prepared with the described
method for 4a, Yield 56%, m.p. 50 oC. FT-IR (KBr, cm-1),
3050, 2950, 1720, 1600, 1560, 1440, 1250, 1100, 700; 1H
NMR (CDCl3, ppm) 5.5 (s, 2H, CH2), 6.7 (s, 1H, isoxazole-
H), 7.3-8.1 (m, 9H, Ar-H); 13C NMR (CDCl3, ppm) 57.2,
102.6, 108.2, 123.4, 125.8, 128.9, 129.5, 130.3, 130.9,
131.1, 133.5, 133.9, 161.8, 166.2, 168.1; Anal. Calc. for
C17H12NO3Br: C, 57.01; H, 3.38; N, 3.91; Found: C, 56.35;
H, 3.31; N, 3.75.
Preparation of 3-(4-methylphenyl)-5-[methyl(phenyl-
carboxylate)]isoxazole (5b)
This compound was prepared with the described
method for 4a. Yield 82%; m.p. 73 oC; FT-IR (KBr, cm-1):
3100, 2900, 1720, 1600, 1445, 1425, 1260, 1310, 1185,
1100, 1060, 910, 810, 700; 1H NMR (CDCl3, ppm) 2.42 (s,
3H, CH3), 5.5 (s, 2H, CH2), 6.7 (s, 1H, isoxazole-H),
7.25-8.15 (m, 9H, Ar-H); 13C NMR (CDCl3, ppm) d: 21.8,
57.3, 102.6, 127.1, 128.9, 129.5, 130, 130.2, 132, 133.9,
140.7, 164, 166, 167.4; Anal. Calc. for C18H15NO3: C,
93.71; H, 5.15; N, 4.78; Found: C, 73.41; H, 5.14; N, 4.78.
Preparation of 5-isoxazolemethanol, 3-phenyl, 5-ben-
zoate (5c)12
Preparation of 3-(2-phenylethyl)-5-[methylphenylcar-
boxylate)]isoxazole (5g)
This compound was prepared with the described
method for 4a, Yield 71% as viscous oil. FT-IR (neat, cm-1)
3050, 2900, 1720, 1600, 1580, 1490, 1430, 1100, 700. 1H
NMR (CDCl3, ppm) 3 (s, 4H, CH2-CH2), 5.4 (s, 2H, CH2),
6.2 (s, 1H, isoxazole-H), 7.2-8.15 (m, 10H, Ar-H); 13C
NMR (CDCl3, ppm) 28.4, 34.8, 57.3, 104.5, 126.8, 128.8,
128.9, 129, 129.5, 130, 140.8, 163.9, 166.3, 166.8; Anal.
Calc. for C19H17NO3: C, 74.25; H, 5.58; N, 5.60; Found: C,
74.14; H, 5.76; N, 5.39.
This compound was prepared with the described
method for 4a, Yield 85%; m.p. 76 oC; FT-IR (KBr, cm-1):
3100, 2950, 1720, 1605, 1440, 1400, 1360, 1266, 1100,
900. 1H NMR (CDCl3, ppm) 5.50 (s, 2H, CH2), 6.72 (s, 1H,
isoxazole-H), 7.25-8.15 (m, 10H, Ar-H); 13C NMR (CDCl3,
ppm) 57.3, 102.7, 108, 119, 127.2, 128.9, 129.3, 130.2,
130.5, 133.9, 148, 163, 170.3; Anal. Calc. for C17H13NO3:
C, 73.11; H, 4.69; N, 5.02; Found: C, 73.14; H, 4.65; N,
4.94.
Received June 23, 2008.

Synthesis of New Isoxazoles
J. Chin. Chem. Soc., Vol. 55, No. 6, 2008 1325
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