A novel synthesis of isoxazoles via 1,3-dipolar cycloaddition of nitrile oxides to acetyl acetone

Article abstract of DOI:10.1081/SCC-120004066

Nitrile oxides (2) isolated from the oxidative dehydrogenation of aldoximes (1) by chloramines-T react with acetyl acetone (3) to afford 4-acetyl-3-aryl-5-methyl isoxazoles (5) in good yield. All new compounds were characterized by IR, ¹H NMR,

Full text of DOI:10.1081/SCC-120004066

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A NOVEL SYNTHESIS OF ISOXAZOLES VIA 1,3-DIPOLAR
CYCLOADDITION OF NITRILE OXIDES TO ACETYL
ACETONE
K. B. Umesha a , K. Ajay Kumar a & K. M. Lokanatha Rai b
a Department of Studies in Chemistry , University of Mysore , Manasagangotri, Mysore, 570
005, India
b Department of Studies in Chemistry , University of Mysore , Manasagangotri, Mysore, 570
005, India
Published online: 17 Oct 2011.
To cite this article: K. B. Umesha , K. Ajay Kumar & K. M. Lokanatha Rai (2002) A NOVEL SYNTHESIS OF ISOXAZOLES VIA 1,3-
DIPOLAR CYCLOADDITION OF NITRILE OXIDES TO ACETYL ACETONE, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:12, 1841-1846, DOI: 10.1081/SCC-120004066
To link to this article: http://dx.doi.org/10.1081/SCC-120004066
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SYNTHETIC COMMUNICATIONS, 32(12), 1841–1846 (2002)
A NOVEL SYNTHESIS OF ISOXAZOLES
VIA 1,3-DIPOLAR CYCLOADDITION OF
NITRILE OXIDES TO ACETYL ACETONE
K. B. Umesha, K. Ajay Kumar, and
*
K. M. Lokanatha Rai
Department of Studies in Chemistry, University of
Mysore, Manasagangotri, Mysore 570 005, India
ABSTRACT
Nitrile oxides (2) isolated from the oxidative dehydrogenation
of aldoximes (1) by chloramines-T react with acetyl acetone
(3) to afford 4-acetyl-3-aryl-5-methyl isoxazoles (5) in good
yield. All new compounds were characterized by IR,
1H NMR, 13C NMR, MS studies and elemental analysis.
1,3-Dipolar cycloaddition reactions are the useful tool for constructing
biologically potent five membered heterocyclic compounds.[1] Cycloaddition
of nitrile oxide to olefinic or acetylenic compounds are of synthetic interest,
since the products isoxazolines and isoxazoles obtained respectively are the
versatile intermediates for the synthesis of bifunctional compounds.[2]
Apart from the various dipolarophiles known, nitrile oxides have been
extensively used.
*Corresponding author.
1841
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1842
UMESHA, AJAY KUMAR, AND LOKANATHA RAI
The usual synthesis of nitrile oxides involves the oxidative dehydro-
genation of aldoximes using oxidants such as lead tetraacetate,[3] alkali
hypohalite,[4] N-bromosuccinimide in DMF followed by base treatment,[5]
chloramine-T,[6] mercuric acetate,[7] or 1-chlorobenzotriazole[8] as well as
the reactions of nitro compounds with aryl isocyanate[9] and di-ter-butyl
dicarbonate in presence of DMAP.[10]
In continuation of our work on 1,3-dipolar cycloaddition reactions, we
thought of using acetyl acetone as dienophyle for the cycloaddition of pre-
formed nitrile oxides to get isoxazoles and successfully carried out the reac-
tion at room temperature. In a typical reaction, a mixture of the preformed
3,4-dimethoxybenzonitrile oxide 2c (0.895 g, 5.0 mmol) isolated from
3,4-dimethoxybenzaldehyde oxime 1c was treated with excess of acetyl
acetone 3 (1.0 g, 10 mmol) in dichloromethane was well stirred at room
temperature for 6 h. After the usual workup, the product isoxazole 5c was
obtained in 64% (0.835 g) yield.
5a) R5C6H5, b) R54-H3COC6H4, c) R53,4-(H3CO)2C6H3, d) R5
3,4,5-(H3CO)3C6H2, e) R54-ClC6H4, f) R53,4-(OCH2O)C6H3.
The structure proof of the cycloadducts were provided by IR,
1H NMR 13C NMR, MS studies and elemental analysis. For instance, in
IR spectra, the signals expected due to OH group in the region
1
3590–3650 cmꢀ1 was found absent. In H NMR spectra all cycloadducts
gave the signals due to aromatic and substituent protons at the expected
region. The signals expected due to COCH3 and methyl protons appear as
singlet in the region ꢀ 2.11–2.20 ppm and ꢀ 2.65–2.70 ppm respectively. The
signals expected due to methylene protons of the starting acetyl acetone
were found absent. It is note worthy to observe that the signals expected
at downfield due to C4-H and C5-OH protons as in the case of simple
cycloaddition of nitrile oxides to ene system were also found absent.
Scheme 1.

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SYNTHESIS OF ISOXAZOLES
1843
The absence of these signals suggests that the reaction proceeded with the
elimination of water from the intermediate isoxazolines 4 after cycloaddition
to form the cycloadducts 5.
In 13C NMR spectra, all showed the significantly consistent pattern
signals due to newly formed C4 carbon as singlet in the region ꢀ
117.24–117.48 ppm. While, C3 and C5-carbon appear as singlet in the
region ꢀ 161.60–161.82 ppm and ꢀ 174.40–174.58 ppm respectively. Further
all cycloadducts gave the signals due to aromatic and substituent carbons
at the expected region. All cycloadducts showed MHþ ion peak as base
peak. All gave significantly stable molecular ion peaks with a relative
abundance ranging from 11–86%, which strongly favours the formation
of the cycloadducts. Further, the formation of the cycloadducts was
provided by satisfactory elemental analysis.
EXPERIMENTAL SECTION
Melting points were recorded in open capillaries using Thomus
Hoover apparatus and were uncorrected. The compounds were routinely
checked for their purity by TLC using silica gel-G. IR spectra were recorded
1
on Shimadzu FT 8300 spectrometer. H NMR spectra were recorded on a
Bruker 300 MHz spectrometer; 13C NMR spectra were measured on Jeol
GSX 400 (75 MHz) instrument using CDCl3 as solvent. Chemical shifts
are expressed in (ꢀ) and the values are in parts per million downfield from
the tetramethyl silane. Mass spectra were obtained on Maspec MSW 9629
spectrometer and the important fragments are given with the relative inten-
sities given in the bracket. Chromatographic separations were carried out on
a silica gel (70–230 mesh, Merck.) column. The proportion of the solvents
for the chromatography was given as volume/volume.
General Procedure for the Isolation of Nitrile Oxide 2
Oxime (1 mmol) dissolved in 95% ethanol (5 ml) was treated with chlor-
amine-T (1.2 mmol) at room temperature. After 2 min swirling, the solvent
was evaporated. The residue was extracted with ether (25 ml) and the organic
layer was washed successively with water (2 Â 15 ml), 1 N NaOH (1 Â 10 ml),
brine solution (2 Â 20 ml) and dried over anhydrous sodium sulfate.
Evaporation of the solvent yielded the nitrile oxide in good yield (70–90%).
In 13C NMR, the nitrile oxide carbon of 2d absorbed at 104.69 ppm.
Typical procedure for the preparation of 4-Acetyl-5-methyl-3-(30,40-
dimethoxyphenyl)-isoxazole 5c: A mixture of 3,4-dimethoxy benzonitrile

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1844
UMESHA, AJAY KUMAR, AND LOKANATHA RAI
oxide 2c (0.895 g, 5.0 mmol), freshly distilled acetyl acetone 3 (1.0 g, 10 mmol)
in dichloromethane (20 ml) were well stirred at room temperature 6 h. The
progress of the reaction was monitered by TLC. After the completion of the
reaction the solvent was evaporated in vacuo. The residual mass was
extracted into ether (25 ml), washed successively with water (2 Â 20 ml),
brine solution (1 Â 15 ml) and dried over anhydrous sodium sulphate.
Evaporation of the solvent afforded white mass, which gave one major spot
corresponding to the product and two minor spots related to the starting
materials in TLC, which was purified by column chromatography using ben-
xene:ethyl acetate (8 : 1) as eluent. 5c was obtained as white solid in 64%
(0.835 g) yield. M.p. 72–73ꢁC. H NMR (CDCl3): ꢀ 2.15 (s, 3H, COCH3),
1
2.69 (s, 3H, CH3), 3.93 (s, 6H, OCH3), 6.97 (s, 1H, 50-H), 7.09 (s, 2H, 20, 60-
H); 13C NMR (CDCl3): ꢀ 13.52 (q, 1C, CH3), 30.45 (q, 1C, COCH3), 55.95 (q,
2C, OCH3), 110.98 (d, 1C, 50-C), 111.81 (d, 1C, 20-C), 117.26 (s, 1C, 4-C),
120.98 (s, 1C, 10-C), 121.97 (s, 1C, 60-C), 148.95 (s, 1C, 30-C), 150.40 (s, 1C,
40-C), 161.61 (s, 1C, 3-C), 174.44 (s, 1C, 5-C), 193.52 (s, 1C, CO); MS (relative
abundance): m/z for C14H15NO4, 262 (MHþ, 100), 246 (10), 218 (45), 204
(80), 179 (18), 163 (15). Anal. calcd C, 64.36, H, 5.74, N, 5.36%; Found: C,
64.24, H, 5.65, N, 5.28%. The same procedure was used in all cases.
4-Acetyl-5-methyl-3-(phenyl)-isoxazole 5a: Obtained from benzonitrile
oxide 2a (0.595 g, 5.0 mmol), acetyl acetone 3 (1.0 g, 10 mmol) as white solid in
59% (0.592 g) yield. M.p. 145–147ꢁC. H NMR (CDCl3); ꢀ 2.14 (s, 3H,
1
COCH3), 2.68 (s, 3H, CH3), 7.12 (s, 1H, 40-H) 7.25 (s, 2H, 30, 50-
H); 7.38(s, 2H, 20, 60-H); 13C NMR (CDCl3):ꢀ 13.50 (q, 1C, CH3), 30.44 (q, 1C,
COCH3), 117.24 (s, 1C, 4-C), 126.88–127.02 (d, 2C, 30, 50-C), 127.88 (s, 1C,
10-C), 128.08–128.66 (d, 2C, 20, 60-C), 130.69 (s, 1C, 40-C), 161.60 (s, 1C, 3-C),
174.44 (s, 1C, 5-C), 193.50 (s, 1C, CO); MS (relative abundance): m/z for
C12H11NO2, 202 (MHþ, 100), 186 (12), 158 (44), 144 (81), 119 (17), 103 (14).
Anal. calcd C, 71. 64, H, 5.47, N, 6.96%; Found: C, 71.52, H, 5.35, N, 6.78%.
4-Acetyl-5-methyl-3-(40-methoxyphenyl)-isoxazole 5b: Obtained from
4-methoxy benzonitrile oxide 2b (0.745 g, 5.0 mmol), acetyl acetone 3 (1.0 g,
10 mmol) as white solid in 68% (0.785 g) yield. M.p. 55–57ꢁC. H NMR
1
(CDCl3); ꢀ 2.12 (s, 3H, COCH3), 2.66 (s, 3H, CH3), 3.90 (s, 3H, OCH3)
6.99 (d, 2H, 30, 50-H); 7.46 (d, 2H, 20, 60-H); 13C NMR (CDCl3): ꢀ 13.52
(q, 1C, CH3), 30.67 (q, 1C, COCH3), 55.68 (q, 1C, OCH3), 114.38–114.88
(d, 2C, 30, 50-C), 117.38 (s, 1C, 4-C), 121.16 (s, 1C. 10-C), 128.86–129.08 (d, 2C,
20, 60-C), 156.48 (s, 1C, 40-C), 161.71 (s, 1C, 3-C), 174.54 (s, 1C, 5-C), 193.53
(s, 1C, CO); MS (relative abundance: m/z for C13H13NO3, 232 (MHþ, 100),
216 (11), 188 (46), 174 (80), 149 (14), 133 (14). Anal. calcd C, 67.53, H, 5.62,
N, 6.06%; Found: C, 67.44, H, 5.50, N, 5.97%.
4-Acetyl-5-methyl-3-(30,40,50-trimethoxyphenyl)-isoxazole 5d: Obtained
from 3,4,5-trimethoxy benzonitrile oxide 2d (0.995 g, 5.0 mmol), acetyl

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SYNTHESIS OF ISOXAZOLES
1845
acetone 3 (1.0 g, 10 mmol) as white solid in 81% (1.12 g) yield. M.p.
52–54ꢁC. H NMR (CDCl3); ꢀ 2.14 (s, 3H, COCH3), 2.68 (s, 3H, CH3),
1
3.84 (s, 6H, OCH3) 3.96 (s, 3H, OCH3), 7.23 (s, 2H, 20,60-H); 13C NMR
(CDCl3): ꢀ 13.48 (q, 1C, CH3), 30.42 (q, 1C, COCH3), 55.87 (q, 2C, 30, 50-
OCH3), 60.08 (q, 1C, 40-OCH3), 117.38 (s, 1C, 4-C), 121.03 (s, 2C, 20, 60-C),
121.48 (s, 1C, 10-C), 148.98 (s, 2C, 30, 50-C), 151.38 (s, 1C, 40-C), 161.58 (s,
1C, 3-C), 174.53 (s, 1C, 5-C), 193.67 (s, 1C, CO); MS (relative abundance):
m/z for C15H17NO5, 292 (MHþ, 100), 276 (14), 248 (43), 234 (86), 209 (17),
193 (14). Anal. calcd C, 61.85, H, 5.84, N, 4.81%; Found: C, 61.71, H, 5.77,
N, 4.74%.
4-Acetyl-5-methyl-3-(40-chlorophenyl)-isoxazole 5e: Obtained from
4-chloro benzonitrile oxide 2e (0.765 g, 5.0 mmol), acetyl acetone 3 (1.0 g,
10 mmol) as white solid in 54% (0.637 g) yield. M.p. 135–137ꢁC. H NMR
1
(CDCl3); ꢀ 2.11 (s, 3H, COCH3), 2.67 (s, 3H, CH3), 7.05 (d, 2H, 20, 60-H)
7.31 (d, 2H, 30, 50-H); 13C NMR (CDCl3): ꢀ 13.51 (q, 1C, CH3), 30.44 (q, 1C,
COCH3), 113.52 (s, 2C, 30, 50-C), 117.32 (s, 1C, 4-C), 121.02 (s, 1C, 10-C),
126.99 (s, 2C. 20, 60-C), 155.32 (s, 1C, 40-C), 161.68 (s, 1C, 3-C), 174.48 (s,
1C, 5-C), 193.51 (s, 1C, CO); MS (relative abundance): m/z for
C12H10NO2Cl, 238 (MHþ, Cl37, 33), 236 (MHþ, Cl35, 100), 220 (13), 192
(46), 178 (81), 153 (10), 137 (15). Anal. calcd C, 61.27, H, 4.25, N, 5.95,
15.08%; Found: C, 61.21, H, 4.17, N, 5.85, 15.01%.
4-Acetyl-5-methyl-3-(30,40-methylenedioxyphenyl)-isoxazole
5f:
Obtained from 3,4,-methylenedioxy benzonitrile oxide 2f (0.825 g,
5.0 mmol), acetyl acetone 3 (1.0 g, 10 mmol) as white solid in 62% (0.750 g)
yield. M.p. 58–61ꢁC. 1H NMR (CDCl3); ꢀ 2.12 (s, 3H, COCH3), 2.65 (s, 3H,
CH3), 5.98 (s, 2H, OCH2O), 7.08 (d, 2H, 20, 60-H), 7.12 (s, 1H, 50-H);
13C NMR (CDCl3): ꢀ 13.46 (q, 1C, CH3), 30.43 (q, 1C, COCH3), 101.32
(t, 1C, OCH2O), 117.48 (s, 1C, 4-C), 120.58 (s, 2C, 20, 60-C), 120.88 (s, 2C,
50-C), 121.09 (s, 1C, 10-C), 148.99) (s, 2C, 30, 40-C), 151.38 (s, 1C, 40-C),
161.82 (s, 1C, 3-C), 174.58 (s, 1C, 5-C), 193.62 (s, 1C, CO); MS (relative
abundance): m/z for C13H11NO4, 246 (MHþ, 100), 230 (11), 202, (43), 188
(76), 163 (14), 147 (14). Anal. calcd C, 63.67, H, 4.48, N, 5.71%; Found:
C, 63.60, H, 4.41, N, 5.65%.
ACKNOWLEDGMENTS
One of the authors (KBU) is grateful to Prof. Alfred Hassner,
Chemistry Department, Bar-Ilan University, Israel for spectral studies for
the synthesised compounds and to the University of Mysore for the award
of Teacher Fellow and financial support.

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1846
UMESHA, AJAY KUMAR, AND LOKANATHA RAI
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Received in the Netherlands June 27, 2001