An efficient one-pot synthesis of 3-aryl-5-methylisoxazoles from aryl aldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.05.104

An efficient protocol for the one-pot preparation of alkyl 3-aryl-5-methylisoxazole-4-carboxylates from aryl aldehydes is described. This method is readily amenable to the large scale preparation of isoxazoles as well as the parallel synthesis of isoxazole libraries.

Full text of DOI:10.1016/j.tetlet.2011.05.104

Tetrahedron Letters 52 (2011) 4001–4004
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An efficient one-pot synthesis of 3-aryl-5-methylisoxazoles from aryl aldehydes
⇑
Shirong Zhu , Shuhao Shi, Samuel W. Gerritz
Early Discovery Chemistry, Bristol-Myers Squibb Co., Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the one-pot preparation of alkyl 3-aryl-5-methylisoxazole-4-carboxylates from
aryl aldehydes is described. This method is readily amenable to the large scale preparation of isoxazoles
as well as the parallel synthesis of isoxazole libraries.
Received 4 April 2011
Revised 15 May 2011
Accepted 23 May 2011
Available online 30 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated with affection to Professor
Theodore Cohen of University of Pittsburgh
on the occasion of his 80th birthday
Keywords:
One-pot synthesis
Isoxazoles
Parallel synthesis
Library synthesis
1,3-Dipolar cycloaddition
1. Introduction
A frequently-cited and robust synthetic route to 3-aryl-5-
methylisoxazole carboxylates is the 1,3-dipolar cycloaddition of
Isoxazole derivatives have been widely studied as potential phar-
maceutical agents.1 For example, structures containing the 3-aryl-5-
methylisoxazole-4-carboxamide moiety have been reported as
modulators of the ghrelin receptor (1),2 selective antagonists of
alkenes and alkynes with nitrile oxides.5b This procedure involves
three discrete steps: (1) conversion of an aldehyde to the corre-
sponding oxime; (2)
a-chlorination of the oxime using N-chloro-
succinimide (NCS), usually initiated by HCl gas; and (3) reaction
of the resulting hydroximinoyl chloride with a dipolarophile such
as an alkyne,6 the enolate of a b-ketoester or b-ketoamide7 or the
enamine of a b-ketoester.8 As shown in Scheme 1 for the reaction
with the enamine of a b-ketoester, a different solvent (or solvent
mixture) is used in each of the three reactions: (1) water/ethanol;
(2) DMF; and (3) ethanol. In practice, the oxime and hydroximinoyl
chloride intermediates are usually isolated via extraction and used
in the next step without further purification. Although this
three-step procedure is quite general, we found that the chemistry
was not amenable to the parallel synthesis of libraries of isoxazoles
due to the number of extraction, filtration, and solvent evaporation
the a
1a adrenergic receptor (2),3 and allosteric metabotropic gluta-
mate receptor 7 antagonists (isoxazolopyridone 3 was prepared
from 4 in two steps).4 Isoxazoles have also served as versatile build-
ing blocks in organic synthesis.5
F3C
F
O
N
N
Cl
O
N
N
H
H
N
O
Cl
N
N
O
O
2
1
steps. We sought
limitations.
a one-pot procedure to overcome these
N
Our initial breakthrough in this effort was the discovery that the
final step (dipolar cycloaddition) could be carried out in an EtOH/
DMF solvent mixture. This allowed us to combine the chlorination
and the 1,3-dipolar cycloaddition steps and eliminate the isolation
of hydroximinoyl chlorides from DMF. Our standard procedure in-
volved adding a solution of the enamine of ethyl acetoacetate and
triethylamine in ethanol to the chlorination reaction mixture.9 Fur-
ther efficiency was gained by generating the oximes in DMF rather
than an ethanol/water mixture. In order to promote oxime forma-
tion, it was necessary to add triethylamine to the mixture of
N
O
3
O
N
N
N
H
O
N
O
MeO
4
⇑
Corresponding author. Tel.: +1 203 677 7362.
E-mail address: shirong.zhu@bms.com (S. Zhu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.104

4002
S. Zhu et al. / Tetrahedron Letters 52 (2011) 4001–4004
R
is complete overnight. We generally use a slight excess of NCS to
R
R
NCS, HCl (g)
DMF
NH2OH⋅HCl, NaOH
drive the chlorination step to completion. Finally, a solution of
the enamine of ethyl acetoacetate and triethylamine in ethanol
was added. The 1,3-dipolar cycloaddition can take from 2 to 16 h.
All three reaction steps can be conveniently monitored by LC/MS.
The overall yield of isoxazoles generated in the one-pot synthesis
is usually higher than the yield obtained via the three-step proce-
dure described previously. This is exemplified by direct compari-
Cl
H
H
EtOH/ H2O
N
N
O
N
OH
OH
O
O
R
O
O
son of the yield of the same isoxazoles (compounds 1, 4 and 5)
8b
Et3N, EtOH
synthesized by our one-pot method and that reported in Ref.
.
N
O
We have achieved yields very similar to those reported in the liter-
ature when we carried out the synthesis following the three-step
procedure.
Scheme 1.
(1) NH2OH⋅HCl, Et3N, DMF, RT
R
aldehyde and hydroxylamine hydrochloride in DMF. These solvent
changes provided an efficient one-pot synthesis of isoxazoles from
aldehydes (Eq. 1). The oxime-forming step is usually complete
within 1 h at room temperature. The chlorination was done by
simply adding N-chlorosuccinimide all at once to the oxime reac-
tion mixture. It is not necessary to add NCS slowly in portions or
use HCl gas or heat10 to initiate the reaction and the chlorination
(2) NCS, RT, 16 h
R
O
O
H
O
O
(3)
Et3N, RT
N
N
O
O
ð1Þ
Table 1
Isoxazoles prepared from aldehydes by one-pot synthesis
Compd No.
1
Structure of product
Yield (%)a of one-pot syn.
Yield (%) of multi-step syn.
40d, (100,78,51)
Purity (%)
98.1
O
OEt
93b
MeO
Br
N
O
O
OEt
2
3
84c
79c
99.2
99.3
MeO
F
N
O
O
CN
OEt
N
O
O
OEt
4
5
6
90
79
69
68d, (96,94,75)
47d, (69, 90,75)
99.6
99.0
98.3
Cl
N
O
O
OEt
Cl
Cl
N
O
O
OEt
N
O
OMe
O
OEt
7
60
99.7
MeO
N
O
O
F
OEt
8
9
67
85
99.4
98.5
Cl
N
O
O
OEt
N
Br
N
O
a
b
c
Isolated yields for products purified by preparative HPLC unless noted otherwise.
Yield of crude product.
Products purified by flash chromatography.
d
Yields for individual steps in parentheses as reported in Ref. 8b.

S. Zhu et al. / Tetrahedron Letters 52 (2011) 4001–4004
4003
Table 2
At a small scale as 50–100 mg, this one-pot synthesis can be
Isoxazoles from aliphatic aldehydes or other dipolarophiles
easily carried out at room temperature in glass vials sealed with
Teflon caps. The products are purified by preparative HPLC by
injecting the reaction mixture. For reactions with precipitate in
the reaction mixture, we can either add small amount of water
to make a clear solution, or filter to remove the precipitate prior
to injection for purification. Consistently good yields were ob-
served for all isoxazoles synthesized in the library format.
With minor modifications, this one-pot synthesis was carried
out at a scale greater than 10 g of product. We have observed that
the oxime formation and the chlorination steps are exothermic.
Therefore, triethylamine was added dropwise as a solution in
DMF and both triethylamine and NCS were added at 0 °C. For com-
pound 1, the product isolated by extraction is clean by NMR anal-
ysis. It was hydrolyzed to give the isoxazole carboxylic acid 10, the
desired product of our program. The isoxazole acid did not require
purification other than extraction following the ester saponifica-
tion step and the acid was even cleaner than its ester precursor.
All products were characterized by HPLC (purity reported in Table
1) and NMR.11 The new compounds were also characterized by
high resolution mass spectrometry.
Aldehyde
Dipolarophile
Products (compd No., %yield)
O
O
CHO
N
O
(11, 38%)
O
O
N
O
CHO
O
O
ONa O
(12, 60%)
O
O
N
O
CHO
O
O
O
O
O
(12, 61%)
(13, 4%)
O
N
O
O
O
O
N
O
O
O
CHO
O
O
O
(14, 65%)
N
2. Representative procedures
2.1. Procedure for large scale synthesis
(0.059 mL, 0.427 mmol) in ethanol (0.9 mL) was added and the
resulting reaction mixture was stirred at room temperature for
16 h. The product was purified by preparative HPLC (0.1% TFA,
MeOH/H2O) to give 148.1 mg. 1H NMR (400 MHz, CDCl3) d 7.60
(d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H),
2.75 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d
176.0, 161.8, 161.6, 136.0, 130.8 (s, 2C), 128.2 (s, 2C), 127.0,
108.4, 60.8, 14.0, 13.6.
2.1.1. Ethyl 3-(2-methoxyphenyl)-5-methylisoxazole-4-
carboxylate (1)
To the mixture of 2-methoxybenzaldehyde (7.18 g, 52.7 mmol)
and hydroxylamine hydrochloride (3.66 g, 52.7 mmol) in a 1000-
mL round bottomed flask was added 100 mL of DMF. The suspen-
sion was stirred at 0 °C while a solution of triethylamine (5.34 g,
52.7 mmol) in 35 mL of DMF was added dropwise. The ice-water
bath was removed once the addition of triethylamine was finished
and the reaction mixture was stirred at rt for 2 h. The reaction mix-
ture was cooled to 0 °C, followed by the addition of NCS (7.04 g,
52.7 mmol). The reaction mixture was stirred overnight, while
the temperature rose from 0 °C to rt slowly. A solution of (E)-ethyl
3-(pyrrolidin-1-yl)but-2-enoate (10.15 g, 55.4 mmol) and triethyl-
amine (3.20 g, 31.6 mmol) in ethanol (50.0 mL) was added drop-
wise and the resulting reaction mixture was stirred at rt for 16 h.
Water (400 mL) was added to the reaction mixture and the aque-
ous layer was extracted with ether (4 ꢀ 150 mL). The combined or-
ganic extracts were washed with water (2 ꢀ 100 mL), and dried
over anhydrous sodium sulfate. Solvent was evaporated to give
12.85 g of the product (93%, theoretical yield 13.78 g). 1H NMR
(400 MHz, CDCl3) d 7.49–7.36 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H),
6.95 (d, J = 8.3 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 2.72 (
s, 3H), 1.11 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 17 4.
1, 162.2, 160.2, 157.5, 131.1, 130.3, 120.4, 118.4, 110.5, 110.2, 60
.3, 55.4, 13.9, 13.0.
2.3. Procedure for hydrolysis of the ethyl ester to carboxylic acid
2.3.1. 3-(2-Methoxyphenyl)-5-methylisoxazole-4-carboxylic
acid (10)
The reaction mixture of ethyl 3-(2-methoxyphenyl)-5-methy-
lisoxazole-4-carboxylate (12.85 g, 49.2 mmol) and sodium hydrox-
ide (9.84 g, 246 mmol) in MeOH (100 mL) and water (10 mL) in a
500-mL round bottomed flask was stirred at 65 °C for 20 h. The
reaction mixture was concentrated by removing methanol by ro-
tary evaporation. The concentrated reaction mixture was trans-
ferred to a 500-mL separatory funnel with 150 mL of water and
100 mL of ether. Two layers were separated and the organic layer
was discarded. The aqueous layer was acidified by adding concen-
trated HCl (26 mL). The product precipitated and was separated by
filtration and dried under high vacuum.
The yield of the product, 10.63 g, is 93% for the hydrolysis and
86.4% from 2-methoxybenzaldehyde used in the previous step.
1H NMR (400 MHz, CD3OD) d 7.49–7.42 (m, 1H), 7.33 (dd, J = 7.4,
1.6 Hz, 1H), 7.09–6.98 (m, 2H), 3.77 (s, 3H), 2.69 (s, 3H). 13C NMR
(100 MHz, CD3OD) d 175.6, 165.1, 162.1, 159.4, 132.5, 131.1,
121.5, 119.6, 112.3, 111.9, 56.1, 13.0.
2.2. Procedure for small scale synthesis
2.2.1. Ethyl 3-(4-chlorophenyl)-5-methylisoxazole-4-
carboxylate (6)
3. Broadening applications
To the mixture of 4-chlorobenzaldehyde (100 mg, 0.711 mmol)
and hydroxylamine hydrochloride (49.4 mg, 0.711 mmol) in an 8-
mL vial was added 1.5 mL of DMF, followed by the addition of
triethylamine (0.099 mL, 0.711 mmol). The vial was capped and
stirred at ambient temperature for 1 h. NCS (0.095 g, 0.711 mmol)
was added and the reaction vial was capped and stirred at ambient
temperature overnight. Additional 15 mg of NCS was added and
the reaction continued for 6 h. A solution of (E)-ethyl 3-(pyrroli-
din-1-yl)but-2-enoate (130 mg, 0.711 mmol) and triethylamine
To explore the scope and limitations of the methodology, we
studied aliphatic aldehydes and other dipolarophiles, as illustrated
in Table 2. Alkynes (1.2 equiv relative to aldehyde) were added
with equimolar triethylamine in ethanol to the reaction mixture.
Enolates also be used as the dipolarophile: sodium methoxide
(1 equiv to aldehyde) in methanol was added to the reaction mix-
ture prior to the addition of the enolate, which was prepared by
mixing equimolar b-ketoester and sodium methoxide in methanol.

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S. Zhu et al. / Tetrahedron Letters 52 (2011) 4001–4004
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Caravella, J. A.; Chen, L.; Creech, K. L.; Deaton, D. N.; Madauss, K. P.; Marr, H. B.;
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Bioorg. Med. Chem. Lett. 2009, 19, 2969–2973.
All other reaction conditions remained the same as described in
Section 2.2.
Only one example in Table 2 provided a mixture of two regio-
isomers, and in that instance the regioselectivity was >15:1 in fa-
vor of the desired product. These preliminary results demonstrate
that the one-pot approach can be used for the synthesis of isoxaz-
oles with a variety of substitution patterns.
8. (a) Mosher, M. D.; Natale, N. R. J. Heterocycl. Chem. 1995, 32, 779–781; (b)
Zamponi, G. W.; Stotz, S. C.; Staples, R. J.; Andro, T. M.; Nelson, J. K.; Hulubei, V.;
Blumenfeld, A.; Natale, N. R. J. Med. Chem. 2003, 46, 87–96.
9. While this manuscript was in preparation, we noticed a similar protocol under
different reaction conditions Nakamura, M.; Kurihara, H.; Suzuki, G.; Mitsuya,
M.; Ohkubo, M.; Ohta, H. Bioorg. Med. Chem. Lett. 2010, 20, 726–729.
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11. Analytical data.
4. Conclusion
Spectral data for ethyl 3-(5-bromo-2-methoxyphenyl)-5-methylisoxazole-4-
carboxylate (2): 1H NMR (400 MHz, CDCl3) d 7.57–7.49 (m, 2H), 6.83 (d,
J = 8.5 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 2.72 (s, 3H), 1.14 (t,
J = 7.2 Hz, 3H).
We have simplified the synthesis of isoxazoles from aldehydes
by combining the formation of oximes, chlorination of the oximes
and the 1,3-dipolar cycloaddition of the commonly used dipolaro-
philes with the nitrile oxides generated in situ by the reaction of
the hydroximinoyl chlorides with triethyl amine into a one-pot
reaction. We have found this procedure to be particularly useful
in the parallel synthesis of libraries of isoxazole analogs. Significant
time and cost savings were also achieved when we synthesized
isoxazoles at a large scale.
13C NMR (100 MHz, CDCl3) d 174.4, 161.9, 159.0, 156.7, 133.7, 133.0, 120.3,
112.4, 112.3, 110.1, 60.4, 55.7, 13.9, 13.0.
HRMS: calcd for C14H15BrNO4, (MH+) 340.0185, found 340.0179.
Spectral data for ethyl 3-(3-cyano-4-fluorophenyl)-5-methylisoxazole-4-
carboxylate (3): 1H NMR (400 MHz, CDCl3) d 8.00 (dd, J = 6.0, 2.0 Hz, 1H),
7.94 (ddd, J = 8.8, 5.0, 2.3 Hz, 1H), 7.31 (t, J = 8.7 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H),
2.77 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 176.6, 165.1,
162.4, 161.4, 160.0, 136.3, 136.2, 125.9, 116.4, 116.2, 113.3, 108.2, 101.7, 101.5,
61.1, 14.0, 13.7.
HRMS: calcd for C14H12FN2O3, (MH+) 275.0832, found 275.0824.
Spectral data for ethyl 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylate
(4): 1H NMR (400 MHz, CDCl3) d 7.51–7.31 (m, 4H), 4.15 (q, J = 7.0 Hz, 2H), 2.77
(s, 3H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 175.2, 161.6, 160.8,
134.1, 130.9, 130.7, 129.3, 128.8, 126.5, 109.9, 60.6, 13.6, 13.1.
Spectral data for ethyl 3-(3-chlorophenyl)-5-methylisoxazole-4-carboxylate
(5): 1H NMR (400 MHz, CDCl3) d 7.65 (t, J = 1.6 Hz, 1H), 7.53 (dt, J = 7.7, 1.3 Hz,
1H), 7.48–7.43 (m, 1H), 7.42–7.35 (m, 1H), 4.26 (q, J = 7.3 Hz, 2H), 2.75 (s, 3H),
1.26 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 176.1, 161.7, 161.3, 133.8,
130.2, 129.7, 129.6, 129.2, 127.6, 108.4, 60.8, 13.9, 13.5.
Acknowledgment
We thank Weixu Zhai for useful discussion of some experimen-
tal details.
Supplementary data
Spectral data for ethyl 3-(2,5-dimethoxyphenyl)-5-methylisoxazole-4-
carboxylate (7): 1H NMR (400 MHz, CDCl3) d 7.00–6.94 (m, 2H), 6.90–6.81
(m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.71 (s, 3H), 1.13 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 174.0, 162.1, 160.0, 153.3, 151.7,
118.8, 116.3, 115.6, 111.8, 110.2, 60.3, 55.9, 55.8, 13.8, 12.9.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.104.
HRMS: calcd for C15H18NO5, (MH+) 292.1185, found 292.1174.
References and notes
Spectral data for ethyl 3-(2-chloro-4-fluorophenyl)-5-methylisoxazole-4-
carboxylate (8): 1H NMR (400 MHz, CDCl3) d 7.40 (dd, J = 8.5, 6.0 Hz, 1H),
7.24 (dd, J = 8.5, 2.5 Hz, 1H), 7.08 (td, J = 8.3, 2.5 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H),
2.77 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 175.4, 164.5,
162.0, 161.5, 160.1, 135.3, 135.2, 132.2, 132.1, 125.0 (d, J = 3.9 Hz, 1C), 117.1,
116.9, 114.0, 113.8, 109.8, 60.7, 13.7, 13.2.
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Med. Chem. Lett. 2010, 20, 1363–1367.
Spectral data for methyl 3-(2-methoxyphenyl)-4-methylisoxazole-5-
carboxylate (13): 1H NMR (400 MHz, CDCl3) d 7.53–7.44 (m, 1H), 7.39 (dd,
J = 7.5, 1.8 Hz, 1H), 7.12–6.99 (m, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 2.21 (s, 3H). 13
C
NMR (100 MHz, CDCl3) d 163.1, 158.4, 157.3, 154.7, 131.6, 131.3, 122.6, 120.8,
117.3, 111.1, 55.5, 52.4, 8.6.
Spectral data for 1-(3-(2-methoxyphenyl)-5-phenylisoxazol-4-yl)ethanone
(14): 1H NMR (400 MHz, CDCl3) d 7.90 (dd, J = 7.8, 1.8 Hz, 2H), 7.64 (dd,
J = 7.5, 1.8 Hz, 1H), 7.56–7.48 (m, 4H), 7.13 (td, J = 7.5, 1.0 Hz, 1H), 7.01 (d,
J = 8.3 Hz, 1H), 3.80 (s, 3H), 2.17 (s, 3H). 13C NMR (101 MHz, chloroform-d) d
194.9, 169.6, 159.7, 156.7, 132.0, 131.2, 130.5, 128.7 (s, 2C), 128.6 (s, 2C), 126.9,
121.2, 118.0, 117.6, 111.0, 55.1, 29.9.
7. (a) Maloney, P. R.; Parks, D. J.; Haffner, C. D.; Fivush, A. M.; Chandra, G.; Plunket,
K. D.; Creech, K. L.; Moore, L. B.; Wilson, J. G.; Lewis, M. C.; Jones, S. A.; Willson,