Synthesis of 3,5-disubstituted isoxazoles via cope-type hydroamination of 1,3-dialkynes

Article abstract of DOI:10.1021/ol300872e

An efficient method for the synthesis of 3,5-disubstituted isoxazoles is described. The reactions of 1,3-dialkynes with hydroxylamine proceeded smoothly in DMSO under mild reaction conditions to produce 3,5-disubstituted isoxazoles in satisfactory to excellent yields.

Full text of DOI:10.1021/ol300872e

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2418–2421
Synthesis of 3,5-Disubstituted Isoxazoles
via Cope-Type Hydroamination of
1,3-Dialkynes
Liangguang Wang, Xiaoqiang Yu,* Xiujuan Feng, and Ming Bao*
State Key Laboratory of Fine Chemicals, Dalian University of Technology,
Dalian 116023, China
yuxiaoqiang@dlut.edu.cn; mingbao@dlut.edu.cn
Received April 5, 2012
ABSTRACT
An efficient method for the synthesis of 3,5-disubstituted isoxazoles is described. The reactions of 1,3-dialkynes with hydroxylamine proceeded
smoothly in DMSO under mild reaction conditions to produce 3,5-disubstituted isoxazoles in satisfactory to excellent yields.
The development of convenient and efficient methods for
the synthesis of isoxazoles has attracted considerable atten-
tion. Isoxazoles represent an interesting structural motif
found frequently in various bioactive molecules and natural
products.1 Over the past four decades, many methods have
been developed for the construction of the isoxazole nucleus,
including the [3 þ 2] cycloaddition of alkenes/alkynes with
nitrile oxides (1,3-dipoles derivated from hydroximinoyl
chlorides, nitro compounds, and aldoximes);2 the reaction
of hydroxylamine with a three-carbon atom component
(such as 1,3-dicarbonyl compound, R,β-unsaturated carbo-
nyl compound, and R,β-unsaturated nitrile);3 the cyclization
of alkynyl oxime ethers;4 and others.5 Although mono- and
polysubstituted-isoxazoles can be obtained using these meth-
ods, the synthesis frequently suffers from drawbacks, such as
multistep reactions, harsh reaction conditions (strong bases
or strong mineral acids are often required, or prolonged
heating to high temperature is necessary), and the use of
transition-metal catalysts or special starting materials.
(1) For reviews, see: (a) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug
Discovery Dev. 2005, 8, 723. (b) Lakhvich, F. A.; Koroleva, E. V.;
Akhrem, A. A. Chem. Heterocycl. Compd. 1989, 25, 359.
(2) For the [3 þ 2] cycloaddition of alkenes/alkynes with nitrile
oxides, see: (a) Gray, T. C.; Hasanayn, F.; Richardson, D. P.; Markgraf,
J. H. J. Heterocycl. Chem. 2009, 46, 1318. (b) Grecian, S.; Fokin, V. V.
Angew. Chem., Int. Ed. 2008, 47, 8285. (c) Cecchi, L.; Sarlo, F. D.;
Machetti, F. Eur. J. Org. Chem. 2006, 4852. (d) Sheng, S.-R.; Xin, Q.;
Liu, X.-L.; Sun, W.-K.; Guo, R.; Huang, X. Synthesis 2006, 2293. (e)
Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.;
Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210. (f)
Hansen, T. V.; Wu, P.; Fokin, V. V. J. Org. Chem. 2005, 70, 7761. (g)
Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005, 70, 2839. (h)
Moriya, O.; Urataa, Y.; Endo, T. J. Chem. Soc., Chem. Commun. 1991,
884. (i) Moriya, O.; Urataa, Y.; Endo, T. J. Chem. Soc., Chem. Commun.
1991, 17.
(4) For the cyclization of alkynyl oxime ethers, see: (a) Ueda, M.;
Ikeda, Y.; Sato, A.; Ito, Y.; Kakiuchi, M.; Shono, H.; Miyoshi, T.;
Naito, T.; Miyata, O. Tetrahedron 2011, 67, 4612. (b) Ueda, M.; Sato, A.;
Ikeda, Y.; Miyoshi, T.; Naito, T.; Miyata, O. Org. Lett. 2010, 12, 2594.
(c) Waldo, J. P.; Larock, R. C. J. Org. Chem. 2007, 72, 9643. (d) Waldo,
J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203.
(5) Other methods for synthesis of isoxazoles, see: (a) Burkhard,
J. A.; Tchitchanov, B. H.; Carreira, E. M. Angew. Chem., Int. Ed. 2011,
50, 5379. (b) Debleds, O.; Gayon, E.; Ostaszuk, E.; Vrancken, E.;
Campagne, J.-M. Chem.;Eur. J. 2010, 16, 12207. (c) Brahma, S.;
Ray, J. K. J. Heterocycl. Chem. 2008, 45, 311. (d) Willy, B.; Rominger,
(3) For the reaction of hydroxylamine with a three-carbon atom
component, see: (a) Tang, S.; He, J.; Sun, Y.; He, L.; She, X. J. Org.
Chem. 2010, 75, 1961. (b) Praveen, C.; Kalyanasundaram, A.; Perumal,
P. T. Synlett 2010, 777. (c) Valizadeh, H.; Amiri, M.; Gholipur, H. J.
Heterocyclic Chem. 2009, 46, 108. (d) Tang, S.; He, J.; Sun, Y.; He, L.;
She, X. Org. Lett. 2009, 11, 3982. (e) Heravi, M. M.; Derikvand, F.;
Haeri, A.; Oskooie, H. A.; Bamoharram, F. F. Synth. Commun. 2008, 38,
135. (f) Rosa, F. A.; Machado, P.; Bonacorso, H. G.; Zanatta, N.;
Martins, M. A. P. J. Heterocyclic Chem. 2008, 45, 879. (g) Ahmed,
M. S. M.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487. (h)
Cuadrado, P.; Gonzalez-Nogal, A. M.; Valero, R. Tetrahedron 2002,
58, 4975. (i) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V. J.
Org. Chem. 2001, 66, 6787. (j) Kashima, B. C.; Shirai, S. I.; Yoshiwara,
N.; Omote, Y. J. Chem. Soc., Chem. Commun. 1980, 826.
€
F.; Muller, T. J. J. Synthesis 2008, 293. (e) Bourbeau, M. P.; Rider, J. T.
Org. Lett. 2006, 8, 3679. (f) Padwa, A.; Stengel, T. Arkivoc 2005, 21. (g)
Itoh, K.-I.; Sakamaki, H.; Nakazato, N.; Horiuchi, A.; Horn, E.;
Horiuchi, C. A. Synthesis 2005, 3541. (h) Kato, T.; Yamanaka, H.;
Yasuda, N. J. Org. Chem. 1967, 32, 3593.
(6) (a) Xu, Z.; Yu, X.; Feng, X.; Bao, M. J. Org. Chem. 2011, 76, 6901.
(b) Feng, X.; Zhao, Z.; Yang, F.; Jin, T.; Ma, Y.; Bao, M. J. Organomet.
Chem. 2011, 696, 1479. (c) Du, X.; Dai, Y.; He, R.; Lu, S.; Bao, M. Synth.
Commun. 2009, 39, 3940.
r
10.1021/ol300872e
Published on Web 04/26/2012
2012 American Chemical Society

Table 1. Reaction Conditions Screeninga
Scheme 1. Synthesis of 3,5-Disubstituted Isoxazoles via Cope-
Type Hydroamination of 1,3-Dialkynes
entry
solvent
base
NEt3
temp (°C)
yield (%)b
1
toluene
dioxiane
ethanol
IPA
110
110
110
110
110
110
110
110
110
110
110
110
110
90
NRc
10
10
15
NRc
10
86
80
82
80
60
68
70
55
70
2
NEt3
3
NEt3
4
NEt3
In the course of our continuous research on alkyne che-
mistry,6 we found that 3,5-disubstituted isoxazoles can be
readily obtained from the reaction of 1,3-dialkynes with
hydroxylamine (H2NOH) (Scheme 1). The intermolecular
Cope-type hydroamination reaction of 1,3-dialkynes 1
with hydroxylamine occurred during heating to produce
intermediate A upon a proton-transfer process.7,8 The iso-
merization of A subsequently took place to produce an
allenyl oxime intermediate B, which then transformed into
a 3,5-disubstituted isoxazole 2 via intramolecular electro-
philicaddition. Inthepresentpaper, a methodofpreparing
3,5-disubstituted isoxazoles was reported using simple and
readily available starting materials under mild conditions.
In our initial studies, the reaction of 1,4-diphenylbuta-
5
THF
NEt3
6
DMF
NEt3
7
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NEt3
8
iPr2NEt
NnBu3
NHEt2
K2CO3
K3PO4
NaOAc
NEt3
9
10
11
12
13
14
15
NEt3
100
a Reaction conditions: 1,4-diphenylbuta-1,3-diyne (1a, 0.4 mmol, 81.0 mg),
hydroxylamine hydrochloride (2.5 equiv, 69.5 mg), base (4.0 equiv), and
solvent (3.0 mL) in sealed flask. b Isolated yield. c No reaction.
The reactions of symmetric 1,3-dialkynes 1aꢀ1h with
hydroxylamine hydrochloride were performed under opti-
mized conditions, and the results are summarized in Table 2.
3,5-Disubstituted isoxazole 2aꢀ2f were obtained from
the reactions of aromatic 1,3-dialkynes 1aꢀ1f in good to
excellent yields (entries 1ꢀ6, 81%ꢀ98%). The formation
of 3,5-disubstituted isoxazole in relatively higher yield from a
1,3-dialkyne bearing an electron-withdrawing group on
benzene ring than those from a 1,3-dialkyne bearing an
electron-donating group on benzene ring was observed
(entries 5 and 6 vs entries 1ꢀ4). This result indicated that
1,3-dialkyne can be activated by decreasing its electron
density. The aliphatic 1,3-dialkynes 1g and 1h were also
employed successfully in the synthesis of 3,5-disubstituted
isoxazoles. The corresponding products 2g and 2h were
obtained in 66% and 89% yields, respectively (entries 7
and 8). These results indicated that the reactivity of cyclic
alkyl-substituted 1,3-dialkynes was higher than that of the
normal alkyl-substituted analogues. It was considered that
the formation of Z-oxime isomer (intermediate B, Scheme 1)
was accelerated by the bulky substituent group, such as aryl
and c-hexyl groups.
The successful acquisition of 3,5-disubstituted iso-
xazoles from the reaction of symmetric 1,3-dialkynes
with hydroxylamine hydrochloride encouraged the cur-
rent authors to examine the reaction of unsymmetric
1,3-dialkynes with hydroxylamine hydrochloride. The
results are summarized in Table 3. The reactions of
unsymmetric 1,3-dialkynes 3aꢀ3c having the same
p-methoxyphenyl group with hydroxylamine hydro-
chloride proceeded smoothly to produce a mixture of
two products, which can be separated with chromato-
graphy. Products 4aꢀ4c and 5aꢀ5c were obtained in
1,3-diyne (1a) with hydroxylamine hydrochloride (H2NOH
3
HCl) was chosen as a model to optimize the reaction
conditions. The optimization included the selection of the
most suitable solvents, bases, and reaction temperature. The
results are shown in Table 1. Nonpolar (toluene) and polar
[dioxiane, ethanol, isopropyl alcohol (IPA), tetrahydrofur-
ane (THF), N,N-dimethylformamide (DMF), and dimethyl
sulfoxide (DMSO)] solvents were examined (entries 1ꢀ7).
DMSO proved to be the best solvent (entry 7). The yield of
the desired product, 5-benzyl-3-phenylisoxazole (2a), dra-
matically increased to 86% when DMSO was used as a
solvent (entry 7 vs entries 1ꢀ6). However, the reason behind
this behavior remains unclear. The bases were then screened
i
using DMSO as solvent, which included NEt3, Pr2NEt,
NnBu3, NHEt2, K2CO3, K3PO4, and NaOAc (entries 7ꢀ13).
Among the tested bases, the use of NEt3 led to the formation
of 2a in relatively high yield (entry 7, 86% yield). The effect
of reaction temperature on the yield of 2a was evaluated
(entries 7, 14, and 15). The obtained results indicated that the
yield of 2a increased with the enhanced reaction tempera-
ture. A reaction temperature of 110 °C was essential in
achieving good yield of 2a. Therefore, the subsequent reac-
tions of the symmetric (1aꢀ1h) and unsymmetric (3aꢀ3h)
1,3-dialkynes with hydroxylamine hydrochloride were per-
formed in the presence of NEt3 as the base in DMSO solvent
at 110 °C for 20 h.
(7) For the Cope-type hydroamination reaction of alkynes, see: (a)
Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M.-E.; Bedard, A.-C.;
Seguin, C.; Beauchemin, A. M. J. Am. Chem. Soc. 2008, 130, 17893.
(b) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; Bedard, A. C.;
Seguin, C.; Seguin, C.; Dimitrijevic, E.; Zhang, L.; Gorelsky, S .I.
Angew. Chem., Int. Ed. 2008, 47, 1410.
(8) For the proton-transfer process, see:Cooper, N. J.; Knight, D. W.
Tetrahedron 2004, 60, 243.
Org. Lett., Vol. 14, No. 9, 2012
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Table 2. Synthesis of 3,5-Disubstituted Isoxazoles from Sym-
metric 1,3-Dialkynesa
Table 3. Synthesis of 3,5-Disubstituted Isoxazoles from Un-
symmetric 1,3-Dialkynesa
yield of 4 yield of 5
entry
alkyne 3
(%)b
(%)b
1
2
3
4
5
6
7
8
3a, R1 = Ph R2 = p-MeOC6H4
4a, 47
4b, 52
5a, 35
5b, 31
5c, 30
5d, 27
5e, 11
5f, 18
5g, 0
3b, R1 = p-FC6H4 R2 = p-MeOC6H4
3c, R1 = p-NO2C6H4 R2 = p-MeOC6H4 4c, 58
3d, R1 = p-NO2C6H4 R2 = Ph
3e, R1 = Ph R2 = n-Hexyl
4d, 54
4e, 72
4f, 70
4g, 88
4h, 90
3f, R1 = Ph R2 = c-Hexyl
3g, R1 = p-NO2C6H4 R2 = n-Hexyl
3h, R1 = p-NO2C6H4 R2 = c-Hexyl
5h, 0
a Reaction conditions: unsymmetric 1,3-dialkyne (3aꢀ3h, 0.4 mmol),
hydroxylamine hydrochloride (2.5 equiv, 69.5 mg), and NEt3 (4.0 equiv,
162.0 mg) in DMSO (3.0 mL) at 110 °C for 20 h. b Isolated yield.
alkyl group led to the formation of 3,5-disubstituted
isoxazole 4g or 4h as a sole product (entry 7, 4g: 88%
yield; entry 8, 4h: 90% yield).
Finally, the one-pot synthesis of 3,5-disubstituted iso-
xazoles from alkynes was examined, and the results are
summarized in Table 4. After the Cu-catalyzed homocou-
pling reaction of alkyne was completed,10 hydroxylamine
hydrochloride and triethylamine were added to the resul-
tant mixture. The reaction mixture was then treated at
110 °C for 20 h. The same good yield of 2a was observed in
the reaction of phenylacetylene (6a) (entry 1, 86%). The
reactions of arylacetylenes 6bꢀ6d bearing an electron-
donating group (MeO, Me) on the para or meta position
of benzene ring produced the desired products 2bꢀ2d in
good yields (entries 2ꢀ4, 78%ꢀ81%). However, the
reaction of o-methyl phenylacetylene (6i) produced 3,5-
disubstituted isoxazole 2i in low yield (entry 9, 65%).
The poor reactivity of 6i was considered due to the steric
effect of the o-methyl group in alkyne substrate. The
relatively high yields were also observed in the reactions
of arylacetylenes 6e, 6f, 6j, and 6k bearing an electron-
withdrawing group on benzene ring. The desired pro-
ducts, 3,5-disubstituted isoxazoles 2e, 2f, 2j, and 2k, were
isolated in 88%ꢀ95% yields (entries 5, 6, 10, and 11).
The aliphatic alkynes 6g and 6h were also utilized
successfully for the synthesis of 3,5-disubstituted isoxa-
zoles. Products 2g and 2h were obtained in 60% and 86%
yields, respectively (entries 7 and 8). Finally, the reactions of
a Reaction conditions: symmetric 1,3-dialkyne (1aꢀ1h, 0.4 mmol),
hydroxylamine hydrochloride (2.5 equiv, 69.5 mg), and NEt3 (4.0 equiv,
162.0 mg) in DMSO (3.0 mL) at 110 °C for 20 h. b Isolated yield.
47%ꢀ58% and 30%ꢀ35% yields, respectively (entries
1ꢀ3). The ratios of the two isolated products in-
creased in the order 4a to 5a, 4b to 5b, and 4c to 5c.
Interestingly, this order was consistent with those of
Hammett substituent constants (σp: H, 0; F, þ0.15;
NO2, þ0.81).9 The reactions of unsymmetric 1,3-dia-
lkynes 3dꢀ3f having the same phenyl group with hy-
droxylamine hydrochloride also provided two
products. Products 4dꢀ4f and 5dꢀ45 were isolated in
54%ꢀ72% and 11%ꢀ27% yields, respectively (entries
4ꢀ6). Surprisingly, the use of unsymmetric 1,3-dia-
lkynes 3g and 3h having a p-nitrophenyl group and an
(10) For the Cu-catalyzed homo-coupling reaction of alkynes, see:
Yin, K.; Li, C.; Li, J.; Jia, X. Green Chem. 2011, 13, 591.
(11) The structural assignment was based on the analysis of the H
1
and 13C NMR spectra. The product 5a was further identified by
determining its X-ray structure.
(9) March, J. Advanced Organic Chemistry: Reactions, Mechanisms,
and Structure, 4th ed.; John Wiley & Sons:, New York, 1992; p 280.
2420
Org. Lett., Vol. 14, No. 9, 2012

Table 4. One-Pot Synthesis of 3,5-Disubstituted Isoxazoles from Alkynesa,b
a Reaction conditions for first step: alkyne (6aꢀ6n, 0.6 mmol) and CuI (5 mol %, 3.0 mg) in DMSO (3.0 mL) at 90 °C in air for 8 h. b Reaction
conditions for second step: hydroxylamine hydrochloride (1.5 equiv, 62.5 mg) and NEt3 (2.5 equiv, 152.0 mg) at 110 °C for 20 h. c Isolated yield.
d 3.0 equiv and 4.0 equiv of hydroxylamine hydrochloride and NEt3, respectively, were used.
1-naphthylacetylene (6l), 3-pyridinylacetylene (6m), and
3-thienylacetylene (6n) were investigated under the same
conditions. The corresponding products 2lꢀ2m were ob-
tained in moderate to excellent yields (entries 12ꢀ14, 60%,
88%, and 92%, respectively). All the new products 2aꢀ2n,
4aꢀ4 h, and 5aꢀ5f were identified through their NMR and
HRMS data as well as IR spectra.11
In summary, a novel and general method for the synthesis of
3,5-disubstituted isoxazoles was developed using simple and
readily available starting materials, namely, 1,3-dialkynes/
alkynes and hydroxylamine hydrochloride. The intermolecu-
lar Cope-type hydroamination reaction of 1,3-dialkynes
with hydroxylamine and the subsequent electrophilic addition
proceeded smoothly under very mild conditions to produce
3,5-disubstituted isoxazoles in satisfactory to excellent yields.
The wide availability of the starting materials, mild reaction
conditions, and experimental simplicity must make the present
methodology more useful in organic synthesis. Further study
focusing on the extension of the reaction scope using hydra-
zines is underway.
Acknowledgment. We are grateful to the National Nat-
ural Science Foundation of China (nos. 20972021 and
21173032) for their financial support. This work was also
supported by the Specialized Research Fund for the
Doctoral Program of Higher Education (no. 200900411-
10012).
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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