Methyl 3-Substituted-isoxazole-5- Carboxylates syntheses on solid supports via wang resin-bound 2,3-dibromopropionate

Article abstract of DOI:10.1002/hc.21035

A novel Wang resin-bound 2,3-dibromopropionate reagent has been developed and used as a potential dipolarophile for the facile preparation of methyl 3-substituted-isoxazole-5-carboxylates through triethylamine, promoting a sequence of reactions involving the in situ generation of 2-bromoacrylate resin and nitrile oxide, regioselective 1,3-dipolar cycloaddition, and loss of hydrogen bromide in one pot, and then cleavage from the resin with sodium methoxide. The advantages of this method include simple operation and mild conditions with good yield and high purity of the products. Copyright

Full text of DOI:10.1002/hc.21035

Heteroatom Chemistry
Volume 00, Number 0, 2012
Methyl 3-Substituted-Isoxazole-5-
Carboxylates Syntheses on Solid Supports via
Wang Resin-Bound 2,3-Dibromopropionate
Shou-Ri Sheng, Ai-Ying He, Mei-Hong Wei, Ai-Li Zhu, and
Ming-Zhong Cai
1College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022,
People’s Republic of China
Received 9 February 2012; revised 1 June 2012
INTRODUCTION
ABSTRACT:
A novel Wang resin-bound 2,3-
dibromopropionate reagent has been developed and
used as a potential dipolarophile for the facile prepara-
tion of methyl 3-substituted-isoxazole-5-carboxylates
through triethylamine, promoting a sequence of
reactions involving the in situ generation of 2-
bromoacrylate resin and nitrile oxide, regioselective
1,3-dipolar cycloaddition, and loss of hydrogen bro-
mide in one pot, and then cleavage from the resin with
sodium methoxide. The advantages of this method
include simple operation and mild conditions with
The solid-phase organic synthesis (SPOS) is a
method in which molecules are bound on a bead
and synthesized step by step in a reactant solution;
compared with normal synthesis in a liquid state,
it is easier to remove excess reactant or by-product
from the product [1]. Now, SPOS has become a cen-
tral feature in the synthesis of organic materials with
repetitive units. It is an attractive approach for the
rapid preparation of a large number of compounds
and for discovering new active molecules [2,3]. The
isoxazole skeleton is present in a variety of natural
products and represents useful synthetic building
blocks [4]. In addition, they have shown consider-
able anti-inflammatory [5], antiviral [6], as well as
antitubulin [7] activities. Therefore, the preparation
of this family of heterocycles continues to be of in-
terest [8, 9]. Although several groups have studied
the synthesis of isoxazoles by using the SPOS tech-
nology [10] by the condensation of 1,3-dicarbonyl
compounds with hydroxylamine [11,12], the addi-
tion of nitrile oxides to the supported alkynes [13–
16], the anchoring of a nitrile oxide precursor onto
the solid phase [17,18], and with polymer-supported
vinyl ethers as chameleon catches [19], as well as
using polymeric selenium reagent [20–22], the facile
preparation of functionalized isoxazole libraries for
lead discovery is highly desirable. Herein, we wish
to report our preliminary study on the solid-phase
synthesis of methyl isoxazole-5-carboxylates using
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C
good yield and high purity of the products.
2012
Wiley Periodicals, Inc. Heteroatom Chem 00:1–5, 2012;
View this article online at wileyonlinelibrary.com. DOI
10.1002/hc.21035
Correspondence to: Shou-Ri Sheng; e-mail: shengsr@
jxnu.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 21062007.
Contract grant sponsor: Natural Science Foundation of Jiangxi
Province.
Contract grant number: 2009GZH0016.
Contract grant sponsor: Research Program of Jiangxi Province
Department of Education.
Contract grant numbers: GJJ10385, GJJ11380.
2012 Wiley Periodicals, Inc.
c
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2
Sheng et al.
SCHEME 1 SPOS route to methyl 3-substituted-isoxazole-5-carboxylate.
a novel Wang resin-bound 2,3-dibromopropionate
reagent, as shown in Scheme 1.
1.20 mmol/g via an ester linkage in the presence
of N, N-diisopropylethylamine (DIPEA). The resin-
bound acrylate 2 was characterized by FTIR mi-
croscopy [24], which showed complete disappear-
ance of the hydroxyl stretch and the appearance
of a C O stretch at 1725 cm−1 and a C C stretch
at 1651 cm−1. The 2,3-dibromopropionate resin 3
was obtained efficiently by treatment of resin 2 with
bromine in dichloromethane after stirring for 1 h.
Conversion of 2 to 3 seemed to be quantitative, be-
cause FTIR of 3 revealed the appearance of a new
strong carbonyl absorption at 1742 cm−1, a moderate
strong C Br band at 572 cm−1, and the complete dis-
appearance of absorptions at 1725 and 1651 cm−1.
It should be noted that this new resin-bound 2,3-
dibromopropionate reagent 3 is stable and can be
stored at room temperature for a long time without
diminution of capacity.
In the next step, subjecting 3 to the dehydro-
bromination and cycloaddition reaction with hy-
droximoyl chlorides in the presence of triethylamine
afforded the resin-bound isoxazole-5-carboxylates 6
(no bromine was found by microanalysis of resin
6), which was evidenced by their FTIR spectra,
featuring a strong carbonyl absorption near 1725
cm−1, and with the complete disappearance of C Br
(572 cm−1) absorption. In fact, Wang resin-bound
2-bromoacrylate (4) could be easily obtained from
the resin 3 through the loss of hydrogen bromide
through triethylamine promotion. After isolation
and washing, the resin 4 could react with nitrile ox-
ides and then dehydrobrominated to generate resin
6 almost with the same results as the above proce-
dure. However, we have found it most convenient to
carry out this conversion from 3 to 6 in one pot.
RESULTS AND DISCUSSION
In
this
study,
Wang
resin-bound
2,3-
dibromopropionate (3) was chosen because it ap-
pears to facilitate the generation of 2-bromoacrylate
as a dipolarophile promoted by base, which would
have sufficient activity to react with nitrile oxides
via 1,3-dipolar cycloaddition for the construction
of functional bromosubstituted isoxazolines, whose
hydrogen bromide can be eliminated easily with
base to form a double bond in the final products.
Besides, in the recent study of the synthesis of func-
tionalized 5,5-disubstituted isoxazolines, isoxazoles
were obtained as the sole products instead of bro-
moisoxazolines between 1,3-dipolar cycloaddition
reactions of 2-bromoacrylic acid methyl ester with
various aromatic nitrile oxides in the presence of
triethylamine [23]. Encouraged by these results, we
tried to carry out our idea to synthesize functional-
ized methyl 3-substituted-isoxazole-5-carboxylates
on the basis of this new polymeric reagent 3.
Wang resin, 4-benzyloxybenzyl alcohol resin, is
the most popular support for SPOS. As a standard
support, it can be used for the solid-phase immo-
bilization of acids and phenols for SPOS. The ester
linkage may be achieved, which has good stability to
a variety of reaction conditions, but can be readily
removed with trifluoroacetic acid or sodium methox-
ide [1]. So, Wang resin has been selected as support
for our investigation. Initially, acryloyl chloride was
quantitatively anchored to Wang resin 1 loaded with
Heteroatom Chemistry DOI 10.1002/hc

Methyl 3-Substituted-Isoxazole-5-Carboxylates Syntheses on Solid Supports via Wang Resin-Bound 2,3-Dibromopropionate
3
TABLE
1 Yields and Purity of Methyl 3-Substituted-
EXPERIMENTAL
General
isoxazole-5-carboxylates (7a–7i)
Entry
R
Product Yield (%)a Purity (%)b
Melting points were uncorrected. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Bruker AVANCE (400 MHz) spec-
trometer (Billerica, MA), using CDCl3 as the solvent
and TMS as an internal standard. Mass spectra (EI,
70 eV) were recorded on a HP5989B mass spec-
trometer (Palo Alto, CA). FTIR spectra were taken
on a Perkin-Elmer SP One FTIR spectrophotome-
ter (Waltham, MA). Microanalyses were performed
with a Carlo Erba 1106 elemental analyzer (Milan,
Italy). HPLC was performed on an Agilent 1100 high-
performance liquid chromatograph (Santa Clara,
CA). Wang resin (1.20 mmol/g) and other starting
materials were purchased from commercial sup-
pliers and used without further purification. 1,2-
Dichloroethane was refluxed with phosphorous pen-
toxide, and distilled. THF was distilled from sodium-
benzophenone immediately prior to use.
1
2
3
4
5
6
7
8
9
C6H5
7a
7b
7c
7d
7e
7f
7g
7h
7i
90
87
88
85
72
80
81
85
82
98
97
95
94
92
93
95
96
95
4-CH3C6H4
4-MeOC6H4
4-ClC6H4
2,6-Cl2C6H3
4-NO2C6H4
4-FC6H4
2-Furyl
CH3CH2CH2
aOverall yields based on Wang resin-bound 2,3-dibromopropionate
3 (1.86 mmol Br/g).
bDetermined by HPLC of a crude cleavage product.
Eventually, cleavage of the product from
isoxazole-5-carboxylate resins 6 was achieved read-
ily by transesterification (NaOMe, MeOH/THF (1:4),
reflux for 18 h) to provide methyl 3-substituted-
isoxazole-5-carboxylates 7 in good yields and purity
(Table 1). Besides, this process also exhibited
excellent regioselectivity. Methyl isoxazole-5-
carboxylates 7 were formed exclusively, indicating
that the cycloaddition of resin 4 with nitrile oxides
occurred with complete regioselectivity. On the
other hand, as observed from Table 1, the present
method was effective for reaction substrates, hy-
droximoyl chlorides derived from both aromatic
(either with electron-withdrawing or electron-
donating group) and aliphatic aldehydes. However,
compound 7e (Table 1, entry 5) showed a decrease
in yield of 72%, which might have resulted from the
steric hindrance of two chlorosubstituents in the or-
tho position of a benzene ring of the corresponding
hydroximoyl chloride.
Preparation of Wang Resin-Bound
2,3-Dibromopropionate (3)
Wang resin 1 (1.0 g, 1.2 mmol, loading 1.20 mmol/g)
was swollen in CH2Cl2 (10 mL), DIPEA (0.65 g,
5.0 mmol) acryloyl chloride (0.45 g, 5.0 mmol) was
added, and the reaction mixture was shaken at room
temperature for 4 h. After which, the mixture was
filtered and the resin was washed sequentially with
DMF (2 × 10 mL), H2O (2 × 10 mL), MeOH (2 ×
20 mL), CH2Cl2 (2 × 10 mL), and ether (2 × 10 mL)
and dried overnight in a vacuum oven at 40◦C to
afford resin 2. To the resultant resin 2 swollen in
CH2Cl2 (10 mL) for 30 min, bromine (1.5 mmol)
was added. After 1 h of shaking the mixture at room
temperature, the resin was collected on a filter and
washed successively with CH2Cl2 (2 × 10 mL), H2O
(2 × 10 mL), THF (2 × 10 mL), and ether (2 × 10 mL)
and then dried under vacuum overnight to afford a
white resin 3 with a loading value of 1.86 Br mmol/g
by elementary analysis. FTIR (KBr): ν = 3042, 2927,
1742, 1595, 1455, 1248, 1180, 1106, 995, 965, 826,
765, 572 cm−1.
CONCLUSIONS
In summary, a novel strategy for the facile solid-
phase synthesis of methyl 3-substituted-isoxazole-5-
carboxylates has been developed from Wang resin-
bound 2,3-dibromopropionate reagent through a
sequence of reactions involving in situ generat-
ing of resin-bound 2-bromoacrylate and nitrile ox-
ide, regioselective 1,3-dipolar cycloaddition, and
loss of hydrogen bromide to form the correspond-
ing Wang resin-bound isoxazole-5-carboxylate, fol-
lowed by cleaving from resin with sodium methox-
ide. A simple workup procedure replaces the time-
consuming isolation and purification steps in the
corresponding solution-phase synthesis. Further in-
vestigations based on this novel polymeric reagent
are now in progress.
General Procedure for the Preparation of Methyl
3-Substituted-Isoxazole-5-Carboxylates (7a–7i)
Under a positive pressure of nitrogen, to a suspen-
sion of the swollen resin 3 (1.0 mmol, 1.08 g) in
CH2Cl2 (15 mL), hydroximoyl chloride (2.0 mmol)
was added and shortly thereafter triethylamine
(0.63 mL, 4.5 mmol) was also added. After shaking
the mixture for 10 h at room temperature, resin 6
Heteroatom Chemistry DOI 10.1002/hc

4
Sheng et al.
was collected by filtration, washed successively with
THF/H2O (1:1) (2 × 10 mL), DMF (2 × 10 mL), THF
(2 × 10 mL), MeOH (2 × 10 mL), and CH2Cl2 (2 ×
10 mL). Then, resin 6 was cleaved in a mixture of
THF (8 mL) and MeOH (2 mL) in the presence of
45 mg of sodium methoxide at 70◦C for 18 h. Af-
ter cooling, the resin was filtered and washed with
THF/H2O (1/1) (3 × 10 mL), MeOH (3 × 5 mL), and
Et2O (3 × 5 mL). Evaporation of the solvent from the
filtrate afforded crude products 7a–7i with 92%–98%
purity determined by HPLC, which were further pu-
rified by passing the crude product through a silica
gel chromatographic column (ethyl acetate–hexane
as the eluent, 1:4), affording the pure products for
their structure analyses. All of the isolated products
for this study were unambiguously characterized by
1H NMR, 13C NMR, IR, and for regiochemical as-
signment. All analytical data are consistent with the
literature data.
(KBr): ν = 3062, 2981, 1750, 1445, 1295, 1245, 1026,
765 cm−1.
Methyl 3-(4-nitrophenyl)isoxazole-5-carboxylate
(7f). Yellow solid, mp 168–169◦C; 1H NMR: δ = 8.20
(d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.30 (s,
1H), 4.02 (s, 3H); 13C NMR: δ = 163.4, 161.2, 156.8,
135.8, 127.6, 126.1, 123.8, 107.8, 53.2; IR (KBr): ν =
3440, 2961, 1735, 1550, 1520, 1385, 1246, 1080, 928,
858 cm−1; EIMS: m/z(%) = 248 (M+); Anal. Calcd
for C11H8N2O5: C, 53.23; H, 3.25; N, 11.29. Found: C,
53.35; H, 3.37; N, 11.22.
Methyl 3-(4-fluorophenyl)isoxazole-5-carboxyl-
1
ate (7g). Colorless oil; H NMR: δ = 7.85–7.80 (m,
2H), 7.27–7.23 (m, 2H), 7.25 (s, 1H), 3.92 (s, 3H);
13C NMR: δ = 164.0, 163.2, 161.2, 156.8, 129.4,
124.3, 116.8, 107.2, 52.8; IR (film): ν = 3443, 3133,
2982, 1731, 1448, 1284, 1246, 1023, 925, 830, 762
cm−1. EIMS: m/z(%) = 221 (M+); Anal. Calcd for
C11H8FNO3: C, 59.73; H, 3.65; N, 6.33. Found: C,
59.61; H, 3.77; N, 6.39.
Methyl 3-phenylisoxazole-5-carboxylate (7a).
1
Colorless solid, mp 107–108◦C (107–109◦C [23]); H
Methyl 3-(2-furyl)isoxazole-5-carboxylate (7h).
Colorless oil; 1H NMR: δ = 7.48 (d, J = 7.5 Hz,
1H), 7.37–7.42 (m, 1H), 6.71 (d, J = 3.0 Hz, 1H),
7.28 (s, 1H), 3.95 (s, 3H); 13C NMR: δ = 163.0, 160.1,
156.5, 151.0, 126.5, 114.7, 110.5, 102.8, 52.8; EIMS:
m/z(%) = 193; IR (film): ν = 3058, 2933, 1722, 1435,
1385, 1225, 1205, 1170, 1031, 770 cm−1; Anal. Calcd
for C9H7NO4: C, 55.96; H, 3.65; N, 7.25. Found: C,
55.90; H, 3.74; N, 7.18.
Methyl 3-(n-propyl)isoxazole-5-carboxylate (7i).
Colorless oil; 1H NMR: δ = 7.20 (s, 1H), 3.88 (s, 3H),
2.65 (t, J = 7.5 Hz, 2H), 2.12–1.50 (m, 2H), 0.98 (t,
J = 7.5 Hz, 3H); 13C NMR: δ = 163.5, 156.3, 154.8,
107.2, 52.1, 29.2, 22.1, 13.7; IR (film): ν = 3060, 2985,
1725, 1445, 1295, 1375, 1242, 1165, 1023, 760 cm−1;
EIMS: m/z(%) = 169 (M+); Anal. Calcd for C8H11NO3:
C, 56.80; H, 6.55; N, 8.28. Found: C, 56.86; H, 6.63;
N, 8.37.
NMR: δ = 7.85–7.81 (m, 2H), 7.49–7.44 (m, 3H), 7.26
(s, 1H), 3.98 (s, 3H); 13C NMR: δ = 163.0, 160.5, 157.1,
130.5, 129.0, 128.2, 126.8, 107.4, 52.8; IR (KBr): ν =
3425, 2982, 1745, 1450, 1294, 1245, 1025, 770 cm−1.
Methyl 3-(4-methylphenyl)isoxazole-5-carboxyl-
◦
1
ate (7b). Colorless solid, mp 112–113 C; H NMR:
δ = 7.73 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H),
7.27 (s, 1H), 3.95 (s, 3H), 2.40 (s, 3 H); 13C NMR: δ =
163.3, 161.1, 157.2, 141.0, 129.8, 127.5, 127.0, 107.7,
52.7, 21.5; IR (KBr): ν = 3430, 2985, 1730, 1447,
1294, 1248, 1021, 820, 766 cm−1; EIMS: m/z(%) =
217 (M+); Anal. Calcd for C12H11NO3: C, 66.35; H,
5.10; N, 6.45. Found: C, 66.28; H, 5.18; N, 6.38.
Methyl 3-(4-methoxyphenyl)isoxazole-5-carbo-
xylate (7c). Colorless solid, mp 117–119◦C (118–
1
119◦C [23]); H NMR: δ = 7.75 (d, J = 8.8 Hz, 2H),
7.21 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.99 (s, 3H),
3.84 (s, 3H); 13C NMR: δ = 162.5, 161.4, 160.2, 157.2,
128.2, 120.1, 114.6, 107.2, 55.5, 52.8; IR (KBr): ν =
3062, 2981, 1735, 1445, 1295, 1245, 1026, 765 cm−1.
Methyl 3-(4-chlorophenyl)isoxazole-5-carboxyl-
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Heteroatom Chemistry DOI 10.1002/hc

Methyl 3-Substituted-Isoxazole-5-Carboxylates Syntheses on Solid Supports via Wang Resin-Bound 2,3-Dibromopropionate
5
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Heteroatom Chemistry DOI 10.1002/hc