Polystyrene-supported 2-bromoallyl sulfone as an efficient reagent for synthesis of 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1080/10426507.2019.1655420

A facile method has been developed for the solid-phase organic synthesis of 3,5-disubstituted isoxazoles from polystyrene-supported 2-bromoallyl sulfone. The advantages of this method include a straightforward and convenient procedure, high product yield,

Full text of DOI:10.1080/10426507.2019.1655420

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Polystyrene-supported 2-bromoallyl sulfone as an
efficient reagent for synthesis of 3,5-disubstituted
isoxazoles
Liang Zhang, Xue-Chun Mao, Qiu-Ying Wang, Yang Pan & Jun-Min Chen
To cite this article: Liang Zhang, Xue-Chun Mao, Qiu-Ying Wang, Yang Pan & Jun-Min Chen
(2019): Polystyrene-supported 2-bromoallyl sulfone as an efficient reagent for synthesis of
3
1
,5-disubstituted isoxazoles, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
0.1080/10426507.2019.1655420
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2019.1655420
Polystyrene-supported 2-bromoallyl sulfone as an efficient reagent for synthesis
of 3,5-disubstituted isoxazoles
Liang Zhang, Xue-Chun Mao, Qiu-Ying Wang, Yang Pan , and Jun-Min Chen
Key Laboratory of Functional Small Organic Molecule of Ministry of Education, Jiangxi Normal University, Nanchang, China
ABSTRACT
ARTICLE HISTORY
A facile method has been developed for the solid-phase organic synthesis of 3,5-disubstituted iso-
xazoles from polystyrene-supported 2-bromoallyl sulfone. The advantages of this method include
a straightforward and convenient procedure, high product yield, and good stability of this new
polymeric reagent.
Received 6 June 2019
Accepted 9 August 2019
KEYWORDS
3
,5-disubstituted isoxazole;
solid-phase organic
synthesis; polystyrene-
supported 2-bromoallyl
sulfone; 2-bromoallyl
phenyl sulfone;
GRAPHICAL ABSTRACT
nitrile oxides
Introduction
isolated usually before they are incorporated into the
cycloaddition process. Furthermore, some of them are
unstable and quickly decompose after their isolation.
It is well known that the use of polymer-supported
reagents in solid-phase organic synthesis (SPOS) provides
many advantages such as utilizing unstable or toxic inter-
mediates conveniently by immobilization on the resin, driv-
ing the reaction to completion by the use of excess reagents,
removing excessive or unconsumed reagents by a simple fil-
Isoxazole moieties are important constituents that com-
monly exist in biologically active natural products and
synthetic compounds of medicinal interest.
not surprising that many methods have been developed
for the construction of this useful scaffold.
many exciting advances in the synthesis and functionaliza-
tion of isoxazoles have been reported in recent years. It
is well known that the major synthetic route towards the
[
1,2]
Thus, it is
[
3–5]
Especially,
[
6]
tration workup operation, and isolating products easily by
[
7,8]
isoxazole nucleus is 1,3-dipolar cycoaddition.
For the
[13]
filtration from the solid support.
Therefore, the develop-
synthesis of isoxazoles, alkynes are often used as the
dipolarophile in the 1,3-dipolar cycloaddition reaction
with nitrile oxides (1,3-dipoles generated in situ mainly
from aldoximes, primary nitro compounds and hydroxi-
minoyl chlorides), however, regioselectivity issues often
ment of polymer-bound bromoalkenes reagents might be an
ideal methodology for the construction of isoxazoles.
Sulfone is a vital functional group in organic chemistry,
which has valuable synthetic capabilities due to its activating
[
14]
and electron-withdrawing effects.
resin has been efficiently prepared and utilized in SPOS and
simple alkenes, but an additional oxidation step is usually the resulting sulfone linker has been found to be both a robust
Sulfinate-functionalized
[
9]
arise.
Moreover, isoxazoles can be synthesized from
[
10,11]
[15–24]
required.
On the other hand, geminally disubstituted and a versatile traceless linker. Some research groups
alkenes with a bromine atom as one of the substituents have developed sulfone-linking strategies for SPOS method to
have been shown to be effective alkyne surrogates that explore sulfone-based chemical transformation. Among them,
lead to the isolation of only one isoxazole regioisomer only 3-monosubstituted isoxazoles have been prepared
[
11,12]
[25]
without the isolation of an isoxazoline intermediate.
through SPOS from polymer-supported vinyl sulfone.
However, these bromoalkenes need to be synthesized and Therefore, based on the importance of isoxazole molecules
CONTACT Yang Pan
panyang@jxnu.edu.cn; Jun-Min Chen
jxnuchenjm@163.com
College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, 330022 P. R. China.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2019.1655420.
ß 2019 Taylor & Francis Group, LLC

2
L. ZHANG ET AL.
Scheme 1. Sulfinate SPOS route to 3,5-disubstituted isoxazoles.
Scheme 2. Solution-phase pathway to 3,5-disubstituted isoxazoles.
and the advantages of polymeric regents in organic synthesis, studies were undertaken as shown in Scheme 2. It was
we herein wish to report the application of polystyrene/1% reported that 2-bromoallyl phenyl sulfone (9) could be
divinylbenzene sodium sulfinate (1) for convenient traceless obtained in 58% yield by equimolar reactions of sodium
synthesis of 5-vinyl isoxazoles and 5-methyl isoxazoles, as out- benzenesulfinate (8) and 2,3-dibromopropene in N,N-dime-
[
26]
lined in Scheme 1. Key steps include (i) sulfinate S-alkylation, thylformamide
(DMF)
at
room
temperature.
(
ii) sequential [3 þ 2] cycloaddition with nitrile oxides and Interestingly, 9 could be obtained in 97% yield by treating 8
elimination with a loss of HBr, (iii) a-sulfonyl carbanion with excess 2,3-dibromopropene in the presence of NBu I/
4
monoalkylation with alkyl halides, and (iv) traceless product KI/DMF at room temperature for 8 h. Subsequent tandem
release by elimination or reductive desulfonylation reaction.
reaction afforded the 5-phenylsulfonylmethylisoxazole (11)
in 93% yield, which involved [3 þ 2] cycloaddition reaction
of 9 with nitrile oxides generated in situ from N-hydroxy-
benzimidoyl chloride, 1,2-elimination reaction with a loss of
Results and discussion
Firstly, in order to find the most suitable SPOS reaction HBr from the corresponding isoxazoline intermediates in
ꢀ
conditions for our purpose, preliminary solution-phase the presence of Et N in THF at 60 C. It should be pointed
3

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Figure 2. FTIR spectrum for the resin 2.
Figure 1. FTIR spectrum for the resin 1.
out that compound 9 might produces a mixture of allenyl
[
26]
sulfone and propargyl sulfone
in the presence of Et N
3
before its addition reaction with phenyl nitrile oxide in the
process of conversion of compound 9 to 11. Then, a-mono-
alkylation of 11 with ethyl bromide using the previously
[
22]
procedure
generated 3-phenyl-5-[(1-phenylsulfonyl)pro-
pyl]isoxazole (12) in 90% yield. After sulfinate b-elimination
of 12 by treatment with potassium tert-butoxide formed the
expected 3-phenyl-5-(1-E-propenyl)isoxazole (6a) in 95%
yield. It should be noted that some other bases such as 8-
diazabicyclo[5.4.0]undec-7-ene (DBU) and Et N could also
3
be used for this reaction, but the yield of 6a was relatively
low. Further study indicated that in the course of the trans-
formation of 12 into 6a, one-pot procedure could be also
1
1
Figure 3. FTIR spectrum for the resin 4 (R ¼ 4-NO C H –).
2
6 4
carried out smoothly with good yield (87%). H NMR ana-
lysis of 6a indicates its only (E)-stereoisomer, as assigned
from the coupling constant (J ¼ 15.6 Hz) between the two of
olefinic protons.
resin 4, which could not be reliably analyzed with FTIR.
But, by employing N-hydroxy-4-nitrobenzimidoyl chloride
as a potential 1,3-dipole, the corresponding conversion could
be monitored by appearance of characteristic stretches at
In addition, as a synthetic alternative, compound 11 was
submitted to reductive desulfonation with Na-Hg/Na HPO4
2
ꢁ
1
1
533 and 1352 cm
assigned to the asymmetric and
in MeOH at room temperature, yielding 3-phenyl-5-methyli-
symmetric stretching of the nitro group in the KBr FTIR
soxazole (7a) in 96% yield using a similar procedure
1
[
27]
(
4 where R ¼ 4-NO C H –), as shown in Figure 3.
described in the literature.
some other reducing agents
It should be pointed out that
such as Al/Hg, zinc-acetic
2
6
4
[
28]
Furthermore, the transformation resulted in the complete
disappearance of C–Br (549 cm ) absorption and found to
have lost all its bromine from the resin 4 by elemental ana-
ꢁ
1
acid and SmI could also been used to transform 11 into 7a,
2
with moderate to good yields (70–84%).
lysis except from the corresponding polymeric intermediates
Secondly, following the solution-phase pathway to isoxa-
1
zoles established, treatment of a DMF-swollen suspension of 4 (4 where R ¼ 4-BrC
H –).
6 4
polystyrene/1% divinylbenzene sodium sulfinate (1, 100-200
Then, reaction of the resin 4 with dimsyl anion at room
mesh) with 2,3-dibromopropene in the presence of NBu I/ temperature generated the corresponding a-sulfonyl mono-
4
KI at room temperature generated in almost quantitative carbanion, followed by the monoalkylation reaction with
formation of polymer-supported 3-phenylsulfonyl-2-bromo- alkyl halides furnished the resin 5. Since this transformation
propene (2) (elemental analysis Br, 1.60 mmol/g), which was exhibited no reliably diagnostic absorption peaks in the sin-
easily monitored by FTIR spectroscopies for the disappear- gle bead FTIR spectrum, subsequent release the target mole-
ꢁ
1
ance of the sulfinate absorption at 1029 and 960 cm for cules 6 from the resin support was undertaken by treated
resin 1 (Figure 1), as well as the appearance of the sulfone with potassium tert-butoxide via traceless linker sulfinate
ꢁ
1
ꢁ1
stretches (ꢀasym ¼ 1313 cm
and ꢀsym ¼1144 cm ), the elimination cleavage as above solution-phase protocols. As
ꢁ
1
expected new bands for C ¼ C stretch at 1625 cm
and illustrated in Table 1, various primary alkyl halides such as
methyl iodide, ethyl bromide, benzyl chloride, allyl bromide
ꢁ
1
C–Br stretch at 549 cm (Figure 2).
Thirdly, as described in Scheme 1, 1,3-dipolar cycloadd- and methyl bromoacetate were employed in the monoalkyla-
ition of the resin 2 with nitrile oxides, generated in situ tion step, and the corresponding 3-substituted-5-vinylisoxa-
from hydroximinoyl chlorides, and subsequent 1,2-elimin- zoles 6a–6l were obtained in good overall yields (80–95%)
ꢀ
ation reactions with loss of HBr in THF at 60 C gave the from resin 2. HPLC analysis of the crude products cleaved

4
L. ZHANG ET AL.
from the resin directly indicated their high purities in all substituted-5-methyl-isoxazoles in good yields and purities
cases (90–98%).
has been developed based on a new polymer-supported 2-
It is noteworthy that no significant difference in reactivity bromoallyl sulfone reagent. The use of a sulfone moiety as a
was observed for all examined hydroximyl chlorides. In gen- traceless linker in the reaction benefits the solid-phase syn-
eral, aromatic hydroximyl chlorides bearing electron-with- thetic route as it not only makes isolation of the product
drawing groups such as chloro, bromo, nitro, as well as
electron-donating groups such as methyl and methoxy, and
even N-hydroxy-2-chlorobenzimidoyl chloride bearing a o-
chloro substituent (Table 1, entry 5) could afford the desired
easier but its chemical versatility also adds to the diversity
of the isoxazole heterocycle library.
product in good yields. It was also observed that aliphatic Experimental
hydroximyl chlorides like N-hydroxybutylimidoyl chloride
Melting points were measured with a Beijing-Taike X-4
apparatus without corrected. The H and C NMR spectra
were recorded with a Bruker Avance (400 MHz) spectrom-
(Table 1, entry 6) produced the corresponding compound 6f
1
13
in relatively low yield. Besides, for the examined primary
alkyl halides, experiments were performed smoothly and the
corresponding isoxazole derivatives were obtained.
Furthermore, the stereochemistry of the final products 6a–6j
eter, using CDCl as the solvent and TMS as an internal
3
standard. The FTIR spectra were measured with a Perkin-
Elmer SP One FTIR spectrophotometer. Microanalyses were
performed with a Carlo Erba 1106 Elemental Analyzer. Mass
spectra (EI, 70 eV) were recorded on a HP5989B mass spec-
trometer. High performance liquid chromatography (HPLC)
analysis was performed with an Agilent 1100 automated sys-
tem using a photodiode array (PDA) detector (k ¼ 254 nm).
Polystyrene/1% divinylbenzene sodium sulfinate (2.0 mmol
1
was determined by H NMR spectroscopy. As expected, all
the coupling constants (J ¼ 15.6–16.0 Hz) of the two olefinic
protons indicated the exclusive production of E-isomers.
On the other hand, the use of chloromethyltrimethylsi-
lane as an alkylating agent instead of methyl iodide was fur-
ther investigated. A typical example was shown in Scheme 3,
the monoalkylation by treating monocarbanion of the resin
–
SO Na/g) was purchased from Tianjin Nankai Hecheng
2
4
a with chloromethyltrimethylsilane yielded the resin 13,
[
29]
Science and Technology Company of China (100–200
mesh). Hydroximyl chlorides were prepared from the corre-
sponding readily available aldehydes through the reported
which was treated with TBAF
in THF for 6 h delivered
the target molecule 3-phenyl-5-ethenylisoxazole (6k) in high
yield (89% yield).
[
30]
Finally, cleavage of the immobilized intermediate 4 with method.
N,N-Dimethylformamide (DMF) and dimethyl-
Na(Hg)/Na HPO in THF-MeOH at room temperature sulfoxide (DMSO) were freshly distilled from calcium
2
4
formed efficiently 3-aryl-5-methylisoxazoles 7 in excellent hydride under reduced pressure. Triethylamine (TEA) was
yields (91–94%), following the solution-phase conditions as freshly distilled from calcium hydride, and tetrahydrofuran
described above. Several typical examples are listed in (THF) was freshly distilled from sodium-benzophenone
Table 2.
before use. The other reagents and solvents were pure, ana-
In summary, an efficient and convenient method for the lytical grade materials purchased from commercial sources
synthesis of 3-vinyl-5-substituted-isoxazoles and 3- and were used without further purification, unless otherwise
stated. The Supplemental Materials contain sample NMR
and HPLC spectra of the products.
Table 1. Yields and purities of 3-substituted-5-vinylisoxazoles (6a–6l).
1
2
a
b
Entry
R
Reagent
Product (R ) Yield (%) Purity (%)
1
2
3
4
5
6
7
8
9
C6H5
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Br
Br
Br
Br
Br
Br
6a (CH
6b (CH )
3
)
3
)
95
94
92
92
90
80
90
92
89
88
90
93
95
98
97
97
95
90
92
94
96
94
92
93
Preparation of 2-bromoallyl phenyl sulfone (9)
4-CH
4-NO
3
C
C
6
H
4
2
6
H
4
6c (CH
6d (CH
3
Sodium benzenesulfinate 8 (410 mg, 2.5 mmol) was dissolved
4-BrC
2-ClC
n-C
6
H
4
3
)
)
in DMF (10 mL), in which NBu I (90 mg, 0.25 mmol), KI
6
H
7
4
6e (CH
6f (CH
6g (C
3
4
3
H
3
)
5
(500 mg, 3.0 mmol) and 2,3-dibromopropene (600 mg,
4-CH
4-CH
4-CH
3
3
3
C
6
H
H
4
6
C H
5
CH
2
Cl
6
H
)
3
.0 mmol) were added. The mixture was stirred at room
C
6
4
CH
3
CH
2
CH
2
CH
3
CH
3
OOCH
2
Br
2
3
6h (CH OO)
OC
H
6
H
4
4
¼CHCH
Br 6i (CH
Br 6j (CH
6k (H)
2
¼CH)
temperature for 8 h (by TLC). After which, the DMF was
removed by vacuum distillation and a residual solid was
purified by column chromatography on silica gel (25%
EtOAc in petroleum ether as eluent) to afford 9 (633 mg,
1
1
1
a
0
1
2
4-ClC
6
4
¼CHCH
2
2
¼CH)
C H
6 5
I
I
4-CH
3
OC
6
H
6l (H)
Isolated yields based on the functional loading of resin 2 (1.60 mmol Br/g).
b
ꢀ
[26]
ꢀ
77–79 C).
Determined by HPLC of crude cleavage product.
97%) as a white crystal, mp ¼ 80–81 C (lit.
2 3
Scheme 3. Solid-phase monoalkylation with ClCH SiMe .

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
Table 2. Yields and purities of 3-aryl-5-methylisoxazoles (7a–7d).
(Ph-C), 129.4 (Ph-C), 128.7 (Ph-C), 126.8 (Ph-C), 117.4
1
a
b
Entry
R
Product
Yield (%)
Purity (%) (CH¼CHCH ), 99.2 (C-4), 19.2 (CH ). IR (KBr): ꢀ ¼ 3048,
3
3
ꢁ
1
1
2
3
4
a
C
4-CH
4-CH
6
H
5
7a
7b
7c
7d
93
94
94
91
94
96
97
95
2975, 1662, 1559, 1525, 1430, 1383, 965, 796, 695 cm
.
3
C
6
H
6
4
H
Anal. Calcd for C H NO: C, 77.81, H, 6.00, N, 7.56; found:
1
2
11
3
OC
4
þ
C, 77.72, H, 6.13, N, 7.77. MS (EI, 70 eV): m/z ¼ 185 (M ).
6 4
4-ClC H
Isolated yields based on the functional loading of resin 2 (1.60 mmol Br/g).
b
Determined by HPLC of crude cleavage product.
Preparation of 3-phenyl-5-methylisoxazole (7a)
Preparation of 3-phenyl-5-
To a stirred solution of sulfone 11 (1.0 mmol) and anhyd-
rous disodium hydrogen phosphate (560 mg, 4.0 mmol) in
(phenylsulfonylmethyl)isoxazole (11)
1
0 mL of dry methanol was added 1.5 g of pulverized 6%
The N-hydroxybenzimidoyl chloride (460 mg, 3.0 mmol) and
TEA (0.42 mL, 3.0 mmol) was added to a solution of 9
ꢀ
sodium amalgam (freshly prepared) at 0 C. The reaction
mixture was vigorously stirred until TLC showed complete
conversion. The mixture was poured into water (30 mL) and
extracted with diethyl ether (3 ꢂ 10 mL). The combined
organic layers were dried over anhydrous Na SO and
evaporated, and the crude product was purified by flash
chromatography to afford 7a (153 mg, 96% yield) as a white
solid, mp 40–42 C (lit.
(
652 mg, 2.5 mmol) in THF (10 mL), and the reaction mix-
ꢀ
ture was then warmed up to 60 C and stirred continuously
at this temperature until the completion of the reaction (by
TLC). After which, the resulting mixture was cooled to
room temperature and diluted with water (5 mL), extracted
with ethyl acetate (2 ꢂ 10 mL). The combined organic phase
was washed with brine (5 mL), dried with anhydrous magne-
sium sulfate, and concentrated. The crude product was puri-
fied by column chromatography on silica gel (20% EtOAc in
petroleum ether as eluent) to afford the compound 11
2
4
ꢀ
[31]
ꢀ
41–42 C).
Preparation of polymer-supported 3-phenylsulfonyl-2-
bromopropene (2)
ꢀ
1
(
673 mg, 90%) as a yellow solid, mp ¼ 109–110 C.
H
The resin 1 (1.0 g, 2.0 mmol/g) was swollen in DMF (15 mL)
under nitrogen for 30 min. Then, 2,3-dibromopropene
NMR (400 MHz, CDCl ): d ¼ 7.82–7.76 (m, 4 H, Ph-H), 7.68
3
(
t, J ¼ 7.6 Hz, 1 H), 7.55 (t, J ¼ 7.8 Hz, 2 H, Ph-H), 7.47–7.45
(
(
5 mmol), KI (5 mmol) and tetrabutylammonium iodide
1 mmol) were added, and the mixture was shaken at room
(
m, 3 H, Ph-H), 6.73 (s, 1 H, CHC ¼ N), 4.60 (s, 2 H, CH ).
2
1
3
C NMR (100 MHz, CDCl ): d ¼ 161.9 (C-5), 160.9 (C-3),
3
1
1
1
1
8
37.8 (Ph-C). 134.6 (Ph-C), 129.8 (Ph-C), 129.5 (Ph-C), temperature for 12 h. The resin was filtered and washed
28.9 (Ph-C), 128.7 (Ph-C), 128.4 (Ph-C), 126.8 (Ph-C), sequentially with DMF (2 ꢂ 5 mL), H
O (2 ꢂ 5 mL), ethanol
2
04.0 (C-4), 54.1 (CH ). IR (KBr): ꢀ ¼ 3081, 2939, 2850, (2 ꢂ 5 mL), CH
Cl
2 2
(2 ꢂ 5 mL) and diethyl ether (2 ꢂ 5 mL),
2
ꢀ
608, 1581, 1470, 1442, 1408, 1317, 1309, 1248, 1149, 1084, and dried overnight in a vacuum oven at 50 C to produce
ꢁ
1
33, 761, 688 cm . Anal. Calcd for C H NO S: C, 64.20, the resin 2 in the form of yellow beads with a loading value
16
13
3
H, 4.38, N, 4.68; found: C, 64.04, H, 4.52, N, 4.76. MS (EI, of 1.60 Br mmol/g by bromine elementary analysis. IR
þ
7
0 eV): m/z ¼ 299 (M ).
(KBr): ꢀ ¼ 3038, 2923, 1625, 1495, 1448, 1313, 1144, 822,
ꢁ1
7
54, 697, 549 cm .
One-pot preparation of 3-phenyl-5-(1-E-
propenyl)isoxazole (6a)
SPOS of 3-substituted-5-vinyl isxoxazoles (6a–6l):
general procedure
BuLi (2.0 mmol, 1 mL, 2.0 M hexane solution) was added to
ꢀ
DMSO (4.0 mmol, 310 mg) in THF (5 mL) at 0 C and To a suspension of the swollen resin 2 (625 mg, 1.0 mmol)
stirred for 5 min. The resulting dimsyl anion solution was in THF (10 mL) was added hydroximyl chloride (2.0 mmol)
transferred to a solution of 11 (1.0 mmol) in THF (5 mL) at and triethylamine (0.28 mL, 2.0 mmol), and the resulting
ꢀ
room temperature. After stirring for 30 min, ethyl bromide reaction mixture was shaken at 60 C for 12 h. After filtra-
(
1.1 mmol) was added to this mixture. The reaction mixture tion, the resin was washed successively with THF, MeOH,
ꢀ
was stirred for 1 h, then cooled to 0 C, 1 M potassium tert-
H
2
O and CH
Cl
2
2
(2 ꢂ 5 mL of each), and dried in vacuum
butoxide in THF (1 mL) was added subsequently, and stirred to afford resin 4 as a pale yellow beads. Under nitrogen
at the same temperature for 30 min. The reaction mixture BuLi (2.0 mmol, 1 mL, 2.0 M) was added to DMSO (310 mg,
ꢀ
was warmed to room temperature with stirring continuously 4.0 mmol) in THF (5 mL) at 0 C and stirred for 5 min. The
for 30 min again, and then quenched with water (10 mL). resulting dimsyl anion solution was transferred to a suspen-
After usual workup with EtOAc, the organic layer was sion of resin 4 pre-swollen in THF (10 mL). After shaking
evaporated, and the residue was subjected to column chro- for 30 min, alkyl halide (2.0 mmol) was added to this mix-
matography on silica gel (20% EtOAc in petroleum ether as ture and shaken for 2 h, the color of the breads turned light
ꢀ
eluent) to give 6a (161 mg, 87%) as a pale yellow solid, mp orange. The reaction mixture was then cooled to 0 C, 1 M
ꢀ
¼
64–65 C. d ¼ 7.82 (d, J ¼ 7.2 Hz, 2 H, Ph-H), 7.54–7.50 potassium tert-butoxide in THF (4 mL) was added subse-
(
m, 1 H, CH¼CHCH ), 7.43–7.35 (m, 3 H, Ph-H), 6.44 (d, quently, and shaken at the same temperature for 30 min.
3
J ¼ 15.6 Hz, 1 H, CH ¼ CHCH ), 6.38 (s, 1 H, CHC ¼ N), The reaction mixture was warmed to room temperature
3
13
1
.97 (d, J ¼ 7.2 Hz, 3 H, CH ). C NMR (100 MHz, CDCl ): with stirring for 30 min again, and then quenched with 10%
3
3
d ¼ 169.4 (C-5), 162.5 (C-3), 134.2 (CH ¼ CHCH ), 129.9 HCl (aq.). The residual resin was collected by filtration and
3

6
L. ZHANG ET AL.
washed with CH Cl (3 ꢂ 5 mL), and the organic extracts 9.96; found: C, 71.56, H, 5.75, N, 9.90. MS (EI, 70 eV): m/
2
2
þ
were washed with water, dried over anhydrous MgSO and z ¼ 201 (M ).
4
concentrated to afford product 6 with 91–98% purity (deter-
mined by HPLC). The crude product was purified by flash
SPOS of 3-Aryl-5-methylisoxazoles (7a–7d):
general procedure
chromatography for structural analysis. The compounds
[
31]
[31]
[31]
[31]
[31]
[31]
[32]
6
b,
6d,
6 g,
6 h,
6i,
6j
and 6k
are
known, and our spectral data were in accordance with those To a suspension of the swollen resin 4, derived from the
in the literatures.
-(4-Nitrophenyl)-5-(1-E-propenyl)isoxazole
resin 2 (1.0 mmol) in THF-MeOH (1:1, 20 mL) was added
anhydrous Na HPO (4.0 mmol) and 1.5 g of pulverized 6%
3
(6c).
2
4
ꢀ
1
ꢀ
Yellow solid; mp ¼ 92–93 C. H NMR (400 MHz, CDCl ):
3
sodium amalgam (freshly prepared) at 0 C, and the result-
ing reaction mixture was vigorously stirred for 2 h. The
residual resin was collected by filtration and successively
with THF, MeOH, H O and CH Cl (2 ꢂ 5 mL of each), and
d ¼ 8.27 (d, J ¼ 8.8 Hz, 2 H, Ph-H), 7.96 (d, J ¼ 8.8 Hz, 2 H,
Ph-H), 7.64–7.60 (m, 1 H, CH¼CHCH ), 6.48 (d,
3
J ¼ 16.0 Hz, 1 H, CH ¼ CHCH ), 6.39 (s, 1 H, CHC ¼ N),
3
2
2
2
1
3
1
.93 (d, J ¼ 6.4 Hz, 3 H, CH ). C NMR (100 MHz, CDCl ):
3
3
the organic extracts were washed with water, dried over
d ¼ 169.9 (C-5), 160.0 (C-3), 148.5 (Ph-C), 135.4 (Ph-C),
anhydrous Na SO4 and concentrated to afford product 7
2
1
(
2
6
1
34.1 (CH ¼ CHCH ), 127.3 (Ph-C), 124.8 (Ph-C), 117.3 with 94–97% purity (determined by HPLC). Further purifi-
3
CH¼CHCH ), 99.8 (C-4), 19.2 (CH ). IR (KBr): ꢀ ¼ 3048, cation was carried out through flash chromatography their
3
3
[32] [31]
975, 1662, 1559, 1525, 1430, 1383, 1350, 965, 825, 796, structural analyses. Structures of compounds 7a,
7 b,
have been already described, our character-
ꢁ
1
[31]
[31]
92 cm . Anal. Calcd for C H N O : C, 62.61, H, 4.38, N, 7c
and 7d
12
10 2 3
2.17; found: C, 62.73, H, 4.53, N, 12.25. MS (EI, 70 eV): m/ ization data were in accordance with those in the literatures.
þ
z ¼ 230 (M ).
3
-(2-Chlorophenyl)-5-(1-E-propenyl)isoxazole (6e). Pale
ꢀ
1
Disclosure statement
yellow solid; mp ¼ 68–69 C. H NMR (400 MHz, CDCl ):
3
d ¼ 7.55–7.51 (m, 1 H, CH¼CHCH ), 7.16–7.13 (m, 2 H, Ph-
3
No potential conflict of interest was reported by the authors.
H), 6.95–6.87 (m, 2 H, Ph-H), 6.47 (d, J ¼ 15.6 Hz, 1 H,
CH ¼ CHCH ), 6.34 (s, 1 H, CHC ¼ N), 1.95 (d, J ¼ 7.2 Hz,
3
1
3
Funding
3
1
H, CH ). C NMR (100 MHz, CDCl ): d ¼ 169.6 (C-5),
3
3
62.5 (C-3), 134.4 (CH ¼ CHCH ), 133.0 (Ph-C), 131.1 (Ph- National Natural Science Foundation of China (No. 21762022), the
3
C), 130.8 (Ph-C), 130.1 (Ph-C), 128.1 (Ph-C), 127.1 (Ph-C), Opening Foundation of National Research Center for Carbohydrate
Synthesis (No. GJDTZX-KF-201414) and the Opening Foundation of
1
ꢀ
8
4
7
17.3 (CH¼CHCH ), 99.7 (C-4), 19.1 (CH ). IR (KBr):
3
3
Key Laboratory of Functional Small Organic Molecule of Ministry of
Education (No. KLFS-KF-201411, KLFS-KF-201706) is gratefully
acknowledged.
¼ 3065, 2942, 1660, 1604, 1586, 1448, 1426, 1372, 971, 962,
ꢁ
1
36, 752 cm . Anal. Calcd for C H ClNO: C, 65.61, H,
12
10
.59, N, 6.38; found: C, 65.74, H, 4.71, N, 6.47. MS (EI,
þ
0 eV): m/z ¼ 219 (M ).
3
-(n-Propyl)-5-(1-E-propenyl)isoxazole (6f). Pale yellow
1
ORCID
oil. H NMR (400 MHz, CDCl ): d ¼ 7.40–7.38 (m, 1 H,
3
CH¼CHCH ), 6.47 (d, J ¼ 16.0 Hz, 1 H, CH ¼ CHCH ), 6.33
3
3
Yang Pan
http://orcid.org/0000-0002-9429-1296
(
1
s, 1 H, CHC ¼ N), 2.36 (t, J ¼ 6.8 Hz, 2 H, CH CH CH ),
2
2
3
.95 (d, J ¼ 7.2 Hz, 3 H, CH ), 1.67–1.64 (m, 2 H,
13
3
References
CH CH CH ), 1.11 (t, J ¼ 7.2 Hz, 3 H, CH CH CH ).
C
2
2
3
2
2
3
NMR (100 MHz, CDCl ): d ¼ 166.5 (C-5), 157.2 (C-3), 133.6
3
[1] Lakhvich, F. A.; Koroleva, E. V.; Akhrem, A. A. Synthesis,
Chemical Transformation, and Application of Isoxazole
Derivatives in the Total Chemical Synthesis of Natural
Compounds (Review). Chem. Heterocycl. Compd. 1989, 25,
359–372. DOI: 10.1007/BF00480746.
(
(
(
9
CH ¼ CHCH ), 115.9 (CH¼CHCH ), 98.5 (C-4), 29.9
3
3
CH CH CH ), 19.9 (CH CH CH ), 19.0 (CH ), 13.8
2
2
3
2
2
3
3
CH CH CH ). IR (neat): ꢀ ¼ 3045, 2971, 1655, 1450, 1386,
2
2
3
ꢁ
1
60, 832, 760, 696 cm . Anal. Calcd for C H NO: C, 71.49,
9
13
[2] Taylor, R. D.; MacCoss, M.; Lawson, D. G. Rings in Drugs. J.
H, 8.67, N, 9.26; found: C, 71.36, H, 8.70, N, 9.35. MS (EI,
Med. Chem. 2014, 57, 5845–5859. DOI: 10.1021/jm4017625.
þ
7
0 eV): m/z ¼ 151 (M ).
[3] Pinho, e. M.; Teresa, M. V. D. Recent Advances on the
Synthesis and Reactivity of Isoxazoles. Curr. Org. Chem. 2005,
9, 925–958. DOI: 10.2174/1385272054368420.
3
-(4-Methoxyphenyl)-5-ethenylisoxazole (6 l). Pale yel-
ꢀ
1
low solid; mp ¼ 44–45 C. H NMR (400 MHz, CDCl3):
d ¼ 7.89 (d, J ¼ 8.0 Hz, 2 H, Ph-H), 6.99 (d, J ¼ 8.0 Hz, 2 H,
Ph-H), 6.93 (s, 1 H, CHC ¼ N), 6.75–6.67 (m, 1 H,
CH¼CH ), 5.93 (d, J ¼ 18.4 Hz, 1 H, trans-CH ¼ CH ), 5.43
[
4] Hu, F.; Szostak, M. Recent Developments in the Synthesis and
Reactivity of Isoxazoles: Metal Catalysis and beyond. Adv.
Synth. Catal. 2015, 357, 2583–2614. DOI: 10.1002/adsc.
201500319.
2
2
13
(
d, J ¼ 11.2 Hz, 1 H, cis-CH ¼ CH ), 3.85 (s, 3 H, OCH ).
C
[5] Singh, M. S.; Chowdhury, S.; Koley, S. Progress in 1,3-Dipolar
Cycloadditions in the Recent Decade: An Update to Strategic
Development towards the Arsenal of Organic Synthesis.
Tetrahedron 2016, 72, 1603–1644. DOI: 10.1016/j.tet.2016.02.
2
3
NMR (100 MHz, CDCl ): d ¼ 169.2 (C-5), 161.4 (C-3), 158.7
3
(
(
(
6
Ph-C), 148.9 (CH ¼ CH ), 128.1 (Ph-C), 121.2 (Ph-C), 117.1
2
CH¼CH ), 114.3 (Ph-C), 104.4 (C-4), 55.3 (OCH ). IR
2
3
031.
KBr): ꢀ ¼ 3055, 1646, 1497, 1452, 1382, 1245, 991, 916, 765,
[6] Morita, T.; Yugandar, S.; Fuse, S.; Nakamura, H. Recent
ꢁ
1
90 cm . Anal. Calcd for C H NO : C, 71.63, H, 5.51, N,
Progresses in the Synthesis of Functionalized Isoxazoles.
1
2
11
2

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Tetrahedron Lett. 2018, 59, 1159–1171. DOI: 10.1016/j.tetlet.
018.02.020.
Trisubstituted Oxindoles. J. Comb. Chem. 2007, 9, 566–568.
DOI: 10.1021/cc070010x.
2
[
[
[
7] Caramella, P.; Grunanger, P. 1,3-Dipolar Cycloaddition [21] Chang, Y.-F.; Jiang, Y.-R.; Cheng, W.-C. Traceless Sulfone
Chemistry (Ed.: Padwa, A.), Wiley, New York, NY, 1984.
8] Gr u€ nanger, P.; Vita-Finzi, P. Isoxazoles In The Chemistry of
Heterocyclic Compounds, John Wiley: New York, 1991.
Linker Cleavage Triggered by Ozonolysis: Solid-Phase Synthesis
of Diverse a,b-Unsaturated Carbonyl Compounds. Tetrahedron
Lett. 2008, 49, 543–547. DOI: 10.1016/j.tetlet.2007.11.064.
9] Heaney, F. Nitrile Oxide/Alkyne Cycloadditions–a Credible [22] Li, X.; Sheng, S.-R.; Su, H.-Y.; Liu, L.; Liu, X.-L. Polymer-
Platform for Synthesis of Bioinspired Molecules by Metal-Free
Molecular Clicking. Eur. J. Org. Chem. 2012, 2012, 3043–3058.
DOI: 10.1002/ejoc.201101823.
Bound Phenylselenenylmethyl Sulfone as an Efficient Reagent
for the Solid-Phase Synthesis of (E)-Vinyl Phenyl Selenides.
React. Funct. Polym. 2014, 77, 18–22. DOI: 10.1016/j.reactfunct-
polym.2014.02.001.
[
[
10] Simoni, D.; Grisolia, G.; Giannini, G.; Roberti, M.; Rondanin,
R.; Piccagli, L.; Baruchello, R.; Rossi, M.; Romagnoli, R.;
Invidiata, F. P.; et al. Heterocyclic and Phenyl Double-Bond-
Locked Combretastatin Analogues Possessing Potent Apoptosis-
Inducing Activity in HL60 and in MDR Cell Lines. J. Med.
Chem. 2005, 48, 723–736. DOI: 10.1021/jm049622b.
[
[
[
[
23] He, A.-Y.; Sheng, S.-R.; Huang, Z.-Z.; Li, L.; Cai, M.-Z. Solid-
Phase Organic Synthesis of 1,4-N-Vinyl- and 1,4-N-Allyl-
Triazoles with the Sulfonate Linker. J. Hetercyclic. Chem. 2014,
5
1, 1862–1965. DOI: 10.1002/jhet.1857.
24] Wang, Z.; Sheng, S.-R.; Wei, M.-H.; Liu, X.-L. Simple Synthesis
of 1-Substituted-4-Vinyl-1,2,3-Triazoles Based on Polystyrene-
Supported Sulfonyl Chloride. Synth. Commun. 2016, 46,
11] Easton, C. J.; Heath, G. A.; Hughes, C. M. M.; Lee, C. K. Y.;
Savage, G. P.; Simpson, G. W.; Tiekink, E. R. T.; Vuckovic,
G. J.; Webster, R. D. Electrochemical and Yeast-Catalysed
Ring-Opening of Isoxazoles in the Synthesis of Analogues of
226–231. DOI: 10.1080/00397911.2015.1130228.
25] Wu, G.-J.; Sheng, S.-R.; Li, D.; Xu, L.-F.; Huang, Z.-Z. Polymer-
Supported Vinyl Sulfone as an Efficient Reagent for the
Synthesis of 3-Monosubstituted Isoxazoles. Synth. Commun.
V
R
the Herbicide Grasp . J. Chem. Soc, Perkin Trans. 2001, 1,
168–1174. DOI: 10.1039/b008081k.
1
2
013, 43, 3034–3043. 18 DOI: 10.1080/00397911.2012.7627.
26] Undeela, S.; Thadkapally, S.; Nanubolu, J. B.; Singarapu, K. K.;
Menon, R. S. Catalyst-Controlled Divergence in
Cycloisomerisation Reactions of N-propargyl-N-Vinyl
[
[
12] Dadiboyena, S.; Xu, J. P.; Hamme, A. T. II. Isoxazoles from 1,1-
Disubstituted Bromoalkenes. Tetrahedron Lett. 2007, 48,
1
295–1298. DOI: 10.1016/j.tetlet.2006.12.005.
13] Young, D. D.; Deiters, A. Solid-Phase Organic Synthesis:
Concepts, Strategies, and Applications; Toy, P. H.; Lam, Y. Eds.;
John Wiley & Sons, Inc.: Hoboken, NJ, 2012.
14] Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993.
15] Huang, W. Q.; Cheng, S. L.; Sun, W. M. 2-Polystyrylsulfonyl
Ethanol Supports for the Solid-Phase Syntheses of Hydantoins
and Ureas. Tetrahedron Lett. 2001, 42, 1973–1974. DOI: 10.
Sulfonamides: Gold-Catalysed Synthesis of 2-Sulfonylmethyl
Pyrroles and Dihydropyridines. Chem. Commun. 2015, 51,
13748–13751. DOI: 10.1039/C5CC04871K.
[
[
[
27] Mart ꢀı n, T.; Rodr ꢀı guez, C. M.; Mart ꢀı n, V. S. A New Approach to
Functionalized Cyclobutanes: Stereoselective Synthesis of the
Enantiomers of Grandisol and Fraganol. Tetrahedron:
Asymmetry 1995, 6, 1151–1164. DOI: 10.1016/0957-
4166(95)00141-B.
1
016/S0040-4039(01)00057-0.
[
28] N ꢀa jera, C.; Yus, M. Desulfonylation Reactions: Recent
Developments. Tetrahedron 1999, 55, 10547–10658. DOI: 10.
[
[
16] D’herde, J. N. P.; De Clercq, P. J. Carbon-Carbon Bond
Formation on Solid Support. Application of the Classical
Julia–Lythgoe Olefination. Tetrahedron Lett. 2003, 44,
1016/S0040-4020(99)00600-6.
[
29] Kim, S. H.; Jin, Z. D.; Ma, S.; Fuchs, P. L. Conversion of Vinyl
Sulfones to Regiospecifically Functionalized Trisubstituted
Olefins. Tetrahedron Lett. 1995, 36, 4013–4014. DOI: 10.1016/
6
657–6659. DOI: 10.1016/S0040-4039(03)01637-X.
17] Hwang, J. Y.; Choi, H.-S.; Lee, D.-H.; Gong, Y.-D. Solid-Phase
Synthesis of 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives
via Selective, Reagent-Based Cyclization of Acyldithiocarbazate
Resins. J. Comb. Chem. 2005, 7, 816–819. DOI: 10.1021/
cc0500957.
0040-4039(95)00701-D.
[
30] Dubrovskiy, A. V.; Larock, R. C. Synthesis of Benzisoxazoles by
the [3 þ 2] Cycloaddition of in Situ Generated Nitrile Oxides
and Arynes. Org. Lett. 2010, 12, 1180–1183. DOI: 10.1021/
ol902921s.
[
18] McAllister, L. A.; Turner, K. L.; Brand, S.; Stefaniak, M.;
Procter, D. J. Solid Phase Approaches to N-Heterocycles Using [31] Xu, W. M.; Tang, E.; Huang, X. Preparation of Isoxazol(in)yl
a Sulfur Linker Cleaved by SmI
497–6507. DOI: 10.1021/jo060940n.
19] Gao, Y.-N.; Lam, Y.-L. [3 þ 2] Cycloaddition Reactions in the
2
. J. Org. Chem. 2006, 71,
Substituted Selenides and Their Further Deselenenylation
Reaction to Synthesize 3,5-Disubstituted Isoxazoles. Tetrahedron
2005, 61, 501–506. DOI: 10.1016/j.tet.2004.10.071.
6
[
[
Solid-Phase Synthesis of 1,2,3-Triazoles. Org. Lett. 2006, 8, [32] Hwang, S. H.; Kurth, M. J. 1,3-Dipolar Cycloaddition of Nitrile
3
283–3285. DOI: 10.1021/ol0611494.
Oxides to 1-Phenylsulfonyl-1,3-Butadienes: synthesis of 3-(4,5-
Dihydroisoxazol-5-yl)Pyrroles. Tetrahedron Lett. 2002, 43,
53–56. DOI: 10.1016/S0040-4039(01)02069-X.
20] Xie, J. W.; Sun, J.; Zhang, G. L.; Houghten, R. A.; Yu, Y. P. A
Traceless Approach for the Solid-Phase Parallel Synthesis of