Polymer-supported vinyl sulfone as an efficient reagent for the synthesis of 3-monosubstituted isoxazoles

Article abstract of DOI:10.1080/00397911.2012.762718

Polystyrene-supported vinyl sulfone reagent has been developed and used for solid-phase organic synthesis of 3-monosubstituted isoxazoles by 1,3-dipolar cycloaddition reaction with nitrile oxides and subsequent cleavage from the polymer support through an

Full text of DOI:10.1080/00397911.2012.762718

This article was downloaded by: [University of Haifa Library]
On: 29 July 2013, At: 06:07
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Polymer-Supported Vinyl Sulfone as an Efficient
Reagent for the Synthesis of 3-monosubstituted
Isoxazoles
Guo-Jian Wu a , Shou-Ri Sheng a , Dan Li a , Li-Fan Xu a & Zhen-Zhong Huang a
a College of Chemistry and Chemical Engineering, Jiangxi Normal University , Nanchang , P.
R. China
Accepted author version posted online: 18 Jun 2013.
To cite this article: Synthetic Communications (2013): Polymer-Supported Vinyl Sulfone as an Efficient Reagent for the
Synthesis of 3-monosubstituted Isoxazoles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2012.762718
To link to this article: http://dx.doi.org/10.1080/00397911.2012.762718
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
Polymer-Supported Vinyl Sulfone as An Efficient Reagent for the Synthesis of 3-
Monosubstituted Isoxazoles
Guo-Jian Wu1, Shou-Ri Sheng1,, Dan Li1, Li-Fan Xu1, Zhen-Zhong Huang1
1College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang,
P. R. China
Correspondence to: Shou-Ri Sheng; , E-mail: shengsr@jxnu.edu.cn
Abstract
Polystyrene-supported vinyl sulfone reagent has been developed and used for solid-phase
organic synthesis of 3-monosubstituted isoxazoles by 1,3-dipolar cycloaddition reaction
with nitrile oxides, and subsequent cleavage from the polymer support through
elimination reaction in the presence of potassium tert-butoxide. The advantages of this
method include straightforward operation, good yield and high purity of the crude
products.
KEYWORDS: Solid-phase organic synthesis, 3-monosubstituted isoxazole, polystyrene-
supported vinyl sulfone, 1,3-dipolar cycloaddition, elimination reaction
INTRODUCTION
The preparation of structurally diverse compounds is an important facet of modern drug
discovery programs.[1] One of the most commonly employed methods in library
production is solid-phase organic synthesis (SPOS), which has provided many
advantages in terms of separation and purification of materials and unique opportunities
in controlling organic reactions.[2] Heterocyclic compounds have received special
attention because of their broad range of biological activities. As a result, an increasing
number of pharmaceutically useful heterocyclic compounds have been prepared using
solid-phase methodologies. [3] Isoxazole moieties are found in various biologically active
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
compounds because they are readily transformed into various biodynamic agents,
including those with antithrombotic, PAF antagonist, and hypolipidemic properties.[4]
Because of their importance, many practical synthetic methods have been utilized for the
preparation of various isoxazoles.[5–7] However, there are only a few reports concerning
synthetic methods for 3-monosubstituted isoxazoles.[8,9] It is well known that the sulfonyl
group is widely recognized as an important activating moiety introduced in an
intermediate molecule for the construction of carbon-carbon bond and other
transformations.[10] Especially, the sulfonyl group is readily converted to a leaving group
making carbon-carbon double bond via a base-promoted β-elimination route.[11]
Furthermore, sulfinate-functionalized resins have been developed efficiently and utilized
in SPOS, and the resulting sulfone linker has been found to be both robust and
versatile.[12] Previous and recent reports from Kurth and co-workers,[13] Lam’s research
group, [14] other laboratories[15] and ours[16] have detailed sulfone-linking strategies for
SPOS methods to explore sulfone-based chemical transformations. As a part of our
ongoing research program focused on the use a versatile traceless sulfone linker in SPOS,
we herein have developed an efficient SPOS methodology for the preparation of 3-
monosubstituted isoxazoles based on polymer-supported vinyl sulfone reagent. To our
knowledge, this is a previously unreported method.
Firstly, we investigated the procedure for the preparation of polymer-supported vinyl
sulfone 3. As outlined in Scheme 1, polystyrene/1% divinylbenzene sodium sulfinate 1
(1.80 mmol –SO2Na/g) was allowed to react with 2-chloroethanol in DMF-THF (1/2) in
the presence of tetrabutylammonium iodide (TBAI) and KI to afford polymer-supported
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
2-phenylsulfonylethanol 2, which was amenable to FTIR monitoring for the appearance
of the expected a large hydroxyl stretch at 3500 cm–1, as well as the characteristic sulfone
absorption bands at 1317 and 1119 cm–1. Besides, the hydroxyl group attachment on the
resin 2 was calculated to be 1.65 mmol –CH2CH2OH/g from the nitrogen elemental
analysis of its corresponding 3,5-dinitrobenzoate intermediate prepared by treatment of 2
with 3,5-dinitrobenzoyl chloride according to the method described in literature.[17]
Polymer-supported vinyl sulfone 3 was then obtained in near quantitative yield from 2-
hydroxy sulfone resin 2 by acetylation followed by in situ elimination in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It should be noted that reaction 2 → 3 was
not amenable to FTIR analysis, nevertheless, the complete conversion of the hydroxy
group of resin 2 to 3 was further confirmed by treating 3 with AcCl/Et3N: no acetoxy
absorption band was observed in the FTIR spectrum of the product. On the other hand,
the loading of vinyl functional group of resin 3 was determined to be 1.67 mmol/g
following the published protocol.[18]
Next, we set out to engineer the construction of the isoxazolyl heterocycles using
polymer-supported vinyl sulfone 3 (Scheme 2). On the basis of solution-phase studies on
the 1,3-dipolar cycloaddition of phenyl vinyl sulfone with nitrile oxides with high
regioselectivity,[19] treatment of resin 3 with nitrile oxides, generated by reaction of
aldoximes with an excess of commercially available aqueous NaOCl in CH2Cl2/THF (1:1)
effected the 1,3-dipolar cycloaddition to give resin-bound isoxazolines 4 regioselectively.
Since this transformation exhibited no reliably diagnostic absorption peaks in the FTIR
spectra, the elimination release step was undertaken. After a number of basic (Et3N, DBU
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
and t-BuOK) elimination conditions were evaluated, and optimal results were obtained by
treating resin 4 with potassium tert-butoxide in THF at room temperature for 12 h to
afford the expected 3-monosubstituted isoxazoles 5a–5k together with the polymer-
supported phenylsulfinic acid (6) as a residual resin, and the results are summarized in
Table 1. As disclosed in Table 1, besides of good isolated yields of the target compounds
5a–5k, HPLC analysis directly of the crude products cleaved from the resin indicated
their high purities in all cases (94–98 %). It is noteworthy that substrate aldoximes
carrying either an electron donating substituent, such as methyl and methoxy (Table 1,
entries 2 and 3) or an electron with drawing group including halogens (Table 1, entries 4–
6), nitro (Table 1, entry) and trifluoromethyl (Table 1, entry 8) could perform efficiently
with good to excellent yields. However, aldoxime bearing an ortho-substituent (e.g., the
chloro group) (Table 1, entry 5) showed a slight decrease in yield (80 %) due to the steric
hindrance. For other aldoximes such as cinnamaldehyde oxime, 2-furaldehyde oxime and
propionaldehyde oxime, higher yields were also obtained (Table 1, entries 9–11).
In addition, the residual resin 6 with its infrared absorption identical to the previously
reported data [14a] could be converted to resin 1 for recycle by treatment of it with NaOH
in DMF-H2O (v/v = 3:1) for 1h. For instance, 3-phenylisoxazole (5a) was obtained in
88 % yield under the same reaction condition using the recovered resin 1 (second run),
and in 82 % yield after second recycle (i.e. third run). It was shown that recycling 2-3
times led to a gradual deterioration of the resin 1.
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
In summary, a facile protocol for the traceless solid-phase synthesis of 3-monosubstituted
isoxazoles has been developed by 1,3-dipolar cycloaddition reaction of polystyrene-
supported vinyl sulfone with nitrile oxides, and subsequent elimination reaction. This
method provides a novel access to 3-aryl-, alkyl- and styryl-isoxazoles in good yields and
purities with simplification of product work-up, which are important heterocycle
compounds in medicinal chemistry and materials science. Further studies on the
application of the present methodology to the synthesis of biological active compounds
are proceeding.
EXPERIMENTAL
Melting points were determined on an X4 melting point apparatus and are uncorrected. 1H
(400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker Avance (400
MHz) spectrometer, using CDCl3 as the solvent and tetramethylsilane (TMS) as an
internal standard. FTIR spectra were taken on a Perkin-Elmer SP One FTIR
spectrophotometer. Microanalyses were performed with a Carlo Erba 1106 Elemental
Analyzer. High performance liquid chromatography (HPLC) analysis was performed on
an Agilent 1100 automated system having a photodiode array (PDA) detector (λ max
=
254 nm used for this study) using a gradient with CH3CN /H2O on a RP-18e column (150
×4.6 mm). Polystyrene/1% divinylbenzene sodium sulfinate (1.8 mmol –SO2Na/g) (1)
was purchased from Tianjin Nankai Hecheng Science and Technology Co. (100–200
mesh). Oximes [20] were prepared according to procedures in literature. The other
chemicals were obtained from commercial suppliers (Aldrich, USA and Shanghai
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
Chemical Company, China) and used without purification prior to use. All organic
solvents were dried by standard methods.
Preparation Of Polystyrene-Supported 2-Phenylsulfonylethanol (2)
Resin 1 (2.0 g, 3.6 mmol) was swollen in a mixture of DMF (10 mL) and THF (20 mL)
by gently shaking the resin-DMF-THF mixture at room temperature for 30 min. Then 2-
chloroethanol (2.4 mL), tetrabutylammonium iodide (0.3 g), and potassium iodide (1.8 g)
were added to this mixture and the resulting reaction mixture was shaken at 80 °C under
a nitrogen atmosphere for 24 h. After filtration, the resin was washed successively with
DMF, H2O, CH3OH and Et2O (2 × 10 mL of each), and then dried under reduced
pressure over phosphorous pentoxide at 50–60oC to afford resin 2 as yellow beads.
For analytical purposes following the published method,[17] the 3,5-dinitrobenzoate of
resin 2 was prepared by reaction of resin 2 (0.5 g) with 3,5-dinitrobenzoyl chloride (0.5 g)
in dry pyridine (10 mL). After being stirred at 80 oC for 1.5 h, the resin was collected on
a filter and washed successively with THF, H2O, MeOH and Et2O (2 × 10 mL of each),
and dried as described above to yield the corresponding 3,5-dinitrobenzoate resin (0.64 g)
containing a strong carbonyl absorption at 1732 cm–1 in its FTIR spectrum.
Preparation Of Polystyrene-Supported Vinyl Sulfone (3)
Resin 2 (2.0 g) was swollen in THF (30 mL) at 0 °C, and acetic anhydride (1.3 g, 13.0
mmol) and DBU (3.0 g, 20.0 mmol) were added. The reaction mixture was shaken at
room temperature for 12 h, the resin was then collected by filtration, washed with H2O (2
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
× 15 mL), THF/H2O (1:1, 2 × 10 mL), THF (2 × 10 mL), and Et2O (2 × 10 mL), and
dried in a vacuum overnight to afford polymer 3 as yellow beads: IR (KBr): v = 2924,
2855, 1600, 1490, 1450, 1377, 1315, 1147 cm–1.
According to the reported method,[18] reaction of polymeric 3 with 5-ethoxy-l,2,3,4-
tetrahydroisoquinoline, followed by treated with MeI and diisopropylethylamine
successively to release N-methyl-5-ethoxy-l,2,3,4-tetrahydroisoquinoline; the vinyl
functional loading of polymeric 3 based on the amount of N-methyl-5-ethoxy-l,2,3,4-
tetrahydroisoquinoline was calculated to be 1.67 mmol/g.
General Procedure For The Synthesis Of 3-Monosubstituted Isoxazoles (5a–5k)
Aldoxime (3.0 mmol) were added to a suspension of resin 3 (1.0 g) in CH2Cl2 /THF (1:1,
20 mL), and aqueous NaClO (5%, 12 g, 8.0 mmol) was added dropwise over 30 min at
0°C, and the reaction mixture was allowed to warmed to room temperature for 12h. The
resin was collected by filtration, washed with H2O (2 ×15 mL), THF/H2O (1/1, 2 × 10
mL), THF (2 ×10 mL), CH2Cl2 (2 ×10 mL) and Et2O (2 × 10 mL), and dried in a vacuum
overnight, affording polymer 4 as yellow beads. Subsequently, resin 4 was swollen in
THF (15 mL) for 1h. Then potassium tert-butoxide (0.4 g, 3.5 mmol) was added to the
suspension at 0°C. The reaction mixture was stirred at the same temperature for 1 h, and
then was warmed to room temperature and then shaken for 12 h. After which the resin
was filtered and washed with THF (2 × 10 mL), THF/ H2O (1/1, 2 × 10 mL), and H2O (2
× 10 mL). The combined filtrate and washings were concentrated to remove organic
solvent, and the residue was extracted with AcOEt, dried over anhydrous magnesium
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
sulfate, and then concentrated under reduced pressure to give crude products 5a–5k with
over 93 % purity determined by HPLC, which were further purified by passing the crude
product through silica gel column chromatography eluted with ethyl acetate/hexane to
provide pure products for their NMR analyses.
3-Phenylisoxazole (5a)
Colorless oil (lit.[8d]); 1H NMR: δ = 8.45 (d, J = 1.8 Hz, 1H), 7.84–7.81 (m, 2H), 7.47–
7.44 (m, 3H), 6.65 (d, J = 1.8 Hz, 1H); 13C NMR: δ = 161.5, 158.9, 130.0, 128.8, 128.6,
126.7, 102.3.
3-(4-Methylphenyl)Isoxazole (5b)
Pale yellow oil (lit.[20]); 1H NMR: δ = 8.43 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H),
7.26 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 1.6 Hz, 1H), 2.41 (s, 3H); 13C NMR: 161.6, 158.9,
140.2, 129.8, 126.9, 126.0, 102.5, 21.5.
3-(4-Methoxyphenyl)Isoxazole (5c)
Light yellow solid, mp 47–48 °C (lit.[20]); 1H NMR: δ = 8.41 (d, J = 1.8 Hz, 1H), 7.76 (d,
J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.60 (d, J = 1.8 Hz, 1H), 3.85 (s, 3H); 13C NMR:
δ = 161.2, 161.0, 158.6, 128.5, 121.4, 114.5, 102.3, 55.5.
3-(4-Chlorophenyl)Isoxazole (5d)
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
Light yellow solid, mp 70–71 °C (lit.[9d]); 1H NMR: δ = 8.48 (d, J = 1.6 Hz, 1H), 7.77 (d,
J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 1.6 Hz, 1H); 13C NMR: δ = 160.6,
159.0, 135.9, 129.3, 128.0, 127.3, 102.2.
3-(2-Chlorophenyl)Isoxazole (5e)
Colorless oil (lit.[8d]); 1H NMR: δ = 8.48 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H),
7.50 (d, J = 7.6 Hz, 1H), 7.45–7.36 (m, 2H), 6.83 (d, J = 1.6 Hz, 1H); 13C NMR: δ =
160.2, 158.0, 132.9, 131.3, 130.7, 130.5, 128.0, 127.2, 105.6.
3-(4-Fluorophenyl)Isoxazole (5f)
Colorless oil (lit.[20]); 1H NMR: δ = 8.45 (d, J = 1.8 Hz, 1H), 7.84–7.80 (m, 2H), 7.18–
7.13 (m, 2H), 6.62 (d, J = 1.8 Hz, 1H); 13C NMR: δ = 163.8, 160.4, 159.0, 128.6, 124.8,
116.2, 102.4.
3-(4-Nitrophenyl)Isoxazole (5g)
Yellow solid, mp 169–170°C (lit.[8d]); 1H NMR: δ = 9.10 (d, J = 1.8 Hz, 1H), 8.35 (d, J =
8.6 Hz, 2H), 8.18 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 1.8 Hz, 1H); 13C NMR: δ = 161.8,
159.7, 148.2, 134.6, 128.2, 124.3, 103.5.
3-(4-Trifluoromethylphenyl)Isoxazole (5h)
Yellow solid, mp 98–100°C (lit.[20]); 1H NMR: δ = 8.47 (d, J = 1.7 Hz, 1H), 7.89 (d, J =
8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 1.7 Hz, 1H); 13C NMR: δ = 160.5,
159.3, 132.3, 131.6, 127.0, 125.9, 123.7, 102.5.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
(E)-1-Styrylisoxazole (5i)
Colorless oil (lit.[9f]); 1H NMR: δ = 8.38 (d, J = 1.6 Hz, 1H), 7.58–7.54 (m, 2H), 7.42–
7.24 (m, 3H), 7.27 (s, 1H), 7.22 (s, 1H), 6.62 (d, J = 1.6 Hz, 1H); 13C NMR: δ = 160.6,
158.2, 136.1, 135.8, 129.1, 128.8, 126.9, 115.7, 101.4.
3-(2-Furyl)Isoxazole (5j)
Colorless oil (lit.[9f]); 1H NMR: δ = 8.43 (d, J = 1.8 Hz, 1H), 7.56 (s, 1H), 6.94 (d, J = 3.6
Hz, 1H), 6.62 (d, J = 1.8 Hz, 1H), 6.53 (dd, J = 3.3, 1.5 Hz, 2H); 13C NMR: δ = 158.6,
153.8, 144.2, 143.8, 111.8, 110.2, 102.2.
3-(N-Propyl)Isoxazole (5k)
Colorless oil (lit.[8b]); 1H NMR: δ = 8.40 (d, J = 2.0 Hz, 1H), 6.22 (d, J = 2.0 Hz, 1H),
2.65 (t, J = 7.0 Hz, 2H), 2.39–1.14 (m, 2H), 1.01 (t, J = 7.0 Hz, 3H); 13C NMR: δ = 161.2,
158.7, 102.4, 27.2, 19.6, 13.6.
ACKNOWLEDGEMENT
We gratefully acknowledge financial support from the National Natural Science
Foundation of China (No. 21062007) and the Research Program of Jiangxi Province
Department of Education (No. GJJ10385, GJJ10733 and GJJ11380).
REFERENCES
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
1. (a) Ziegert, R. E.; Torang, J.; Knepper, K.; Brase, S. The recent impact of solid-phase
synthesis on medicinally relevant benzoannelated oxygen heterocycles. J. Comb. Chem.
2005, 7, 147–169; (b) Feliu, L.; Vera-Luque, P.; Albericio, F.; Alvarez, M. Solid-phase
synthesis of biologically active benzoannelated nitrogen heterocycles: An update. J.
Comb. Chem. 2009, 11, 175–197.
2. (a) Döwald, F. Z. Organic Synthesis on Solid Phase: Supports, Linkers, Reactions,
2ed.; Wiley-VCH: Weinehim, 2002. (b) Scott, P. Linker Strategies in Solid-Phase
Organic Synthesis, Wiley-VHC: Weinheim, 2009.
3. (a) Franzen, R. G. Recent advances in the preparation of heterocycles on solid support:
A review of the literature. J. Comb. Chem. 2000, 2, 195–214; (b) Krchnak, V.; Holladay,
M. W. Solid phase heterocyclic chemistry. Chem. Rev. 2002, 102, 61–92; (c) Blaney, P.;
Grigg, R.; Sridharan, V. Traceless solid-phase organic synthesis. Chem. Rev. 2002, 102,
2607–2624.
4. (a) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer,
J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: A potent and
selective inhibitor of COX-2. J. Med. Chem. 2000, 43, 775–777; (b) Lee, Y. S.; Kim, B.
H. Heterocyclic nucleoside analogues: design and synthesis of antiviral, modified
nucleosides containing isoxazole heterocycles. Bioorg. Med. Chem. Lett. 2002, 12, 1395–
1397; (c) Srivastava, S.; Bajpai, L. K.; Batra, S.; Bhaduri, A. P.; Maikhuri, J. P.; Gupta,
G.; Dhar, J. D. In search of new chemical entities with spermicidal and anti-HIV
activities. Bioorg. Med. Chem. 1999, 7, 2607–2613; (d) Simoni, D.; Grisolia, G.;
Giannini, G.; Roberti, M.; Rondanin, R.; Piccagli, L.; Baruchello, R.; Rossi, M.;
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
Romagnoli, R.; Invidiata, F. P.; Grimaudo, S.; Jung, M. K.; Hamel, E.; Gebbia, N.;
Crosta, L.; Abbadessa, V.; Di Cristina, A.; Dusonchet, L.; Meli, M.; Tolomeo, M.
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; (e) Kaffy, J.; Pontikis, R.; Carrez, D.; Croisy, A.; Monneret, C.; Florent, J. C.
Isoxazole-type derivatives related to combretastatin A-4, synthesis and biological
evaluation. Bioorg. Med. Chem. 2006, 14, 4067–4077.
5. For recent reviews, see: (a) Wakefield, B. J. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Shaumann, E., Ed.; Georg Thieme Verlag:
Stuttgart, 2001; Vol. 11, pp 229–288. (b) Jäger, V.; Colinas, P. A. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Ed.; Wiley: Hoboken, 2002; Vol. 59, pp 361–472. (c) Pinho eMelo,
T. M. V. D. Recent advances on the synthesis and reactivity of isoxazoles. Curr. Org.
Chem. 2005, 9, 925–958. (d) Stanley, L. M.; Sibi, M. P. Enantioselective copper-
catalyzed 1,3-dipolar cycloadditions. Chem. Rev. 2008, 108, 2887–2902.
6. For recent studies on the synthesis of disubstituted isoxazoles, see: (a) Debleds, O.;
Gayon, E.; Ostaszuk, E.; Vrancken, E.; Campagne, J.-M. A versatile iron-catalyzed
protocol for the one-pot synthesis of isoxazoles or isoxazolines from the same
propargylic alcohols. Chem. Eur. J. 2010, 16, 12207–12213; (b) Tang, S.; He, J.; Sun, Y.;
He, L.; She, X. Efficient and regioselective synthesis of 5-hydroxy-2-isoxazolines:
Versatile synthons for isoxazoles, β-lactams, and γ-amino alcohols. J. Org. Chem. 2010,
75, 1961–1966; (c) Conti, P.; Pinto, A.; Tamborini, L.; Dunkel, P.; Gambaro, V.; Viscoti,
G. L.; Micheli, C. D. A regioselective route to 5-substituted isoxazole- and isoxazoline-3-
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
phosphonates. Synthesis 2009, 591–596; (d) Bhosale, S.; Kurhade, S.; Prasad, U. V.;
Palle, V. P.; Bhuniya, D. Efficient synthesis of isoxazoles and isoxazolines from
aldoximes using Magtrieve™ (CrO2). Tetrahedron Lett. 2009, 50, 3948–3951; (e)
McClendon, E.; Omollo, A. O.; Valente, E. J.; Hamme, A. T., II. Oxonium ion-mediated
synthesis of 4-substituted spiro-isoxazolines. Tetrahedron Lett. 2009, 50, 533–535; (f)
Grecian, S.; Fokin, V. V. Ruthenium-catalyzed cycloaddition of nitrile oxides and
alkynes: Practical synthesis of isoxazoles. Angew. Chem., Int. Ed. 2008, 47, 8285–8287;
(g) Willy, B.; Rominger, F.; Muller, T. J. J. Novel microwave-assisted one-pot synthesis
of isoxazoles by a three-component coupling-cycloaddition sequence. Synthesis 2008,
293–303; (h) Girardin, M.; Alsabeh, P. G.; Lauzon, S.; Dolman, S. J.; Ouellet, S. G.;
Hughes, G. Synthesis of 3-aminoisoxazoles via the addition−elimination of amines on 3-
bromoisoxazolines. Org. Lett. 2009, 11, 1159–1162; (i) Ueda, M.; Ikeda, Y.; Sato, A.; Ito,
Y.; Kakiuchi, M.; Shono, H.; Miyoshi, T.; Naito, T.; Miyata, O. Silver-catalyzed
synthesis of disubstituted isoxazoles by cyclization of alkynyl oxime ethers. Tetrahedron.
2011, 67, 4612–4615; (j) Murarka, S.; Studer, A. Zinc triflate catalyzed aerobic cross-
dehydrogenative coupling (CDC) of alkynes with nitrones: A new entry to isoxazoles.
Org. Lett. 2011, 13, 2746–2749; (k) Itoh, K.-I.; Aoyama, T.; Satoh, H.; Fujii, Y.;
Sakamaki, H.; Takido, T.; Kodomari, M. Application of silica gel-supported
polyphosphoric acid (PPA/SiO2) as a reusable solid acid catalyst to the synthesis of 3-
benzoylisoxazoles and isoxazolines. Tetrahedron Lett. 2011, 52, 6892–6895; (l)
Dissanayake, A. A.; Odom, A. L. Regioselective conversion of alkynes to 4-substituted
and 3,4-disubstituted isoxazoles using titanium-catalyzed multicomponent coupling
reactions. Tetrahedron. 2012, 68, 807–812; (m) Tang, N.; Sheng, S.-R.; Hu, Q.-S.; Qu,
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
H.-E.; Cai, M.-Z. Solid-phase synthesis of isoxazole-5-carboxylates based on Wang
resin-bound 1-phenylselenoacrylate. Synth. Commun. 2012, 42, 3279–3287.
7. For recent studies on the synthesis of trisubstituted isoxazoles, see: (a) Denmark, S.
E.; Kallemeyn, J. M. Synthesis of 3,4,5-trisubstituted isoxazoles via sequential [3+2]
cycloaddition/silicon-based cross-coupling reactions. J. Org. Chem. 2005, 70, 2839–2842;
(b) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow, R. A.; York, M.; Johnson,
C. N.; Harrity, J. P. A. Investigation of the scope of a [3+2] cycloaddition approach to
isoxazole boronic esters. Tetrahedron. 2005, 61, 6707–6714; (c) Bourbeau, M. P.; Rider,
J. T. A convenient synthesis of 4-alkyl-5-aminoisoxazoles. Org. Lett. 2006, 8, 3679–3680;
(d) Waldo, J. P.; Mehta, S.; Neuenswander, B.; Lushington, G. H.; Larock, R. C. Solution
phase synthesis of a diverse library of highly substituted isoxazoles. J. Comb. Chem.
2008, 10, 658–663; (e) Minakata, S.; Okumura, S.; Nagamachi, T.; Takeda, Y.
Generation of nitrile oxides from oximes using t-BuOI and their cycloaddition. Org. Lett.
2011, 13, 2966–2969; (f) Okitsu, T.; Sato, K.; Potewar, T. M.; Wada, A. Iodocyclization
of hydroxylamine derivatives based on the control of oxidative aromatization leading to
2,5-dihydroisoxazoles and isoxazoles. J. Org. Chem. 2011, 76, 3438–3449; (g) Chappell,
B.; Dedman, N.; Wheeler, S. Studies on the palladium-catalysed direct alkenylation of
1,2-azoles. Tetrahedron Lett. 2011, 52, 3223–3225; (h) Rajender, P. S.; Sridevi, G.;
Reddy, K. K. Synthesis of novel isoxazole fused heterocycles. Synth. Commun. 2012, 42,
2191–2200.
8. (a) Shvekhgeimer, G. A.; Baranski, A.; Grzegozek, M. Reaction of benzonitrile
oxides with conjugated nitroalkenes. Synthesis 1976, 612–614; (b) Barber, G. N.; Olofson,
R. A. A useful, regiospecific synthesis of isoxazoles. J. Org. Chem. 1978, 43, 3015–3021;
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
(c) Padwa, A.; MacDonald, J. G. Utilization of vinylsilanes in [4+2]-cycloaddition
reactions. J. Org. Chem. 1983, 48, 3189–3195; (d) Di Nunno, L.; Scilimati, A. Synthesis
of 3-aryl-4, 5-dihydro-5-hydroxy-1,2-oxazoles by reaction of substituted benzonitrile
oxides with the enolate ion of acetaldehyde. Tetrahedron. 1987, 43, 2181–2189.
9. For recent studies on the synthesis of 3-monosubstituted isoxazoles, see: (a) Sheng, S.
R.; Liu, X. L.; Xu, Q.; Song, C. S. One-pot synthesis of 3-substituted isoxazoles from
phenyl vinylic selenide. Synthesis 2003, 2763–2764; (b) Cermola, F.; Di Gioia, L.;
Graziano, M. L.; Iesce, M. R. Ring-opening reactions of cyclopropanes. Part 8.1
Nitrosation of donor-acceptor cyclopropanes. J. Chem. Res. 2005, 677–681; (c) Sheng,
S.-R.; Xin, Q.; Liu, X.-L.; Sun, W.-K.; Guo, R.; Huang, X. Traceless solid-phase
synthesis of 3-substituted isoxazoles and 3-substituted 5-iodoisoxazolines using
polystyrene-supported vinyl selenide Synthesis 2006, 2293–2296; (d) Di Nunno, L.;
Vitale, P.; Scilimati, A. Effect of the aryl group substituent in the dimerization of 3-
arylisoxazoles to syn 2,6-diaryl-3,7-diazatricyclo[4.2.0.0 2,5]octan-4,8-diones induced by
LDA. Tetrahedron 2008, 64, 11198–11204; (e) Rosa, F. A.; Machado, P.; Bonacorso, H.
G.; Zanatta, N.; Martins, M. A. P. Reaction of β-dimethylaminovinyl ketones with
hydroxylamine: A simple and useful method for synthesis of 3- and 5-substituted
isoxazoles. J. Heterocycl. Chem. 2008, 45, 879–885; (f) Tang, S.; He, J.; Sun, Y.; He, L.;
She, X. Efficient and regiospecific one-pot synthesis of 3-substituted and 3,5-
disubstituted isoxazoles. Org. Lett. 2009, 11, 3982–3985.
10. Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford, 1993.
11. Najera, C.; Yus, M. Desulfonylation reactions: Recent developments. Tetrahedron.
1999, 55, 10547–10658.
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
12. (a) Kirsteen Gordon, K.; Balasubramanian, S. Solid phase synthesis–designer linkers
for combinatorial chemistry: A review. J. Chem. Technol. Biotechnol. 1999, 74, 835–851;
(b) Blaney, P.; Grigg, R.; Sridharan, V. Traceless solid-phase organic synthesis. Chem.
Rev. 2002, 102, 2607–2624; (c) McAllister, L. A.; McCormick, R. A.; Procter, D. J.
Sulfide- and selenide-based linkers in phase tag-assisted synthesis. Tetrahedron. 2005, 61,
11527–11576.
13. (a) Cheng, W. C.; Lin, C. C.; Kurth, M. J. Dimsyl anion in the monoalkylation of
solid-phase alkyl sulfones. Tetrahedron Lett. 2002, 43, 2967–2970; (b) Hwang, S. H.;
Olmstead, M. M.; Kurth, M. J. Solid-phase synthesis of an isoxazolinopyrrole library. J.
Comb. Chem. 2004, 6, 142–148.
14. (a) Li, W. W.; Lam, Y. L. Solid-phase synthesis of 3,4-dihydro-1H-pyrimidine-2-
ones using sodium benzenesulfinate as a traceless linker. J. Comb. Chem. 2005, 7, 721–
725; (b) Kong, K.-H.; Tan, C.-K.; Lam, Y. L. Traceless solid-phase synthesis of 6-amino-
and 6-hydroxyimino-1,3,5-triazine-2,4-diones and 1,3,5-triazine-2,4,6-triones. J. Comb.
Chem. 2009, 11, 1050–1060.
15. (a) Huang, W.; Cheng, S.; Sun, W. 2-Polystyrylsulfonyl ethanol supports for the
solid-phase syntheses of hydantoins and ureas. Tetrahedron Lett. 2001, 42, 1973–1974;
(b) 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, 6657–
6659; (c) 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; (d) McAllister, L. A.
Turner, K. L.; Brand, S.; Stefaniak, M.; Procter, D. J. Solid phase approaches to N-
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
heterocycles using a sulfur linker cleaved by SmI2. J. Org. Chem. 2006, 71, 6497–6507;
(e) Xie, J. W.; Sun, J.; Zhang, G. L.; Houghten, R. A.; Yu, Y. P. Traceless approach for
the solid-phase parallel synthesis of trisubstituted oxindoles. J. Comb. Chem. 2007, 9,
566–568; (f) Chang, Y.-F.; Jiang, Y.-R.; Cheng, W.-C. Traceless sulfone linker cleavage
triggered by ozonolysis: Solid-phase synthesis of diverse a-b-unsaturated carbonyl
compounds. Tetrahedron Lett. 2008, 49, 543–547; (g) Lee, T.; Lee, T. D.; Lee, I. Y.;
Gong, Y.-D. Solid-phase synthesis of thiazolo[4,5-b]pyridine derivatives using
Friedländer reaction. J. Comb. Chem. 2010, 12, 95–99.
16. (a) Sheng, S.-R.; Huang, P.-G.; Zhou, W.; Luo, H.-R.; Lin, S.-Y.; Liu, X.-L. A facile
solid-phase synthesis of substituted 2(5H)-furanones with sulfone traceless linker. Synlett.
2004, 2603–2605; (b) Sheng, S.-R.; Xu, L.; Zhang, X.-L.; Liu, X.-L.; Wei, M.-H. Solid-
phase synthesis of substituted butenolides and butyrolactones using a traceless sulfone
linker. J. Comb. Chem. 2006, 8, 805–807; (c) Liu, X.-L.; Sheng, S.-R.; Zhou, W.; Wang,
Q.-Y.; Zhang, X.-L.; Gong, B. A facile solid-phase synthesis of cycloalkylphosphonates
and 1-cycloalkenylphosphonates using polymer-supported
phenylsulfonylmethylphosphonates. Synth. Commun. 2007, 37, 119–127; (d) Yu, L.-M.;
Tang, N.; Sheng, S.-R.; Chen, R.-B.; Liu, X.-L.; Cai, M.-Z. Solid-phase organic synthesis
of aryl vinyl ethers using sulfone-linking strategy. Chin. J. Chem. 2012, 30, 1027–1030.
17. Farrall, M. J.; Frėchet, J. M. J. Bromination and lithiation: two important steps in the
functionalization of polystyrene resins. J. Org. Chem. 1976, 41, 3877–3882.
18. Heinonen, P.; Lönnberg, H. A novel solid support for derivatization and subsequent
N-alkylation ofsecondary amines: Preparation of N-alkylated 5- and 6-aikoxy-l,2,3,4-
tetrahydroisoquinolines via Mitsunobu reaction. Tetrahedron Lett. 1997, 38, 8569–8572.
ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
19. J. Xu, A. T. Hamme II, Efficient access to isoxazoles from alkenes. Synlett. 2008,
919–923.
20. Di Nunno, L.; Vitale, P.; Scilimati, A.; Simone, L.; Capitelli, F. Stereoselective
dimerization of 3-arylisoxazoles to cage-shaped bis-β-lactams syn 2,6-diaryl-3,7-
diazatricyclo[4.2.0.0 2,5]-octan-4,8-diones induced by hindered lithium amides.
Tetrahedron. 2007, 63, 12388–12395.
ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
Table 1. Yields and purities of 3-monosubstituted isoxazoles (5a–5k)
Entry
R
Product
5a
Yield a (%)
Purity b (%)
1
C6H5
90
91
90
88
80
88
85
89
84
85
83
97
98
97
95
94
95
94
97
94
96
94
2
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
4-NO2C6H4
4-CF3C6H4
(E)-Styryl
2-Furyl
5b
5c
3
4
5d
5e
5
6
5f
7
5g
8
5h
5i
9
10
5j
11
n-C3H7
5k
a Overall isolated yields based on polystyrene-supported vinyl sulfone 3.
b Determined by HPLC of crude cleavage product.
ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of polystyrene-supported vinyl sulfone 3.
ACCEPTED MANUSCRIPT
20

ACCEPTED MANUSCRIPT
Scheme 2. Solid-phase organic synthesis of 3-monosubstituted isoxazoles 5a–5k.
ACCEPTED MANUSCRIPT
21