Solid-phase organic synthesis of vinyl-substituted 1,3,4-oxadiazoles using polymer-bound α-selenopropionic acid

Article abstract of DOI:10.1080/00397910802324518

Vinyl-substituted 1,3,4-oxadiazoles can be efficiently synthesized through acylation, cyclocondensation, and oxidation-elimination reaction from polystyrene-supported α-selenopropionic acid and acid hydrazides. This new solid-phase organic synthesis metho

Full text of DOI:10.1080/00397910802324518

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Solid-Phase Organic Synthesis
of Vinyl-Substituted 1,3,4-
Oxadiazoles Using Polymer-
Bound α-Selenopropionic Acid
Gui-Yun Fu a , Shou-Ri Sheng a , Xiao-Ling Liu a
Ming-Zhong Cai a & Xian Huang a b
,
a College of Chemistry and Chemical Engineering,
Jiangxi Normal University , Nanchang, China
b Department of Chemistry , Zhejiang University,
Xixi Campus , Hangzhou, China
Published online: 31 Oct 2008.
To cite this article: Gui-Yun Fu , Shou-Ri Sheng , Xiao-Ling Liu , Ming-Zhong Cai
& Xian Huang (2008) Solid-Phase Organic Synthesis of Vinyl-Substituted 1,3,4-
Oxadiazoles Using Polymer-Bound α-Selenopropionic Acid, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:23, 4240-4249, DOI: 10.1080/00397910802324518
To link to this article: http://dx.doi.org/10.1080/00397910802324518
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Synthetic Communications1, 38: 4240–4249, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802324518
Solid-Phase Organic Synthesis of
Vinyl-Substituted 1,3,4-Oxadiazoles Using
Polymer-Bound a-Selenopropionic Acid
Gui-Yun Fu,1 Shou-Ri Sheng,1 Xiao-Ling Liu,1 Ming-Zhong Cai,1
and Xian Huang1,2
1College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, China
2Department of Chemistry, Zhejiang University, Xixi Campus,
Hangzhou, China
Abstract: Vinyl-substituted 1,3,4-oxadiazoles can be efficiently synthesized
through acylation, cyclocondensation, and oxidation–elimination reaction from
polystyrene-supported a-selenopropionic acid and acid hydrazides. This new
solid-phase organic synthesis method could provide the target compounds in
good yield and purity, with advantages of decreased volatility and simplification
of workup procedure.
Keywords: Polystyrene-supported a-selenopropionic acid, solid-phase organic
synthesis, vinyl-substituted 1,3,4-oxadiazole
Heterocycles are important elements in many pharmacologically active
compounds. Combinatorial synthesis of the heterocycle libraries is an
effective way for the development of drug candidates, and solid-phase
organic synthesis (SPOS) is arguably the most important method for
the high-speed synthesis of heterocycles in combinatorial synthesis.[1]
1,3,4-Oxadiazoles constitute a class of heterocycles that has attracted
significant interest in medicinal and pesticide chemistry[2,3] and polymer
Received February 25, 2008.
Address correspondence to Shou-Ri Sheng, College of Chemistry and Chemi-
cal Engineering, Jiangxi Normal University (Yaohu Campus), Nanchang 330022,
China. E-mail: shengsr@jxnu.edu.cn
4240

SPOS of Vinyl-Substituted 1,3,4-Oxadiazoles
4241
and material science.[4,5] Although solution-phase[6] or solid-phase[7]
synthetic methods for 1,3,4-oxadiazoles are well documented, efforts
are continuing for the development of more efficient methods with
experimental simplicity. Among the 1,3,4-oxadiazoles, vinyl-substituted
derivatives have now attracted considerable attention because of their
biological properties,[8] such as antiallergic, antibacterial, and anti-HIV
activity. In addition, vinyl-substituted 1,3,4-oxadiazoles are versatile
intermediates for the preparation of complex natural products and play
an important role as useful additives in material chemistry.[9] However,
in view of the fact that vinyl-substituted heterocycles are easily polymer-
ized because of their highly reactive terminal double bond connected
directly with an electron-withdrawing heterocyclic group,[10] the incor-
poration of vinyl substituents into heterocycles is seldom reported.[11] It
is well known that phenylseleno group is readily converted to a leaving
group, giving access to carbon–carbon double bond via oxidation
followed by b-elimination under extremely mild conditions.[12] Moreover,
the polymeric selenium reagents[13] have been now developed for SPOS
with a combined advantage of decrease volatility and simplification of
product workup. In continuation of our interest in solid-phase organose-
lenium chemistry,[14] we sought to develop a convenient and efficient
preparation of vinyl-substituted 1,3,4-oxadiazoles from polystyrene-
supported a-selenopropionic acid (Scheme 1).
Polymer-supported a-selenopropionic acid 2 was prepared by
treatment of a THF-swollen suspension of cross-linked (1%) polystyrene-
bound selenium bromide 1[13a] with LiBH4, followed by treatment with
2-bromopropionic acid according to our previous method.[14a] The
minimum loading of COOH of resin 2 verified by their Fourier transform
infrared (FT-IR) spectra showing a strong carbonyl absorption at
1726 cmꢀ1 was determined by acid–base titration[15] to be 1.20 mmol=g.
With resin 2 in hand, the acylation of the polymeric a-selenopropionic
acid 2 with various acid hydrazides, the key for the success of this
protocol was investigated. Here, the diacylhydrazination reaction was
Scheme 1. Solid-phase synthesis of the route of vinyl-substituted 1,3,4-oxadiazoles.

4242
G.-Y. Fu et al.
investigated starting from resin 2 and benzoic hydrazide. When DCC
(dicyclohexyl carbodiimide) or HBTU (O-benzotriazol-1-yl-N,N,N0,N0-
tetramethyluronium hexafluorophosphate) was used as a coupling
reagent to promote this reaction at room temperature or under reflux
in CH2Cl2 or THF for 10 h or even for longer time, the diacylhydrazina-
tion on solid phase was not complete as monitored by FT-IR study,
which showed two strong peaks of carbonyl absorptions near 1726 and
1595 cmꢀ1. It has been reported that in the presence of DMC (2-
chloro-1,3-dimethylimidazolinium chloride), 1,3,4-oxadiazoles can be
obtained in good yields from carboxylic acids and acid hydrazides in
CH2Cl2 at ambient temperature.[16] Interestingly, when DMC was added
to the suspension of resin 2 with benzoic hydrazide in CH2Cl2 at room
temperature, the conversion of resin 2 to polymer-bound diacyl hydrazide
3a was complete. The FT-IR (Fourier transform infrared) spectrum of
resin 3a showed a single strong carbonyl peak at 1595 cmꢀ1, with disap-
pearance of the band at 1726 cmꢀ1. Next, the cyclodehydration of diacyl
hydrazide resin 3a treated with a variety of dehydrating agents, such as
thionyl chloride, phosphorous oxychloride, phosphorous pentoxide,
triphenylphosphine, and trifluoromethane-sulfonic anhydride, was per-
formed in our hands. After a series of experiments, the cyclocondensation
reaction of resin 3 in the presence of phosphorus oxychloride was carried
out efficiently according to the reported method[11] to furnish resin 4, fol-
lowed by selenoxide syn elimination with excess of 30% hydrogen perox-
ide to afford the corresponding vinyl-substituted 1,3,4-oxadiazoles 5 in
moderate to good yields (74–81%) and with good purities (90–95%) of
crude materials in all cases (Table 1). The residual resin, polystyrene-
supported phenylseleninic acid, was obtained as a by-product whose
Table 1. Yields and purities of vinyl-substituted 1,3,4-oxadiazoles 5
Entry
R
Products
Yield (%)a
Purity (%)b
1
2
3
4
5
6
7
C6H5
5a
5b
5c
5d
5e
5f
80
81
78
76
77
75
74
95
94
93
91
92
92
90
p-CH3OC6H4
p-ClC6H4
p-NO2C6H4
C6H5CH2
n-C6H13
i-C3H7
5g
aOverall yields based on polystyrene-supported a-selenopropionic
acid 2 (1.20 mmol COOH=g).
bDetermined by HPLC (high-performance liquid chromatography)
of crude cleavage product (k ¼ 254 nm).

SPOS of Vinyl-Substituted 1,3,4-Oxadiazoles
4243
infrared data was identical to the previously reported data[17] and showed
no residual C¼N and O–N group absorptions, indicating the oxidation–
elimination was complete.
In summary, a novel and efficient procedure for the solid-phase
synthesis of vinyl-substituted 1,3,4-oxadiazoles in moderate to good
yields and with good purities using polymer-supported a-selenopropionic
acid with advantages of decreased volatility and simplification of product
workup has been developed.
EXPERIMENTAL
Melting points were determined on X4 melting-point apparatus and are
1
uncorrected. H NMR (400-MHz) and 13C NMR (100-MHz) spectra
were recorded on a Bruker Avance (400-MHz) spectrometer using CDCl3
as the solvent and TMS as an internal standard. FT-IR spectra were
taken on a Perkin-Elmer SP One FT-IR spectrophotometer. Microana-
lyses were performed with a PE 2400 elemental analyzer. Mass spectra
(EI, 70 eV) were recorded on a HP5989B mass spectrometer. HPLC
analysis was carried out on Agilent 1100 (250 ꢁ 4.6 mm C18 column, gra-
dient elution 50=20=30 THF=CH3OH=H2O (v=v), 1 mL=min, UV detec-
tion at k ¼ 254 nm). Polystyrene (H 1000, 100–200 mesh, cross-linked
with 1% divinylbenzene) for the preparation of polystyrene-supported
selenium bromide[13a] and other starting materials were purchased from
commercial suppliers and used without further purification. CH2Cl2
was distilled from phosphorous pentoxide, and THF was distilled from
sodium-benzophenone immediately prior to use.
General Procedure for the Preparation of 5-Vinyl-1,3,4-oxadiazoles
(5a–5g)
Resin 2 (0.84 g, 1.0 mmol) was swelled in anhydrous CH2Cl2 (20 mL)
at room temperature for 30 min. Acid hydrazides (2.0 mmol), DMC
(0.20 g, 1.2 mmol), and triethylamine (2.0 mmol) were added under
nitrogen to the mixture. After 24 h with stirring at room temperature,
the mixture was filtered and the resin was washed thoroughly succes-
sively with H2O, THF, MeOH, and CH2Cl2 (2 ꢁ 5 mL of each) and
then dried under vacuum to afford resin 3. Then the resin 3 and phos-
phorus oxychloride (25 mL) were refluxed for 12 h under a nitrogen
atmosphere. After completion of the reaction, the mixture was cooled
to room temperature, and the resin 4 was collected by filtration and
washed successively with DMF (1 ꢁ 10 mL), DMSO (1 ꢁ 10 mL),

4244
G.-Y. Fu et al.
THF (1 ꢁ 10 mL), THF=H2O (1:1) (2 ꢁ 10 mL), H2O (2 ꢁ 10 mL), and
CH2Cl2 (2 ꢁ 10 mL). The washed resin 4 was then suspended in THF
(15 mL), and 30% hydrogen peroxide (0.5 mL, 5.8 mmol) was added; the
mixture was stirred for 30 min at 0 ꢂC, followed by 1 h at room temperature.
The mixture was filtered, and the residual resin was washed with CH2Cl2
(3 ꢁ 10 mL). The filtrate was washed with H2O (2 ꢁ 20 mL), dried over
MgSO4, and evaporated to dryness under vacuum to obtain the crude
products 5. Further purification was via flash chromatography with
1
EtOAc=n-hexane (1=2-1=1 v=v) as the eluent for H NMR, 13C NMR,
and microanalysis.
Data
5-Phenyl-2-vinyl-1,3,4-oxadiazole (5a)
Colorless oil (lit.[11] oil); 1H NMR: d ¼ 8.11–8.08 (m, 2 H), 7.56–7.50 (m,
3 H), 6.82–6.78 (m, 1 H), 6.40–5.95 (m, 2 H); 13C NMR: d ¼ 164.5, 163.4,
131.9, 128.9, 127.1, 124.8, 123.8, 120.2; IR (film): n ¼ 3069, 2925, 1626,
1550, 1535, 1460, 980, 730, 705 cmꢀ1; EIMS: m=z (%) ¼ 172 (Mþ). Anal.
calcd. for C10H8N2O: C, 69.76; H, 4.68; N, 16.27. Found: C, 69.70; H,
4.73; N, 16.31.
5-(p-Methoxyphenyl)-2-vinyl-1,3,4-oxadiazole (5b)
1
White solid, mp 80–81 ꢂC (lit.[11] mp 80–82 ꢂC); H NMR: d ¼ 7.85 (d,
J ¼ 8.8 Hz, 2 H), 6.95 (d, J ¼ 8.8 Hz, 2 H), 6.65–6.60 (m, 1 H), 6.20–
5.71 (m, 2 H), 3.74 (s, 3 H); 13C NMR: d ¼ 163.5, 162.5, 161.7, 128.3,
124.1, 119.4, 115.5, 114.2, 55.1; IR (KBr): n ¼ 3065, 2986, 2845, 1645,
1530, 1368, 1270, 1086, 1020, 940, 695 cmꢀ1; EIMS: m=z (%) ¼ 202
(Mþ). Anal. calcd. for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found:
C, 65.29; H, 5.05; N, 13.80.
5-(p-Chlorophenyl)-2-vinyl-1,3,4-oxadiazole (5c)
White solid, mp 88–90 ꢂC; 1H NMR: d ¼ 7.89 (d, J ¼ 8.5 Hz, 2H), 7.02 (d,
J ¼ 8.5 Hz, 2H), 6.73–6.68 (m, 1H), 6.21–6.04 (m, 2H); 13C NMR:
d ¼ 164.6, 163.9, 137.3, 129.0, 128.7, 128.3, 124.8, 120.2; IR (KBr):
n ¼ 3060, 2925, 1620, 1550, 1470, 1412, 1093, 980, 828, 790, 500 cmꢀ1
;
EIMS: m=z (%) ¼ 206 (Mþ). Anal. calcd. for C10H7ClN2O: C, 58.13; H,
3.41; N, 13.56. Found: C, 58.07; H, 3.46; N, 13.61.

SPOS of Vinyl-Substituted 1,3,4-Oxadiazoles
4245
5-(p-Nitrophenyl)-2-vinyl-1,3,4-oxadiazole (5d)
Light yellow solid, mp 135–137 ꢂC; 1H NMR: d ¼ 8.05 (d, J ¼ 8.7 Hz, 2 H),
7.12 (d, J ¼ 8.7 Hz, 2 H), 6.78–6.71 (m, 1 H), 6.23–6.11 (m, 2 H); 13C NMR:
d ¼ 165.2, 164.3, 145.5, 135.8, 128.7, 125.1, 123.3, 120.5; IR (KBr):
n ¼ 3060, 2961, 1618, 1595, 1528, 1470, 1412, 1350, 1225, 1098, 1028, 860,
836, 727, 610 cmꢀ1; EIMS: m=z (%) ¼ 217 (Mþ). Anal. calcd. for
C10H7N3O3: C, 55.30; H, 3.25; N, 19.35. Found: C, 55.34; H, 3.30; N, 19.41.
5-Benzyl-2-vinyl-1,3,4-oxadiazole (5e)
Colorless oil; 1H NMR: d ¼ 7.37–7.32 (m, 2 H), 7.27–7.24 (m, 3 H), 6.68–
6.61 (m, 1 H), 6.05–5.87 (m, 2 H), 4.20 (s, 2 H); 13C NMR: d ¼ 164.5,
163.8, 133.2, 128.8, 128.6, 127.1, 124.5, 120.1, 31.6; IR (film): n ¼ 3033,
2925, 1567, 1528, 1496, 1031, 982, 945, 731, 696 cmꢀ1; EIMS: m=z
(%) ¼ 186 (Mþ). Anal. calcd. for C11H10N2O: C, 70.95; H, 5.41; N,
15.04. Found: C, 70.91; H, 5.46; N, 15.08.
5-(n-Hexyl)-2-vinyl-1,3,4-oxadiazole (5f)
Colorless oil (lit.[11] oil); 1H NMR: d ¼ 6.65–6.58 (m, 1H), 6.12–5.88 (m, 2
H), 2.79–2.74 (m, 2 H), 1.76–1.70 (m, 2 H), 1.35–1.20 (m, 6 H), 0.83 (t,
J ¼ 7.1 Hz, 3 H); 13C NMR: d ¼ 166.5, 163.8, 124.5, 120.2, 31.2, 28.9,
26.5, 25.3, 22.6, 13.9; IR (film): n ¼ 2958, 2930, 2872, 1572, 1530, 1380,
1030, 981, 942, 765 cmꢀ1; EIMS: m=z (%) ¼ 180 (Mþ). Anal. calcd. for
C10H16N2O: C, 66.63; H, 8.95; N, 15.54. Found: C, 66.68; H, 9.01; N, 15.58.
5-(i-Propyl)-2-vinyl-1,3,4-oxadiazole (5g)
1
Colorless oil (lit.[11] oil); H NMR: d ¼ 6.65–6.58 (m, 1 H), 6.22–6.08 (m,
1 H), 5.79–5.70 (m, 1 H), 3.15–3.08 (m, 1 H), 1.33 (s, 3 H), 1.31 (s, 3 H);
13C NMR: d ¼ 170.1, 163.5, 124.0, 120.1, 26.2, 19.9; IR (film): n ¼ 2978,
2938, 2879, 1565, 1387, 1370, 1012, 980, 942 cmꢀ1; EIMS: m=z (%) ¼ 138
(Mþ). Anal. calcd. for C7H10N2O: C, 60.85; H, 7.30; N, 20.28. Found: C,
60.90; H, 7.36; N, 20.32.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the National Natural
Science Foundation of China (No. 20562005) and NSF of Jiangxi
Province (Nos. 0620021 and 2007GZW0185).

4246
G.-Y. Fu et al.
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