Facile solid-phase organic synthesis of 5-vinyl-substituted 1,2,4-oxadiazoles from polymer-bound α-selenopropionic acid

Article abstract of DOI:10.1002/jccs.200800115

Cyclocondensation of polystyrene-supported α-selenopropionic acid with amidoximes in the presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by oxidative deselenation efficiently afforded 5-vinyl 1,2,4-oxadiazoles in good yield and purity with a facile work-up procedure.

Full text of DOI:10.1002/jccs.200800115

768
Journal of the Chinese Chemical Society, 2008, 55, 768-771
Facile Solid-Phase Organic Synthesis of 5-Vinyl-Substituted
1,2,4-Oxadiazoles from Polymer-Bound a-Selenopropionic Acid
Qiao-Sheng Hua (
), Shou-Ri Shengb,* (
), Xiao-Ling Liub (
),
Fang Hub (
) and Ming-Zhong Caib (
)
aCollege of Chemistry and Life Science, Gannan Normal University, Ganzhou 341000, P. R. China
bCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, P. R. China
Cyclocondensation of polystyrene-supported a-selenopropionic acid with amidoximes in the pres-
ence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by oxidative
deselenation efficiently afforded 5-vinyl 1,2,4-oxadiazoles in good yield and purity with a facile work-up
procedure.
Keywords: Solid-phase organic synthesis; Polystyrene-supported a-selenopropionic acid; 5-Vi-
nyl-substituted 1,2,4-oxadiazole.
Polymer-supported reagents have attracted growing
as versatile organic synthetic intermediates,10 the incorpo-
ration of vinyl substituent into 1,2,4-oxadiazole ring using
SPOS methodology, has little been investigated. In recent
years, polymer-bound phenylseleno group has been proven
to be a versatile pro-vinyl safety-catch traceless linker,
which can give access to carbon-carbon double bond via
oxidation followed by b-elimination.11 Meanwhile, the use
of the selenium reagents immobilized on polymer-resin has
provided significant advantages, including decrease vola-
tility and simplification of product work-up. As a continua-
tion of our studies toward the development of new methods
for the synthesis of heterocyclic compounds based on
solid-phase organoselenium chemistry,12 we report herein a
convenient and efficient approach to 5-vinyl 1,2,4-oxadi-
azoles from polystyrene-supported a-selenopropionic acid
(Scheme I).
interest because they can provide attractive and practical
methods for combinatorial chemistry and solid-phase or-
ganic synthesis (SPOS) in recent years.1 SPOS using insol-
uble solid supports such as polystyrene resins takes advan-
tage of the simple removal of excess or consumed reagents
by a simple filtration workup operation. The design and
synthesis of pharmacologically relevant heterocyclic mole-
cules using SPOS methodology is now recognized as a val-
uable tool for acceleration of drug discovery. 1,2,4-Oxadi-
azoles are a class of important heterocycles, which have
been well documented throughout the literature due to their
biological importance. 1,2,4-Oxadiazoles have often been
used as bioisosteres of esters and amides2 and as dipeptide
mimetics3 in a number of pharmacologically important
molecules. They can also be found in a number of biologi-
cally important molecules, such as muscarinic agonists,4
serotoninergic (5-HT3) antagonists,5 benzodiazepine re-
ceptor agonists,6 and dopamine ligands.7 Generally, 1,2,4-
oxadiazoles are synthesized by (i) cyclodehydration of
O-acylamidoximes; (ii) cyclization of N-acylamidoximes;
(iii) 1,3-dipolar cycloaddition of nitrile oxides to nitriles;
(iv) electrocyclic ring closure of nitrenoids; and (v) oxida-
tion of 4,5-dihydro-1,2,4-oxadiazoles.8 Recently, the use
of a polymer support for the preparation of 5-isoxazol-4-
yl-[1,2,4]oxadiazole diheterocyclics, which proceed through
an alkynoate intermediate has been reported.9 However, in
view of the fact that vinyl substituted heterocycles are used
Polymer-supported a-selenopropionic acid 2 was pre-
pared by treatment of a THF-swollen suspension of cross-
linked (1%) polystyrene bound selenium bromide 111b with
LiBH4, followed by treatment with 2-bromopropionic acid
according to our previous method.12a The minimum load-
ing of COOH of resin 2 verified by their FT-IR spectra
showing a strong carbonyl absorption at 1726 cm-1 were
determined by acid-base titration13 to be 1.20 mmol/g. With
resin 2 in hand, the secondary condensation reaction of
polymeric a-selenopropionic acid 2 with various amidox-
imes, the key for the success of this protocol was investi-
gated. Ordinarily, dicyclohexyl carbodiimide (DCC), 1-
* Corresponding author. E-mail: shengsr@jxnu.edu.cn

SPOS of Vinyl-Substituted 1,2,4-Oxadiazoles
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 769
Scheme I
CH3
LiBH4
SeBr
THF, rt, 1h
CH3CH(Br)COOH
rt, 6 h
SeLi
SeCHCOOH
1
2
H2O2, THF
0 oC, 30 min,
1) RC(NH2) = NOH, EDC
DMF, 65 oC, Overnight
R
N
Se
H3C
N
O
R
N
O
N
then r.t. 1 h
2) 115 oC, 5h
4
3
(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDC), 1,1-carbonyldiimidazole (CDI), O-(1H-ben-
zotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoro-
borate, 1,2,3-benzotriazole-1-hydroxide (HOBt), or O-
benzotriazol-1-yl-N,N,N’,N’-tetr-amethyluronium hexa-
fluorophosphate (HBTU) have been used as a coupling re-
agent to promote the condensation of carboxylic acids with
amidoximes.14,15 After considerable experimentation, the
best result was obtained by treatment of resin 2 with ami-
doximes in the presence of excess EDC in DMF through a
two-step one-pot condensation. The cyclocondensation on
polymer was complete as monitored by FT-IR study of the
resin 3 showing a new moderate strong absorption near
1654 cm-1 corresponding to C=N stretch group in oxadi-
azole ring, with disappearance of the band at 1726 cm-1. As
expected, subsequent oxidation-elimination of resin 3 was
very rapid and efficient with excess of 30% hydrogen per-
oxide to afford the corresponding 5-vinyl 1,2,4-oxadia-
zoles 4 in good yields (72-80%) and purities (90-96%) of
crude materials in all cases (Table 1). The residual resin,
polystyrene-supported phenylseleninic acid, was obtained
as a by-product, whose infrared data was identical to the
previously reported data.16 The polystyrene-supported
phenylseleninic acid could be converted to resin 1 for recy-
cle by treatment of it with KI/Na2S2O3 17 followed by bro-
mine.11b For example, 3-phenyl-5-vinyl-1,2,4-oxadiazole
(4a) was obtained in 75% yield under the same reaction
condition using the recovered selenenyl bromide resin 1
(second run), and in 70% 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.
In conclusion, a novel and efficient method for the
solid-phase traceless synthesis of 5-vinyl 1,2,4-oxadia-
zoles in good yields and purities by cyclocondensation of
polymer-supported a-selenopropionic acid with amidox-
imes and subsequent oxidation-elimination has been devel-
oped. The advantages of the present method include de-
creasing volatility and simplification of product work-up.
EXPERIMENTAL SECTION
Melting points were determined on X4 melting point
1
apparatus and are uncorrected. H NMR (400 MHz) and
13C NMR (100 MHz) spectra were recorded on a Bruker
Avance (400 MHz) spectrometer using CDCl3 as the sol-
vent and TMS as an internal standard. FT-IR spectra were
taken on a Perkin-Elmer SP One FT-IR spectrophotometer.
Microanalyses 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, gradient
elution 50/20/30 THF/CH3OH/H2O (v/v), 1 mL/min, UV
detection at l = 254 nm). Polystyrene (H 1000, 100-200
mesh, cross-linked with 1% divinylbenzene) for the prepa-
ration of polystyrene-supported selenium bromide11b and
other starting materials were purchased from commercial
suppliers and used without further purification. DMF was
distilled from calcium hydride and THF was stilled from
sodium-benzophenone immediately prior to use.
Table 1. The yields and purities of 5-vinyl 1,2,4-oxadiazoles 4
Entry
R
Product Yield (%)a Purity (%)b
1
2
3
4
5
6
7
8
9
C6H5
4a
4b
4c
4d
4e
4f
78
80
79
76
77
74
74
73
72
95
96
93
93
94
90
92
92
91
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
2-ClC6H4
3-BrC6H4
4-FC6H4
4g
4h
4i
C6H5CH2
i-C3H7
a Overall yields based on polystyrene-supported a-seleno-
propionic acid 2 (1.20 mmol COOH/g).
b Determined by HPLC of crude cleavage product (l = 254 nm).

770 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Hu et al.
General procedure for the synthesis of vinyl-substi-
tuted 1,2,4-oxadiazoles (4a-4i)
3-(4-Chlorophenyl)-5-vinyl-1,2,4-oxadiazole (4d)
White solid, mp 58-60 °C; 1H NMR: d = 8.01 (d, J =
8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 6.78-6.73 (m, 1H),
6.60-6.54 (m, 1H), 6.01-5.98 (m, 1H); 13C NMR = 174.4,
167.5, 137.5, 129.1, 128.7, 128.5, 125.2, 120.2; IR (KBr):
Under a positive pressure of nitrogen, amidoximes
(1.5 mmol) and EDC (0.48 g, 2.5 mmol) was added to a sus-
pension of the swollen polymeric a-phenylselenopropionic
acid 2 (0.5 g, 0.60 mmol) in anhydrous DMF (20 mL) and
heated to 65 °C overnight. The mixture was then refluxed at
115 °C for another 5 h at which time the new formed resin 3
was washed thoroughly successively with DMF (2 ´ 10
mL), DCM (2 ´ 10 mL), MeOH (2 ´ 10 mL), and DCM (2 ´
10 mL). The washed resin 3 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 °C, fol-
lowed by 1 h at room temperature. The mixture was fil-
tered, 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 vac-
uum to obtain the crude products 4. Further purification
was via flash chromatography with EtOAc/n-hexane (1/10-
1/20 v/v) as the eluent for 1H NMR, 13C NMR, and micro-
analysis.
n
max = 3060, 2925, 1815, 1545, 1470, 1412, 1093, 982, 838,
790, 500 cm-1; EI-MS: m/z (%) = 206 (M+); Anal. Calcd for
C10H7ClN2O: C, 58.13; H, 3.41; N, 13.56. Found: C, 58.20;
H, 3.49; N, 13.63.
3-(2-Chlorophenyl)-5-vinyl-1,2,4-oxadiazole (4e)
Oil; 1H NMR: d = 7.92-7.90 (m, 1H), 7.55-7.52 (m,
1H), 7.42-7.37 (m, 2H), 6.80-6.78 (m, 1H), 6.63-6.58 (m,
1H), 6.04-6.01 (m, 1H); 13C NMR = 173.8, 167.5, 133.5,
131.5, 131.2, 130.9, 128.8, 126.7, 125.7, 120.2; IR (neat):
nmax = 3065, 2925, 2855, 1645, 1542, 1470, 1344, 1055,
955, 767, 735 cm-1; EI-MS: m/z (%) = 206 (M+); Anal.
Calcd for C10H7ClN2O: C, 58.13; H, 3.41; N, 13.56. Found:
C, 58.19; H, 3.50; N, 13.63.
3-(3-Bromophenyl)-5-vinyl-1,2,4-oxadiazole (4f)
White solid, mp 62-63 °C; 1H NMR: d = 8.26-8.24
(m, 1H), 8.06-8.04 (m, 1H), 7.66-7.64 (m, 1H), 7.37-7.34
(m, 1H), 6.81-6.74 (m, 1H), 6.62-6.14 (m, 2H); 13C NMR =
174.6, 167.4, 134.2, 130.5, 130.3, 129.1, 128.6, 125.7,
122.7, 120.2; IR (KBr): nmax = 2925, 1645, 1542, 1470,
1398, 1360, 956, 786, 730, 675 cm-1; EI-MS: m/z (%) = 250
(M+); Anal. Calcd for C10H7BrN2O: C, 47.84; H, 2.81; N,
11.16. Found: C, 47.90; H, 2.90; N, 11.22.
3-Phenyl-5-vinyl-1,2,4-oxadiazole (4a)
Oil; 1H NMR: d = 8.11-8.08 (m, 2H), 7.51-7.46 (m,
3H), 6.80-6.57 (m, 2H), 6.00-5.97 (m, 1H); 13C NMR =
174.5, 168.4, 131.2, 128.8, 128.5, 127.3, 126.8, 120.5; IR
(neat): nmax = 3070, 2926, 1646, 1543, 1445, 1360, 956,
910, 770, 705 cm-1; EI-MS: m/z (%) = 172 (M+); Anal.
Calcd for C10H8N2O: C, 69.76; H, 4.68; N, 16.27. Found:
C, 69.82; H, 4.77; N, 16.33.
3-(4-Fluorophenyl)-5-vinyl-1,2,4-oxadiazole (4g)
White solid, mp 42-44 °C; 1H NMR: d = 8.10-8.04
(m, 2H), 7.21-7.16 (m, 2H), 6.78-6.72 (m, 1H), 6.61-5.97
(m, 2H); 13C NMR = 174.5, 167.7, 164.5 (J = 249.4 Hz),
129.3 (J = 8.6 Hz), 129.0, 122.6 (J = 3.2 Hz), 120.4, 115.5
(J = 22.2 Hz); IR (KBr): nmax = 3061, 2926, 1917, 1610,
1472, 1422, 1215, 965, 846, 790, 516 cm-1; EI-MS: m/z (%)
= 190 (M+); Anal. Calcd for C10H7FN2O: C, 63.16; H, 3.71;
N, 14.73. Found: C, 63.23; H, 3.80; N, 14.79.
3-(4-Methoxylphenyl)-5-vinyl-1,2,4-oxadiazole (4b)
White solid, mp 50-51 °C; 1H NMR: d = 7.98 (d, J =
8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.76-6.72 (m, 1H),
6.58-5.71 (m, 2H), 3.85 (s, 3H); 13C NMR = 174.2, 168.5,
161.2, 129.1, 128.5, 120.4, 119.0, 114.2, 55.3; IR (KBr):
nmax = 3320, 3035, 2925, 1615, 1540, 1478, 1415, 1358,
810, 787, 695 cm-1; EI-MS: m/z (%) = 202 (M+); Anal.
Calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found:
C, 65.41; H, 5.07; N, 13.92.
3-Benzyl-5-vinyl-1,2,4-oxadiazole (4h)
Oil; 1H NMR: d = 7.38-7.36 (m, 2H), 7.27-7.25 (m,
3H), 6.69-6.61 (m, 2H), 5.95-5.87 (m, 1H), 4.20 (s, 2H);
13C NMR = 173.9, 167.8, 132.9, 128.6, 128.4, 127.1, 125.3,
120.2, 31.5; IR (neat): nmax = 3035, 2925, 1567, 1528,
1496, 1031, 980, 945, 730, 696 cm-1; EI-MS: m/z (%) = 186
(M+); Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N,
15.04. Found: C, 71.02; H, 5.51; N, 15.10.
3-(4-Methylphenyl)-5-vinyl-1,2,4-oxadiazole (4c)
Oil; 1H NMR: d = 8.01 (d, J = 8.0 Hz, 2H), 7.30 (d, J =
8.0 Hz, 2H), 6.78-6.72 (m, 1H), 6.60-5.95 (m, 2H), 2.42 (s,
3H); 13C NMR = 174.1, 168.5, 141.5, 129.5, 128.4, 127.1,
123.8, 120.3, 21.3; IR (neat): nmax = 3000, 2935, 2841,
1614, 1540, 1476, 1422, 1358, 1254, 1108, 840, 787, 690
cm-1; EI-MS: m/z (%) = 186 (M+); Anal. Calcd for
C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C, 70.99;
H, 5.48; N, 15.12.
3-(i-Propyl)-5-vinyl-1,2,4-oxadiazole (4i)
Oil; 1H NMR: d = 6.65-6.58 (m, 1H), 6.23-6.08 (m,
1H), 5.87-5.75 (m, 1H), 3.12-3.05 (m, 1H), 1.33 (s, 3H),

SPOS of Vinyl-Substituted 1,2,4-Oxadiazoles
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 771
1.31 (s, 3H); 13C NMR = 175.1, 167.8, 125.0, 120.2, 26.2,
19.8; IR (neat): nmax = 2978, 2938, 2879, 1645, 1565, 1385,
1370, 1012, 980, 943 cm-1; EI-MS: m/z (%) = 138 (M+);
Anal. Calcd for C7H10N2O: C, 60.85; H, 7.30; N, 20.28.
Found: C, 60.91; H, 7.41; N, 20.35.
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ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from
the National Natural Science Foundation of China (No.
20562005), NSF of Jiangxi Province (No. 0620021 and
No. 2007GZW0185) and the Research Program of Jiangxi
Province Department of Education (No. GJJ08165).
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