Polycyclic N-heterocyclic compounds. Part 66: Synthesis of N-[2-([1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes and their evaluation as inhibitors of platelet aggregation

Article abstract of DOI:10.1002/jhet.564

N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes were synthesized by fusion of (6,7-dihydro-5H-cyclopenta[1,2-d]pyrimidin-4-yl) amidines and/or their amide oximes with hydroxylamine hydrochloride through a subsequent rearrangement reaction. A

Full text of DOI:10.1002/jhet.564

May 2011
Polycyclic N-Heterocyclic Compounds. Part 66: Synthesis of
N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide Oximes
and Their Evaluation as Inhibitors of Platelet Aggregation [1]
715
Kensuke Okuda,a* Ying-Xue Zhang,b Hiromi Ohtomo,b Takashi Hirota,b
and Kenji Sasakib
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University,
Gifu 501-1196, Japan
bFaculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama 700-8530, Japan
*E-mail: okuda@gifu-pu.ac.jp
Received February 5, 2010
DOI 10.1002/jhet.564
Published online 4 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes were synthesized by fusion of (6,7-
dihydro-5H-cyclopenta[1,2-d]pyrimidin-4-yl)amidines and/or their amide oximes with hydroxylamine
hydrochloride through a subsequent rearrangement reaction. Assay of the products for anti-platelet
aggregation activity revealed that certain of them showed promising inhibitory effect on arachidonic
acid-induced platelet aggregation.
J. Heterocyclic Chem., 48, 715 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
Platelet activation and aggregation are the most criti-
cal steps in the development of acute ischemic syn-
dromes such as acute coronary syndrome or ischemic
stroke, major causes of death in the developed world.
Drugs designed to interfere with platelet activation and
aggregation are thus important for the prevention and
treatment of these syndromes. Unfortunately, current
antiplatelet drugs often have drawbacks that include side
effects and less than ideal efficacy. Accordingly, there
continues to be much research directed to the develop-
ment of new drugs for this purpose [2–7].
We initiated the synthetic efforts with the aliphatic 5-
membered ring-fused amidine 5. As shown in Scheme
1, amidines 5, required as starting materials, were syn-
thesized by the previously reported method [8]. Thus,
amidines 5a and 5b were prepared by reaction of 4-
amino-6,7-dihydro-5H-cyclopenta[1,2-d]pyrimidine (4)
with commercially available N,N-dimethylformamide (or
acetamide) dimethyl acetal in refluxing toluene. Other
amidines 5c–g were prepared by the reaction of com-
pound 4 with the Vilsmeier reagent prepared from the
corresponding N,N-dimethylamide and phosphoryl chlo-
ride [9].
We have previously reported that N-[2-(3-substituted
[1,2,4]oxadiazol-5-yl)cyclohexen-1-yl]formamide oximes
(2) are accessible by reaction of N1,N1-dimethyl-N2-
(5,6,7,8-tetrahydroquinazolin-4-yl)amidines (1) and/or
their amide oximes with hydroxylamine hydrochloride
followed by pyrimidine ring cleavage and 1,2,4-oxadia-
zole ring closure (Fig. 1). A study of biological proper-
ties of these compounds revealed that one member of
the group (R ¼ 4-Cl-Ph) had considerable activity as an
inhibitor of arachidonic acid-induced platelet aggrega-
tion [8]. To develop more active compounds in this se-
ries, we decided to explore the structure–activity rela-
tionships of the related compounds, N-[2-(3-substituted
[1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes
(3). In this report, we describe the synthesis and evalua-
tion of these compounds in detail.
When a hydrogen is attached to the amidine moiety
(R ¼ H), the reaction of 5a with 1.2 equiv of hydroxyl-
amine hydrochloride in methanol at room temperature
gave the amide oxime (6a) in 87% yield. Compound 6a
was converted to the desired 1,2,4-oxadiazole derivative
3a in 86% yield by reaction with 6 equiv of hydroxyla-
mine hydrochloride in a refluxing methanol (Scheme 1).
When an alkyl group was attached to the amidine
moiety (R ¼ Me and Et), the reaction of 5b and 5c with
1.5 equiv of hydroxylamine hydrochloride in methanol
at room temperature did not produce amide oximes (6b
and 6c), but gave exclusively oxadiazole 3b (53%) and
3c (45%), respectively. Other amidines 5d–g having an
aryl group substituted in the amidine moiety required an
excess amount of hydroxylamine hydrochloride to
C
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K. Okuda, Y.-X. Zhang, H. Ohtomo, T. Hirota, and K. Sasaki
Vol 48
mamide oximes (3) through the reaction of N-(6,7-dihy-
dro-5H-cyclopenta[1,2-d]pyrimidin-4-yl)amidines (5)
with hydroxylamine hydrochloride. The reaction
involves a ring cleavage of a pyrimidine component
accompanied by a ring closure to the 1,2,4-oxadiazole.
Among the series, compound 3e showed the best inhibi-
tory activity against platelet aggregation and had activity
comparable with that of the clinically used Cilostazol.
Figure 1. Substrate (1) and rearranged products (2 and 3).
consume starting materials completely. In such cases,
the reaction did not produce amide oximes (6d–g), but
gave the desired oxadiazoles 3d–g by the reaction with
6–8 equiv of hydroxylamine hydrochloride. These phe-
nomena are in full accord with previous examples [8].
The activities of 3a–g as inhibitors of arachidonic acid-
induced platelet aggregation were assayed. This was car-
ried out by a turbidimetric method developed by Born and
Cross [10] using an aggregometer. As shown in Table 1, a
comparison of the inhibition rate at the final concentration
of 30 mmol/L with that of Cilostazol [11] showed that 3b
and 3e had potency comparable with Cilostazol. Consid-
ering that 2e (R ¼ 4-Cl-Ph, % inhibition: 75.2 6 10.8) is
the most potent and 2b (R ¼ Me, % inhibition:42.6 6
14.8) is the second potent among 2, which were synthe-
sized previously [8], it seems that methyl and 4-chloro-
phenyl groups are key substituents for the activity.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-
melting point apparatus, and were uncorrected. Elemental analy-
ses were performed on a Yanagimoto MT-5 CHN Corder ele-
mental analyzer. The fast atom bombardment (FAB) mass spec-
tra were obtained on a VG 70 mass spectrometer and m-nitro-
benzyl alcohol was used as the matrix. Their spectra were
recorded on a Japan Spectroscopic FT/IR-200 spectrophotome-
ter with potassium bromide and frequencies are expressed in
cmꢀ1. The H-NMR spectra were recorded on a Varian VXR-
1
200 instrument operating at 200 MHz with tetramethylsilane as
an internal standard. Chemical shifts are given in ppm (d) and J
values in Hz. The signals are designated as follows: s, singlet; d,
doublet; t, triplet; q, quartet; br, broad; m, multiplet. Column
chromatography was performed on aluminium oxide active neu-
tral (Merck). Thin layer chromotography (TLC) was carried out
on Kieselgel 60F254 (Merck).
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyr-
imidin-4-yl)formamidine (5a). A mixture of 4-amino-6,7-dihy-
dro-5H-cyclopenta[1,2-d]pyrimidine (4, 300 mg, 2.22 mmol) and
In summary, we have synthesized various N-[2-(3-
alkyl(or aryl)[1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]for-
Scheme 1. Synthesis of 3.
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DOI 10.1002/jhet

May 2011
Synthesis of N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide
Oximes and Their Evaluation as Inhibitors of Platelet Aggregation
717
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyri-
midin-4-yl)benzamidine (5d). To a dry chloroform solution of
4 (500 mg, 3.70 mmol), N,N-dimethylbenzamide (610 mg,
4.09 mmol), phosphoryl chloride (0.42 mL, 4.51 mmol), and
triethylamine (1.80 mL, 12.9 mmol) were added sequentially,
and then the reaction mixture was refluxed for 37 h. The resi-
due was purified by column chromatography (ethyl acetate/n-
hexane, 1:2), recrystallized from ethyl acetate/n-hexane to give
5d (280 mg, 28%) as colorless fine crystals, m.p. 113–115ꢁC;
1H-NMR (deuterochloroform): d 1.93 (m, 2H, H6), 2.61
(t, 2H, J ¼ 7.4 Hz, H5), 2.84 (t, 2H, J ¼ 7.4 Hz, H7), 3.07
(s, 6H, N(CH3)2), 7.22 (m, 5H, Ph), 8.43 (s, 1H, H2); FAB-
ms: m/z 267 (MHþ). Anal. Calcd. for C16H18N4: C, 72.15; H,
6.81; N, 21.04. Found: C, 71.90; H, 6.87; N, 20.81.
Table 1
Effects of 3a–g on rabbit platelet aggregation in vitro.
Compound
% Inhibition
Compound
% Inhibition
3a
3b
3c
3d
31.9 6 1.8
70.4 6 11.2a
13.8 6 6.9
5.0 6 14.8
3e
3f
83.6 6 5.4a
1.9 6 0.9
27.06 7.5
96.5 6 1.3a
3g
Cilostazol
Data represent % inhibition of the vehicle control group (Mean 6 S.E.
of three experiments).
a Means significantly different from the vehicle control group at P <
0.01 (Dunnett’s multiple range test).
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyrimi-
din-4-yl)-4-chlorobenzamidine (5e). To a dry chloroform solu-
tion of 4 (3.00 g, 22.2 mmol), N,N-dimethyl-4-chlorobenza-
mide (4.49 g, 24.5 mmol), phosphoryl chloride (3.15 mL, 33.8
mmol), and triethylamine (10.9 mL, 8.1 mmol) were added
sequentially, and then the reaction mixture was refluxed for 50
h. The residue was purified by column chromatography (ethyl
acetate/n-hexane, 1:6) to give 5e (270 mg, 4%) as a colorless
N,N-dimethylformamide dimethyl acetal (319 mg, 2.68 mmol) in
dry toluene (40 mL) was refluxed for 10 h. After removal of sol-
vent in vacuo, the residue was recrystallized from n-hexane to
give 5a (389 mg, 92%) as yellow needles, m.p. 73–74ꢁC; 1H-
NMR (deuterochloroform): d 2.11 (m, 2H, H6), 2.95 (m, 4H, H5
and H7), 3.14 (s, 6H, N(CH3)2), 8.57 (s, 1H, CHN(CH3)2), 8.63
(s, 1H, H2); FAB-ms: m/z 191 (MHþ). Anal. Calcd. for
C10H14N4ꢂ0.2H2O: C, 61.96; H, 7.49; N, 28.90. Found: C, 62.28;
H, 7.25; N, 29.08.
1
oil; H-NMR (deuterochloroform): d 2.05 (m, 2H, H6), 2.72 (t,
2H, J ¼ 7.5 Hz, H5), 2.90 (t, 2H, J ¼ 7.5 Hz, H7), 3.06 (br s,
6H, N(CH3)2), 7.18 (d, 2H, J ¼ 8.7 Hz, Ph-30 and 50), 7.28 (d,
2H, J ¼ 8.7 Hz, Ph-20 and 60), 8.39 (s, 1H, H2); FAB-ms: m/z
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyr-
imidin-4-yl)acetamidine (5b). A mixture of compound 4 (350
mg, 2.59 mmol) and N,N-dimethylacetamide dimethyl acetal
(776 mg, 5.83 mmol) in dry toluene (40 mL) was refluxed for
54 h. After removal of solvent in vacuo, the residue was puri-
fied by column chromatography (ethyl acetate/n-hexane, 1:7)
301 (MHþ), 303 (MHþ
þ
2). Anal. Calcd. for
C16H17ClN4ꢂ0.1AcOEt: C, 63.42; H, 6.10; N, 18.04. Found: C,
63.57; H, 6.07; N, 18.08.
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyri-
midin-4-yl)-4-fluorobenzamidine (5f). To a dry chloroform
solution of 4 (3.20 g, 23.7 mmol), N,N-dimethyl-4-fluoroben-
zamide (4.35 g, 26.0 mmol), phosphoryl chloride (3.35 mL,
35.9 mmol), and triethylamine (9.95 mL, 71.1 mmol) were
added sequentially, and then the reaction mixture was refluxed
for 20 h. The residue was purified by column chromatography
(ethyl acetate/n-hexane, 1:6), recrystallized from petroleum
ether to give 5f (1.35 g, 20%) as colorless fine crystals, m.p.
79–80ꢁC; 1H-NMR (deuterochloroform): d 1.99 (m, 2H, H6),
2.65 (t, 2H, J ¼ 7.5 Hz, H5), 2.88 (t, 2H, J ¼ 7.5 Hz, H7),
3.06 (br s, 6H, N(CH3)2), 6.97 (m, 2H, Ph-30 and 50), 7.22 (m,
2H, Ph-20 and 60), 8.40 (s, 1H, H2); FAB-ms: m/z 285 (MHþ).
Anal. Calcd. for C16H17FN4: C, 67.59; H, 6.03; N, 19.70.
Found: C, 67.55; H, 6.14; N, 19.63.
1
to give 5b (244 mg, 46%) as a colorless oil; H-NMR (deuter-
ochloroform): d 2.08 (m, 2H, H6), 2.11 (s, 3H, CH3), 2.78 (t,
2H, J ¼ 7.5 Hz, H5), 3.00 (t, 2H, J ¼ 7.4 Hz, H7), 3.12 (s,
6H, N(CH3)2), 8.62 (s, 1H, H2); FAB-ms: m/z 205 (MHþ).
Anal. Calcd. for C11H16N4ꢂ0.2H2O: C, 63.56; H, 7.95; N,
26.95. Found: C, 63.94; H, 7.84; N, 26.63.
General procedure for the reaction of 4 with N,N-dime-
thylamide to give 5c–g. To a solution of 4 in dry chloroform
(ca. 20 mL), N,N-dimethylamide, phosphoryl chloride, and
triethylamine were added sequentially, and then the mixture
was refluxed for the appropriate time. Water was added to
quench the reaction, and the mixture was basified with satu-
rated aqueous sodium bicarbonate solution, then extracted with
chloroform. The organic phase was washed with saturated
brine, dried over anhydrous sodium sulfate, and then evapo-
rated in vacuo. The residue was purified by column chroma-
tography and/or recrystallization to give 5.
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyri-
midin-4-yl)-3-methylbenzamidine (5g). To a dry chloroform
solution of 4 (500 mg, 3.70 mmol), N,N-dimethyl-3-methyl-
benzamide (663 mg, 4.06 mmol), phosphoryl chloride (0.40
mL, 4.29 mmol), and triethylamine (0.90 mL, 6.43 mmol)
were added sequentially, and then the reaction mixture was
refluxed for 43 h. The residue was purified by column chroma-
tography (ethyl acetate/n-hexane, 1:3) to give 5g (91.0 mg,
9%) as a colorless oil; 1H-NMR (deuterochloroform): d 1.93
(m, 2H, H6), 2.26 (s, 3H, CH3), 2.61 (t, 2H, J ¼ 7.7 Hz, H5),
2.81 (t, 2H, J ¼ 7.7 Hz, H7), 3.00 (br s, 6H, N(CH3)2), 6.95–
7.17 (m, 4H, Ph), 8.44 (s, 1H, H2); FAB-ms: m/z 281 (MHþ).
Anal. Calcd. for C17H20N4ꢂ1/3H2O: C, 71.30; H, 7.27; N,
19.56. Found: C, 71.42; H, 7.17; N, 19.25.
N1,N1-Dimethyl-N2-(6,7-dihydro-5H-cyclopenta[1,2-d]pyrimi-
din-4-yl)propionamidine (5c). To a dry chloroform solution of
4 (2.50 g, 18.5 mmol), N,N-dimethylpropionamide (2.06 g,
20.4 mmol), phosphoryl chloride (2.60 mL, 27.9 mmol), and
triethylamine (7.50 mL, 53.8 mmol) were added sequentially,
and then the reaction mixture was refluxed for 30 h. The resi-
due was purified by column chromatography (n-hexane),
recrystallized from petroleum ether to give 5c (1.03 g, 26%)
as colorless fine crystals, m.p. 58–59ꢁC; 1H-NMR (deutero-
chloroform): d 1.11 (t, 3H, J ¼ 7.6 Hz, CH3), 2.08 (m, 2H,
H6), 2.54 (q, 2H, J ¼ 7.6 Hz, CH2CH3), 2.77 (t, 2H, J ¼ 7.4
Hz, H5), 3.01 (t, 2H, J ¼ 7.4 Hz, H7), 3.12 (s, 6H, N(CH3)2),
8.60 (s, 1H, H2); FAB-ms: m/z 219 (MHþ). Anal. Calcd. for
C12H18N4: C, 66.02; H, 8.31; N, 25.67. Found: C, 65.83; H,
8.10; N, 25.71.
N-(6,7-Dihydro-5H-cyclopenta[1,2-d]pyrimidin-4-yl)forma-
mide oxime (6a). To a solution of 5a (220 mg, 1.16 mmol) in
dry methanol (10 mL) was added hydroxylamine hydrochlor-
ide (96.7 mg, 1.39 mmol), and the reaction was then stirred at
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K. Okuda, Y.-X. Zhang, H. Ohtomo, T. Hirota, and K. Sasaki
Vol 48
room temperature for 4 h. Water was added, and the mixture
was then basified with saturated aqueous sodium bicarbonate
solution. The resulting precipitate was filtered, washed with
water, and the solid was recrystallized from dioxane/methanol
to give 6a (178.5 mg, 87%) as a white powder, m.p. 124–
(d, 1H, J ¼ 10.3 Hz, deuterium oxide exchangeable, NH),
10.48 (s, 1H, deuterium oxide exchangeable, OH); FAB-ms:
m/z 223 (MHþ). Anal. Calcd. for C10H14N4O2: C, 54.04; H,
6.35; N, 25.21. Found: C, 53.73; H, 6.35; N, 24.96.
N-[2-(3-Phenyl[1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]forma-
mide oxime (3d). Compound 5d (67.4 mg, 0.25 mmol) was
allowed to react with hydroxylamine hydrochloride (106 mg,
1.53 mmol) in dry methanol (4.0 mL) for 5 h. Compound 3d
(62.0 mg, 91%) was obtained as colorless needles, m.p. 190–
192ꢁC; ir (potassium bromide): 3260, 3200 (br, NH or OH),
126ꢁC; ir (potassium bromide): 3410, 3190 (NH or OH) cmꢀ1
;
1H-NMR (DMSO-d6): d 2.01 (m, 2H, H6), 2.84 (m, 4H, H5,
and H7), 7.94 (d, 1H, J ¼ 9.7 Hz, changed to singlet after
addition of deuterium oxide, NCH¼¼NO), 8.49 (s, 1H, H2),
8.62 (d, 1H, J ¼ 9.7 Hz, deuterium oxide exchangeable, NH),
10.59 (s, 1H, deuterium oxide exchangeable, OH); FAB-ms:
m/z 179 (MHþ). Anal. Calcd. for C8H10N4O: C, 53.92; H,
5.66; N, 31.44. Found: C, 53.72; H, 5.79; N, 31.14.
1
3120 (br, NH or OH) cmꢀ1; H-NMR (DMSO-d6): d 2.04 (m,
2H, H4), 2.77 (t, 2H, J ¼ 7.5 Hz, H5), 2.91 (t, 2H, J ¼ 7.5
Hz, H3), 7.42 (d, 1H, J ¼ 10.4 Hz, changed to singlet after
addition of deuterium oxide, NCH¼¼NO), 7.59 (m, 3H, Ph-30,
40, and 50), 8.07 (m, 2H, Ph-20, and 60), 10.36 (d, 1H, J ¼ 10.4
Hz, deuterium oxide exchangeable, NH), 10.69 (s, 1H, deute-
rium oxide exchangeable, OH); FAB-ms: m/z 271 (MHþ).
Anal. Calcd. for C14H14N4O2ꢂ0.2H2O: C, 61.39; H, 5.30; N,
20.46. Found: C, 61.36; H, 5.37; N, 20.45.
N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide oxime
(3a). To a solution of 6a (58.0 mg, 0.325 mmol) in dry metha-
nol (15 mL) was added hydroxylamine hydrochloride (136 mg,
1.96 mmol), and the reaction was then refluxed for 3 h. Water
was added, and the mixture was then basified with saturated
aqueous sodium bicarbonate solution. The precipitate was fil-
tered, washed with water, and the solid was recrystallized
from methanol to give 3a (54.2 mg, 86%) as colorless needles,
m.p. 193–195ꢁC; ir (potassium bromide): 3260 (br, NH or
N-{2-[3-(4-Chlorophenyl)[1,2,4]oxadiazol-5-yl]cyclopenten-
1-yl}formamide oxime (3e). Compound 5e (190.0 mg, 0.63
mmol) was allowed to react with hydroxylamine hydrochloride
(264 mg, 3.80 mmol) in dry methanol (6.0 mL) for 19 h. Com-
pound 3e (140.8 mg, 73%) was obtained as yellow needles,
m.p. 200–203ꢁC; ir (potassium bromide): 3220, 3140 (br, NH
1
OH) cmꢀ1; H-NMR (DMSO-d6): d 2.01 (m, 2H, H4), 2.74 (t,
2H, J ¼ 7.4 Hz, H5), 2.88 (t, 2H, J ¼ 7.4 Hz, H3), 7.35 (d,
1H, J ¼ 10.4 Hz, changed to singlet after addition of deute-
rium oxide, NCH¼¼NO), 8.59 (s, 1H, H30), 9.98 (d, 1H, J ¼
10.4 Hz, deuterium oxide exchangeable, NH), 10.57 (s, 1H,
deuterium oxide exchangeable, OH); FAB-ms: m/z 195
(MHþ). Anal. Calcd. for C8H10N4O2ꢂ0.1H2O: C, 49.03; H,
5.25; N, 28.59. Found: C, 49.07; H, 5.38; N, 28.64.
General procedure for the reaction of 5b–g with hydrox-
ylamine hydrochloride to give 3b–g. To a solution of amidine
(5) in dry methanol, hydroxylamine hydrochloride was added,
and then the mixture was stirred at room temperature for the
appropriate time. Water was added, and the mixture was then
basified with saturated aqueous sodium bicarbonate solution.
The precipitate was filtered, washed with water, and the solid
was recrystallized from methanol to give 3.
1
or OH) cmꢀ1; H-NMR (DMSO-d6): d 2.04 (m, 2H, H4), 2.77
(t, 2H, J ¼ 7.5 Hz, H5), 2.91 (t, 2H, J ¼ 7.5 Hz, H3), 7.43 (d,
1H, J ¼ 10.4 Hz, changed to singlet after addition of deute-
rium oxide, NCH¼¼NO), 7.65 (m, 2H, Ph-30 and 50), 8.05 (m,
2H, Ph-20 and 60), 10.27 (d, 1H, J ¼ 10.4 Hz, deuterium oxide
exchangeable, NH), 10.69 (s, 1H, deuterium oxide exchange-
able, OH); FAB-ms: m/z 305 (MHþ), 307 (MHþ þ 2). Anal.
Calcd. for C14H13ClN4O2: C, 55.18; H, 4.30; N, 18.39. Found:
C, 55.23; H, 4.49; N, 18.39.
N-{2-[3-(4-Fluorophenyl)[1,2,4]oxadiazol-5-yl]cyclopenten-
1-yl}formamide oxime (3f). Compound 5f (291.7 mg, 1.03
mmol) was allowed to react with hydroxylamine hydrochloride
(430 mg, 6.19 mmol) in dry methanol (10 mL) for 6 h. Com-
pound 3f (202.9 mg, 69%) was obtained as yellow crystals,
m.p. 206–209ꢁC; ir (potassium bromide): 3280, 3180 (br, NH
N-[2-(3-Methyl[1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]forma-
mide oxime (3b). Compound 5b (188 mg, 0.90 mmol) was
allowed to react with hydroxylamine hydrochloride (96.0 mg,
1.38 mmol) in dry methanol (6.0 mL) for 9 h. Compound 3b
(98.7 mg, 53%) was obtained as pale yellow needles, m.p.
185–187ꢁC; ir (potassium bromide): 3240 (br, NH or OH)
1
or OH) cmꢀ1; H-NMR (DMSO-d6): d 2.04 (m, 2H, H4), 2.77
(t, 2H, J ¼ 7.4 Hz, H5), 2.91 (t, 2H, J ¼ 7.4 Hz, H3), 7.40
(m, 2H, Ph-30, and 50), 7.41 (d, 1H, J ¼ 10.0 Hz, changed to
singlet after addition of deuterium oxide, NCH¼¼NO), 8.09 (m,
2H, Ph-20, and 60), 10.29 (d, 1H, J ¼ 10.0 Hz, deuterium oxide
exchangeable, NH), 10.69 (s, 1H, deuterium oxide exchange-
able, OH); FAB-ms: m/z 289 (MHþ). Anal. Calcd. for
C14H13FN4O2: C, 58.33; H, 4.55; N, 19.44. Found: C, 58.04;
H, 4.71; N, 19.25.
1
cmꢀ1; H-NMR (DMSO-d6): d 2.00 (m, 2H, H4), 2.33 (s, 3H,
CH3), 2.70 (t, 2H, J ¼ 7.3 Hz, H5), 2.86 (t, 2H, J ¼ 7.3 Hz,
H3), 7.33 (d, 1H, J ¼ 10.4 Hz, changed to singlet after addi-
tion of deuterium oxide, NCH¼¼NO), 9.89 (d, 1H, J ¼ 10.4
Hz, deuterium oxide exchangeable, NH), 10.50 (s, 1H, deute-
rium oxide exchangeable, OH); FAB-ms: m/z 209 (MHþ).
Anal. Calcd. for C9H12N4O2ꢂ0.1H2O: C, 51.47; H, 5.86; N,
26.68. Found: C, 51.50; H, 5.88; N, 26.85.
N-{2-[3-(3-Methylphenyl)[1,2,4]oxadiazol-5-yl]cyclopenten-
1-yl}formamide oxime (3g). Compound 5g (182.0 mg, 0.649
mmol) was allowed to react with hydroxylamine hydrochloride
(361 mg, 5.19 mmol) in dry methanol (8.0 mL) for 22 h. Com-
pound 3g (146 mg, 79%) was obtained as colorless needles,
m.p. 193–194ꢁC; ir (potassium bromide): 3240, 3120 (br, NH
N-[2-(3-Ethyl[1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]forma-
mide oxime (3c). Compound 5c (420.0 mg, 1.92 mmol) was
allowed to react with hydroxylamine hydrochloride (200 mg,
2.88 mmol) in dry methanol (10 mL) for 28 h. Compound 3c
(193.3 mg, 45%) was obtained as colorless needles, m.p. 155–
1
or OH) cmꢀ1; H-NMR (DMSO-d6): d 2.05 (m, 2H, H4), 2.40
(s, 3H, CH3), 2.77 (t, 2H, J ¼ 7.4 Hz, H5), 2.91 (t, 2H, J ¼
7.4 Hz, H3), 7.42 (d, 1H, J ¼ 10.3 Hz, changed to singlet after
addition of deuterium oxide, NCH¼¼NO), 7.45 (m, 2H, Ph-40
and 50), 7.85 (m, 1H, Ph-60), 7.91 (br s, 1H, Ph-20), 10.46 (d,
1H, J ¼ 10.3 Hz, deuterium oxide exchangeable, NH), 10.72
(s, 1H, deuterium oxide exchangeable, OH); FAB-ms: m/z 285
158ꢁC; ir (potassium bromide): 3290 (br, NH or OH) cmꢀ1
;
1H-NMR (DMSO-d6): d 1.24 (t, 3H, J ¼ 7.5 Hz, CH2CH3),
2.00 (m, 2H, H4), 2.70 (m, 4H, H5, and CH2CH3), 2.86
(t, 2H, J ¼ 7.4 Hz, H3), 7.34 (d, 1H, J ¼ 10.3 Hz, changed to
singlet after addition of deuterium oxide, NCH¼¼NO), 10.04
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Synthesis of N-[2-([1,2,4]Oxadiazol-5-yl)cyclopenten-1-yl]formamide
Oximes and Their Evaluation as Inhibitors of Platelet Aggregation
719
(MHþ). Anal. Calcd. for C15H16N4O2ꢂ0.2H2O: C, 62.57; H,
5.74; N, 19.46. Found: C, 62.80; H, 5.87; N, 19.45.
Measurement of platelet aggregation. Preparation of platelet
and measurement of platelet aggregation were done according to
the method described previously [8].
[4] Wang, T. C.; Chen, I. L.; Lu, P. J.; Wong, C. H.; Liao, C.
H.; Tsiao, K. C.; Chang, K. M.; Chen, Y. L.; Tzeng, C. C. Bioorg
Med Chem 2005, 13, 6045.
[5] Hsieh, P. W.; Hwang, T. L.; Wu, C. C.; Chiang, S. Z.; Wu,
C. I.; Wu, Y. C. Bioorg Med Chem Lett 2007, 17, 1812.
[6] Chen, I. L.; Chang, K. M.; Miaw, C. L.; Liao, C. H.; Chen,
J. J.; Wang, T. C. Bioorg Med Chem 2007, 15, 6527.
Acknowledgment. The authors thank SC-NMR Laboratory of
Okayama University for 200 MHz H-NMR experiments. They
also thank Dr. K. L. Kirk (NIDDK, NIH) for helpful suggestions.
1
[7] Hsieh, P. W.; Chiang, S. Z.; Wu, C. C.; Lo, Y. C.; Shih, Y.
T.; Wu, Y. C. Bioorg Med Chem 2008, 16, 5803.
[8] Okuda, K.; Zhang, Y.-X.; Ohtomo, H.; Hirota, T.; Sasaki,
K. Chem Pharm Bull 2010, 58, 369.
REFERENCES AND NOTES
[9] It seemed that amidines 5 decomposed slightly during reac-
tion as well as purification by column chromatography. In the case of
5e and 5g, severe decomposition occurred to cause quite law yield (5
and 9%, respectively).
[1] Part 65: Okuda, K.; Deguchi, H.; Hirota, T.; Sasaki, K.
Chem Pharm Bull 2010, 58, 755.
[2] Hsieh, P. W.; Hwang, T. L.; Wu, C. C.; Chang, F. R.;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet