Polycyclic N-heterocyclic compounds, part 77: Synthesis of [1]benzothieno[3',2':2,3]oxepino[4,5-d]pyrimidines and evaluation of their antiplatelet aggregation activity

Article abstract of DOI:10.1080/00397911.2012.656295

Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino- 2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[30,20:2, 3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[20,30:6, 7]oxepino[4,5-e]imidazo[1,2-c] pyrimidine heterocyclic system. The new compounds described in this report were evaluated as inhibitors of platelet aggregation in vitro. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2012.656295

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Polycyclic N-Heterocyclic
Compounds, Part 77: Synthesis of
[1]Benzothieno[3′,2′:2,3]oxepino[4,5-
d]pyrimidines and Evaluation of Their
Antiplatelet Aggregation Activity
Kensuke Okuda a , Takashi Nikaido b , Takashi Hirota b & Kenji Sasaki
b
a Laboratory of Medicinal and Pharmaceutical Chemistry, Gifu
Pharmaceutical University, Gifu, Japan
b Laboratory of Pharmaceutical Chemistry, Faculty of
Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama,
Japan
Accepted author version posted online: 18 May 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Kensuke Okuda , Takashi Nikaido , Takashi Hirota & Kenji Sasaki (2013): Polycyclic
N-Heterocyclic Compounds, Part 77: Synthesis of [1]Benzothieno[3′,2′:2,3]oxepino[4,5-d]pyrimidines
and Evaluation of Their Antiplatelet Aggregation Activity, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:12, 1619-1625
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Synthetic Communications1, 43: 1619–1625, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.656295
POLYCYCLIC N-HETEROCYCLIC COMPOUNDS,
PART 77: SYNTHESIS OF
[1]BENZOTHIENO[3’,2’:2,3]OXEPINO[4,5-
d]PYRIMIDINES AND EVALUATION OF THEIR
ANTIPLATELET AGGREGATION ACTIVITY
Kensuke Okuda,1 Takashi Nikaido,2 Takashi Hirota,2 and
Kenji Sasaki2
1Laboratory of Medicinal and Pharmaceutical Chemistry,
Gifu Pharmaceutical University, Gifu, Japan
2Laboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical
Sciences, Okayama University, Kita-ku, Okayama, Japan
GRAPHICAL ABSTRACT
Abstract Reaction of 3-(3-cyanopropoxy)[1]benzothiophene-2-carbonitrile with sodium
hydride gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo[2,3-b]pyridine and 5-amino-
2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile. The latter compound served as a
convenient scaffold for the synthesis of the new heterocycles [1]benzothieno[30,20:2,
3]oxepino[4,5-d]pyrimidines and the parent 1,2,4,5-tetrahydro[1]benzothieno[20,30:6,
7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine heterocyclic system. The new compounds
described in this report were evaluated as inhibitors of platelet aggregation in vitro.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Antiplatelet aggregation; cyclization; Thorpe–Ziegler reaction; Truce–Smiles
rearrangement; Vilsmeier reagent
INTRODUCTION
As part of our research to develop new medicinally active compounds, we have
been investigating the syntheses and biological evaluation of heterocycles containing
new ring systems that are accessible by rearrangement reactions. During the course
Received October 26, 2011.
Address correspondence to Kensuke Okuda, Laboratory of Medicinal and Pharmaceutical
Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan. E-mail:
okuda@gifu-pu.ac.jp
1619

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K. OKUDA ET AL.
Scheme 1. Substrates (1 and 3) with base and products (2, 4, and 5).
of this work, we have developed a new synthetic method for aromatic fused 2,3-
dihydrofuro[2,3-b]pyridines (2) based on reactions of 2-(3-cyanopropoxy)aryl-
1-carbonitriles (1) with bases (Scheme 1). This process involves a Truce–Smiles
rearrangement followed by intramolecular cyclization.[1–5] When we applied this
strategy to 3-(3-cyanopropoxy)[1]benzofuran-2-carbonitriles (3), we found that the
formation of the expected product, 5-amino-1,2-dihydro[1]benzofuro[3,2-d]furo
[2,3-b]pyridines (4), was accompanied by formation of 5-amino-2,3-dihydro[1]benzo-
furo[3,2-b]oxepin-4-carbonitrile (5).[6] Thus, because the key step of Truce–Smiles
rearrangement is a nucleophilic attack at an ipso position of an aromatic ring, the
less-reactive electron-rich benzofuran is a poor substrate for this rearrangement
and the Thorpe–Ziegler reaction can compete to give 5. This was the first time we
had observed a product of the Thorpe–Ziegler reaction in our studies.
Previously, we found that the reaction of 3-(3-cyanopropoxy)[1]benzothiophene-
2-carbonitrile (6) with base gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]furo
[2,3-b]pyridine (7) in modest yield.[3] Because benzothiophene is also a somewhat
electron-rich aromatic, we reasoned that 5-amino-2,3-dihydro[1]benzothieno[3,2-b]-
oxepin-4-carbonitrile (8) could also be a product of this reaction. Here we describe
the synthesis of 8, which is formed along with 7. We also describe the preparation
of tetracyclic [1]benzothieno[30,20:2,3]oxepino[4,5-d]pyrimidines (9 and 10) and penta-
cyclic 1,2,4,5-tetrahydro[1]benzothieno[20,30:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine
(11), which are accessible from 8. Because current antiplatelet drugs are known
to have certain detrimental side effects and low efficacy and thus much research is
directed to the development of new drugs in this class,[7–13] we tested these new analogs
for antiplatelet aggregation activity.
Reaction of 6 and sodium hydride in dry 1,4-dioxane gave 8 in 18%, as we had
anticipated, as well as 7, which was formed in 25% (Scheme 2). The characteristic amino
and cyano bands in the infrared (IR) spectrum of 8 clearly supported the isomer
identification. In Contrast to the case of benzofuran,[6] in which the Truce–Smiles
Scheme 2. Substrate (6) with base and products (7 and 8).

[1]BENZOTHIENO[30,20:2,3]OXEPINO[4,5-d]PYRIMIDINES
1621
Scheme 3. Synthesis of 9 and 10.
rearrangement product 4 is the minor product and the Thorpe–Ziegler reaction
product 5 is a major product, the Truce–Smiles rearrangement product 7 is the
major product and the Thorpe–Ziegler reaction product 8 is a minor product.
To access additional potential pharmaceuticals, the functionality present
in compound 8 was exploited for the construction of a pyrimidine ring leading to
the new heterocyclic ring system [1]benzothieno[30,20:2,3]oxepino[4,5-d]pyrimidine.
Thus, reaction of 8 with Vilsmeier reagent gave 9a–d in 64–88% yield. Structures
of 9a–d were determined based on the disappearance of the enamine and nitrile
groups and appearance of chlorine atoms in their IR and mass (MS) spectra.
In addition, the NMR spectra and elemental analyses supported these structures.
Next, 9a–d were treated with ethanolamine to give 10a–d in 78–85% yield
(Scheme 3). Finally, unprecedented pentacyclic 1,2,4,5-tetrahydro[1]benzothieno
[20,30:6,7]oxepino[4,5-e]imidazo[1,2-c]pyrimidine (11) was prepared in 83% yield by
cyclodehydration of 10a (Scheme 4).
With these compounds in hand, the antiplatelet aggregation activities were
examined to explore the structure–activity relationships using a random in vitro
screening test for atherothrombosis. The inhibitory activities of compounds 9–11
using dimethylsulfoxide (DMSO, final concentration 0.83%) as a cosolvent against
platelet aggregation induced by collagen (final concentration 14.3 mg=ml) was assayed
to demonstrate the possible therapeutic potential of these compounds.
The inhibitory assay was executed by a turbidimetric method developed by
Born and Cross[14] using an aggregometer. Comparison of the inhibition rate of
10a (21.7 ꢀ 2.1%), 10b (17.4 ꢀ 1.8%), and 11 (22.3 ꢀ 2.8%) at a final concentration
of 25 mM with that of aspirin (15.7 ꢀ 1.0%) revealed that 10a, 10b, and 11 had
potency comparable to aspirin. Unfortunately, other compounds 9–10 did not
have sufficient water solubility to execute this assay. We are currently exploring
development of derivatives with antiplatelet aggregation activity that possess good
solubility.
Scheme 4. Synthesis of 11.

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K. OKUDA ET AL.
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-melting-point
apparatus and are uncorrected. Elemental analyses were performed on a Yanagi-
moto MT-5 CHN Corder elemental analyzer. The electron impact (EI) mass and fast
atom bombardment (FAB) mass (m-nitrobenzyl alcohol was used as the matrix)
were obtained on a VG70-SE mass spectrometer. The IR spectra were recorded
on a Japan Spectroscopic diffraction grating A-102 spectrophotometer and frequen-
cies are expressed in cmꢁ1. The 1H NMR spectra were recorded on a Varian
VXR-200 instrument operating at 200 MHz or a Hitachi R-1500 instrument operat-
ing at 60 MHz with tetramethylsilane (TMS) as an internal standard. Chemical shifts
are given in parts per million (ppm) (d) and J values in hertz (Hz), and the signals are
designated as follows: s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet;
br, broad; m, multiplet.
5-Amino-2,3-dihydro[1]benzothieno[3,2-b]oxepin-4-carbonitrile (8)
NaH (60% oil dispersion, 2.05 g, 51.3 mmol) and 3 drops of tert-BuOH were
added to a solution of 6[3] (9.95 g, 41.1 mmol) in 1,4-dioxane (200 mL) and the result-
ing mixture was refluxed for 5 h. After removal of solvent in vacuo, ice water
(200 mL) was added to the residue. The resulting mixture was extracted with ethyl
acetate (100 mL ꢂ 3). The organic layer was washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and then evaporated in vacuo. The residue
was chromatographed on silica gel. The eluate of benzene was evaporated in vacuo,
and the solid residue was recrystallized from benzene to give 8 (1.80 g, 18%) as pale
yellow prisms, mp 159–161 ꢃC; IR (KBr) cmꢁ1: 3440, 3320, 3230 (NH), 2175 (CN);
1H NMR (60 MHz, CDCl3): d 2.65–2.90 (m, 2H, H3), 4.39–4.69 (m, 2H, H2), 4.57
(br s, 2H, deuterium oxide exchangeable, NH2), 7.24–7.58 (m, 2H, H8 and 9),
7.58–7.88 (m, 2H, H7 and 10); FAB-ms m=z 243 (MHþ). Anal. calcd. for
C13H10N2OS: C, 64.44; H, 4.16; N, 11.56. Found: C, 64.20; H, 4.31; N, 11.39.
The further eluate of benzene–ethyl acetate (4:1) was evaporated in vacuo, and
the solid residue was recrystallized from acetonitrile to give 7 (2.53 g, 25%) as pale
brown prisms, mp 269–271 ꢃC.[3]
Preparation of 2-Substituted 4-Chloro-5,6-
dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]pyrimidine (9)
A mixture of the corresponding N,N-dimethylamide (3.00 mmol) and phos-
phorus oxychloride (0.840 mL, 9.01 mmol) was stirred at 0 ꢃC for 30 min. Then 8
(242 mg, 1.00 mmol) was added, and the resulting mixture was stirred at 70–80 ꢃC
for 1 h. After removal of solvent in vacuo, ice water (100 mL) was added to the resi-
due, followed by basification with sodium bicarbonate. The aqueous mixture was
extracted with ethyl acetate (30 mL ꢂ 3). The combined organic layer was washed
with water and saturated brine, dried over anhydrous magnesium sulfate, and eva-
porated in vacuo. The residue was purified by recrystallization to give 9.
4-Chloro-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]pyrimidine
(9a). Yield 88%, brown prisms from benzene, mp 179–181 ꢃC.

[1]BENZOTHIENO[30,20:2,3]OXEPINO[4,5-d]PYRIMIDINES
1623
4-Chloro-2-methyl-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]-
pyrimidine (9b). Yield 68%, colorless plates from ethyl acetate, mp 188–190 ꢃC.
4-Chloro-2-ethyl-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]-
pyrimidine (9c). Yield 64%, colorless plates from cyclohexane, mp 129–130 ꢃC.
4-Chloro-2-phenyl-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]-
pyrimidine (9d). Yield 70%, colorless prisms from benzene, mp 169–170 ꢃC.
Preparation of 2-Substituted 2-(5,6-Dihydro[1]benzothieno[3’,2’:2,3]-
oxepino[4,5-d]pyrimidin-4-yl)amino]ethanols (10)
2-Aminoethanol (0.605mL, 10.0 mmol) was added to a solution of 9 (1.00 mmol)
in a few mL of 1,4-dioxane, and the mixture was then stirred at 60–80 ꢃC for 2 h.
Ice water (50 mL) was added to the reaction mixture. The precipitate was collected
by filtration, washed with cold water, and then recrystallized to give 10.
2-(5,6-Dihydro-[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]pyrimidin-4-
yl)amino]ethanol (10a). Yield 85%, brown scales from acetonitrile, mp 185–187 ꢃC.
2-[(2-Methyl-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]pyrimi-
din-4-yl)amino]ethanol (10b). Yield 79%, pale yellow needles from ethyl acetate,
mp 194–196 ꢃC.
2-[(2-Ethyl-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]pyrimidin-
4-yl)amino]ethanol (10c). Yield 78%, colorless prisms from benzene, mp 170–
171 ꢃC.
2-[(2-Phenyl-5,6-dihydro[1]benzothieno[3’,2’:2,3]oxepino[4,5-d]pyrimidin-
4-yl)amino]ethanol (10d). Yield 80%, brown powder from benzene, mp 220–
221 ꢃC.
1,2,4,5-Tetrahydro[1]benzothieno[2’,3’:6,7]oxepino[4,5-e]imidazo-
[1,2-c]pyrimidine Hydrochloride (11)
A mixture of 10a (157 mg, 0.501 mmol) and phosphorus oxychloride (2.0 mL,
21.4 mmol) was stirred at 70–80 ꢃC for 1 h. After removal of solvent in vacuo, ice
water (50 mL) was added to the residue. The precipitate was collected by filtration,
washed with cold water, and then recrystallized from methanol to give 11 (138 mg,
1
83%) as yellow scales; mp 279–281 ꢃC; H NMR (200 MHz, DMSO-d6): d 3.21 (br
t, 2H, J ¼ 3.7 Hz, H4), 4.00 (t, 2H, J ¼ 9.9 Hz, H1 or 2), 4.60–4.72 (m, 4H, H1 or
2 and 5), 7.42–7.62 (m, 2H, H8 and 9), 7.83 (d, 1H, J ¼ 7.7 Hz, H7 or 10), 7.96 (d,
1H, J ¼ 7.9 Hz, H7 or 10), 8.82 (s, 1H, H13), 10.32 (s, 1H, deuterium oxide exchange-
able, NþH); FAB-ms m=z 296 (MHþ-HCl). Anal. calcd. for C16H14ClN3OS: C,
57.91; H, 4.25; N, 12.66. Found: C, 58.10; H, 4.38; N, 12.80.

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K. OKUDA ET AL.
SUPPLEMENTARY MATERIAL
Full spectroscopic and characterization data for 9a–d and 10a–d including
elemental analysis, NMR spectra of all new compounds, and details for the platelet
aggregation assay are available online in the Supplementary Material.
ACKNOWLEDGMENTS
We are grateful to the Superconducting (SC)-NMR Laboratory of Okayama
1
University for 200-MHz H NMR experiments. We also thank Hiromi Ohtomo,
Kaori Ueda, Yoko Ohkuma (Laboratory of Pharmaceutical Chemistry, Faculty of
Pharmaceutical Sciences, Okayama University), and Taiji Nakayama (deceased)
(Faculty of Pharmaceutical Sciences, Okayama University) for their experimental
assistance, and K. L. Kirk (National Institute of Diabetes and Digestive and Kidney
Diseases, National Institute of Health) for helpful comments on the manuscript.
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