Polycyclic N-heterocyclic compounds. Part 80: Synthesis and evaluation of effects on in vitro pentosidine formation of 5,6-dihydro[1]benzothieno[3′, 2′:2,3]thiepino[4,5-d]pyrimidine and related compounds

Article abstract of DOI:10.1002/jhet.1709

Reaction of 3-(3-cyanopropylthio)[1]benzothiophene-2-carbonitrile with tert-BuONa gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]thieno[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]thiepin-4-carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles, [1]benzothieno[3′,2′:2,3]thiepino[4,5-d]pyrimidines. All of our new tetracyclic products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products. Copyright

Full text of DOI:10.1002/jhet.1709

July 2014
Polycyclic N-Heterocyclic Compounds. Part 80: Synthesis and Evaluation
of Effects on In Vitro Pentosidine Formation of 5,6-Dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine and Related Compounds
891
a
b
b
b
*
Kensuke Okuda, Yutaka Itsuji, Takashi Hirota, and Kenji Sasaki
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
bLaboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Okayama University, Kita-ku, Okayama
700-8530, Japan
*
E-mail: okuda@gifu-pu.ac.jp
Received February 7, 2012
DOI 10.1002/jhet.1709
Published online 9 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
Reaction of 3-(3-cyanopropylthio)[1]benzothiophene-2-carbonitrile with tert-BuONa gave 5-amino-1,2-
dihydro[1]benzothieno[3,2-d]thieno[2,3-b]pyridine and 5-amino-2,3-dihydro[1]benzothieno[3,2-b]thiepin-4-
carbonitrile. The latter compound served as a convenient scaffold for the synthesis of the new heterocycles,
[1]benzothieno[30,20:2,3]thiepino[4,5-d]pyrimidines. All of our new tetracyclic products were evaluated for
in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation
end products.
J. Heterocyclic Chem., 51, 891 (2014).
INTRODUCTION
along with 7. We also describe the preparation of tetracyclic
[1]benzothieno[30,20:2,3]thiepino[4,5-d]pyrimidines (9–17).
An in vitro screening evaluation of these compounds to
measures their effects on anti-pentosidine activity was
performed as part of our continuing program to develop
agents for hyperglycemia related diseases [11,12].
Formation of carbon–carbon (C–C) bonds is a central
issue in synthetic organic chemistry. In this regard, the
Truce–Smiles rearrangement is among those useful rear-
rangement reactions that provide access to complex
structures from simple precursors through formation of
new C–C bonds [1–5].
We have been investigating the syntheses and biological
evaluation of heterocycles containing new ring systems.
During the course of this work, we have developed a new
synthetic method for aromatic fused furo[2,3-b]pyridines
(2) based on reactions of 2-(3-cyanopropoxy)aryl-1-carbo-
nitriles (1) with bases (Scheme 1). This process involves a
Truce–Smiles rearrangement followed by intramolecular
cyclization [6–9].
Previously, we had disclosed that the reaction of 3-(3-cya-
nopropylthio)[1]benzothiophene-2-carbonitrile (6) with base
gave 5-amino-1,2-dihydro[1]benzothieno[3,2-d]thieno[2,3-
b]pyridine (7) in modest yield [8]. 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 benzothiophene is a poorer substrate for this
rearrangement as already described for 3-(3-cyanopropoxy)
[1]benzofuran-2-carbonitriles (3) [10]. In those cases, forma-
tion of 5-amino-2,3-dihydro[1]benzofuro[3,2-b]oxepin-4-
carbonitrile (5), which is the Thorpe–Ziegler reaction
product, also was formed. Therefore, 5-amino-2,3-dihydro
[1]benzothieno[3,2-b]thiepin-4-carbonitrile (8) should also
be obtainable from 3-(3-cyanopropylthio)[1]benzothio-
phene-2-carbonitrile (6) by a similar Thorpe–Ziegler reac-
tion. Here, we describe the synthesis of 8 that is formed
RESULTS AND DISCUSSION
Reaction of 6 and tert-BuONa in dry 1,4-dioxane gave
8 in 50%, as we had anticipated, as well as 7 that was
formed in 8% (Scheme 2). The characteristic amino and
cyano bands in the infrared spectrum of 8 clearly supported
the isomer identification. Similar to the case of benzofuran
(3) [10], in which case the Smiles rearrangement product 4
is the minor product and the Thorpe–Ziegler reaction
product 5 is a major product, the Smiles rearrangement
product 7 is the minor product and the Thorpe–Ziegler
reaction product 8 is the major product in the transformation
of benzothiophene (6). If the base was changed from tert-
BuONa to hexamethyldisilazane sodium salt, the reaction
gave 7 exclusively in 85% yield. It seems likely that the
stronger basicity and/or greater bulkiness of hexamethyldisi-
lazane sodium salt compared with tert-BuONa has changed
reactivity to give 7.
In order 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]thiepino
[4,5-d]pyrimidine. Thus, reaction of 8 with the Vilsmeier
reagent gave 9a–e in 72–82% yield (Scheme 3). Structures
© 2013 HeteroCorporation

892
K. Okuda, Y. Itsuji, T. Hirota, and K. Sasaki
Vol 51
Scheme 1. Substrates (1 and 3) and their products (2, 4, and 5) with base.
Scheme 2. Synthesis of 7 and 8.
Scheme 3. Preparation of 9.
of 9a–e were determined based on the disappearance of the
enamine and nitrile groups and appearance of chlorine
atoms in their IR and MS spectra. In addition, the NMR
spectra and elemental analyses supported these structures.
Next, 9a–e were treated with several amine nucleophiles
such as methylamine to give 10a–e in 66–84% yield,
ethylamine to give 11a–e in 66–83% yield, dimethylamine
to give 12a–e in 74–96% yield, and 2-aminoethanol to give
13a–e in 66–83% yield, respectively (Scheme 4). We
also used oxygen nucleophiles as reactants. Thus, sodium
methoxide gave 14a–e in 67–84% yield, sodium ethoxide
gave 15a–e in 83–91% yield, and ethylene glycol with
potassium carbonate gave 16a–e in 50–77% yield,
respectively (Scheme 5). Finally, the sulfur nucleophile
2-sulfanylethanol was used in the presence of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) to give 17a–e in 43–86%
yield (Scheme 6). All derivatives 10–17 satisfy Lipinski’s
rule of five, and thus, they are expected to have drug-like
properties [13].
Scheme 4. Preparation of 10–13.
With these derivatives (10–17) in hand, effects on the
formation of pentosidine, which is one of representative
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6-Dihydro
[1]benzothieno[30,20:2,3]thiepino[4,5-d]pyrimidine and Related Compounds
893
Scheme 5. Preparation of 14–16.
over anhydrous magnesium sulfate, and evaporated. The resulting
viscous oil was chromatographed on silica gel. The eluate of n-
hexane-ethyl acetate (19:1) was evaporated in vacuo, and the
residue was recrystallized from ethanol to give 8 (500 mg, 50%)
as pale yellow scales. mp 144–145ꢂC; IR (nujol) cmꢀ1: 3450,
3340, 3230 (NH), 2180 (CN); 1H-NMR (200 MHz,
deuterochloroform): d 2.56 (t, 2H, J= 6.0 Hz, H3), 3.60 (t, 2H,
J=6.0Hz, H2), 4.70 (br s, 2H, deuterium oxide exchangeable,
NH2), 7.42–7.52 (m, 2H, H8 and 9), 7.85 (dd, 1H, J= 6.3, 1.5 Hz,
H10), 8.00 (dd, 1H, J=6.1, 1.7Hz, H7); FAB-MS m/z: 259 (MH+).
Anal. Calcd. for C13H10N2S2: C, 60.44; H, 3.90; N, 10.84. Found:
C, 60.35; H, 3.95; N, 10.77.
A further eluate of n-hexane-ethyl acetate (9:1) was evaporated in
vacuo and the residue was recrystallized from benzene to give 7
(80 mg, 8%) as pale yellow needles, mp 207–208ꢂC [8].
5-Amino-1,2-dihydro[1]benzothieno[3,2-d]thieno[2,3-b]pyridine
(7). To a solution of 6 (1.00 g, 3.87mmol) in dry 1,4-dioxane
(100mL) was added hexamethyldisilazane sodium salt [40% in
tetrahydrofuran-cumene (3:1)] (8.89 mL, 19.4mmol) and the
reaction was stirred at room temperature for 0.5h. After
evaporation of solvent in vacuo, ice-water (200mL) was poured
into the residue. The precipitated solid was collected on a filter
and was recrystallized from benzene to give 7 (850 mg, 85%) as
pale yellow needles, mp 207–208ꢂC [8].
Scheme 6. Preparation of 17.
General procedure for the preparation of 9a–e from 8 with
Vilsmeier reagent. To a Vilsmeier reagent prepared from the
corresponding N,N-dimethylamide (3.0 eq. to 8) and phosphoryl
chloride (10 mL) under ice-water cooling for 1 h was added
8 (2.00 g, 7.74 mmol) and the mixture was then stirred at 80ꢂC
for 1 h. After removal of phosphoryl chloride in vacuo, ice-
water (100 mL) was poured into the residue and the solution
was neutralized with sodium bicarbonate. The mixture was
extracted with ethyl acetate (5 ꢁ 50 mL). The combined organic
phase was washed with sat. brine, dried over anhydrous
magnesium sulfate, and evaporated in vacuo. The residue was
purified by recrystallization to give 9a–e.
advanced glycation end products AGEs, were examined
using an in vitro screening test according to the literature
procedure [11]. Aminoguanidine hydrochloride [14,15]
was used as a positive control. None showed any signifi-
cant inhibitory activity (less than 20% inhibition compared
with 46.0% for the positive control).
4-Chloro-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino[4,5-d]
pyrimidine (9a).
Using N,N-dimethylformamide gave 9a
EXPERIMENTAL
(80%) as yellow needles from ethanol, mp 134–135ꢂC; 1H-
NMR (200 MHz, deuterochloroform): d 3.52 (s, 4H, H5 and 6),
7.41 (td, 1H, J = 7.3, 1.8 Hz, H9), 7.48 (td, 1H, J = 7.3, 1.7 Hz,
H10), 7.83–7.90 (m, 2H, H8 and 11), 8.83 (s, 1H, H2); FAB-
MS m/z: 305 (MH+), 307 (MH+ + 2). Anal. Calcd. for
C14H9ClN2S2: C, 55.16; H, 2.98; N, 9.19. Found: C, 54.99; H,
3.12; N, 9.05.
All melting points were determined on a Yanagimoto micro-
melting point apparatus and are uncorrected. Elemental analyses
were performed on a Yanagimoto MT-5 CHN Corder elemental
analyzer. The 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 Spectro-
scopic diffraction grating A-102 spectrophotometer, a FT/IR-200,
or a FT/IR-230 spectrophotometer and frequencies are expressed in
cmꢀ1. The 1H NMR spectra were recorded on a Varian VXR-200 in-
strument with tetramethylsilane as an internal standard. Chemical
shifts are given in ppm (d) and J values in Hz, and the signals
are designated as follows: s, singlet; d, doublet; dd, double dou-
blet; t, triplet; q, quartet; br, broad; m, multiplet. TLC (Kieselgel
60F254 (Merck) or silica gel 70FM (Wako)) was used to monitor
the completion of reactions.
5-Amino-2,3-dihydro[1]benzothieno[3,2-b]thiepin-4-carbonitrile
(8) and 5-amino-1,2-dihydro[1]benzothieno[3,2-d]thieno[2,3-b]
pyridine (7). To a preheated solution of 6 (1.00 g, 3.87mmol)
in dry benzene (200 mL) was added tert-BuONa (1.86 g,
19.4mmol), and the mixture was refluxed for 1 h. After
evaporation of solvent, ice-water (30 mL) was poured into the
residue, and the mixture was extracted with ethyl acetate
(3 ꢁ 30mL). The organic layer was washed with sat. brine, dried
4-Chloro-2-methyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (9b). Using N,N-dimethylacetamide gave 9b
1
(72%) as yellow scales from ethanol, mp 120–121ꢂC; H-NMR
(200 MHz, deuterochloroform): d 2.72 (s, 3H, CH3), 3.48 (s, 4H,
H5 and 6), 7.36–7.51 (m, 2H, H9 and 10), 7.79–7.93 (m, 2H, H8
and 11); FAB-MS m/z: 319 (MH+), 321 (MH+ + 2). Anal. Calcd.
for C15H11ClN2S2: C, 56.50; H, 3.48; N, 8.79. Found: C, 56.40;
H, 3.63; N, 8.69.
4-Chloro-2-ethyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (9c). Using N,N-dimethylpropionamide gave
9c (72%) as yellow needles from ethanol, mp 98–99ꢂC; 1H-NMR
(200MHz, deuterochloroform): d 1.42 (t, 3H, J = 7.6Hz, CH3),
2.97 (q, 2H, J = 7.6 Hz, CH2CH3), 3.49 (s, 4H, H5 and 6), 7.35–
7.51 (m, 2H, H9 and 10), 7.79–7.91 (m, 2H, H8 and 11); FAB-
MS m/z: 333 (MH+), 335 (MH+ + 2). Anal. Calcd. for
C16H13ClN2S2: C, 57.73; H, 3.94; N, 8.42. Found: C, 57.71; H,
4.03; N, 8.40.
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DOI 10.1002/jhet

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K. Okuda, Y. Itsuji, T. Hirota, and K. Sasaki
Vol 51
4-Chloro-2-phenyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (9d). Using N,N-dimethylbenzamide
1H-NMR (200MHz, deuterochloroform): d 3.10 (t, 2H, J = 5.5Hz,
H5), 3.20 (d, 3H, J = 4.0Hz, CH3), 3.46 (t, 2H, J = 5.5Hz, H6),
5.34 (br s, 1H, deuterium oxide exchangeable, NH), 7.35–7.56
(m, 5H, H9, 10, and 30, 40, 50), 7.81–7.89 (m, 2H, H8 and 11),
8.46–8.58 (m, 2H, H20 and 60); FAB-MS m/z: 376 (MH+). Anal.
Calcd. for C21H17N3S2: C, 67.17; H, 4.56; N, 11.19. Found: C,
67.23; H, 4.76; N, 11.19.
gave 9d (78%) as yellow needles from acetonitrile, mp 170–
172ꢂC; 1H-NMR (200 MHz, deuterochloroform): d 3.44–3.62
(m, 4H, H5 and 6), 7.36–7.57 (m, 5H, H9, 10, and 30, 40, 50),
7.82–7.91 (m, 2H, H9 and 10), 8.45–8.57 (m, 2H, H20 and 60);
FAB-MS m/z: 381 (MH+), 383 (MH+ + 2). Anal. Calcd. for
C20H13ClN2S2: C, 63.06; H, 3.44; N, 7.35. Found: C, 63.21; H,
3.67; N, 7.38.
4-Methylamino-2-p-tolyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (10e).
The reaction time was 24h.
4-Chloro-2-p-tolyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
Recrystallization of the residue from acetonitrile gave 10e (81%)
as colorless needles, mp 208–209ꢂC; IR (nujol) cmꢀ1: 3460 (NH);
1H-NMR (200 MHz, deuterochloroform): d 2.43 (s, 3H, 20-CH3),
3.10 (t, 2H, J= 5.0 Hz, H5), 3.20 (d, 3H, J=4.2Hz, NCH3), 3.47
(t, 2H, J= 5.0 Hz, H6), 5.44 (br, 1H, deuterium oxide
exchangeable, NH), 7.28 (d, 2H, J=8.5Hz, H30 and 50), 7.35–7.47
(m, 2H, H9 and 10), 7.80–7.89 (m, 2H, H8 and 11), 8.39 (d, 2H,
J=8.5Hz, H20 and 60); FAB-MS m/z: 390 (MH+). Anal. Calcd. for
C22H19N3S2: C, 67.83; H, 4.92; N, 10.79. Found: C, 67.80; H,
5.05; N, 10.68.
[4,5-d]pyrimidine (9e).
Using N,N-dimethyl-4-methyl-
benzamide [16] gave 9e (82%) as yellow needles from ethyl
acetate, mp 225–226ꢂC; 1H-NMR (200 MHz, deuterochloroform):
d 2.44 (s, 3H, CH3), 3.44–3.61 (m, 4H, H5 and 6), 7.31 (d, 2H,
J = 8.3Hz, H30 and 50), 7.36–7.51 (m, 2H, H9 and 10), 7.83–7.91
(m, 2H, H8 and 11), 8.40 (br d, 2H, J = 8.3Hz, H20 and 60); FAB-
MS m/z: 395 (MH+), 397 (MH+ + 2). Anal. Calcd. for
C21H15ClN2S2: C, 63.86; H, 3.83; N, 7.09. Found: C, 64.11; H,
4.00; N, 7.03.
General procedure for the reaction of 9a–e with methylamine
to give 10a–e. To a solution of 9 (100 mg) in THF (10 mL) was
added 40% methanolic methylamine (10 mL), and the reaction was
stirred at room temperature for the time required for completion of
the reaction. After evaporation of the reaction mixture in vacuo,
ice-water (50 mL) was poured into the residue. The resulting
precipitate was collected on a filter and purified by recrystallization
to give 10.
General procedure for the reaction of 9a–e with ethylamine
to give 11a–e. To a solution of 9 (100 mg) in THF (5.0 mL) was
added 70% aqueous ethylamine (10 mL), and the mixture was
stirred at room temperature for the time required for completion of
the reaction. After evaporation of the reaction mixture in vacuo,
ice-water (50 mL) was poured into the residue. The resulting
precipitate was collected on a filter and purified by recrystallization
to give 11.
4-Methylamino-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
4-Ethylamino-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (10a).
The reaction time was 1 h.
[4,5-d]pyrimidine (11a).
The reaction time was 5 h.
Recrystallization of the residue from ethanol gave 10a (74%) as
colorless scales, mp 177–178ꢂC; IR (nujol) cmꢀ1: 3440 (NH); 1H-
NMR (200 MHz, deuterochloroform): d 3.03 (t, 2H, J=5.7Hz,
H5), 3.11 (d, 3H, J=4.7Hz, CH3), 3.49 (t, 2H, J=5.7Hz, H6),
5.38 (br s, 1H, deuterium oxide exchangeable, NH), 7.38–7.42 (m,
2H, H9 and 10), 7.82–7.87 (m, 2H, H8 and 11), 8.59 (s, 1H, H2);
FAB-MS m/z: 300 (MH+). Anal. Calcd. for C15H13N3S2: C, 60.17;
H, 4.38; N, 14.03. Found: C, 60.15; H, 4.54; N, 13.98.
Recrystallization of the residue from acetonitrile gave 11a (68%)
as colorless needles, mp 173–174ꢂC; IR (nujol) cmꢀ1: 3220 (NH);
1H-NMR (200 MHz, deuterochloroform): d 1.31 (t, 3H, J = 7.2 Hz,
–CH2CH3), 3.03 (t, 2H, J = 5.7Hz, H5), 3.51 (t, 2H, J = 5.7Hz,
H6), 3.69 (dq, 2H, J = 7.2, 5.5Hz, –CH2CH3), 5.43 (br s, 1H,
deuterium oxide exchangeable, NH), 7.36–7.49 (m, 2H, H9 and
10), 7.79–7.94 (m, 2H, H8 and 11), 8.57 (s, 1H, H2); FAB-MS m/
z: 314 (MH+). Anal. Calcd. for C16H15N3S2: C, 61.31; H, 4.82; N,
13.41. Found: C, 61.45; H, 4.93; N, 13.30.
2-Methyl-4-methylamino-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (10b).
The reaction time was 10 h.
4-Ethylamino-2-methyl-5,6-dihydro[1]benzothieno[30,20:2,3]
Recrystallization of the residue from ethanol gave 10b (70%) as
thiepino[4,5-d]pyrimidine (11b).
The reaction time was
1
yellow prisms, mp 234–235ꢂC; IR (nujol) cmꢀ1: 3480 (NH); H-
18 h. Recrystallization of the residue from ethanol gave 11b (70%)
as yellow prisms, mp 155–156ꢂC; IR (nujol) cmꢀ1: 3440 (NH);
1H-NMR (200 MHz, deuterochloroform): d 1.29 (t, 3H, J=7.2Hz,
–CH2CH3), 2.57 (s, 3H, 2-CH3), 2.96 (t, 2H, J= 6.0 Hz, H5), 3.47
(t, 2H, J= 6.0 Hz, H6), 3.60 (dq, 2H, J= 7.2, 5.3 Hz, –CH2CH3),
5.15 (br, 1H, deuterium oxide exchangeable, NH), 7.37–7.43 (m,
2H, H9 and 10), 7.78–7.93 (m, 2H, H8 and 11); FAB-MS m/z:
328 (MH+). Anal. Calcd. for C17H17N3S2: C, 62.35; H, 5.23; N,
12.83. Found: C, 62.29; H, 5.32; N, 12.59.
NMR (200 MHz, deuterochloroform): d 2.57 (s, 3H, 2-CH3), 2.90
(t, 2H, J = 5.7Hz, H5), 3.10 (d, 3H, J =4.8 Hz, NCH3), 3.46 (t,
2H, J = 5.7Hz, H6), 5.27 (br, 1H, deuterium oxide exchangeable,
NH), 7.34–7.41 (m, 2H, H9 and 10), 7.81–7.89 (m, 2H, H8 and
11); FAB-MS m/z: 314 (MH+). Anal. Calcd. for C16H15N3S2: C,
61.31; H, 4.82; N, 13.41. Found: C, 61.41; H, 4.95; N, 13.32.
2-Ethyl-4-methylamino-5,6-dihydro[1]benzothieno[30,202,3]
thiepino[4,5-d]pyrimidine (10c).
The reaction time was 16 h.
Recrystallization of the residue from acetonitrile gave 10c (66%)
as colorless plates, mp 191–192ꢂC; IR (nujol) cmꢀ1: 3470 (NH);
1H-NMR (200 MHz, deuterochloroform): d 1.38 (t, 3H, J = 7.6Hz,
2-CH2CH3), 2.84 (q, 2H, J = 7.6 Hz, 2-CH2CH3), 3.00 (t, 2H,
J = 5.5Hz, H5), 3.10 (d, 3H, J = 4.8Hz NCH3), 3.43 (t, 2H,
J = 5.5Hz, H6), 4.79 (br s, 1H, deuterium oxide exchangeable,
NH), 7.36–7.41 (m, 2H, H9 and 10), 7.78–7.91 (m, 2H, H8 and
11); FAB-MS m/z: 328 (MH+). Anal. Calcd. for C17H17N3S2: C,
62.35; H, 5.23; N, 12.83. Found; C,62.35; H, 5.20; N,12.78.
4-Methylamino-2-phenyl-5,6-dihydro[1]benzothieno[30,20:2,3]
2-Ethyl-4-ethylamino-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (11c).
The reaction time was 20h.
Recrystallization of the residue from methanol gave 11c (66%) as
yellow prisms, mp 106–107ꢂC; IR (nujol) cmꢀ1: 3440 (NH); H-
1
NMR (200 MHz, deuterochloroform): d 1.25–1.42 (m, 6H,
2 ꢁ ꢀCH2CH3), 2.80–2.96 (m, 4H, H5 and 2-CH2CH3), 3.45 (t,
2H, J =6.3 Hz, H6), 3.62 (dq, 2H, J = 7.1, 5.5Hz, NCH2CH3),
6.10 (br, 1H, deuterium oxide exchangeable, NH), 7.32–7.45 (m,
2H, H9 and 10), 7.79–7.88 (m, 2H, H8 and 11); FAB-MS m/z:
342 (MH+). Anal. Calcd. for C18H19N3S2: C, 63.31; H, 5.61; N,
12.30. Found; C,63.39; H, 5.73; N,12.10.
thiepino[4,5-d]pyrimidine (10d).
The reaction time was 24 h.
Recrystallization of the residue from acetonitrile gave 10d (84%)
4-Ethylamino-2-phenyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (11d).
as yellow plates, mp 181–182ꢂC; IR (nujol) cmꢀ1: 3460 (NH);
The reaction time was 12 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6-Dihydro
[1]benzothieno[30,20:2,3]thiepino[4,5-d]pyrimidine and Related Compounds
895
Recrystallization of the residue from acetonitrile gave 11d (83%) as
deuterochloroform): d 3.17 (s, 6H, N(CH3)2), 3.21 (t, 2H,
J = 5.7 Hz, H5), 3.62 (t, 2H, J = 5.7 Hz, H6), 7.36–7.54 (m, 5H,
H9, 10, and 30, 40, 50), 7.82–7.96 (m, 2H, H8 and 11), 8.49–8.58
(m, 2H, H20 and 60); FAB-MS m/z: 390 (MH+). Anal. Calcd. for
C22H19N3S2: C, 67.83; H, 4.92; N, 10.79. Found: C, 68.04; H,
5.00; N, 10.78.
1
yellow scales, mp 158–159ꢂC; IR (nujol) cmꢀ1: 3440 (NH); H-
NMR (200 MHz, deuterochloroform): d 1.34 (t, 3H, J = 7.2 Hz, –
CH2CH3), 3.09 (t, 2H, J = 5.6 Hz, H5), 3.49 (t, 2H, J = 5.6Hz,
H6), 3.64–3.82 (m, 2H, –CH2CH3), 5.90 (br, 1H, deuterium
oxide exchangeable, NH), 7.37–7.43 (m, 2H, H9 and 10),
7.44–7.55 (m, 3H, H30, 40, and 50), 7.81–7.94 (m, 2H, H8
and 11), 8.42–8.55 (m, 2H, H20 and 60); FAB-MS m/z: 390
(MH+). Anal. Calcd. for C22H19N3S2: C, 67.83; H, 4.92; N,
10.79. Found: C, 68.13; H, 5.27; N, 10.78.
4-Dimethylamino-2-p-tolyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (12e).
The reaction time was 24h.
Recrystallization of the residue from acetonitrile gave 12e (92%)
as colorless prisms, mp 200–201ꢂC; 1H-NMR (200MHz,
deuterochloroform): d 2.43 (s, 3H, 20-CH3), 3.16 (s, 6H, N(CH3)
2), 3.20 (t, 2H, J = 6.0 Hz, H5), 3.61 (t, 2H, J = 6.0Hz, H6), 7.28
(d, 2H, J = 8.0Hz, H30 and 50), 7.37–7.47 (m, 2H, H9 and 10),
7.83–7.95 (m, 2H, H8 and 11), 8.42 (d, 2H, J = 8.0Hz, H20 and
60); FAB-MS m/z: 404 (MH+). Anal. Calcd. for C23H21N3S2: C,
68.45; H, 5.24; N, 10.41. Found: C, 68.39; H, 5.33; N, 10.29.
General procedure for the reaction of 9a–e with 2-aminoethanol
to give 13a–e. To a solution of 9 (100 mg) in dry 1,4-dioxane
(5.0mL) was added 2-aminoethanol (10 eq. to 9), and the mixture
was then refluxed for the time required for completion of the
reaction. After evaporation of the reaction mixture in vacuo, ice-
water (50 mL) was poured into the residue. The resulting
4-Ethylamino-2-p-tolyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (11e).
The reaction time was 30 h.
Recrystallization of the residue from acetonitrile gave 11e (79%)
as yellow plates, mp 161–162ꢂC; IR (nujol) cmꢀ1: 3440 (NH);
1H-NMR (200 MHz, deuterochloroform):
d 1.34 (t, 3H,
J = 7.2Hz, –CH2CH3), 2.43 (s, 3H, 20-CH3), 3.09 (t, 2H,
J = 5.6Hz, H5), 3.49 (t, 2H, J = 5.6 Hz, H6), 3.62–3.80 (m, 2H, –
CH2CH3), 5.91 (br, 1H, deuterium oxide exchangeable, NH), 7.28
(d, 2H, J = 8.0 Hz, H30 and 50), 7.37–7.45 (m, 2H, H9 and 10),
7.81–7.92 (m, 2H, H8 and 11), 8.35 (d, 2H, J = 8.0Hz, H20 and
60); FAB-MS m/z: 404 (MH+). Anal. Calcd. for C23H21N3S2: C,
68.45; H, 5.24; N, 10.41. Found: C, 68.53; H, 5.46; N, 10.34.
General procedure for the reaction of 9a–e with dimethylamine
to give 12a–e. To a solution of 9 (100mg) in THF (5.0mL) was
added 50% aqueous dimethylamine (10mL), and the mixture was
then stirred at room temperature for the time required for
completion of the reaction. After evaporation of the reaction
mixture in vacuo, ice-water (50mL) was poured into the residue.
The resulting precipitate was collected on a filter and purified by
recrystallization to give 12.
precipitate was collected on
a
filter and purified by
recrystallization to give 13.
4-(2-Hydroxyethylamino)-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (13a). The reaction time was 10 h.
Recrystallization of the residue from acetonitrile gave 13a
(68%) as colorless scales, mp 172–173ꢂC; IR (nujol) cmꢀ1
:
1
3400, 3170 (NH, OH); H-NMR (200 MHz, DMSO-d6): d 3.06
(t, 2H, J = 5.3 Hz, H5), 3.45–3.63 (m, 6H, NCH2CH2O and
H6), 4.76, 7.32 (each t, each 1H, J = 5.3, 5.0 Hz, deuterium
oxide exchangeable, NH and OH), 7.40–7.53 (m, 2H, H9
and 10), 7.76–7.87, 7.97–8.05 (each m, each 1H, H8 and
11), 8.39 (s, 1H, H2); FAB-MS m/z: 330 (MH+). Anal.
Calcd. for C16H15N3OS2: C, 58.33; H, 4.59; N, 12.76.
Found: C, 58.33; H, 4.76; N, 12.57.
4-Dimethylamino-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (12a).
The reaction time was 1 h.
Recrystallization of the residue from cyclohexane gave 12a
1
(80%) as colorless plates, mp 155–156ꢂC; H-NMR (200 MHz,
deuterochloroform): d 3.11 (t, 2H, J = 5.6 Hz, H5), 3.13 (s, 6H,
N(CH3)2), 3.66 (t, 2H, J = 5.6 Hz, H6), 7.38–7.47 (m, 2H, H9
and 10), 7.82–7.98 (m, 2H, H8 and 11), 8.62 (s, 1H, H2); FAB-
MS m/z: 314 (MH+). Anal. Calcd. for C16H15N3S2: C, 61.31;
H, 4.82; N, 13.41. Found: C, 61.14; H, 4.90; N, 13.22.
4-(2-Hydroxyethylamino)-2-methyl-5,6-dihydro[1]benzothieno
[30,20;2,3]thiepino[4,5-d]pyrimidine (13b).
The reaction time
was 22 h. Recrystallization of the residue from acetonitrile gave
13b (69%) as colorless needles, mp 179–180ꢂC; IR (nujol) cmꢀ1
2-Methyl-4-dimethylamino-5,6-dihydro[1]benzothieno[30,20:2,3]
:
thiepino[4,5-d]pyrimidine (12b).
The reaction time was 1 h.
3450, 3400, 3150 (NH, OH); 1H-NMR (200 MHz, DMSO-d6):
d 2.38 (s, 3H, 2-CH3), 3.02 (t, 2H, J = 5.3 Hz, H5), 3.43–3.62 (m,
6H, NCH2CH2O and H6), 4.76, 7.15 (each t, each 1H, J = 5.3,
5.1 Hz, each deuterium oxide exchangeable, NH and OH), 7.40–
7.52 (m, 2H, H9 and 10), 7.78–7.83, 7.95–8.00 (each m, each 1H,
H8 and 11); FAB-MS m/z: 344 (MH+). Anal. Calcd. for
C17H17N3OS2ꢃ1/4 H2O: C, 58.68; H, 5.07; N, 12.08. Found: C,
59.03; H, 5.02; N, 12.04.
Recrystallization of the residue from acetonitrile gave 12b (79%)
as colorless plates, mp 120–121ꢂC; 1H-NMR (200 MHz,
deuterochloroform): d 2.59 (s, 3H, 2-CH3), 3.07 (t, 2H, J = 5.7Hz,
H5), 3.10 (s, 6H, N(CH3)2), 3.63 (t, 2H, J = 5.7Hz, H6), 7.37–
7.46 (m, 2H, H9 and 10), 7.81–7.97 (m, 2H, H8 and 11); FAB-
MS m/z: 328 (MH+). Anal. Calcd. for C17H17N3S2: C, 62.35; H,
5.23; N, 12.83. Found: C, 62.18; H, 5.22; N, 12.74.
2-Ethyl-4-dimethylamino-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (12c).
2-Ethyl-4-(2-hydroxyethylamino)-5,6-dihydro[1]benzothieno
The reaction time was 1 h.
[30,202,3]thiepino[4,5-d]pyrimidine (13c).
The reaction time
was 26 h. Recrystallization of the residue from acetonitrile gave
13c (66%) as colorless scales, mp 163–164ꢂC; IR (nujol) cmꢀ1
Recrystallization of the residue from acetonitrile gave 12c (74%)
as colorless prisms, mp 125–126ꢂC; 1H-NMR (200MHz,
deuterochloroform): d 1.37 (t, 3H, J = 7.5Hz, CH2CH3), 2.85 (q,
2H, J = 7.5Hz, CH2CH3), 3.08 (t, 2H, J = 5.8Hz, H5), 3.10 (s,
6H, N(CH3)2), 3.62 (t, 2H, J = 5.8Hz, H6), 7.36–7.45 (m, 2H, H9
and 10), 7.81–7.95 (m, 2H, H8 and 11); FAB-MS m/z: 342
(MH+). Anal. Calcd. for C18H19N3S2: C, 63.31; H, 5.61; N, 12.30.
Found: C, 63.41; H, 5.56; N, 12.32.
:
3450, 3400, 3160 (NH, OH); 1H-NMR (200MHz, DMSO-d6):
d 1.26 (t, 3H, J =7.5 Hz, 2-CH2CH3), 2.65 (q, 2H, J = 7.5Hz, 2-
CH2CH3), 3.04 (t, 2H, J = 5.5Hz, H5), 3.43–3.63 (m, 6H,
NCH2CH2O and H6), 4.76, 7.16 (each t, each 1H, J = 5.4, 5.2Hz,
deuterium oxide exchangeable, NH and OH), 7.40–7.50 (m, 2H,
H9 and 10), 7.76–7.84, 7.94–8.03 (each m, each 1H, H8 and 11);
FAB-MS m/z: 358 (MH+). Anal. Calcd. for C18H19N3OS2: C,
60.47; H, 5.36; N, 11.75. Found: 60.12; H, 5.34; N, 11.64.
4-Dimethylamino-2-phenyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (12d).
The reaction time was 24h.
Recrystallization of the residue from acetonitrile gave 12d (96%)
4-(2-Hydroxyethylamino)-2-phenyl-5,6-dihydro[1]benzothieno
as colorless prisms, mp 183–184ꢂC; 1H-NMR (200MHz,
[30,20:2,3]thiepino[4,5-d]pyrimidine (13d).
The reaction time
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

896
K. Okuda, Y. Itsuji, T. Hirota, and K. Sasaki
Vol 51
was 33h. Recrystallization of the residue from acetonitrile gave 13d
(83%) as colorless prisms, mp 153–154ꢂC; IR (nujol) cmꢀ1: 3370,
3180 (NH, OH); 1H-NMR (200 MHz, DMSO-d6): d 3.17 (br t,
2H, J = 5.0 Hz, H5), 3.52 (br t, 2H, J = 5.0Hz, H6), 3.63–3.70 (m,
4H, NCH2CH2O), 4.81 (t, 1H, J = 5.5Hz, deuterium oxide
exchangeable, NH or OH), 7.34 (br s, 1H, deuterium oxide
exchangeable, NH or OH), 7.43–7.56 (m, 5H, H9, 10, and 30, 40,
50), 7.79–7.84, 8.01–8.06 (each m, each 1H, H8 and 11), 8.35–
8.46 (m, 2H, H20 and 60); FAB-MS m/z: 406 (MH+). Anal. Calcd.
for C22H19N3OS2: C, 65.16; H, 4.72; N, 10.36. Found: C, 64.89;
H, 4.86; N, 10.30.
Recrystallization of the residue from acetonitrile gave 14d (77%)
as yellow needles, mp 200–201ꢂC; 1H-NMR (200MHz,
deuterochloroform): d 3.43 (br s, 4H, H5 and 6), 4.15 (s, 3H,
OCH3), 7.38–7.59 (m, 5H, H9, 10, and 30, 40, 50), 7.81–7.90 (m,
2H, H8 and 11), 8.44–8.61 (m, 2H, H20 and 60); FAB-MS m/z
377 (MH+). Anal. Calcd. for C21H16N2OS2ꢃ1/4 H2O: C, 66.20; H,
4.37; N, 7.35. Found: C, 66.58; H, 4.38; N, 7.34.
4-Methoxy-2-p-tolyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (14e).
The reaction time was 93 h.
Recrystallization of the residue from acetonitrile gave 14e (71%)
as colorless prisms, mp 198–199ꢂC; 1H-NMR (200MHz,
deuterochloroform): d 2.44 (s, 3H, 20-CH3), 3.42 (s, 4H, H5 and
6), 4.14 (s, 3H, OCH3), 7.30 (d, 2H, J = 8.2 Hz, H30 and 50), 7.38–
7.45 (m, 2H, H9 and 10), 7.82–7.90 (m, 2H, H8 and 11), 8.43 (d,
2H, J =8.2 Hz, H20 and 60); FAB-MS m/z: 391 (MH+). Anal.
Calcd. for C22H18N2OS2: C, 67.66; H, 4.65; N, 7.17. Found: C,
67.47; H, 4.93; N, 7.15.
4-(2-Hydroxyethylamino)-2-p-tolyl-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (13e).
The reaction time
was 20 h. Recrystallization of the residue from acetonitrile
gave 13e (78%) as yellow needles, mp 216–217ꢂC; IR
(nujol) cmꢀ1: 3370, 3180 (NH, OH); 1H-NMR (200 MHz,
DMSO-d6): d 2.39 (s, 3H, 20-CH3), 3.15 (t, 2H, J = 5.3 Hz,
H5), 3.50 (t, 2H, J = 5.3 Hz, H6), 3.58–3.73 (m, 4H,
NCH2CH2O), 4.80 (t, 1H, J = 5.5 Hz, deuterium oxide
exchangeable, NH or OH), 7.32 (d, 2H, J = 8.0 Hz, H30 and
50), 7.41–7.53 (m, 2H, H9 and 10), 7.79–7.83, 8.01–8.05
(each m, each 1H, H8 and 11), 8.30 (d, 2H, J = 8.0 Hz, H20
and 60); FAB-MS m/z: 420 (MH+). Anal. Calcd. for
C23H21N3OS2ꢃ1/3 H2O: C, 64.91; H, 5.13; N, 9.87. Found:
C, 65.15; H, 5.06; N, 9.76.
General procedure for the reaction of 9a–e with sodium
methoxide to give 14a–e. To a methanolic solution (5.0 mL) of
sodium methoxide (2 eq. to 9) was added 9 (100mg) and the
solution was then refluxed for the time required for completion of
the reaction. After removal of solvent in vacuo, ice-water (50mL)
was poured into the residue. The resulting precipitate was
collected on a filter and purified by recrystallization to give 14.
4-Methoxy-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
General procedure for the reaction of 9a–e with sodium
ethoxide to give 15a–e. To an ethanolic solution (5.0 mL) of
sodium ethoxide (2 eq. to 9) was added 9 (100 mg), and the
solution was then refluxed for the time required of completion of
the reaction. After evaporation of solvent in vacuo, ice-water
(50 mL) was poured into the residue. The resulting precipitate was
collected on a filter and purified by recrystallization to give 15.
4-Ethoxy-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino[4,5-d]
pyrimidine (15a). The reaction time was 2 h. Recrystallization
of the residue from ethanol gave 15a (87%) as colorless prisms,
1
mp 167–168ꢂC; H-NMR (200 MHz, deuterochloroform): d 1.46
(t, 3H, J = 7.0 Hz, CH2CH3), 3.33–3.49 (m, 4H, H5 and 6), 4.52
(q, 2H, J = 7.0 Hz, OCH2), 7.40–7.48 (m, 2H, H9 and 10), 7.82–
7.92 (m, 2H, H8 and 11), 8.71 (s, 1H, H2); FAB-MS m/z: 315
(MH+). Anal. Calcd. for C16H14N2OS2: C, 61.12; H, 4.49; N,
8.91. Found: C, 60.95; H, 4.49; N, 8.93.
[4,5-d]pyrimidine (14a).
The reaction time was 3 h.
4-Ethoxy-2-methyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
Recrystallization of the residue from acetonitrile gave 14a (84%)
as yellow needles, mp 171–172ꢂC; 1H-NMR (200 MHz,
deuterochloroform): d 3.30–3.52 (m, 4H, H5 and 6), 4.09 (s, 3H,
OCH3), 7.36–7.54 (m, 2H, H9 and 10), 7.82–7.94 (m, 2H, H8 and
11), 8.75 (s, 1H, H2); FAB-MS m/z: 301 (MH+). Anal. Calcd. for
C15H12N2OS2: C, 59.97; H, 4.03; N, 9.33. Found: C, 59.68; H,
4.31; N, 9.37.
[4,5-d]pyrimidine (15b).
The reaction time was 2 h.
Recrystallization of the residue from ethanol gave 15b (85%) as
colorless needles, mp 160–162ꢂC; 1H-NMR (200MHz,
deuterochloform): d 1.43 (t, 3H, J = 7.0 Hz, CH2CH3), 2.66 (s, 3H,
2-CH3), 3.27–3.32 (m, 2H, H5), 3.41–3.46 (m, 2H, H6), 4.48 (q,
2H, J = 7.0 Hz, OCH2), 7.38–7.43 (m, 2H, H9 and 10), 7.82–7.89
(m, 2H, H8 and 11); FAB-MS m/z: 329 (MH+). Anal. Calcd. for
C17H16N2OS2ꢃ1/3 H2O: C, 61.05; H, 5.02; N, 8.38. Found: C,
61.39; H, 4.89: N, 8.39.
4-Methoxy-2-methyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (14b).
The reaction time was 1.5 h.
Recrystallization of the residue from acetonitrile gave 14b (67%) as
colorless scales, mp 192–193ꢂC; 1H-NMR (200 MHz,
deuterochloroform): d 2.69 (s, 3H, 2-CH3), 3.27 (br t, 2H,
J= 5.0 Hz, H5), 3.44 (br t, 2H, J=5.0Hz, H6), 4.04 (s, 3H, OCH3),
7.35–7.48 (m, 2H, H9 and 10), 7.80–7.91 (m, 2H, H8 and 11);
FAB-MS m/z: 315 (MH+). Anal. Calcd. for C16H14N2OS2ꢃ1/4 H2O:
C, 60.26; H, 4.58; N, 8.78. Found: C, 60.52; H, 4.79; N, 9.01.
2-Ethyl-4-methoxy-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
4-Ethoxy-2-ethyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (15c).
The reaction time was 1 h.
Recrystallization of the residue from ethanol gave 15c (83%) as
colorless needles, mp 113–114ꢂC; 1H-NMR (200 MHz,
deuterochloform): d 1.39 (t, 3H, J=7.5Hz, 2-CH2CH3), 1.44 (t, 3H,
J=7.1Hz, OCH2CH3), 2.96 (q, 2H, J=7.5Hz, 2-CH2CH3), 3.25–
3.35 (m, 2H, H5), 3.39–3.48 (m, 2H, H6), 4.51 (q, 2H, J=7.1Hz,
OCH2CH3), 7.34–7.47 (m, 2H, H9 and 10), 7.81–7.91 (m, 2H, H8
and 11); FAB-MS m/z: 343 (MH+). Anal. Calcd. for C18H18N2OS2:
C, 63.13; H, 5.30; N, 8.18. Found: C, 62.88; H, 5.38; N, 8.00.
4-Ethoxy-2-phenyl-5,6-dihydro[1]benzothieno[30,20:2,3]thiepino
[4,5-d]pyrimidine (14c).
The reaction time was 1 h.
Recrystallization of the residue from acetonitrile gave 14c (76%)
as yellow needles, mp 139–140ꢂC; 1H-NMR (200 MHz,
deuterochloroform): d 1.41 (t, 3H, J = 7.5Hz, CH2CH3), 3.03 (q,
2H, J = 7.5 Hz, CH2CH3), 3.23–3.32 (m, 2H, H5), 3.40–3.49 (m,
2H, H6), 4.07 (s, 3H, OCH3), 7.39–7.43 (m, 2H, H9 and 10),
7.82–7.91 (m, 2H, H8 and 11); FAB-MS m/z: 329 (MH+). Anal.
Calcd. for C17H16N2OS2: C, 62.16; H, 4.91; N, 8.53. Found: C,
62.15; H, 5.26; N, 8.48.
[4,5-d]pyrimidine (15d).
The reaction time was 1 h.
Recrystallization of the residue from acetonitrile gave 15d (88%)
as colorless needles, mp 145–146ꢂC; 1H-NMR (200MHz,
deuterochloroform): d 1.50 (t, 3H, J = 7.0Hz, CH2CH3), 3.43 (br s,
4H, H5 and 6), 4.63 (q, 2H, J=7.0Hz, OCH2), 7.31–7.64 (m, 5H,
H9, 10, and 30, 40, 50), 7.82–7.92 (m, 2H, H8 and 11), 8.49–8.58 (m,
2H, H20 and 60); FAB-MS m/z: 391. Anal. Calcd. for C22H18N2OS2:
C, 67.66; H, 4.65; N, 7.17. Found: C, 67.33; H, 4.81; N, 7.09.
4-Methoxy-2-phenyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (14d).
The reaction time was 7h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Evaluation of Effects on In Vitro Pentosidine Formation of 5,6-Dihydro
[1]benzothieno[30,20:2,3]thiepino[4,5-d]pyrimidine and Related Compounds
897
4-Ethoxy-2-p-tolyl-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (15e). The reaction time was 4.5 h.
OCH2CH2OH), 7.39–7.45 (m, 2H, H9 and 10), 7.48–7.52 (m,
3H, H30, 40, and 50), 7.82–7.88 (m, 2H, H8 and 11), 8.46–8.51
(m, 2H, H20 and 60); FAB-MS m/z: 407 (MH+). Anal. Calcd.
for C22H18N2O2S2: C, 65.00; H, 4.46; N, 6.89. Found: C,
64.65; H, 4.67; N, 6.64.
Recrystallization of the residue from acetonitrile gave 15e (91%)
as colorless needles, mp 167–168ꢂC; 1H-NMR (200 MHz,
deuterochloroform): d 1.49 (t, 3H, J = 7.0 Hz, CH2CH3), 2.44 (s,
3H, 40-CH3), 3.42 (s, 4H, H5 and 6), 4.62 (q, 2H, J = 7.0Hz,
OCH2), 7.30 (br d, 2H, J = 8.0 Hz, H30 and 50), 7.37–7.45 (m, 2H,
H9 and 10), 7.82–7.91 (m, 2H, H8 and 11), 8.42 (br d, 2H,
J= 8.0Hz, H20 and 60); FAB-MS m/z: 405 (MH+). Anal. Calcd. for
C23H20N2OS2: C, 68.29; H, 4.98; N, 6.92. Found: C, 67.91; H,
4.93; N, 6.84.
4-(2-Hydroxyethoxy)-2-p-tolyl-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (16e).
The reaction time
was 36h. Recrystallization of the precipitated solid from
acetonitrile gave 16e (76%) as yellow needles, mp 188–189ꢂC; IR
(nujol) cmꢀ1: 3366 (OH); 1H-NMR (200MHz, DMSO-d6): d 2.44
(s, 3H, 20-CH3), 3.38–3.52 (m, 4H, H5 and 6), 4.03–4.11 (m, 2H,
OCH2CH2OH), 4.70–4.78 (m, 2H, OCH2CH2OH), 7.30 (br d,
2H, J = 8.0 Hz, H30 and 50), 7.38–7.46 (m, 2H, H9 and 10), 7.81–
7.89 (m, 2H, H8 and 11), 8.37 (d, 2H, J = 8.0Hz, H20 and 60);
FAB-MS m/z: 421 (MH+). Anal. Calcd. for C23H20N2O2S2: C,
65.69; H, 4.79; N, 6.66. Found: C, 65.29; H, 4.73; N, 6.58.
General procedure for the reaction of 9a–e with 2-
sulfanylethanol to give 17a–e. To a solution of 9 (100mg) in
dry 1,4-dioxane (5.0 mL) were added 2-sulfanylethanol (2 eq. to 9)
and 1,8-diazabicyclo potassium carbonate (2eq. to 9), and the
mixture was then refluxed for the time required for completion of
the reaction. After evaporation of the reaction mixture in vacuo,
ice-water (20 mL) was poured into the residue. The resulting
precipitate was collected on a filter and purified by column
chromatography and/or recrystallization to give 17.
General procedure for the reaction of 9a–e with ethylene glycol
to give 16a–e. To a solution of 9 (100 mg) in dry 1,4-dioxane
(5.0 mL) were added ethylene glycol (2.0 mL), and potassium
carbonate (2 eq. to 9) and the mixture was then stirred at 80ꢂC for
the time required for completion of the reaction. After evaporation of
the reaction mixture in vacuo, ice-water (20 mL) was poured into the
residue. The resulting precipitate was collected on a filter and
purified by column chromatography and/or recrystallization to give 16.
4-(2-Hydroxyethoxy)-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (16a). The reaction time was 2 h. The
precipitated solid was chromatographed on silica gel. The eluate of
n-hexane/ethyl acetate (4:1) was evaporated and the residue was
recrystallized from benzene to give 16a (74%) as colorless
1
needles, mp 123–124ꢂC. IR (nujol) cmꢀ1: 3401, 3315 (OH); H-
NMR (200 MHz, DMSO-d6): d 3.42 (br s, 4H, H5 and 6), 3.99–
4.04 (m, 2H, OCH2CH2OH), 4.59–4.63 (m, 2H, OCH2CH2OH),
7.37–7.48 (m, 2H, H9 and 10), 7.80–7.91 (m, 2H, H8 and 11),
8.65 (s, 1H, H2); FAB-MS m/z: 331 (MH+). Anal. Calcd. for
C16H14N2O2S2: C, 58.16; H, 4.27; N, 8.48. Found: C, 57.92; H,
4.51; N, 8.52.
4-(2-Hydroxyethylsulfanyl)-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (17a).
The reaction time was 33h.
The precipitated solid was collected on a filter and was
chromatographed on silica gel. The eluate of n-hexane/ethyl
acetate (4:1) was evaporated in vacuo and was recrystallized from
acetonitrile to give 17a (43%) as yellow needles, mp 105–106ꢂC;
IR (nujol) cmꢀ1: 3176 (OH); 1H-NMR (200MHz, DMSO-d6):
d 3.31–3.45 (m, 4H, H5 and SCH2CH2OH), 3.51–3.58 (m, 2H,
H6), 3.66 (t, 2H, J = 6.7Hz, SCH2CH2OH), 5.10 (br, 1H,
deuterium oxide exchangeable, OH), 7.42–7.58 (m, 2H, H9 and
10), 7.78–7.85 (m, 1H, H11), 7.98–8.50 (m, 1H, H8), 8.85 (s, 1H,
H2); FAB-MS m/z: 347 (MH+). Anal. Calcd. for C16H14N2OS3ꢃ1/
3 H2O: C, 54.52; H, 4.19; N, 7.95. Found: C, 54.52; H, 4.22; N,
7.76.
4-(2-Hydroxyethoxy)-2-methyl-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (16b).
The reaction time
was 5 h. The precipitated solid was chromatographed on silica gel.
The eluate of n-hexane/ethyl acetate (4:1) was evaporated, and the
residue was recrystallized from cyclohexane to give 16b (72%) as
colorless needles, mp 135–136ꢂC; IR (nujol) cmꢀ1: 3384 (OH);
1H-NMR (200 MHz, DMSO-d6): d 2.67 (s, 3H, 2-CH3), 3.30–3.35
(m, 2H, H5), 3.41–3.46 (m, 2H, H6), 3.98–4.02 (m, 2H,
OCH2CH2OH), 4.59–4.64 (m, 2H, OCH2CH2OH), 7.39–7.44
(m, 2H, H9 and 10), 7.82–7.89 (m, 2H, H8 and 11); FAB-MS m/z:
345 (MH+). Anal. Calcd. for C17H16N2O2S2ꢃ1/4 H2O: C, 58.51;
H, 4.77; N, 8.03. Found: C, 58.81; H, 4.90; N, 7.99.
4-(2-Hydroxyethylsulfanyl)-2-methyl-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (17b).
The reaction time
was 25h. Recrystallization of the precipitated solid from
acetonitrile gave 17b (79%) as yellow needles, mp 125–126ꢂC; IR
(nujol) cmꢀ1: 3188 (OH); 1H-NMR (200MHz, DMSO-d6): d 2.59
(s, 3H, 2-CH3), 3.26–3.37 (m, 4H, H5 and SCH2CH2OH), 3.48–
3.53 (m, 2H, H6), 3.67 (t, 2H, J = 6.5Hz, SCH2CH2OH), 5.10 (br,
1H, deuterium oxide exchangeable, OH), 7.41–7.57 (m, 2H, H9
and 10), 7.79 (br dd, 1H, J = 6.7, 2.0Hz, H11), 8.00 (br dd, 1H,
J = 6.4, 1.8Hz, H8); FAB-MS m/z: 361 (MH+). Anal. Calcd. for
C17H16N2OS3ꢃ1/3 H2O: C, 55.71; H, 4.58; N, 7.64. Found: C,
55.97; H, 4.59; N, 7.67.
2-Ethyl-4-(2-hydroxyethoxy)-5,6-dihydro[1]benzothieno[30,20:2,3]
thiepino[4,5-d]pyrimidine (16c).
Recrystallization of the precipitated solid from cyclohexane gave
16c (77%) as colorless needles, mp 120–121ꢂC; IR (nujol) cmꢀ1
The reaction time was 3 h.
:
3172 (OH); 1H-NMR (200 MHz, DMSO-d6): d 1.39 (t, 3H,
J = 7.5Hz, 2-CH2CH3), 2.95 (q, 2H, J = 7.5 Hz, 2-CH2CH3),
3.32–3.45 (m, 4H, H5 and 6), 3.98–4.02 (m, 2H,
OCH2CH2OH), 4.61–4.65 (m, 2H, OCH2CH2OH), 7.36–7.48
(m, 2H, H9 and 10), 7.79–7.90 (m, 2H, H8 and 11); FAB-MS
m/z: 359 (MH+). Anal. Calcd. for C18H18N2O2S2ꢃ1/3 H2O:
C, 59.31; H, 5.16; N, 7.69. Found: 59.64; H, 5.20; N, 7.74.
4-(2-Hydroxyethoxy)-2-phenyl-5,6-dihydro[1]benzothieno
2-Ethyl-4-(2-hydroxyethylsulfanyl)-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (17c).
The reaction time
was 26h. Recrystallization of the precipitated solid from
acetonitrile gave 17c (43%) as colorless needles, mp 114–115ꢂC;
1
[30,20:2,3]thiepino[4,5-d]pyrimidine (16d).
The reaction time
IR (nujol) cmꢀ1: 3364, 3290 (OH); H-NMR (200MHz, DMSO-
was 18h. The precipitated solid was chromatographed on silica
gel. The eluate of n-hexane/ethyl acetate (9:1) was evaporated,
and the solid was recrystallized from acetonitrile to give 16d
(50%) as yellow needles, mp 93–95ꢂC; IR (nujol) cmꢀ1: 3291
(OH); H-NMR (200MHz, DMSO-d6): d 3.38–3.52 (m, 4H, H5
and 6), 4.04–4.12 (m, 2H, OCH2CH2OH), 4.70–4.78 (m, 2H,
d6): d 1.33 (t, 3H, J = 7.6Hz, 2-CH2CH3), 2.86 (q, 2H, J = 7.6Hz,
2-CH2CH3), 3.27–3.38 (m, 4H, H5 and SCH2CH2OH), 3.48–3.53
(m, 2H, H6), 3.68 (t, 2H, J = 6.4 Hz, SCH2CH2OH), 5.00 (br, 1H,
deuterium oxide exchangeable, OH), 7.46 (td, 1H, J = 7.1, 1.5Hz,
H9), 7.52 (td, 1H, J = 7.1, 1.6Hz, H10), 7.79 (br dd, 1H, J = 7.1,
2.1 Hz, H11), 8.01 (br dd, 1H, J = 7.1, 1.8 Hz, H8); FAB-MS m/z:
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

898
K. Okuda, Y. Itsuji, T. Hirota, and K. Sasaki
Vol 51
375 (MH+). Anal. Calcd. for C18H18N2OS3: C, 57.72; H, 4.84; N,
7.48. Found: 57.93; H, 4.94; N, 7.50.
Acknowledgments. The authors are grateful to the SC-NMR
Laboratory of Okayama University for 200 MHz 1H-NMR
experiments. They also thank Dr. K. L. Kirk (NIDDK, NIH)
for helpful comments on the manuscript.
4-(2-Hydroxyethylsulfanyl)-2-phenyl-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (17d).
The reaction time
was 24 h. Recrystallization of the precipitated solid
from acetonitrile gave 17d (86%) as yellow needles, mp 175–
1
176ꢂC; IR (nujol) cmꢀ1: 3367, 3173 (OH); H-NMR (200 MHz,
REFERENCES AND NOTES
DMSO-d6): d 3.37–3.61 (m, 6H, H5, 6, and SCH2CH2OH), 3.76
(br t, 2H, J = 6.0 Hz, SCH2CH2OH), 5.10 (br s, 1H, deuterium
oxide exchangeable, OH), 7.45–7.68 (m, 5H, H9, 10, and 30, 40,
50), 7.81 (br dd, 1H, J = 6.5, 1.7 Hz, H11), 8.06 (br dd, 1H, J = 7.5,
1.7 Hz, H8), 8.45–8.50 (m, 2H, H20 and 60); FAB-MS m/z: 423
(MH+). Anal. Calcd. for C22H18N2OS3: C, 62.53; H, 4.29; N,
6.63. Found: C, 62.15; H, 4.58; N, 6.61.
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4-(2-Hydroxyethylsulfanyl)-2-p-tolyl-5,6-dihydro[1]benzothieno
[30,20:2,3]thiepino[4,5-d]pyrimidine (17e).
The reaction time
was 24h. The precipitated solid was chromatographed on silica
gel. The eluate of n-hexane/ethyl acetate (4:1) was evaporated,
and the residue was recrystallized from acetonitrile to give 17e
(47%) as yellow needles, mp 188–189ꢂC; IR (nujol) cmꢀ1: 3368,
1
3185 (OH); H-NMR (200 MHz, DMSO-d6): d 2.42 (s, 3H, 20-
CH3), 3.32–3.56 (m, 6H, H5, 6, and SCH2CH2OH), 3.75 (t, 2H,
J = 6.0Hz, SCH2CH2OH), 7.39 (d, 2H, J = 8.2Hz, H30 and 50),
7.42–7.58 (m, 2H, H9 and 10), 7.80 (br dd, 1H, J = 6.6, 1.7Hz,
H11), 8.06 (br dd, 1H, J =6.8, 1.7 Hz, H8), 8.36 (d, 2H,
J = 8.2Hz, H20 and 60); FAB-MS m/z: 437 (MH+). Anal. Calcd.
for C23H20N2OS3: C, 63.27; H, 4.62; N, 6.42. Found: C, 63.02;
H, 4.91; N, 6.35.
Determination of pentosidine formation in vitro. The effects
were assayed according to the literature procedure [11].
Aminoguanidine hydrochloride was used as a reference compound.
[16] Slebocka-Tilk, H.; Brown, R. S. J Org Chem 1988, 53, 1153.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet