Synthesis of 2,2′-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4- ones and their Facile Recyclization to 2,2′-(1,4-Phenylene)bis(pyrimidin- 4-one) and/or 2,2′-(1,4-Phenylene)-bis-(thieno2,3-d]pyrimidin-4(1H)-one) derivatives

Article abstract of DOI:10.1515/znb-2010-0915

An efficient and direct procedure for the synthesis of 2,2′-(1,4- phenylene)bis-3,4-dihydro-2H-1,3- thiazin-4-one derivatives is described. Oxidation of the latter and their base-catalyzed recyclization has been studied. The products were characterized by

Full text of DOI:10.1515/znb-2010-0915

Synthesis of 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
and their Facile Recyclization to 2,2ꢀ-(1,4-Phenylene)bis(pyrimidin-4-one)
and/or 2,2ꢀ-(1,4-Phenylene)-bis-(thieno[2,3-d]pyrimidin-4(1H)-one)
Derivatives
Raafat M. Shaker, Yusria R. Ibrahim, Fathy F. Abdel-Latif, and Asmaa Hamoda
Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
Reprint requests to Prof. Dr. Raafat M. Shaker. E-mail: rmshaker@yahoo.com
Z. Naturforsch. 2010, 65b, 1148 – 1154; received March 18, 2010
An efficient and direct procedure for the synthesis of 2,2ꢀ-(1,4-phenylene)bis-3,4-dihydro-2H-1,3-
thiazin-4-one derivatives is described. Oxidation of the latter and their base-catalyzed recyclization
has been studied. The products were characterized by elemental analyses, and IR, 1H NMR, and 13
NMR spectra.
C
Key words: Terephthalaldehyde, Cyanoacetamide, Phenyl (Phenethyl) Isothiocyanate,
Bis-1,3-thiazin-4-one, Bis-pyrimidin-4-one, Bis-thieno[2,3-d]pyrimidin-4-one
Introduction
1,3-Thiazines are an important type of heterocycles
showing a wide variety of pharmacological proper-
ties. Thus, 1,3-thiazine derivatives have recently been
reported as cholecystokinin antagonists [1], antimy-
cobacterial agents [2], cannabinoid receptor agonists
[3], and inhibitors of NO synthase (NOS) [4], as an-
tibacterial [5], antipyretic [6], anti-inflammatory [6, 7],
analgesic [7], antitumor [8], and antioxidant [9] agents,
and as calcium channel modulators [10]. Furthermore,
the antibiotic activity of cephalosporin is due to the
presence of the 1,3-thiazine moiety [11]. A few meth-
ods have been reported in the literature for the prepa-
ration of 1,3-thiazines [12 – 21], but to the best of our
knowledge, there are no reports in the literature for
the formation of 2,2ꢀ-(1,4-phenylene)bis(3,4-dihydro-
2H-1,3-thiazin-4-one). Considering the above reports
in conjunction with our recent work on the synthesis of
bis- [22 – 26] and polyheterocyclic systems [27– 35],
we wish to describe herein an efficient and direct pro-
cedure for the synthesis of 2,2ꢀ-(1,4-phenylene)bis(3,4-
dihydro-2H-1,3-thiazin-4-one) derivatives and their
base-catalyzed recyclization to bis-pyrimidin-4-one
and bis-thieno[2,3-d]pyrimidin-4-one derivatives.
Scheme 1. Synthesis of bis-1,3-thiazines 3.
with 2 equivalents of 2a, b in the presence of cat-
alytic amounts of p-toluenesulfonic acid (p-TSA) in
boiling ethanol. High yields of the products 3 also
resulted when the reaction was performed in boiling
glacial acetic acid (Scheme 1). Compound 2a was
readily prepared by treatment of cyanoacetamide with
phenyl isothiocyanate according to a literature proce-
dure [36].
The proposed molecular structures of the bis-1,3-
thiazines 3a, b are supported by elemental and spec-
tral analyses. For example, compound 3a exhibits an
IR spectrum with strong absorption bands at 3181
(NH), 2206 (CN), and 1645 cm−1 (CO). Its 1H
NMR spectrum shows a characteristic singlet at δ =
10.18 ppm for the two exocyclic NH protons, a doublet
at 8.52 ppm for the two endocyclic NH protons (J =
3 Hz), a multiplet at 7.22 – 7.48 ppm due to the phenyl
protons and a doublet at 6.13 ppm for the two thi-
Results and Discussion
The bis-1,3-thiazines 3a, b have been synthesized azine protons (2H, J = 3 Hz). Moreover, the 13C NMR
by the cyclocondensation of terephthalaldehyde (1) spectrum of 3a shows signals at δ = 57 (2 × C-2),
c
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R. M. Shaker et al. · 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
1149
Scheme 2. Oxidation of 3a.
Scheme 3. Alkylation of 3.
Scheme 4.
77.51 (2 × C-5), 116.18 (CN), 162.07 (2 × C=O), and
164.93 (2 × C-6), in addition to those of the phenyl
carbons at δ = 125.48– 137.79.
Considering the facile oxidation in the presence of
nitrobenzene [37], 3a was converted into 4 in good
yield (Scheme 2). The structure 4 was confirmed by el-
emental analysis and spectral data. The disappearance
1
of 2-H and 3-NH in the H NMR spectrum indicated
that only these protons were removed from 3a.
Scheme 5. Synthesis of bis-pyrimidines 5a and 6a.
We also studied the alkylation of 3a, b with dimethyl
sulfate and/or ethyl iodide under basic conditions. Un-
expectedly, the reactions proved to involve the sulfur
atom thus affording the S-alkylated-bis(pyrimidin-4-
one) derivatives 5a, b and/or 6a, b, respectively, in high
yields (Scheme 3). The structural assignments of com-
pounds 5 and 6 were confirmed by their spectroscopic
5a showed the absence of exocyclic NH protons, and
in its 13C NMR spectrum the resonances of the aminal
carbon atoms in compounds 5a (δ = 73.71) are shifted
downfield from those of the thioaminal carbon atoms
in compound 3a.
The transformations shown in Scheme 3 can be
data. A distinction between the thiazine and pyrimidine accounted for by the following mechanism: A base
structural types is clearly manifested in the 1H and 13
C
causes proton abstraction from the nitrogen atom in
1
NMR spectra. For example, the HNMR spectrum of position 3 and the thiazine ring opening [17]. Then the
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1150
R. M. Shaker et al. · 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
Scheme 6. Synthesis of the bis-{thieno[2,3-d]-
pyrimidin-4(1H)-one} 9.
Scheme 7. Synthesis of the bis-{thieno[2,3-d]-
pyrimidin-4(1H)-ones} 10 and 12.
resulting intermediate A cyclizes to the stable thiolate starting materials. Thus, benzyl chloride, ethyl bro-
B, and alkylation of the latter in situ yields products 5 moacetate and bromoacetonitrile were used as alky-
and 6, respectively (Scheme 4).
lating agents for further heterocyclization (Schemes
6 – 8). Benzylation of compounds 3a, b with benzyl
chloride in ethanol in the presence of potassium hy-
droxide gave the S-benzylated bis-pyrimidines 8a, b
in high yields (Scheme 6). Upon treatment of com-
pound 8a with sodium ethoxide in ethanol, it under-
went intramolecular Thorpe-Ziegler cyclization [38]
and partial oxidation to furnish the thienopyrimidine 9
(Scheme 6). Compounds 8a, b and 9 gave satisfactory
analytical and spectroscopic data. The IR and 1H NMR
spectra of 9 revealed the absence of bands of CN and
NH groups and signals attributable to the methylene,
methene and NH protons of 8a, respectively.
Compounds 5 and 6 were prepared indepen-
dently from 2-cyano-3-(alkylthio)-3-(phenylamino)-
acrylamide 7a, b obtained from the reaction of cyano-
acetamide with phenyl isothiocyanate in DMF and
in the presence of potassium hydroxide, followed by
treatment with dimethyl sulfate and/or ethyl iodide.
Subsequent reaction of 7a, b with terephthalaldehyde
(1) in boiling ethanol and in the presence of catalytic
amounts of p-toluenesulfonic acid (p-TSA) afforded
5a and/or 6a in excellent yields (Scheme 5). The iden-
tity of the products prepared in Scheme 5 with those
obtained previously in Scheme 3 was confirmed by
comparison of their IR and 1H NMR spectra.
Treatment of 3a with ethyl bromoacetate, in
Next, we moved on to develop a facile and conve- ethanol in the presence of potassium hydroxide, fur-
nient route to polyfunctionally substituted thienopy- nished the bis-{thieno[2,3-d]pyrimidin-4(1H)-one}10
rimidine derivatives using the 1,3-thiazines 3a, b as (Scheme 7).
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R. M. Shaker et al. · 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
1151
2-Cyano-3-mercapto-3-phenethylamino-acrylamide (2b)
This compound was prepared in 88 % isolated yield by
treatment of cyanoacetamide with phenethyl isothiocyanate
using the procedure described for the synthesis of 2a [36];
pale-yellow crystals, m. p. 148 – 150 ◦C. – IR (film): ν =
3423, 3340, 2185, 1635, 1527 cm−1. – 1H NMR (300 MHz,
[D6]DMSO): δ = 2.85 (t, 2H, CH2, J = 7.5 Hz), 3.72 (t,
2H, CH2, J = 7.5 Hz), 6.97 (s, 2H, NH2), 7.21 – 7.36 (m, 5H,
ArH), 8.78 (s, 1H, SH), 10.45 (brs, 1H, NH).
Scheme 8. Synthesis of the bis-{thieno[2,3-d]pyrimidin-
4(1H)-one} 13.
2,2ꢀ-(1,4-Phenylene)-bis(5-cyano-6-arylamino-3,4-dihydro-
2H-1,3-thiazin-4-ones) 3a, b
The elemental analysis and the spectral data are in
good agreement with the proposed structures. The IR
and H NMR spectra of 10 revealed the absence of a
band of a CN group and of signals attributable to the
1
Method A: A mixture of terephthalaldehyde (1) (1.34 g,
0.01 mol), 2a, b (0.02 mol), and p-toluenesulfonic acid
(0.076 g, 0.01 mol) in ethanol (20 mL) was refluxed, a pale-
yellow precipitate was formed after 30 min, and stirring was
continued for 2 h. The precipitate was filtered off, washed
with ethanol, dried, and recrystallized from DMF/EtOH.
Method B: A mixture of terephthalaldehyde (1) (1.34 g,
0.01 mol) and 2a, b (0.02 mol), in glacial acetic acid (20 mL)
two exocyclic NH protons of 3a, respectively.
On the other hand, the condensation of 3b with ethyl
bromoacetate under the previous conditions gave the
bis S-substituted thiopyrimidine 11. The cyclization
and partial oxidation of 11 to the bis-thienopyrimidine
12 proceeds upon treatment with sodium ethoxide in
ethanol (Scheme 7). The structures of 11 and 12 were was boiled, and a pale-yellow precipitate was formed after
30 min. Stirring was continued for 2 h, the precipitate was fil-
tered off, washed with ethanol, dried, and recrystallized from
DMF/EtOH.
established on the basis of their correct elemental anal-
yses as well as compatible spectral data. The IR and
1H NMR spectra of 12 revealed the absence of CN and
NH groups and of signals attributable to the SCH2, CH
and NH protons of 11, respectively.
Finally, as described in Scheme 8, the thienopyrim-
idine derivatives 13a and 13b were prepared in aq.
KOH by cycloalkylation of 3a, b with bromoacetoni-
trile. Based on the spectroscopic data, the structure of
compound 13 is undoubtedly confirmed.
2,2ꢀ-(1,4-Phenylene)-bis(5-cyano-6-phenylamino-3,4-
dihydro-2H-1,3-thiazin-4-one) (3a)
Yellow powder, yield: method A: 84 %; method B: 81 %,
m. p. 286 – 288 ◦C. – IR (film): ν = 3181, 3064, 2206, 1645,
1548 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 6.13 (d,
2H, 2CH, J = 3 Hz), 7.22 – 7.48 (m, 14H, ArH), 8.52 (d, 2H,
2NH, J = 3 Hz), 10.18 (s, 2H, 2NH). – 13C NMR (75 MHz,
[D6]DMSO): δ = 57.49 (C-2, C-2ꢀ), 77.51 (C-5, C-5ꢀ),
116.18 (2CN), 125.48, 126.82, 127.46, 127.71, 128.91,
129.63, 137.49, 137.56, 137.79 (C-Ar), 162.07 (C=O),
164.93 (C-6, C-6ꢀ). – Anal. for C28H20N6O2S2: calcd.
C 62.67, H 3.76, N 15.66, S 11.95; found C 62.59, H 3.87,
N 15.57, S 11.84.
Experimental Section
General procedures
Melting points were measured with a Gallenkamp appara-
tus and are uncorrected. The reactions and purity were mon-
itored by thin layer chromatography (TLC) on aluminum
plates coated with silica gel with fluorescence indicator
(Merck, 60 F254) using CHCl3/CH3OH (10 : 1) as eluent.
The infrared spectra were recorded on a Jasco FT/IR-450
Plus infrared spectrophotometer. The NMR spectra were ob-
tained on a JHA-LAA 400 WB-FT spectrometer (300 MHz
for 1H NMR, 75 MHZ for 13C NMR) with deuterated chlo-
roform (CDCl3) or dimethylsulfoxide ([D6]DMSO) as sol-
vent. Chemical shifts are quoted in δ and are referenced to
the solvent signal. Elemental analyses were measured with a
Vario EL III CHNOS Elemental Analyzer, Germany, in the
Microanalytical Center of Cairo University.
2,2ꢀ-(1,4-Phenylene)-bis(5-cyano-6-phenethylamino-3,4-
dihydro-2H-1,3-thiazin-4-one) (3b)
Pale-yellow powder, yield: method A: 82 %; method B:
79 %, m. p. 242 – 244 ◦C. – IR (film): ν = 3227, 3150, 3020,
2203, 1638, 1565 cm−1. – 1H NMR (300 MHz, [D6]DMSO):
δ = 2.78 – 2.87 (t, 4H, 2CH2N, J = 6 Hz), 3.41 – 3.51 (t, 4H,
2CH2Ph, J= 6 Hz), 6.07 (d, 2H, 2CH, J = 2.4 Hz), 7.14 – 7.30
(m, 14H, ArH), 7.49 (d, 2H, 2NH, J = 2.4 Hz), 8.33 (t, 2H,
2 NH, J = 6 Hz). – 13C NMR (75 MHz, [D6]DMSO): δ =
35.59 (2 CH2Ph), 46.59 (2 CH2N), 57.38 (C-2, C-2ꢀ), 73.72
Compounds 2a [36] and 7a [39] were synthesized using (C-5, C-5ꢀ), 116.94 (CN), 126.37, 127.37, 127.68, 128.21,
the published procedures. 128.36, 128.56, 128.70, 129.56, 136.27, 137.71, 137.80,
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R. M. Shaker et al. · 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
138.03, 143.95 (C-Ar), 165.31 (2CO), 166.60 (C-6, C-6ꢀ). – in DMF (5 mL). The reaction mixture was stirred for 18 –
Anal. for C32H28N6O2S2: calcd. C 64.84, H 4.76, N 14.18, 20 h at r. t. and then poured into cold water. After stirring for
S 10.82; found C 64.72, H 4.65, N 14.06, S 10.75.
15 min, the precipitated product was collected by filtration,
washed with water, dried and crystallized from ethanol.
2,2ꢀ-(1,4-Phenylene)bis(5-cyano-6-phenylamino-4H-1,3-
thiazin-4-one) (4)
2,2ꢀ-(1,4-Phenylene)-bis(5-cyano-6-ethylthio-1-phenyl-
1,2,3,4-tetrahydro-pyrimidin-4-one) (6a)
A solution of compound 3a (2 mmol) was refluxed in
DMF/PhNO2 (1 : 5) for 2 h, and the solvent was evapo-
rated under vacuum. The product 4 was crystallized by us-
ing chloroform/petroleum ether. Pale-grey powder, yield:
73 %, m. p. 210 – 212 ◦C. – IR (film): ν = 3175, 3070,
2202, 1650 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
7.27 – 7.99 (m, 14H, ArH), 10.49 (s, 2H, 2NH). – Anal. for
C28H16N6O2S2: calcd. C 63.14, H 3.03, N 15.78, S 12.04;
found C 63.04, H 3.16, N 15.69, S 11.96.
Pale-yellow crystals, yield: 76 %, m. p. 290 – 292 ◦C. – IR
(film): ν = 3263, 3058, 2969, 2211, 1663, 1513 cm−1. –
1H NMR (300 MHz, [D6]DMSO): δ = 0.92 (t, 6H, 2CH3,
J = 3 Hz), 2.74 (q, 4H, 2CH2, J = 3 Hz), 6.08 (d, 2H,
2CH, J = 4.8 Hz), 7.34 – 7.54 (m, 14H, ArH), 8.84 (d, 2H,
2 NH, J = 4.8 Hz). – 13C NMR (75 MHz, [D6]DMSO):
δ = 14.08 (2CH3), 26.79 (2CH2), 73.57 (2CH), 90.70
(C-5, C-5ꢀ), 115.68 (2CN), 125.82, 125.96, 126.01, 126.54,
127.58, 129.58, 129.71, 139.09, 143.04 (C-Ar), 160.50
(2C=O), 163.49 (C-6, C-6ꢀ). – Anal. for C32H28N6O2S2:
calcd. C 64.84, H 4.76, N 14.18, S 10.82; found C 64.75,
H 4.82, N 14.11, S 10.71.
Synthesis of 5a, b
To a stirred 0.75 N aqueous KOH solution (20 mL), com-
pound 3a b (10 mmol) and dimethyl sulfate (40 mmol)
were added successively. The resulting precipitate was fil-
tered off, washed with water, dried and recrystallized from
DMF/EtOH.
2,2ꢀ-(1,4-Phenylene)bis(5-cyano-6-ethylthio-1-phenethyl-
1,2,3,4-tetrahydropyrimidin-4-one) (6b)
◦
Pale-yellow crystals, yield: 76 %, m. p. 278 – 279 C. –
IR (film): ν = 3163, 3045, 2203, 1665, 1515 cm−1. – 1H
NMR (300 MHz, [D6]DMSO): δ = 1.01 (t, 6H, 2CH3, J =
7.2 Hz), 2.80 (t, 4H, 2CH2N, J = 7.2 Hz), 2.93 (t, 4H,
2CH2Ph, J = 7.2 Hz), 4.41 (q, 4H, 2CH2, J = 7.2 Hz),
6.13 (d, 2H, 2CH, J = 1.5 Hz), 7.23 – 7.35 (m, 14H, ArH),
8.60 (d, 2H, 2 NH, J = 1.5 Hz). – 13C NMR (75 MHz,
[D6]DMSO): δ = 14.55 (2CH3), 28.47 (2CH2), 35.44
(2 CH2Ph), 53.79 (2 CH2N), 68.30 (C-2, C-2ꢀ), 86.31 (C-5,
C-5ꢀ), 120.60 (CN), 125.69, 126.51, 128.31, 128.93, 137.57,
139.43 (C-Ar), 161.60 (2C=O), 162.89 (C-6, C-6ꢀ). – Anal.
for C36H36N6O2S2: calcd. C 66.64, H 5.59, N 12.95, S 9.88;
found C 66.52, H 5.48, N 12.86, S 9.77.
2,2ꢀ-(1,4-Phenylene)bis(5-cyano-6-methylthio-1-phenyl-
1,2,3,4-tetrahydropyrimidin-4-one) (5a)
Yellow crystals, yield: 80 %, m. p. 296 – 298 ◦C. – IR
(film): ν = 3175, 3060, 2206, 1650, 1545 cm−1. – 1H NMR
(300 MHz, [D6]DMSO): δ = 2.12 (s, 6H 2CH3), 6.14 (d,
2H, 2CH, J = 2.4 Hz), 7.39 – 7.60 (m, 14H, ArH), 8.94 (d,
2H, 2 NH, D2O-exchangeable, J = 2.4 Hz). – 13C NMR
(75 MHz, [D6]DMSO): δ = 15.29 (2 SCH3), 73.71 (C-2,
C-2ꢀ), 90.0 (C-5, C-5ꢀ), 115.72 (2CN), 125.40, 125.44,
126.41, 126.69, 126.84, 127.46, 127.59, 129.70, 129.81,
139.33, 142.93 (C-Ar), 160.40 (2CO), 165.02 (C-6, C-6ꢀ). –
Anal. for C30H24N6O2S2: calcd. C 63.81, H 4.28, N 14.88,
S 11.36; found C 63.72, H 4.37, N 14.75, S 11.24.
2-Cyano-3-ethylthio-3-phenylamino-acrylamide (7b)
This compound was prepared in 90 % isolated yield by
treatment of cyanoacetamide with phenyl isothiocyanate and
ethyl iodide using the procedure described for the synthe-
sis of 7a [39]; pale-yellow crystals, m. p. 128 – 130 ◦C. – IR
(film): ν = 3382, 3201, 2195, 1652, 1555 cm−1. – 1H NMR
(300 MHz, [D6]DMSO): δ = 1.20 (t, 3H, CH3, J = 7.5 Hz),
2.63 (q, 2H, CH2, J = 7.5 Hz), 7.25 – 7.42 (m, 7H, ArH +
NH2), 12.44 (s 1H, NH).
2,2ꢀ-(1,4-Phenylene)bis(5-cyano-6-methylthio-1-phenethyl-
1,2,3,4-tetrahydropyrimidin-4-one) (5b)
◦
Pale-yellow crystals, yield: 82 %, m. p. 210 – 214 C. –
IR (film): ν = 3383, 3057, 3028, 2926, 2203, 1649,
1
1525 cm−1. – H NMR (300 MHz, [D6]DMSO): δ = 2.29
(s, 6H, 2CH3), 2.9 (t, 4H, 2CH2N, J = 5.4 Hz), 3.35 (t, 4H,
2CH2-Ph, J = 5.4 Hz), 6.10 (d, 2H, 2CH, J = 4.8 Hz), 7.21 –
7.35 (m, 14H, ArH), 8.65 (d 2H, 2 NH D2O-exchangeable,
J = 4.8 Hz). – Anal. for C34H32N6O2S2: calcd. C 65.78,
H 5.20, N 13.54, S 10.33; found C 65.69, H 5.31, N 13.46,
S 10.24.
Alternative synthesis of 5a and 6a
A mixture of terephthalaldehyde (1) (1.34 g, 0.01 mol),
7a, b (0.02 mol), and p-toluenesulfonic acid (0.076 g,
0.01 mol) in ethanol (20 mL) was refluxed. A yellow pre-
cipitate was formed after 30 min, and stirring was continued
Synthesis of 6a, b
Ethyl iodide (40 mmol) was added to a mixture of 3a, for 2 h. The precipitate was filtered off, washed with ethanol,
b (10 mmol) and anhydrous potassium carbonate (4 mmol) dried, and recrystallized from the appropriate solvents.
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R. M. Shaker et al. · 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
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Synthesis of 8a, b
2,2ꢀ-(1,4-Phenylene)bis(5-amino-6ethoxycarbonyl-1-phen-
yl-2,3-dihydro-thieno[2,3-d]pyrimidin-4(1H)-one) (10)
To a stirred 75 N aqueous KOH solution (20 mL), 3a, b
(10 mmol) and benzyl chloride (40 mmol) were added suc-
cessively. The resulting precipitate was filtered off, washed
with water, dried, and recrystallized from ethanol.
Pale-yellow powder, yield: 82 %, m. p. 274 – 276 ◦C. – IR
(film): ν = 3389, 3059, 1661, 1512, 1428, 1378 cm−1. – 1H
NMR (300 MHz, [D6]DMSO): δ = 2.16 (t, 6H, 2CH3, J =
7.2 Hz), 4.10 (q, 4H, 2CH2, J = 7.2 Hz), 6.15 (d, 2H, 2CH,
J = 1.2 Hz), 6.50 (s, 4H, 2NH2), 7.41 – 7.59 (m, 14H, ArH),
8.98 (d, 2H, 2NH, J = 1.2 Hz). – Anal. for C36H32N6O6S2:
calcd. C 61.00, H 4.55, N 11.86, S 9.05; found C 60.88,
H 4.66, N 11.75, S 8.96.
2,2ꢀ-(1,4-Phenylene)bis(6-benzylthio-5-cyano-1-phenyl-
1,2,3,4-tetrahydropyrimidin-4-one) (8a)
◦
Colorless crystals, yield: 81%, m. p. 280 – 282 C. – IR
(film): ν = 3284, 2979, 2210, 1671, 1535 cm−1. – 1H NMR
(300 MHz, [D6]DMSO): δ = 3.91 (d, 2H, CHAHB, J =
13 Hz), 4.08 (d, 2H, CHAHB, J = 13 Hz), 6.09 (d, 2H, 2CH,
J = 6.6 Hz), 7.03 – 7.53 (m, 24H, ArH), 8.93 (d 2H, NH, J =
6.6 Hz). – Anal. for C42H32N6O2S2: calcd. C 70.37, H 4.50,
N 11.72, S 8.95; found C 70.24, H 4.41, N 11.65, S 8.88.
2,2ꢀ-(1,4-Phenylene)bis(5-cyano-4-oxo-1-phenethyl-1,2,3,4-
tetrahydropyrimidin-6-yl-sulfanylacetic acid ethyl ester)
(11)
Yellowish-white powder, yield: 80 % m. p. 240 – 242 ◦C. –
IR (film): ν = 3286, 3060, 2210, 1727, 1670, 1630,
1535 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 1.08
(t, 6H, 2CH3, J = 4.8 Hz), 2.99 (t, 4H, 2CH2Ph, J = 6.3 Hz),
3.82 (t, 4H, 2CH2N, J = 6.3 Hz), 3.98 (s, 4H, 2CH2S), 4.28
(q, 4H, 2CH2O, J = 6.6 Hz), 6.15 (d, 2H, 2CH, J = 6 Hz),
7.28 – 7.33 (m, 14H, ArH), 8.72 (d, 2H, 2 NH, J = 6 Hz). –
Anal. for C40H40N6O6S2: calcd. C 62.81, H 5.27, N 10.99,
S 8.38; found C 62.70, H 5.35, N 10.91, S 8.29
2,2ꢀ-(1,4-Phenylene)bis(6benzylthio-5-cyano-1-phenethyl-
1,2,3,4-tetrahydropyrimidin-4-one) (8b)
◦
Pale-yellow crystals, yield: 80 %, m. p. 260 – 263 C. –
IR (film): ν = 3361, 3127, 2210, 1678, 1526 cm−1. – 1H
NMR (300 MHz, [D6]DMSO): δ = 2.87 (t, 4H, 2CH2, J =
6 Hz), 3.75 (t, 4H, 2CH2, J = 6 Hz ), 4.14 (d, 2H, CHAHB,
J = 13 Hz), 4.35 (d, 2H, CHAHB, J = 13 Hz), 6.06 (d,
2H, 2CH, J = 4.8 Hz), 7.17–7.32 (m, 14H, ArH), 8.63 (d,
2H, 2NH, J = 4.8 Hz). – 13C NMR (75 MHz, [D6]DMSO):
δ = 35.17 (2 SCH2Ph), 37.87 (2 CH2Ph), 53.68 (2 CH2-
N), 68.78 (2CH), 85.68 (C-5, C-5ꢀ), 117.27 (CN), 125.80,
126.50, 127.81, 128.33, 128.69, 128.81, 136.31, 137.45,
139.09 (C-Ar), 161.47 (2 C=O), 162.46 (C-6, C-6ꢀ). – Anal.
for C46H40N6O2S2: calcd. C 71.48, H 5.22, N 10.87, S 8.30;
found C 71.37, H 5.28, N 10.76, S 8.22.
2,2ꢀ-(1,4-Phenylene)bis(5-amino-6-ethoxycarbonyl-1-
phenethyl-thieno[2,3-d]-pyrimidin-4(1H)-one) (12)
A mixture of compound 11 (0.764 g, 1 mmol) with
sodium ethoxide (0.046 g Na/15 mL ethanol) was heated
under reflux for 2 h, and then allowed to cool. The solid
product was collected by filtration and washed with wa-
ter. Brown powder, yield: 74 %, m. p. 240 – 242 ◦C. – IR
(film): ν = 3745, 3352, 3028, 2921, 1637, 1591 cm−1. –
1H NMR (300 MHz, [D6]DMSO): δ = 1.23 (t, 6H, 2CH3,
J = 6 Hz), 2.92 (t, 4H, 2CH2Ph, J = 6 Hz), 3.82 (t, 4H,
2CH2N, J = 6 Hz), 4.04 (q, 4H, 2CH2O, J = 6.6 Hz),
6.96 (s, 4H, 2NH2), 7.27 – 7.31 (m, 14H, ArH). – Anal. for
C40H36N6O6S2: calcd. C 6314, H 4.77, N 11.05, S 8.43;
found C 6305, H 4.88, N 10.98, S 8.33.
2,2ꢀ-(1,4-Phenylene)bis(5-amino-1,6-diphenylthieno[2,3-
d]pyrimidin-4(1H)-one) (9)
A mixture of compound 8a (1 mmol) and sodium ethoxide
(0.046 g Na/15 mL ethanol) was heated under reflux for 2 h,
and then allowed to cool. The solid product was collected by
filtration and washed with water. Brown powder, yield: 81 %,
m. p. 200 – 202 ◦C. – IR (film): ν = 3745, 3352, 3028, 2921,
1637, 1591 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ =
6.96 (s, 4H 2NH2), 7.27 – 7.51 (m, 24H, ArH). – Anal. for
C42H28N6O2S2: calcd. C 70.77, H 3.96, N 11.79, S 9.00;
found C 70.69, H 3.88, N 11.71, S 8.89.
2,2ꢀ-(1,4-Phenylene)bis(5-amino-1-aryl-6-cyano-2,3-
dihydro-thieno[2,3-d]-pyrimidin-4(1H)-ones) 13a, b
To a stirred 0.75 N aqueous KOH solution (20 mL), 3a b
(10 mmol) and bromoacetonitrile (40 mmol) were added suc-
cessively. The resulting precipitate was filtered off, washed
with water, dried, and recrystallized from ethanol.
Synthesis of compounds 10 and 11
2,2ꢀ-(1,4-Phenylene)bis(5-amino-6-cyano-1-phenyl-2,3-
dihydro-thieno[2,3-d]pyrimidin-4(1H)-one) (13a)
To a stirred 0.75 N aqueous KOH solution (20 mL),
3a b (10 mmol) and ethyl bromoacetate (40 mmol) were
added successively. The resulting precipitate was filtered off,
washed with water, dried, and recrystallized from ethanol.
Yellowish-white powder, yield: 84 %, m. p. 276 –
278 ◦C. – IR (film): ν = 3426, 3325, 3200, 3065, 3028, 2177,
Unauthenticated
Download Date | 9/26/15 4:14 PM

1154
R. M. Shaker et al. · 2,2ꢀ-(1,4-Phenylene)bis-3,4-dihydro-2H-1,3-thiazin-4-ones
1
1659 cm−1. – H NMR (300 MHz, [D6]DMSO): δ = 6.29 2,2ꢀ-(1,4-Phenylene)bis(5-amino-6-cyano-1-phenethyl-
(d, 2H, 2CH, J = 4.8 Hz), 6.77 (s, 4H, 2NH2), 7.24 – 7.41 2,3-dihydro-thieno[2,3-d]pyrimidin-4(1H)-one) (13b)
(m, 14H, ArH), 8.55 (d, 2H, 2NH, J = 4.8 Hz). – 13C NMR
◦
Pale-grey powder, yield: 82 %, m. p. 262 – 264 C. – IR
(75 MHz, [D6]DMSO): δ = 73.77 (C-2, C-2ꢀ), 101.28 (C-6,
(film): ν = 3224, 3155, 3065, 3030, 2165, 1660, 1610,
C-6ꢀ), 115.74 (2CN), 124.19, 126.89, 127.36, 129.70, 139.35
1518 cm−1. – 1H NMR (300 MHz, [D6]DMSO): δ = 2.80 (t,
(C-Ar), 141.35 (C-5a, C-5aꢀ), 155.18 (C-4a, C-4aꢀ), 159.74
4H, 2CH2Ph, J = 6.9 Hz), 3.39 (t, 4H, 2CH2N, J = 6.9 Hz),
(SCN), 160.76 (2C=O). – Anal. for C32H22N8O2S2: calcd.
5.86 (d, 2H, 2CH, J = 2.4 Hz), 6.80 (s, 4H, 2NH2), 7.15 –
C 62.53, H 3.61, N 18.23, S 10.43; found C 62.46, H 3.66,
7.40 (m, 14H, ArH), 8.34 (d, 2H, 2NH, J = 2.4 Hz). – Anal.
N 18.15, S 10.36.
for C36H30N8O2S2: calcd. C 64.46, H 4.51, N 16.70, S 9.56;
found C 64.38, H 4.62, N 16.59, S 9.48.
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