Synthesis of tricyclic systems containing a fused thieno[3,4-d]pyrimidine nucleus

Article abstract of DOI:10.3184/174751912X13400242909892

The synthesis and characterisation of novel tricyclic systems containing a fused thieno[3,4-d]pyrimidine nucleus starting from a useful synthon, ethyl-4-cyano-3-ethoxymethyleneamino-5-phenylamino-2-thiophenecarboxylate, are reported.

Full text of DOI:10.3184/174751912X13400242909892

480 RESEARCH PAPER
AUGUST, 480–483
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis of tricyclic systems containing a fused thieno[3,4-d]pyrimidine
nucleus
Farag A. El-Telbany, Maha Abd El Hakeem, Omneya M. Khalil* and Demiana S. Mikhail
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
The synthesis and characterisation of novel tricyclic systems containing a fused thieno[3,4-d]pyrimidine nucleus
starting from a useful synthon, ethyl-4-cyano-3-ethoxymethyleneamino-5-phenylamino-2-thiophenecarboxylate, are
reported.
Keywords: imidate, aminothiophene-2-carboxylates, thieno[3,4-d]pyrimidine, Dimroth rearrangement, tricyclic heterocycles
Many thieno[3,4-d]pyrimidines have been the focus of interest
because of their remarkable biological properties in pharma-
ceuticals. Condensed thieno[3,4-d]pyrimidines exhibit inter-
esting biological properties such as anti-cancer,1,2 anti-viral,3
anti-allergy,4 anti-hypertensive,5 gastric anti-secretory6 and
aldose reductase inhibitory7 activities. On the other hand,
several condensed diazocines8,9 and diazepines10,11 have been
reported to possess a variety of biological activities. Guided by
these findings, we have invetsigated the synthesis and charac-
terisation of some tricyclic systems in which a thieno[3,4-d]
pyrimidine is fused with either diazocine or diazepine rings.
Our study started with the thiophene derivative 1 which
is considered as a root compound and can be used for the
preparation of the key intermediate 2. In this work, compound
1 was obtained according to Gewald’s procedure.12 Ethyl 4-
cyano-3-ethoxymethyleneamino-5-phenylamino-2-thiophene-
carboxylate 2 was obtained as reported in the literature via
condensation of the 3-aminothiophene-2-carboxylic ester (1)
with triethyl orthoformate as a one carbon donor.
Compounds 3a–f were successfully prepared through heat-
ing of compound 2 with the appropriate primary aromatic
amines as shown in Scheme 1. The sequence of reactions
involves selective aminolysis of compound 2, followed by the
spontaneous cyclisation to less stable intermediate A which
further undergoes a Dimroth-type rearrangement13–15 to yield
the thermodynamically stable pyrimidine 3.
The structures of compounds 3a–f were substantiated from
their elemental analyses, IR, 1H NMR and mass spectroscopy.
The IR spectra showed the disappearance of the CN absorption
band in 2 and the presence of the ester C=O absorption at
1653 cm−1.
Moreover, the 1H NMR spectra of 3a–f revealed the
presence of the triplet and quartet signals from the ester group
in the ranges δ 1.21–1.30 and 4.14–4.24 ppm respectively,
indicating that the ester group was not involved in the reaction.
They also showed a singlet signal in the region δ 8.09–
8.18 ppm for the pyrimidine proton, and two singlets in the
ranges δ 6.59–6.76 and 12.20–12.54 ppm corresponding to
two NH groups.
Further, cyclisation of 3a–f with either oxalyl chloride or
malonyl chloride in dry benzene afforded the corresponding
fused 1,4-diazepine-2,3-diones 4a–f and the 1,5-diazocine-
2,4-diones 5a–f respectively (Scheme 2).
The IR spectra of compounds 4a–f showed the presence of
three C=O absorption bands in the range 1747–1647 cm−1 and
1
the absence of an NH stretching band. Furthermore, the H
NMR spectra of compounds 4a–f indicated the disappearance
of the NH signal from the starting compounds. Meanwhile, the
IR spectra of compounds 5a–f also revealed the presence of
1
three overlapped C=O absorption bands. In addition, the H
NMR spectra showed a singlet signal corresponding to the
methylene protons from the O=C–CH2–C=O unit that ranged
1
from δ 3.70 to 3.40 ppm. Furthermore, the H NMR spectra
revealed the absence of the NH signals from compounds
3a–f.
Ethyl 3-amino-5-phenylamino-4-imino-3,4-dihydrothieno
[3,4-d]pyrimidine-7-carboxylate (6) was prepared as shown in
Scheme 3 via condensation of 2 with hydrazine hydrate in
ethanol, on a boiling water bath for 10–15 min, through nucleo-
philic addition of hydrazine to the imidate group, followed by
elimination of ethanol and intramolecular cyclisation to give
the desired compound 6. The IR spectrum of the latter showed
Scheme 1 Synthesis of compounds 3a–f.
* Correspondent. E-mail: omneyafawzy@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 481
Experimental
Melting points were obtained on a Griffin apparatus and the values
given are uncorrected. IR spectra were recorded on a Shimadzu 435
spectrophotometer, using KBr discs. 1H NMR spectra were recorded
on a Varian Mercury-300BB (300 MHz) or a Varian GEMINI-200
(200 MHz) spectrometer using TMS as internal standard. Mass spec-
tra were recorded on a JEOL JMS-AX 500 Spectrometer. Elemental
analyses for C, H and N were performed at the Microanalytical Center,
Cairo University. The progress of reactions was monitored by TLC
using precoated aluminium sheets (silica gel MERCK 60 F 254)
and visualised by a UV lamp. Compound 1 was prepared adopting
Gewald conditions.12 All the chemicals were purchased from the
Sigma-Aldrich Company.
Synthesis of compounds 3a–f; general procedure
A mixture of 2 (3.43 g, 0.01 mol) and the appropriate amine
(0.01 mol) in absolute ethanol (20 mL) was heated under reflux for
1 h. The reaction mixture was cooled and the separated solid was
filtered, dried and recrystallised from ethanol. Using this method the
following compounds were prepared.
Scheme 2 Synthesis of compounds 4a–f and 5a–f.
Ethyl 5-phenylamino-4-(phenylamino)thieno[3,4-d]pyrimidine-7-
carboxylate (3a): Red solid, yield: 66.6%, m.p. 192–194 °C; IR (KBr)
ν/cm−1 3294 (2 NH), 2978–2893 (CH aliphatic), 1654 (C=O);
1H NMR (200 MHz, DMSO-d6) δ 1.23 (t, 3H, CH3, J = 6.80 Hz),
4.14 (q, 2H, CH2, J = 6.80 Hz), 6.74 (s, 1H, NH, D2O exchangeable),
7.18–7.72 (m, 10H, ArH), 8.12 (s, 1H, pyrimidine), 12.40 (s, 1H, NH,
D2O exchangeable); MS (m/z) (relative abundance %) (26.24), 392.10
(M+2)+. (7.93), 391.10 (M+1)+, 390.10 (M)+. (100). Anal. Calcd for
C21H18N4O2S (390.44): C, 64.59; H, 4.64; N, 14.35. Found: C, 64.70;
H, 4.52; N, 14.51%.
Ethyl5-phenylamino-4-(4-methylphenylamino)thieno[3,4-d]pyrimi-
dine-7-carboxylate (3b): Red solid, yield: 64.3%, m.p. 198–200 °C;
IR (KBr) ν/cm−1 3444, 3282 (2 NH), 2800–2924 (CH aliphatic),
1
1651 (C=O); H NMR (200 MHz, DMSO-d6) δ 1.30 (t, 3H, CH3,
J = 7.00 Hz), 2.36 (s, 3H, CH3), 4.24 (q, 2H, CH2, J = 7.00 Hz),
6.76 (s, 1H, NH, D2O exchangeable), 7.25–7.67 (m, 9H, ArH), 8.18
(s, 1H, pyrimidine), 12.39 (s, 1H, NH, D2O exchangeable); 13C NMR
(DMSO-d6): δ 14.60, 20.45, 38.68, 38.95, 39.23, 39.51, 39.79, 40.06,
40.34, 59.14, 101.07, 120.72, 121.55, 123.49, 129.22, 129.36, 133.86,
134.98, 150.12, 154.62, 159.34; MS (m/z) (relative abundance %):
402 (M-2)+ (100). Anal. Calcd for C22H20N4O2S (404.47): C, 65.32; H,
4.98; N, 13.85. Found: C, 65.40; H, 5.20; N, 13.7.1%.
Ethyl 5-phenylamino-4-(4-ethylphenylamino)thieno[3,4-d]pyrimi-
dine-7-carboxylate (3c): Red solid, yield: 62.2%, m.p. 212–214 °C;
IR (KBr) ν/cm−1 3253 (2 NH), 2872–2962 (CH aliphatic), 1653 (C=O);
1H NMR (200 MHz, DMSO-d6) δ 1.21 (t, 3H, CH3, J = 7.00 Hz), 1.25
(t, 3H, CH3, J = 7.20 Hz), 2.61 (q, 2H, CH2, J = 7.00 Hz), 4.20 (q, 2H,
CH2, J = 7.20 Hz), 7.28–7.32 (m, 9H, ArH), 8.13 (s, 1H, pyrimidine),
12.40 (s, 1H, NH, D2O exchangeable); MS (m/z) (relative abundance
%): 419 (M+1)+ (7.54), 418 (M)+.(26.7). Anal. Calcd for C23H22N4O2S
(418.50): C, 66.00; H 5.29; N, 13.38. Found: C, 66.00; H, 5.20; N,
13.35%.
Scheme 3 Synthesis of compounds 6–9.
the absence of a CN absorption band and the appearance of a
forked band at 3360–3280 cm−1 corresponding to the NH2
1
group. On the other hand, the H NMR spectrum exhibited a
singlet for the =NH proton at δ 5.87 ppm. In addition, it also
revealed the presence of singlets for the pyrimidine proton at δ
8.47 and at δ 11.40 corresponding to NH2 group respectively.
Formation of the tricyclic thienopyrimidine derivatives 7, 8
and 9 was accomplished via cyclisation of 6 with 2-chloropro-
pionyl chloride, oxalyl chloride and malonyl chloride in dry
benzene. Structures of the cyclised compounds were substanti-
ated by spectral data. The IR spectrum of compound 7 indi-
cated the presence of two overlapped C=O bands ranging from
Ethyl5-phenylamino-4-(2-hydroxyphenylamino)thieno[3,4-d]pyrimi-
dine-7-carboxylate (3d): Red solid, yield: 61.5%, m.p. 208–210 °C;
IR (KBr) ν/cm−1 3305 (OH), 3182 (2 NH), 2978–3000 (CH aliphatic),
1
1635 (C=O); H NMR (200 MHz, DMSO-d6) δ 1.21 (t, 3H, CH3,
J = 6.90 Hz), 4.15 (q, 2H, CH2, J = 6.90 Hz), 6.59 (s, 1H, NH, D2O
exchangeable), 6.90–7.37 (m, 9H, ArH), 8.13 (s, 1H, pyrimidine),
10.37 (s, 1H, OH, D2O exch.), 12.54 (s, 1H, NH, D2O exchangeable);
MS (m/z) (relative abundance %) 408.10 (M+2)+ (8.40), 407.10
(M+1)+ (24.80), 406.10 (M)+. (100). Anal. Calcd for C21H18N4O3S
(406.44): C, 62.05; H, 4.46; N, 13.78. Found: C, 62.16; H, 4.69; N,
13.67%.
1
1680 to 1668 cm−1 and its H NMR spectrum revealed the
absence of a =NH proton signal at δ 5.87. It also exhibited
the appearance of a doublet signal corresponding to methyl
protons at δ 1.57, and a quartet at δ 5.02 for the methine proton.
In addition, the IR spectrum of 8 showed the presence of three
Ethyl5-phenylamino-4-(4-hydroxyphenylamino)thieno[3,4-d]pyrimi-
dine-7-carboxylate (3e): Red solid, yield: 64%, m.p. 205–207 °C;
IR (KBr) ν/cm−1 3400–3294 (2 NH,OH), 2850–2950 (CH aliphatic),
C=O absorption bands in the range 1720–1647 cm−1. The H
1
1
1651 (C=O); H NMR (200 MHz, DMSO-d6) δ 1.24 (t, 3H, CH3,
NMR spectrum indicated the absence of a signal for the =NH
proton at δ 5.87, and the presence of only two NH proton
signals at δ 10.47, 12.44 ppm (exchangeable with D2O). The
IR spectrum of 9 indicated the presence of three overlapped
J = 7.00 Hz), 4.22 (q, 2H, CH2, J = 7.00 Hz), 6.78–7.51 (m, 9H, ArH),
8.09 (s, 1H, pyrimidine), 9.52 (s, 1H, OH, D2O exchangeable), 12.20
(s, 1H, NH, D2O exchangeable); MS (m/z) (relative abundance %):
407 (M+1)+ (6.51), 406 (M)+, (30.32). Anal. Calcd for C21H18N4O3S
(406.44): C, 62.05; H, 4.46; N, 13.78. Found: C, 62.00; H, 4.30; N,
13.53%.
C=O absorption band at 1668–1647 cm−1, while its H NMR
1
spectrum showed the absence of =NH proton signal at δ 5.87
ppm in addition to the appearance of a singlet corresponding to
the O=C–CH2–C=O unit at 3.70 ppm.
Ethyl5-phenylamino-4-(4-chlorophenylamino)thieno[3,4-d]pyrimi-
dine-7-carboxylate (3f): Red solid, yield: 61.3%, m.p. 202–204 °C; IR

482 JOURNAL OF CHEMICAL RESEARCH 2012
(KBr) ν/cm−1 3437, 3282 (2 NH), 2800–2950 (CH aliphatic),
1651 (C=O); H NMR (200 MHz, DMSO-d6) δ 1.27 (t, 3H, CH3,
J = 7.20 Hz), 4.19 (q, 2H, CH2, J = 7.20 Hz), 6.76 (s, 1H, NH, D2O
exchangeable), 7.14–7.76 (m, 9H, ArH), 8.15 (s, 1H, pyrimidine),
12.45 (s, 1H, NH, D2O exchangeable); MS (m/z) (relative abundance
%): 425 (M+1)+ (0.72). Anal. Calcd for C21H17ClN4O2S (424.89): C,
59.35; H, 4.03; N, 13.18. Found: C, 59.30; H, 3.90; N, 12.90%.
mixture was cooled, and the separated solid was filtered, dried and
recrystallised from acetonitrile. Using this method the following
compounds were prepared.
1
Ethyl 6-phenyl-7,9-dioxo-10-phenyl-7,8,9,10-tetrahydro-6H-1-thia-
3,5,6,10-tetraazacycloocta[cd]indene-2-carboxylate (5a): Brick red
solid, yield: 56.7%, m.p. 223–225 °C; IR (KBr) ν/cm−1 2978–2931
(CH aliphatic), 1681 (3 overlapped C=O); 1H NMR (200 MHz,
DMSO-d6) δ 1.24 (m, 3H, CH3), 3.41 (s, 2H, CH2), 4.18 (m, 2H, CH2),
7.32–7.67 (m, 10H, ArH), 8.14 (s, 1H, pyrimidine); MS (m/z) (relative
abundance %): 458.40 (M)+., (1.18). Anal. Calcd for C24H18N4O4S
(458.47): C, 62.86; H, 3.95; N, 12.22. Found: C, 62.76, H, 3.74; N,
12.00%.
Ethyl 6-(4-methylphenyl)-7,9-dioxo-10-phenyl-7,8,9,10-tetrahydro-
6H-1-thia-3,5,6,10-tetraazacycloocta[cd]indene-2-carboxylate (5b):
Brick red solid, yield: 63.5%, m.p. 239–241 °C; IR (KBr) ν/cm−1
2978–2870 (CH aliphatic), 1750, 1681 [3 overlapped C=O)]; 1H NMR
(200 MHz, DMSO-d6) δ 1.26 (m, 3H, CH3), 2.33 (s, 3H, CH3), 3.58
(s, 2H, CH2), 4.22 (m, 2H, CH2), 7.26–7.53 (m, 9H, ArH), 8.45 (s, 1H,
pyrimidine). MS (m/z) (relative abundance %): 473 (M+1)+., (1.54).
Anal. Calcd for C25H20N4O4S (472.50): C 63.54; H, 4.26; N, 11.85.
Found: C, 63.39; H, 3.74; N, 11.51%.
Ethyl 6-(4-ethylphenyl)-7,9-dioxo-10-phenyl-7,8,9,10-tetrahydro-
6H-1-thia-3,5,6,10-tetraazacycloocta[cd]indene-2-carboxylate (5c):
Brick red solid, yield: 63.7%, m.p. 247–249 °C; IR (KBr) ν/cm−1
2960–2927 (CH aliphatic), 1740, 1683, 1670 (3 overlapped C=O); 1H
NMR (200 MHz, DMSO-d6) δ 1.18 (br. t, 3H, CH3), 1.23 (br. t, 3H,
CH3), 2.73 (br. q, 2H, CH2), 3.70 (s, 2H, CH2), 4.14 (br. q, 2H, CH2),
6.90–7.60 (m, 9H, ArH), 8.00 (s, 1H, pyrimidine). MS (m/z) (relative
abundance %): 485.20 (M-1)+, (18.84). Anal. Calcd C26H22N4O4S
(486.53): C 64.18; H, 4.55; N, 11.51. Found: C, 64.00; H, 4.39, N,
11.62%.
Ethyl 6-(2-hydroxyphenyl)-7,9-dioxo-10-phenyl-7,8,9,10-tetrahydro-
6H-1-thia-3,5,6,10-tetraazacycloocta[cd]indene-2-carboxylate (5d):
Brick red solid, yield: 63.2%, m.p. 250–252 °C; IR (KBr) ν/cm−1
3421–3244 (OH), 2981–2935 (CH aliphatic); 1740, 1685 (3 over-
lapped C=O); 1H NMR (200 MHz, DMSO-d6) δ 1.23 (br. t, 3H, CH3),
3.40 (s, 2H, CH2), 4.18 (br. q, 2H, CH2), 6.94–7.37 (m, 9H, ArH), 8.44
(s, 1H, pyrimidine), 10.40 (s, 1H, OH, D2O exchangeable); MS (m/z)
(relative abundance %): 475.36 (M+1)+., (7.80), 474.16 (M)+ (14.60).
Anal. Calcd C24H18N4O4S (474.47): C, 60.74; H, 3.82; N, 11.80.
Found: C, 60.54; H, 3.85, N, 11.76%.
Ethyl 6-(4-hydroxyphenyl)-7,9-dioxo-10-phenyl-7,8,9,10-tetrahydro-
6H-1-thia-3,5,6,10-tetraazacycloocta[cd]indene-2-carboxylate (5e):
Brick red solid, yield: 56.9%, m.p. 250–252 °C; IR (KBr) ν/cm−1
3350–3255 (OH), 2954–2848 (CH aliphatic); 1741, 1683 (3 over-
lapped C=O); 1H NMR (200 MHz, DMSO-d6) δ 1.29 (br. t, 3H, CH3),
3.44 (s, 2H, CH2), 4.22 (br. q, 2H, CH2), 6.90–7.80 (m, 9H, ArH), 8.19
(s, 1H, pyrimidine), 12.43 (s, 1H, OH, D2O exchangeable); MS (m/z)
(relative abundance %): 474.80 (M)+ (100). Anal. Calcd C24H18N4O5S
(474.47): C, 60.74; H, 3.82; N, 11.80. Found: C, 60.70; H, 3087, N,
11.86%.
Ethyl 6-(4-chlorophenyl)-7,9-dioxo-10-phenyl-7,8,9,10-tetrahydro-
6H-1-thia-3,5,6,10-tetraazacycloocta[cd]indene-2-carboxylate (5f):
Brick red solid, yield: 65.0%, m.p. 220–222 °C; IR (KBr) ν/cm−1
2873–2978 (CH aliphatic), 1740, 1701, 1685 (3 overlapped C=O); 1H
NMR (200 MHz, DMSO-d6) δ 1.23 (m, 3H, CH3), 3.43 (s, 2H, CH2),
4.23 (m, 2H, CH2), 7.21–7.54 (m, 9H, ArH), 8.20 (s, 1H, pyrimidine);
MS (m/z) (relative abundance %): 492.06 (M)+ (100). Anal. Calcd for
C24H17ClN4O4S (492.92): C 58.47; H, 3.47; N, 11.36. Found: C, 58.25;
H, 3.70, N, 10.96%.
Ethyl 3-amino-5-phenylamino-4-imino-3,4-dihydrothieno[3,4-d]pyri-
midine-7-carboxylate (6): A solution of 2 (3.43 g, 0.01 mol) in abso-
lute ethanol (20 mL) was heated on a water bath for 10–15 min until
the solid dissolved. Hydrazine hydrate (80%) (11 mL, 0.22 mol) was
added and heating was continued for 10 minutes more. The reaction
mixture was cooled, and the separated solid was filtered, dried and
recrystallised from ethanol to give the title compound as a yellowish
brown solid, yield: 82.0%; m.p. 210–212 °C; IR (KBr) ν/cm−1 3400,
3360–3280 (2 NH, NH2), 2950–3000 (CH aliphatic), 1653 (C=O);
1H NMR (300 MHz, DMSO-d6) δ 1.27 (t, 3H, CH3, J = 6.80 Hz), 4.22
(q, 2H, CH2, J = 7.00 Hz), 5.87 (s, 1H, =NH, D2O exchangeable),
7.15–7.47 (m, 5H, ArH), 8.47 (s, 1H, pyrimidine), 11.40 (br s, 2H,
NH2, D2O exchangeable), 13.40 (s, 1H, NH, D2O exchangeable); MS
(m/z) (relative abundance %): 331 (M+2)+ (4.52), 330 (M+1)+ (12.55),
329 (M)+ (47.30). Anal. Calcd for C15H15N5O2S (329.37): C, 54.69; H,
4.59; N, 21.26. Found: C, 54.80; H, 4.70; N, 21.03%.
Synthesis of compounds (4a–f); general procedure
A mixture of 3a–f (0.01 mol) and oxalyl chloride (1.9 g, 0.015 mol) in
dry benzene (20 mL) was heated under reflux for 10 h. The reaction
mixture was cooled and the separated solid was filtered, dried and
recrystallised from acetonitrile. Using this method the following
compounds were prepared.
Ethyl6-phenyl-7,8-dioxo-9-phenyl-6,7,8,9-tetrahydro-1-thia-3,5,6,9-
tetraazabenz[cd]azulene-2-carboxylate (4a): Yellow solid, yield:
58.5%, m.p. 276–278 °C; IR (KBr) ν/cm−1 2978–2890 (CH aliphatic),
1743, 1712, 1651 (3 C=O); 1H NMR (200 MHz, DMSO-d6) δ 1.26 (t,
3H, CH3, J = 7.20 Hz), 4.25 (q, 2H, CH2, J = 7.20 Hz), 7.47–7.68 (m,
10H, ArH), 8.45 (s, 1H, pyrimidine); MS (m/z) (relative abundance
%): 445.10 (M+1)+ (6.47), 444.20 (M)+, (8.56). Anal. Calcd for
C23H16N4O4S (444.45): C, 62.15; H, 3.62; N, 12.60. Found: C, 62.08;
H, 3.92; N, 12.28%.
Ethyl 6-(4-methylphenyl)-7,8-dioxo-9-phenyl-6,7,8,9-tetrahydro-1-
thia-3,5,6,9-tetraazabenz[cd]azulene-2-carboxylate (4b): Yellow solid,
yield: 52.4%, m.p. 270–272 °C; IR (KBr) ν/cm−1 2941–2978 (CH
aliphatic), 1739, 1712, 1647 (3 C=O); 1H NMR (200 MHz, DMSO-d6)
δ 1.23 (t, 3H, CH3, J = 7.00 Hz), 2.34 (s, 3H, CH3), 4.27 (q, 2H, CH2,
J = 7.00 Hz), 7.38–7.70 (m, 9H, ArH), 8.45 (s, 1H, pyrimidine); MS
(m/z) (relative abundance %): 459 (M+1)+ (82.99). Anal. Calcd for
C24H18N4O4S (458.47): C, 62.86; H, 3.95; N, 12.22. Found: C, 62.90;
H, 3.80; N, 12.0%.
Ethyl 6-(4-ethylphenyl)-7,8-dioxo-9-phenyl-6,7,8,9-tetrahydro-1-
thia-3,5,6,9-tetraazabenz[cd]azulene-2-carboxylate (4c): Yellow solid,
yield: 50.8%, m.p. 286–288 °C; IR (KBr) ν/cm−1 2870–2960 (CH
aliphatic), 1743, 1714, 1647 (3 C=O); 1H NMR (200 MHz, DMSO-d6)
δ 1.24 (t, 3H, CH3, J = 7.20 Hz), 1.28 (t, 3H, CH3, J = 7.40 Hz), 2.68
(q, 2H, CH2, J = 7.20 Hz), 4.23 (q, 2H, CH2, J = 7.40 Hz), 7.38–7.68
(m, 9H, ArH), 8.43 (s, 1H, pyrimidine); 13C NMR (DMSO-d6):
δ 14.32, 15.38, 27.87, 38.69, 38.97, 39.25, 39.53, 39.81, 40.09, 40.37,
60.30, 104.64, 120.73, 120.79, 126.78, 128.46, 128.51, 130.28,
130.47, 131.89, 137.02, 144.65, 147.28, 149.69, 153.16, 156.57,
160.78, 161.02; MS (m/z) (relative abundance %): 444 (M-CO)+
(9.50). Anal. Calcd for C25H20N4O4S (472.50): C, 63.54; H, 4.26; N,
11.85. Found: C, 63.60; H, 4.11; N, 11.62%.
Ethyl 6-(2-hydroxyphenyl)-7,8-dioxo-9-phenyl-6,7,8,9-tetrahydro-
1-thia-3,5,6,9-tetraazabenz[cd]azulene-2-carboxylate (4d): Yellow
solid, yield: 45.6%, m.p. 190–192 °C; IR (KBr) ν /cm−1 3350–3500
(OH), 2843–2981 (CH aliphatic), 1735, 1701, 1647 (3 C=O); 1H NMR
(200 MHz, DMSO-d6) δ 1.26 (t, 3H, CH3, J = 7.2 Hz), 4.25 (q, 2H,
CH2, J = 7.2 Hz), 6.94–7.69 (m, 9H, ArH), 8.48 (s, 1H, pyrimidine),
9.8 (s, 1H, OH, D2O exchangeable); MS (m/z) (relative abundance %):
460.79 (M+1)+ (100);Anal. Calcd for C23H16N4O5S (460.45): C, 59.99;
H, 3.5; N, 12.16. Found: C, 59.94; H, 3.5; N, 11.97%.
Ethyl 6-(4-hydroxyphenyl)-7,8-dioxo-9-phenyl-6,7,8,9-tetrahydro-
1-thia-3,5,6,9-tetraazabenz[cd]azulene-2-carboxylate (4e): Yellow
solid, yield: 50%, m.p. 220–222 °C; IR (KBr) ν/cm−1 3271–3184
(OH), 2883–2980 (CH aliphatic), 1741, 1699, 1649 (3 C=O); 1H NMR
(200 MHz, DMSO-d6) δ 1.22 (t, 3H, CH3, J = 7.20 Hz), 4.23 (q, 2H,
CH2, J = 7.20 Hz), 6.92–7.70 (m, 9H, ArH), 8.48 (s, 1H, pyrimidine),
10.40 (s, 1H, OH, D2O exchangeable); MS (m/z) (relative abundance
%): 461.89 (M+2)+ (21.94), 460.89 (M+1)+ (100), 459.89 (M)+.
(27.96). Anal. Calcd for C23H16N4O5S (460.45): C, 59.99; H, 3.5; N,
12.16. Found: C, 59.93; H, 3.5; N, 11.96%.
Ethyl 6-(4-chlorophenyl)-7,8-dioxo-9-phenyl-6,7,8,9-tetrahydro-1-
thia-3,5,6,9-tetraazabenz[cd]azulene-2-carboxylate (4f): Yellow solid,
yield: 50.2%, m.p. 273–275 °C; IR (KBr) ν/cm−1 2929–2983 (CH
aliphatic), 1747, 1708, 1649 (3 C=O); 1H NMR (200 MHz, DMSO-d6)
δ 1.28 (t, 3H, CH3, J = 7.00 Hz), 4.27 (q, 2H, CH2, J = 7.00 Hz),
7.45–7.71 (m, 9H, ArH), 8.47 (s, 1H, pyrimidine). Anal. Calcd for
C23H15ClN4O5S (478.89): C, 57.68; H, 3.15; N, 11.69. Found: C,
57.50; H, 3.00; N, 11.51%.
Synthesis of compounds 5a–f; general procedure
A mixture of 3a–f (0.01 mol) and malonyl dichloride (2.11 g, 0.015 mol)
in dry benzene (20 mL) was heated under reflux for 15 h. The reaction

JOURNAL OF CHEMICAL RESEARCH 2012 483
Ethyl 10-phenylamino-2-methyl-3-oxo-3,4-dihydro-2H-thieno[3′,4′:4,5]
pyrimido[1,6-b][1,2,4]triazine-8-carboxylate (7): A mixture of 6
(0.329 g, 0.001 mol), and 2-chloropropionoyl chloride (0.127 g,
0.001 mol) in dry benzene (10 mL) and few drops of dry pyridine was
heated under reflux for 12 h. The reaction mixture was cooled, water
was added and the separated solid was filtered, dried and recrystal-
lised from ethanol to give a brown solid, yield: 52.2%; m.p. 250–
252 °C; IR (KBr) ν/cm−1 3307, 3246 (2 NH), 2929–2980 (CH
aliphatic), 1680, 1668 (2 overlapped C=O); 1H NMR (300 MHz,
DMSO-d6) δ 1.27 (t, 3H, CH3, J = 7.20 Hz), 1.57 (d, 3H, CH3, J =
6.90 Hz), 4.26 (q, 2H, CH2, J = 6.90 Hz), 5.02 (q, 1H, CH, J =
6.60 Hz), 7.12–7.74 (m, 5H, ArH), 8.45 (s, 1H, pyrimidine), 11.31 (s,
1H, NH, D2O exchangeable), 11.93 (s, 1H, NH, D2O exchangeable);
MS (m/z) (relative abundance %): 381 (M-2)+ (0.07). Anal. Calcd for
C18H17N5O3S (383.42): C, 56.38; H, 4.47; N, 18.26. Found: C, 56.32;
H, 4.46; N, 18.59%.
Ethyl 10-phenylamino-2,3-dioxo-3,4-dihydro-2H-thieno[3′,4′:4,5]
pyrimido[1,6-b][1,2,4]triazine-8-carboxylate (8): A mixture of 6
(0.329 g, 0.001 mol) and oxalyl chloride (0.19 g, 0.0015 mol) in
dry benzene (15 mL) was heated under reflux for 14 h. The reaction
mixture was cooled, and the separated solid was filtered, dried and
recrystallised from acetonitrile to give an orange solid, yield: 52.2%;
m.p. 260–262 °C; IR (KBr) ν/cm−1 3184 (2 NH), 2981–2927 (CH
aliphatic), 1720, 1685, 1647 (3 overlapped C=O); 1H NMR (300 MHz,
DMSO-d6) δ 1.23 (t, 3H, CH3 J = 6.90 Hz), 4.27 (q, 2H, CH2 J =
6.90 Hz), 7.03–7.73 (m, 5H, ArH), 8.45 (s, 1H, pyrimidine), 10.47 (s,
1H, NH, D2O exchangeable), 12.44 (s, 1H, NH, D2O exchangeable);
MS (m/z) (relative abundance %): 384 (M+1)+ (0.22), Anal. Calcd for
C17H13N5O4S (383.37): C, 53.25 H, 3.41; N, 18.26. Found: C, 53.64;
H, 3.32; N, 18.00%.
10.40 (s, 1H, NH, D2O exchangeable), 11.60 (s, 1H, NH, D2O
exchangeable); MS (m/z) (relative abundance %): 396 (M-1)+ (0.31).
Anal. Calcd for C18H15N5O4S (397.40): C, 54.39; H 3.80; N, 17.62.
Found: C, 54.75; H, 3.76; N, 17.65%.
Received 9 March 2012; accepted 7 June 2012
Paper 1201203 doi: 10.3184/174751912X13400242909892
Published online: 8 August 2012
References
1
2
3
4
5
6
7
8
S.A. Patil, B.A. Otter and R.S. Klein, J. Heterocyclic Chem., 1993, 30,
509.
A.E. Shinkwin, W.J.D. Whish and M.D. Threadgill, Bioorg. Med. Chem.,
1999, 7, 297.
M. Hamann, C. Pierra, J.P. Sommadossi, C. Musiu, L. Vargiu, M. Liuzzi,
R. Storer and G. Gosselin, Bioorg. Med. Chem., 2009, 17, 2321.
D.T. Connor, R.J. Sorenson, W.A. Cetenko, J.J. Kerbleski and F.J. Tinney,
J. Med. Chem., 1984, 27, 528.
R.K. Russell, J.B. Press, R.A. Rampulla, J.J. McNally, R. Falotico,
J.A. Keiser, D.A. Bright and A. Tobia, J. Med. Chem., 1988, 31, 1786.
M. Sugiyama, T. Sakamoto, K. Tabata, K. Endo, K. Ito, M. Kobayashi and
H. Fukumi, Chem. Pharm. Bull., 1989, 37, 2122.
K. Ogawva, I. Yamawaki, Y.I. Matsusita, N. Nomura, P.F. Kador and
J.H. Kinoshita, Eur. J. Med. Chem., 1993, 28, 769.
I.J. Enyedy, Y. Ling, K. Nacro, Y. Tomita, X. Wu, Y. Cao, R. Guo, B. Li,
X. Zhu, Y. Huang, Y.-Q. Long, P.P. Roller,| D. Yang and S. Wang, J. Med.
Chem., 2001, 44, 4313.
9
T. Baum and M.I. Gluckman, J. Pharmacol. Exp.Ther., 1967, 158, 510.
10 B. Insuasty, F. Orozco, J. Quiroga, R. Abonia, M. Nogueras and J. Cobo,
Eur. J. Med. Chem., 2008, 43, 1955.
11 B. Insuasty, A. Garcia, J. Quiroga, R. Abonia, M. Nogueras and J. Cobo,
Eur. J. Med. Chem., 2010, 45, 2841.
Ethyl 11-phenylamino-2,4-dioxo-2,3,4,5-tetrahydrothieno[3′,4′:4,5]
pyrimido[1,6-b][1,2,4]triazepine-9-carboxylate (9): A mixture of 6
(0.329 g, 0.001 mol) and malonyl dichloride (2.11 g, 0.015 mol) in
dry benzene (15 mL) was heated under reflux for 15 h. The reaction
mixture was cooled, and the separated solid was filtered, dried and
recrystallised from acetonitrile to give a yellowish-brown solid,
yield: 75.5%; m.p. 225–227 °C; IR (KBr) ν/cm−1 3232, 3188 (2 NH),
2926–2850 (CH aliphatic), 1668, 1647 (3 overlapped C=O); 1H NMR
(300 MHz, DMSO-d6) δ 1.22 (br. t, 3H, CH3), 3.70 (s, 2H, CH2), 4.12
(br. q, 2H, CH2), 7.12–7.46 (m, 5H, ArH), 8.44 (s, 1H, pyrimidine),
12 K. Gewald, U. Hain and M. Schmidt, J. Prakt. Chem., 1986, 328, 459.
13 S.R. Kanth, G.V. Reddy, K.H. Kishore, P.S. Rao, B. Narsaiah and
U.S.N. Murthy, Eur. J. Med. Chem., 2006, 41, 1011.
14 Y. Han, K. Ebinger, L.E Vandevier, J.W. Maloney, D.S. Nirschl and
H.N. Weller, Tetrahedron Lett., 2010, 51, 629.
15 A. Foucourt, C. Dubouilh-Benard, E.Chosson, C. Cobiere, C. Buquet,
M. Iannelli, B. Leblond, F. Marsais and T. Besson, Tetrahedron, 2010, 66,
4495.
16 P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica,
J.T. Warren, H. Bokesch, S. Kenney and M.R. Boyd, J. Natl. Cancer Inst.,
1990, 82, 1107.

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