Synthesis of some pyrimidothienopyrimidine derivatives

Article abstract of DOI:10.1007/PL00000109

The pyrimidothienopyrimidines 5 and 6 have been synthesized via the reaction of compounds 4a, b with CS₂ and were further transformed to related fused heterocyclic systems.

Full text of DOI:10.1007/PL00000109

Monatshefte fuÈr Chemie 129, 523±533 (1998)
Synthesis of Some Pyrimidothienopyrimidine
Derivativesa
Adel M. Kamal El-Dean
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Summary. The pyrimidothienopyrimidines 5 and 6 have been synthesized via the reaction of
compounds 4a, b with CS2 and were further transformed to related fused heterocyclic systems.
Keywords. Synthesis; Heterocycles; Pyrimidines; Thienopyrimidines; Pyrimidothienopyrimidines.
Synthese einiger Pyrimidothienopyrimidin-Derivate
Zusammenfassung. Die Pyrimidothienopyrimidine 5 und 6 wurden durch Reaktion der Verbin-
dungen 4a,b mit CS2 hergestellt und weiter zu verwandten kondensierten heterocyclischen Systemen
umgesetzt.
Introduction
Thienopyrimidines and pyrimidothienopyrimidines have been the subject of
chemical and biological studies due to their interesting pharmacology [1] which
includes analgesic [2], antipyretic [3], and antiin¯ammatory [4, 5] properties. In
view of the above activities and in continuation of our work in the synthesis of
fused heterocycles with thienopyrimidine [6, 7], we report herein the synthesis of
some fused pyrimidothienopyrimidines.
Results and Discussion
Recently, G. Wagner et al. [9] have reported the synthesis of compound 3 by
reaction of dibenzoyldiacetonitrile with cyanothioacetamide. We present its
synthesis from crotononitrile (1) via condensation with benzoylisothiocyanate (2).
The resulting compound 3 was reacted with chloroacetonitrile and with chloro-
acetamide in ethanol in the presence of sodium ethoxide to give S-alkylated
derivatives as intermediates which upon heating cyclized to the thienopyrimidines
4a, b.
3-Amino-4-methyl-6-phenylthieno[2,3-d]pyrimidine-2-carbonitrile (4a) and
3-amino-4-methyl-6-phenylthieno[2,3-d]pyrimidine-2-carboxamide (4b) were
a
An abstract of this paper was published at the 36th IUPAC congress, Geneva, August 17±22, 1997.

524
A. M. Kamal El-Dean
Scheme 1
reacted with CS2 in pyridine to afford pyrimidothienopyrimidines 5 and 6,
respectively.
Reaction of 6 with monobromomalononitrile (9) in ethanol in the presence of
an equivalent of sodium hydroxide resulted in an S-alkylated derivative which was
instable under the reaction condition and cyclized to thiazolopyrimidothienopyr-
imidine (10).
When compound 6 was reacted with hydrazine hydrate in pyridine,
2-hydrazino-9-methyl-7-phenylpyrimido[40,50:4,5]thieno[2,3-d]pyrimidin-2(3H)-
one (11) was obtained. Compound 11 in turn could be transformed to other fused
heterocyclic systems. Condensation with aromatic aldehydes in re¯uxing ethanol
affored the coresponding carbohydrazones 12. Triazolopyrimidothienopyrimidines
13±15 and tetrazolopyrimidothienopyrimidine 16 were produced from the reaction
Scheme 2

Pyrimidothienopyrimidines
525
Scheme 3
of 11 with triethyl orthoformate in the presence of catalytic amounts of acetic acid,
carbon disul®de in pyridine, acetic anhydride, and nitrous acid. When compound
11 was allowed to react with acetylacetone in ethanol, ethoxymethylene
malononitrile, or ethoxymethylene ethylcyanoacetate in ethanol in the presence
of acetic acid or with nitrous acid in acetic acid, compounds 17 and 18a, b were
obtained.
Scheme 4
The o-aminonitrile 4a was condensed with triethyl orthoformate in acetic
anhydride to give 3-ethoxymethyleneamino-4-methyl-6-phenylthieno[2,3-d]pyri-
midin-2-carbonitrile (19). Upon treatment with hydrazine hydrate, 19 afforded the
corresponding hydrazone as intermediate which cyclized to pyrimidothienopyr-
imidine 20 under the reaction conditions.

526
A. M. Kamal El-Dean
Scheme 5
Triazolopyrimidothienopyrimidines 21±24 were produced when 3-N-amino-4-
imino-9-methyl-7-phenylpyrimido[40,50;4,5]thieno[2,3-d]pyrimidine (20) was sub-
jected to a reaction with triethyl orthoformate, acetic anhydride, carbon disul®de in
re¯uxing pyridine, and aromatic aldehydes. Treatment of 20 with ethoxymethle-
nemalononitrile and ethoxymethylene ethylcyanoacetate in re¯uxing ethanol in the
presence of catalytic amounts of acetic acid resulted in pyrimidothienopyrimido-
triazepines 25a, b.
Scheme 6
Experimental
Melting points were determined on a Ko¯er melting point apparatus and are uncorrected. The IR
spectra were recorded as potassium bromide disks on a Pye Unicam spectrophotometer using the
1
KBr wafer technique. H NMR spectra were obtained on Varian 390 90 MHz spectrometer in a
suitable deuterated solvent. Chemical shifts refer to tetramethylsilane as internal standard. Elemental
analyses were obtained on a Perkin Elmer 240 C microanalyzer.
4-Methyl-2-phenyl-6-mercaptopyrimidine-5-carbonitrile (3)
To a freshly prepared solution of benzoyl isothiocyanate (0.01 mol) in dry acetone (20 ml), a solution
of crotononitrile (8.2 g, 0.01 mol) in acetone (10 ml) was added. The mixture was stirred at room

Pyrimidothienopyrimidines
527
temperature for 1 h and then re¯uxed on a steam bath for additional 2 h. The solvent was removed,
and the solid product was collected and recrystallized from ethanol as golden yellow crystals.
Yield; 19.13 g (84%); m.p.: 228±230ꢀC (Refs. [8, 9]: m.p.: 228±232ꢀC).
3-Amino-4-methyl-6-phenylthieno[2,3-d]pyrimidin-2-carbonitrile (4a):
To a stirred sample of compound 3 (2.3 g, 0.001 mol) in ethanol (20 ml) containing 0.7 g (0.01 mol)
sodium ethoxide, chloroacetonitrile (0.01 mol) was added. The mixture was stirred at room
temperature for 0.5 h. Then the reaction mixture was heated at 60±70ꢀC for 0.5 h and allowed to cool.
The solid product was collected and recrystallized from ethanol as yellow crystals.
Yield: 2.34 g (88%); m.p.: 180ꢀC; C14H10N4S (266.32); calc.: C 63.14, H 3.78, N 21.04, S, 12.04;
1
found: C 62.94, H 4.00, N 20.88, S 11.90; IR: ꢀ ˆ 3300, 3200 (NH2), 2220 (CN) cmꢁ1; H NMR
(DMSO-d6): ꢁ ˆ 2.85 (s, 3H, CH3), 6.5 (s, 2H, NH2), 7.4±8.2 (m, 5H, ArH) ppm.
3-Amino-4-methyl-6-phenylthieno[2,3-d]pyrimidin-2-carbxamide (4b)
4b was prepared according to the literature.
Yield: 82%; m.p.: 230ꢀC (Ref. [9]: m.p.: 227±229ꢀC).
7-Phenyl-1,2,3,4-tetrahydro-9-methylpyrimido[40,50:4,5]thieno[2,3-d]pyrimidin-2,4-dithione (5)
A mixture of compound 4a (2.66 g, 0.01 mol) and CS2 (2 ml) in pyridine (15 ml) was re¯uxed for 8 h
and then allowed to cool. The solid product was collected and recrystallized from dioxane as orange
crystals.
Yield: 2.05 g (76%); m.p.: >320ꢀC; C15H10N4S2 (310.39); calc.: C 58.04, H 3.25, N 18.05, S
20.66; found: C 57.82, H 3.06, N 17.88, S 20.80; IR: ꢀ ˆ 3240, 3180 (2NH), 3050 (CH Ar), 2250±
1
2220 (2C=S) cmꢁ1; H NMR (CF3COOD): ꢁ ˆ 2.85 (s, 3H, CH3), 7.6, 8.5 (2m, 5H, ArH) ppm.
7-Phenyl-1,2,3,4-tetrahydro-4-oxo-9-methylpyrimido[40,50:4,5]thieno[2,3-d]pyrimidin-2-thione (6)
6 was prepared from compound 4b according to the procedure reported for the preparation of 5. It
was recrystallized from dioxane as orange crystals.
Yield: 2.3 g (78%); m.p.: >320ꢀC; C15H10N4OS (294.33); calc.: C 61.21, H 3.42, N 19.04, S
10.89; found: C 61.00, H 3.64, N 18.84, S 11.12; IR: ꢀ ˆ 3250, 3180 (2NH), 1680 (C=O), 1250
1
(C=S) cmꢁ1; H NMR (CF3COOD): ꢁ ˆ 2.9 (s, 3H, CH3), 7.65, 8.6 (2m, 5H, ArH) ppm.
2,4-Dialkylmercapto-9-methyl-7-phenylpyrimido[40,50:4,5]thieno[2,3-d]pyrimidines (7a, b)
A mixture of compound 5 (1.55 g, 0.005 mol), sodium acetate (980 mg, 0.012 mol), and halo
compound (0.005 mol) in ethanol (25 ml) was re¯uxed for 2 h and then allowed to cool. The solid
product was collected, washed with water several times, dried, and recrystallized from ethanol. The
physical constants and spectroscopic data of compounds 7a, b are listed in Tables 1 and 2.
2-Alkylmercapto-9-methyl-7-phenlpyrimido[40,50:4,5]thieno[2,3-d]pyrimidine-4-(3H)-ones (8a±h)
Compounds 8a±h were prepared according to the method reported for the synthesis of 7a, b starting
from 6 (1.47 g, 0.005 mol), sodium acetate (490 mg, 0.006 mol), and the appropriate halo compounds
(0.005 mol). The physical constants and spectroscopic data of compounds 8a±h are listed in Tables 1
and 2.

528
A. M. Kamal El-Dean
Table 1. Spectroscopic data of compounds 7a, b and 8a±h
IR
ꢀ (cmꢁ1
1H NMR
)
ꢁ (ppm)
7a 3050 (CH aromatic, 2950 (CH
aliphatic), 1600 (C=N)
DMSO-d6; 3.85 (s, 3H, CH3), 4.0 (s, 6H, 2CH3), 7.3±8.3
(m, 5H, ArH)
7b 3050 (CH aromatic), 1690
(2 C=O), 1600 (C=N)
DMSO-d6; 3.8 (s, 3H, CH3), 4.15 (s, 4H, 2S, CH2), 7.3±8.4
(m, 15H, Ar-H)
8a 3240 (NH), 1670 (C=O)
DMSO-d6; 3.0 (s, 3H, CH3), 3.25 (q, 2H, CH2), 7.45,
8.32 (m, 5H, Ar-H), 12.5 (s, 1H, NH)
8b 3220 (NH), 1710, 1680 (2C=O) DMSO-d6; 1.85 (d, 1H, CH), 3.35, 3.6, 3.95 (3s, 9H,
3CH3), 7.65, 8.3 (2m, 5H, ArH), 12.2 (s, 1H, NH)
8c 3250 (NH), 1700, 1680 (2C=O) DMSO-d6; 2.95, 3.8 (2s, 6H, 2CH3), 4.0 (s, 2H, SCH2),
7.4±8.3 (m, 5H, ArH), 12.4 (s, 1H, NH)
8d 3240 (NH), 1695, 1670 (2C=O) DMSO-d6; 3.2 (s, 3H, CH3), 4.05 (s, 2H, CH2),
7.4±8.35 (m, 10H, ArH), 12.5 (s, 1H, NH)
8e 3240 (NH), 1700, 1675 (2C=O) DMSO-d6; 3.25 (s, 3H, CH3), 4.05 (s, 2H, CH2), 7.4±8.35
(m, 9H, ArH) 12.5 (s, 1H, NH)
8f 3340, 3240 (2NH), 1680, 1670
(2C=O)
CF3COOD; 3.2 (s, 3H, CH3), 4.05 (s, 2H, CH2), 7.4±8.35
(m, 10H, ArH)
8g 3320, 3180 (2NH), 1685, 1670
(2C=O)
DMSO-d6; 3.0 (s, 3H, CH3), 3.7 (s, 3H, OCH3), 4.2 (q,
2H, CH2), 6.8±7.6, 8.4 (2m, 9H, Ar-H), 10.2, 12.3 (2s, 2H,
2NH)
8h 3335, 3220 (2NH), 1690, 1670
(2C=O)
CF3COOD; 3.15 (s, 3H, CH3), 4.05 (s, 2H, CH2),
7.4±8.35 (m, 9H, ArH)
3-Amino-10-methyl-8-phenyl-5-oxothiazolo[200,300:20,30]pyrimido[50,60:4,5]thieno[2,3-d]pyrimi-
dine-2-carbonitrile (10)
To a stirred sample of compound 6 (2.94 g, 0.01 mol) in ethanolic sodium hydroxide solution (4%,
5 ml), bromomalononitrile (1.45 g, 0.01 mol) was added. The mixture was stirred for 15 minutes and
then warmed at 50±60ꢀC for another 15 minutes. The solid product was collected and recrystallized
from dioxane as yellow crystals.
Yield: 3.05 g (78%); m.p.: >300ꢀC; C18H10N6OS2 (390.44); calc.: C 55.37, H 2.58, N 21.52, S
16.42; found: C 55.18, H 2.72, N 21.48, S 16.56; IR: ꢀ ˆ 3350, 3250 (NH2), 1690 (C=O) cmꢁ1
1H NMR (DMSO-d6): ꢁ ˆ 2.85 (s, 3H, CH3), 6.4 (s, 2H, NH2), 7.6±8.6 (m, 5H, ArH) ppm.
2-Hydrazino-9-methyl-7-phenylpyrimido[40,50:4,5]thieno[2,3-d]pyrimidin-4-(3H)-one (11)
A mixture of compound 6 (2.94 g, 0.01 mol) and hydrazine hydrate (1 ml, 0.02 mol) in pyridine
(20 ml) was re¯uxed for 10 h or till H2S evolution ceased. The solid product was collected and
recrystallized from DMF as yellowish white crystals.
Yield: 74%; m.p.: 300ꢀC; C15H12N6OS (324.36); calc.: C 55.54, H 3.73, N 25.91, S 9.88; found:
C 55.74, H 4.00, N 25.72, 10.12; IR: ꢀ ˆ 3400, 3300, 3250, 3200 (2NH, NH2), 1660 (C=O) cmꢁ1
;
1H NMR (DMSO-d6): ꢁ ˆ 2.85 (s, 3H, CH3), 3.8 (br s, 2H, NH2), 6.7 (s, 1H, NH), 7.55±8.6 (m, 5H,
ArH), 10.8 (s, 1H, NH) ppm.

Pyrimidothienopyrimidines
529
Table 2. Physical constants of compounds 7a, b and 8a±h
m.p.
(ꢀC)
Yield
(%)
Molecular Formula Analytical Data
(Mol.Wt.)
C
H
N
S
Cl
7a
254±255
78
82
78
82
86
84
86
82
78
83
C17H14N4S3
(370.50)
55.11
54.92
64.34
64.52
57.61
57.68
55.33
55.18
56.53
56.66
62.15
61.94
57.68
57.44
60.12
60.00
58.88
59.04
55.92
56.12
3.81
4.04
3.83
4.06
3.98
4.08
3.91
4.12
3.69
3.72
3.63
3.88
3.16
3.34
3.73
4.01
3.91
4.12
3.26
3.06
15.12
14.94
9.68
25.96
26.16
16.62
16.76
18.09
17.90
15.54
15.44
16.77
17.00
14.42
14.68
13.39
13.53
13.95
14.12
13.10
13.28
12.98
13.20
7b 194
C31H22N4O2S3
(578.72)
9.60
8a
>300
C17H14N4OS2
(354.44)
15.81
16.00
13.58
13.72
14.65
14.44
12.60
12.44
11.70
11.68
15.24
15.08
14.31
14.23
14.18
13.98
8b 227±229
C19H16N4O3S2
(412.48)
8c
288
C18H14N4O2S2
(382.45)
8d 298±299
C23H16N4O2S2
(444.53)
8e
8f
304
C23H15ClN4O2S2
(478.97)
7.40
7.48
>300
>320
C23H17N5O2S2
(459.54)
8g
C24H19N5O3S2
(489.57)
8h >320
C23H16ClN5O2S2
(493.99)
7.18
6.96
2-Aryledinehydrazino-9-methyl-7-phenylpyrimido[40,50:4,5]thieno[2,3-d]pyrimidin-4(3H)-ones
(12a±d); general procedure
A mixture of compound 11 (1.55 g, 0.005 mol) and the appropriate aldehyde (0.005 mol) in ethanol
(30 ml) was re¯uxed for 3 h and then allowed to cool. The solid product was collected and
recrystallized from acetic acid.
12a: Ar ˆ Ph; yellow crystals; Yield: 72%; m.p.: >320ꢀC; C22H16N6OS (412.47); calc.: C 64.06,
H 3.91, N 20.37, S 7.77; found: C 63.88, H 4.10, N 20.14, S 8.00; IR: ꢀ ˆ 3360, 3270 (2NH), 1660
1
(C=O) cmꢁ1; H NMR (CF3COOD): ꢁ ˆ 2.80 (s, 3H, CH3), 7.35±8.5 (m, 10H, ArH), 9.2 (s, 1H,
CH=N) ppm.
12b: Ar ˆ p±C6H4OCH3; yellow crystals; yield: 80%; m.p.: >320ꢀC; C23H18N6O2S (442.49);
calc.: C 62.43, H 4.10, N 18.99, S 7.25; found: C 62.32, H 4.00, N 119.12, S 7.08; IR: ꢀ ˆ 3340,
1
3270 (2NH), 1660 (C=O) cmꢁ1; H NMR (CF3COOD): ꢁ ˆ 2.85 (s, 3H, CH3, 3.3 (s, 3H, OCH3),
7.55±8.6 (m, 9H, ArH), 8.95 (s, 1H, CH=N) ppm.
12c: Ar ˆ p-C6H4Cl; yellow crystals; yield: 82%; m.p.: >320ꢀC; C22H15ClN6OS (446.91); calc.:
C 59.13, H 3.38, N 18.80, S 7.17, Cl 7.93; found: C 58.90, H 3.44, N 19.00, S 7. 17, Cl 8.05; IR:
1
ꢀ ˆ 3350, 3270 (2NH), 1670 (C=O) cmꢁ1; H NMR (CF3COOD): ꢁ ˆ 2.75 (s, 3H, CH3), 7.55±8.6
(m, 9H, ArH), 8.9 (s, 1H, CH=N) ppm.
12d: Ar ˆ C6H4NO2; yellow crystals; yield: 78%; m.p.: >300ꢀC; C22H15N7O3S (457.47); calc.: C
57.76, H 3.30, N 21.43, S 7.01; found: C 58.00, H 3.12, N 21.64, S 6.98; IR: ꢀ ˆ 3350, 3260 (2NH),
1680 (C=O) cmꢁ1; 1H NMR (CF3COOD): ꢁ ˆ 2.85 (s, 3H, CH3), 7.55±8.6 (m, 9H, ArH), 9.0 (s, 1H,
CH=N) ppm.

530
A. M. Kamal El-Dean
10-Methyl-8-phenyl-1(H)-triazolo[300,400:2,3]pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-5-one (13)
To a mixture of compound 11 (1.55 g, 0.005 mol) and triethyl orthoformate (0.01 mol) in methanol
(20 ml), a few drops of acetic acid were added. The mixture was re¯uxed for 3 h and then allowed to
cool. The solid product was collected and recrystallized from dioxane.
Yellow crystals; m.p.: >300ꢀC; C16H10N6OS (334.36); calc.: C 57.48, H 3.01, N 25.14, S, 9.59;
found: C 57.32, H 3.22, N 24.92, S 9.74; IR: ꢀ ˆ 3380 (NH), 1680 (C=O) cmꢁ1
;
1H NMR
(CF3COOD): ꢁ ˆ 3.80 (s, 3H, CH3), 7.7±8.3 (m, 5H, ArH), 9.2 (s, H, CH triazole) ppm.
3-Mercapto-10-methyl-8-phenyl-1(H)-triazolo[300,400:2,3]pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-
5-one (14)
A mixture of compound 11 (1.55 g, 0.005 mol) and carbon disul®de (2 ml) in pyridine (15 ml) was
re¯uxed on a steam bath for 10 h and then allowed to cool. The solid product was collected and
recrystallized from dioxane.
Orange crystals; yield: 82%; m.p.: >300ꢀC; C1610N6OS2 (366.42); calc.: C 52.45, H 2.75, N
22.94, S 17.50; found: C 52.18, H 3.00, N 23.14, S 17.74; IR: ꢀ ˆ 3050 (CH aromatic), 3220 (NH),
2850±2720 (SH), 1600 (C=N) cmꢁ1; 1H NMR (CF3COOD): ꢁ ˆ 3.85 (s, 3H, CH3), 7.5±8.2 (m, 5H,
ArH), 8.6 (s, 1H, CH pyrimidine) ppm.
3,10-Dimethyl-8-phenyl-1(H)-triazolo[300,400:2,3]pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-5-one
(15)
A sample of compound 11 (1.55 g, 0.05 mol) in acetic anhydride (10 ml) was heated under re¯ux for
3 h, allowed to cool, and poured into cold water. The solid product was collected and recrystallized
from acetic acid. Yellow crystals; yield: 78%; m.p.: >300ꢀC; C17H12N6OS (348.38); calc.: C 58.61,
H 3.47, N 24.12, S 9.20; found: C 58.88, H 3.42, N 23.94, S 9.06; IR: ꢀ ˆ 3320 (NH), 1670 (C=O)
cmꢁ1; 1H NMR (CF3COOD): ꢁ ˆ 3.0, 3.80 (2s, 6H, 2CH3), 7.6±8.0, 8.3 (2m, 5H, ArH), 9.8 (s, 1H,
CH) ppm.
4-Methyl-2-phenyl-6(H)-titrazolo[100,500:2,3]pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-10-one (16)
To a sample of compound 11 (0.05 mol) dissolved in a mixture of acetic acid/HCl (v/v, 10 ml),
sodium nitrite solution (0.01 mol) was added dropwise with stirring during 10 min. The stirring was
continued for additional 2 h; then the mixture was allowed to stand for 3 h. The solid product was
collected and recrystallized from dioxane.
Orange crystals; yield: 68% m.p.: 280±285ꢀC (decomp); C15H9N7OS (307.33); calc.: C 58.62, H
2.95, N 22.79, S 10.43; found: C 58.44, H 3.16, N 23.00, S 10.32; IR: ꢀ ˆ 3320 (NH), 1610 (N=N)
1
cmꢁ1; H NMR (CF3COOD): ꢁ ˆ 3.75 (s, 3H, CH3), 7.3±8.3 (m, 5H, ArH) ppm.
4-Methyl-2-phenyl-6(3,5-dimethylpyrazol-1-yl)pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-8-one (17)
A mixture of compound 11 (0.05 mol), acetyl acetone (0.01 mol), and ethanol (20 ml) was re¯uxed
for 5 h and then allowed to cool. The solid product was collected and recrystallized from acetic acid.
Yellow crystals; yield: 72%; m.p.:>320ꢀC; C20H16N6OS (388.45); calc.: C 61.84, H 4.15, N
21.63, S 8.25; found: C 62.06, H 3.92, N 21.84, S 8.12; IR: ꢀ ˆ 3250 (NH), 1600 (C=N), no bands
1
characterisitc for NH2; H NMR (CF3COOD): ꢁ ˆ 2.4, 2.75, 3.8 (3s, 9H, 3CH3), 6.05 (s, 1H, CH
pyrazole), 7.4±8.3 (m, 5H, ArH) ppm.

Pyrimidothienopyrimidines
531
4-Methyl-2-phenyl-6-(3-amino-4-cyanopyrazol-1-yl)pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-
8-one (18a)
4-Methyl-2-phenyl-6-(3-amino-4-carboethoxy-1-yl)-pyrimido[50,60:4,5]thieno[2,3-d]pyrimidin-
8-one (18b)
To a mixture of compound 11 (0.005 mol) and ethoxymethylenemalononitrile or ethoxymethylene
ethylcyanoacetate (0.005 mol) in methanol, a few drops of acetic acid were added as a catalyst. The
mixture was re¯uxed for 3 h and then allowed to cool. The solid product was collected and
recrystallized from dioxane.
18a: white crystals; yield: 78%; m.p.: >330ꢀC; C19H12N8OS (400.42); calc.: C 56.99, H 3.02, N
27.98, S 8.01; found: C 57.19, H 3.26, N 28.08, S 7.77; IR: ꢀ ˆ 3330, 3230, 3150 (NH2, NH), 2220
(CN), 1600 (C=N) cmꢁ1; 1H NMR (DMSO-d6): ꢁ ˆ 3.80 (s, 3H, CH3), 6.8 (s, 2H, NH2), 7.6±83 (m,
5H, ArH), 8.8 (s, 1H, CH), 12.3 (s, 1H, NH) ppm.
18b: white crystals; yield: 72%; m.p.: >330ꢀC; C21H17N7O3S (447.47); calc.: C 56.37, H 3.83, N
21.91, S 7.16; found: C 56.19, H 4.00, N 22.08, S 7.27; IR: ꢀ ˆ 3300, 3200, 3140 (NH2, NH), 1710
(C=O), 1600 (C=N) cmꢁ1; 1H NMR (DMSO-d6): ꢁ ˆ 1.5 (t, 3H, CH3), 3.5 (q, 2H, CH2), 3.85 (s, 3H,
CH3), 6.75 (s, 2H, NH2), 7.6±845 (m, 5H, ArH), 8.8 (s, 1H, CH), 12.5 (s, 1H, NH) ppm.
3-Ethoxymethyleneamino-4-methyl-6-phenylthieno[2,3-d]pyrimidin-2-carbonitrile (19)
A mixture of compound 4a (0.01 mol), triethyl orthoformate (3 ml), and acetic anhydride (10 ml) was
heated under re¯ux for 4 h and then allowed to cool. The solid product was collected and
recrystallized from dioxane.
Yellow crystals; yield: 74%; m.p.: 142±143ꢀC; C17H14N4OS (322.38); calc.: C 63.34, H 4.38, N
17.38, S 9.94; found: C 63.14, H 4.52, N 17.18, S 10.12; IR: ꢀ ˆ 3050 (CH aromatic), 2225 (CN),
1600 (C=N), no band characterestic for NH2; 1H NMR (DMSO-d6): ꢁ ˆ 1.3 (t, 3H, CH3), 2.75 (s, 3H,
CH3), 4.4 (q, 2H, CH2), 7.5, 8.4 (2m, 6H, ArH, CH=N) ppm.
3-Amino-4-imino-7-phenyl-9-methylpyrimido[40,50:4,5]thieno[2,3,-d]pyrimidine (20)
A mixture of compound 19 (1.61 g, 0.005 mol) and hydrazine hydrate (0.30 ml, 0.06 mol) in ethanol
(20 ml) was re¯uxed for 2 h and then allowed to cool. The solid product was collected and
recrystallized from dioxane.
Yellow crystals; yield: 68%; m.p.: >330ꢀC; C15H12N6S (308.36); calc.: C 58.43, H 3.92, N 27.25,
S 10.40; found: C 58.22, H 4.12, N 27.08, S 10.32; IR: ꢀ ˆ 3340, 3240, 3160 (NH2, NH), 1580
(C=N) cmꢁ1; 1H NMR (DMSO-d6): ꢁ ˆ 3.7 (s, 3H, CH3), 6.7 (s, 2H, NH2), 7.35±8.2 (m, 5H, ArH),
8.95 (s, 1H, CH pyrimidine), 10.7 (s, 1H, NH) ppm.
4-Methyl-2-phenyltriazolo[100,50010,60]pyrimido[40,50:4,5]thieno[2,3-d]pyrimidine (21)
To a mixture of compound 20 (1.54 g, 0.005 mol) and triethyl orthoformate (1.7 ml, 0.01 mol) in
methanol (20 ml), a few drops of acetic acid were added as a catalyst. The mixture was heated under
re¯ux for 2 h and then allowed to cool. The solid product was ®ltered off and recrystallized from
DMF.
Yellow crystals; yield: 72%; m.p.: >333ꢀC; C16H10N6S (318.36); calc.: C 60.37, H 3.17, N 26.40,
S 10.07; found: C 60.22, H 3.32, N 26.48, S 9.92; IR: ꢀ ˆ 3050 (CH aromatic), 1600 (C=N), no
bands characteristic for (NH, NH2); 1H NMR (CF3COOD): ꢁ ˆ 3.80 (s, 3H, CH3), 7.7±8.0, 8.3 (2m,
5H, ArH), 8.45, 9.1 (2s, 2H, 2CH) ppm.

532
A. M. Kamal El-Dean
4,8-Dimethyl-2-phenyltriazolo[100,50010,60]pyrimido[40,50:4,5]thieno[2,3-d]pyrimidine (22)
A sample of compound 20 (1.54 g, 0.005 mol) in acetic anhydride (10 ml) was re¯uxed for 5 h and
then allowed to cool. Under stirring, the reaction mixture was poured into an ice/water mixture
(100 ml). The solid product was collected and recrystallized from dioxane.
Yellow crystals; yield: 68%; m.p.: >320ꢀC; C17H12N6S (332.38); calc.: C 61.43, H 3.64, N 25.28,
S 9.65; found: C 61.65, H 3.83, N 25.06, S 9.48; IR: ꢀ ˆ 3050 (CH aromatic), 2950 (CH aliphatic),
1600 (C=N) cmꢁ1; 1H NMR (DMSO-d6): 3.0, 3.80 (2s, 6H, 2 CH3), 7.6±8.0, 8.3 (2m, 5H, ArH), 9.8
(s, 1H, CH) ppm.
4-Methyl-8-mercapto-2-phenyltriazolo[100,50010,60]pyrimido[40,50:4,5]thieno[2,3-d]pyrimidine (23)
A mixture of compound 20 (1.54 g, 0.005 mol) and carbon disul®de (2 ml) in pyridine (10 ml) was
re¯uxed on a steam bath for 12 h and then allowed to cool. The excess of CS2 was removed, and the
solid product was collected and recrystallized from DMF.
Orange crystals; yield: 75%; m.p.: >330ꢀC; C16H10N6S2 (350.42); calc.: C 54.84, H 2.88, N
23.98, S 18.30; found: C 55.02, H 3.00, N 23.88, S 18.22; IR: ꢀ ˆ 3050 (CH aromatic), 2900±2750
(SH), 1600 (C=N), no bands characteristic for NH and NH2; 1H NMR (CF3COOD): ꢁ ˆ 3.85 (s, 3H,
CH3), 7.75±8.35 (m, 5H, ArH), 8.9 (s, 1H, CH), 10.5 (s, 1H, SH) ppm.
4-Methyl-8-aryl-2-phenyltriazolo[100,50010,60]pyrimido[40,50:4,5]thieno[2,3-d]pyrimidine
(24); general procedure
A mixture of compound 20 (1.54 g, 0.005 mol) and aromatic aldehyde (0.005 mol) in acetic acid
(20 ml) was re¯uxed for 3 h and then allowed to cool. The solid product was collected and
recrystallized from DMF.
24a: Ar ˆ Ph; yellow crystals; yield: 74%; m.p.: >320ꢀC; C22H13N6S (393.45); calc.: C 67.16,
H 3.33, N 21.36, S 8.15; found: C 67.02, H 3.12, N 21.38, S 8.22; IR: ꢀ ˆ 3050 (CH aromatic), 1600
(C=N), no bands characteristic for NH and NH2; 1H NMR (DMSO-d6); ꢁ ˆ 3.80 (s, 3H, CH3),
7.6±8.6 (m, 10H, ArH), 9.8 (s, 1H, CH) ppm.
24b: Ar ˆ p-C6H4NO2; yellow crystals; yield: 74%; m.p.: >320ꢀC; C22H12N7O2S (438.44); calc.:
C 60.27, H 2.76, N 22.36, S, 7.31; found: C 60.02, H 3.00, N 22.38, S 7.22; IR: ꢀ ˆ 3050 (CH
aromatic), 1610 (C=N), no bands characteristic for NH and NH2; 1H NMR (DMSO-d6): ꢁ ˆ 3.85 (s,
3H, CH3), 7.6±8.45 (m, 9H, ArH), 9.8 (s, 1H, CH) ppm.
2-Amino-9-methyl-11-phenylpyrimido[4,5:40,50]thieno[20,30:4,5]pyrimido[1,6-b]triazebine-
3-carbonitrile (25a)
Ethyl 2-amino-9-methyl-11-phenylpyrimido[4,5:40,50]thieno[20,30:4,5]pyrimido[1,6-b]triazebine-
3-carboxylate (25b)
To a mixture of compound 20 (1.54 g, 0.005 mol) and ethoxymethylenemalononitrile (0.61 g,
0.005 mol) or ethoxymethelene ethylcyanoacetate (0.85 g, 0.005 mol) in methanol (20 ml), a few
drops of acetic acid were added. The mixture was re¯uxed for 3 h and allowed to cool. The solid
product was collected and recrystallized from dioxane.
25a: yield: 68%; m.p.: >320ꢀC; C19H12N8S (384.42); calc.: C 59.36, H 3.15, N 29.15, S 8.34;
1
found: C 59.48, H 3.00, N 28.94, S 8.52; IR: ꢀ ˆ 3320, 3220 (NH2), 2220 (CN) cmꢁ1; H NMR
(CF3COOD): ꢁ ˆ 3.80 (s, 3H, CH3), 6.55 (s, 1H, CH triazepine), 7.75±8.35 (m, 5H, ArH), 8.9 (s, 1H,
CH pyrimidine) ppm.
25b: yield: 68%; m.p.: >320ꢀC; C21H17N7O2S (431.47); calc.: C 58.46, H 3.97, N 22.72, S 7.43;
1
found: C 59.36, H 4.00, N 21.92, S 7.42; IR: ꢀ ˆ 3340, 3240 (NH2), 1710 (C=O) cmꢁ1; H NMR

Pyrimidothienopyrimidines
533
(CF3COOD): ꢁ ˆ 1.5 (t, 3H, CH3 ester), 3.80 (s, 3H, CH3), 4.15 (q, 2H, CH2 ester), 6.50 (s, 1H, CH
triazepine), 7.75±8.35 (m, 5H, ArH), 9.0 (s, 1H, CH pyrimidine) ppm.
References
[1] Ralf B, Runland P, Dieter L, Gunter L, Brigitte P (1986) Ger (East) DD, 234 268; (1986) Chem
Abstr 105: 226631e
[2] Dave CG, Shah PR, Dave KC, Patel VJ (1989) J Indian Chem Soc 66: 48
[3] Bousquet E, Romero G, Guerrera F, Caruso A, Roxas MA (1985) Farmaco Ed Sci 40: 869
[4] Vieweg H, Leistner S, Wagner G, Boehm N, Krasset UG, Lohmann RD, Loban G (1988) East
German Patent, DD 257, 830; (1989) Chem Abstr 110: 95262p
[5] Leistner S, Wagner G, Guetscharo M, Glusa E (1986) Pharmazie 41: 54
[6] Kamal El-Dean AM (1996) J Chem Research (M) 1401
[7] Abdel Hafez AA, Kamal El-Dean AM, Hassan AA, El-Kashef HS, Rault S, Robba M (1996) J
Heterocyclic Chemistry 33: 431
[8] Goerdeler J, Wieland D (19967) Chem Ber 100: 47
[9] Wagner G, Vieweg H, Leistner S (1993) Pharmazie 48: 588
Received October 13, 1997. Accepted (revised) January 7, 1998