A convenient synthesis for some new pyrido [4′,3′:4,5]thieno[2,3-d]pyrimidines and related fused 1,2,4-triazolo and 1,3,4-thiadiazolo-derivatives

Article abstract of DOI:10.1080/10426500211720

Diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1 is a convenient and useful starting matrial for the constructions of heterocyclic systems. It was utilized to synthesize derivatives of the novel heterocyclic systems pyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidine 4,10, pyrido[4′,3′:4,5]thieno[2,3-d]-[1,2,4]triazolo-[1,5-a]pyrimidine 7,11a-e and pyrido[4′,3′:4,5]thieno[2,3-d][1,3,4]-thiadiazolo[3,2- a]pyrimidine 12-14.

Full text of DOI:10.1080/10426500211720

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Phosphorus, Sulfur, and Silicon and the Related
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A Convenient Synthesis for Some New
Pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines and Related
Fused 1,2,4-Triazolo and 1,3,4-Thiadiazolo-derivatives
Essam Kh. Ahmed a
a Chemistry Department, Faculty of Science, El-Minia University, El-Minia, Egypt
Published online: 27 Oct 2010.
To cite this article: Essam Kh. Ahmed (2002) A Convenient Synthesis for Some New Pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines
and Related Fused 1,2,4-Triazolo and 1,3,4-Thiadiazolo-derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
177:5, 1323-1336, DOI: 10.1080/10426500211720
To link to this article: http://dx.doi.org/10.1080/10426500211720
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1323–1336
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290092604
A CONVENIENT SYNTHESIS FOR SOME NEW
PYRIDO[40,30:4,5]THIENO[2,3-d]PYRIMIDINES AND
RELATED FUSED 1,2,4-TRIAZOLO AND
1,3,4-THIADIAZOLO-DERIVATIVES
Essam Kh. Ahmed
Chemistry Department, Faculty of Science, El-Minia University,
El-Minia, Egypt
(Received September 24, 2001; accepted December 10, 2001)
Diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate 1 is a convenient and useful starting matrial for the
constructions of heterocyclic systems. It was utilized to synthesize
derivatives of the novel heterocyclic systems pyrido[40,30:4,5]thieno-
[2,3-d]pyrimidine 4,10, pyrido[40,30:4,5]thieno[2,3-d]-[1,2,4]triazolo-
[1,5-a]pyrimidine 7,11a–e and pyrido[40,30:4,5]thieno[2,3-d][1,3,4]-
thiadiazolo[3,2-a]pyrimidine 12–14.
Keywords: Fused S, N-heterocycles; pyrido[40,30:4,5]thieno[2,3-d]-
pyrimidines; pyrido[40,30:4,5]thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimi-
dines; pyrido[40,30:4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimi-
dines; thieno[2,3-c]pyridines
A literature survey revealed that pyridothienopyrimidines possess a
broad spectrum of biological activity. They proved to be analgesic,1
8
antipyretic,2,3 antianaphylactic,4,5 and antiinflammatory6 activity.
Also, some of these compounds are clinically effective antiallergic9 and
a few possess signifficant hypocholesterolenic10 activity. On the other
hand, 1,2,4-triazoles are considered a very interesting heterocyclic ring
system because of their therapeutic importance. Recently derivatives
of 1,2,4-triazole have been found to have significant analgesic11 and
antiseptic12 activity. It was also found that some thiadiazole derivatives
showed diverse biological activities e.g. they are used as antitumour
agents, pesticides, dyes lubricants, and analytical reagents.13 From all
of the forgoing facts, and as a continuation of our interest in the syn-
19
thesis of fused heterocycles with thienopyrimidines.14
We reported
herein the synthesis of the title compounds which might show enhanced
Address correspondence to E. K. Ahmed, Department of Chemistry, Faculty of Science,
El-Minia University, El-Minia 61519, Egypt. E-mail: essamkhaala24@yahoo.com
1323

1324
E. K. Ahmed
biological activity due to the presence of fused pyridothienotriazolo-
pyrimidine and pyridothienothiadiazolopyrimidine.
It has been found that dropwise addition at room temperature
of a solution of hydrazine hydrate in dichloromethane to a stirred
solution of diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-3,6-dicarboxylate 115 in dichloromethane afforded diethyl-
(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-y1)thiosemicarbazide- 3,6-di-
carboxylate 2, which by subsequent heating under reflux in ethanolic
potassium hydroxide solution, gave the potassium salt of ethyl 3-
amino-4-oxo-2-thioxo-3,5,6,8-tetrahydropyrido[40,30:4,5]thieno[2,3-d]-
pyrimidine-7(4H)-carboxylate 3. Acidification of an aqueous solution
of the potassium salt 3, the amino-thioxo derivative 4 was obtained.
Compound 4 was also prepared by adding hydrazine hydrate to
isothiocyanate 1 in benzene and subsequent prolonged heating of the
reaction mixture. Reaction of compound 3 with methyl iodide gave
methylthio derivative 5. Treatment of 5 with hydrazine hydrate gave
the hydrazino derivative 6, which by cyclocondensation with triethyl
orthoformate afforded two isomeric pyrido[40,30:4,5]thieno[2,3-d]-
[1,2,4]triazolo[1,5-a]pyrimidine 7 and pyrido[40,30:4,5]thieno[2,3-e]-
[1,2,4]triazolo[4,3-a]pyrimidine 8, dependent on the cyclization which
took place either to nitrogen at position 1 or at position 3. The structure
1
determination of both systems is based on the H NMR spectra. The
chemical shifts of H-1 in triazolo[4,3-a] fused system (8) appear at
lower field = 9.80 than H-2 in triazolo[1,5-a]fused system = 9.30 (7)
(Scheme 1).
As an extension of our studies, we have been interested in
preparing the interesting tetracyclic system 11 by another route.
Thus,
pyrido[40,30:4,5]thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines
11a–e were prepared by cycling the corresponding ethyl 3-amino-
2-ary-laminopyrido[40,30:4,5]thieno[2,3-d]pyrimidin-4(3H)-one-7-carb-
oxylate 10a–e with triethyl orthoformate in the presence of p-toluene-
sulfonic acid. The starting derivatives 10a–e were synthesized
by reaction of hydrazine hydrate with the appropriate diethyl
2-({[(aryl)amino]carbothioyl}amino)-4,5,6,7-tetrahydrothieno[2, 3-c]-
pyridine-3,6-dicarboxylate 9a–e obtained from the isothiocyanate 1
with commercially available substituted arylamines (Scheme 2).
With a view to expand the scope of our investigation, ethyl 3-amino-
4-oxo-2-thioxo-1,3,4,5,6,8-hexahydropyrido[40,30:4,5]thieno[2,3-d]pyri-
midine-7(2H)-carboxylate 4 was used as a key intermediate to synthe-
size tetracyclic ring system pyrido[40,30:4,5][2,3-d][1,3,4]thiadiazolo[3,
2-a]pyrimidine. Thus compound 4 was converted to the ethyl 10-
oxo-8,9-dihydro-10 H-pyrido[40,30:4,5][ 2,3-d][1,3,4]thiadiazolo[3,2-a]
pyrimidine-7-(6H)carboxylate 12 and 2-methyl analog 13 by

S,N-Heterocycles
1325
SCHEME 1
reaction with triethyl orthoformate and acetic acid, respectively.
The ethyl 2-phenyl-10-oxo-8, 9-dihydro-10H-pyrido[40,30:4,5][2,3-
d]-[1,3,4]thiadiazolo[3,2-a]pyrimidine-7(6H)-carboxylate
14
was
obtained by reaction of
(Scheme 3).
4 with benzoic acid/POCl3 mixture.
Structural assignments of all novel compounds were made on the ba-
sis of elemental analyses, nmr and infrared spectra (see Experimental
section).

1326
E. K. Ahmed
SCHEME 2
SCHEME 3

S,N-Heterocycles
1327
EXPERIMENTAL
All m.p.s were recorded on a Gallen kamp apparatus and are un-
corrected. Microanalyses were performed at the Microanalytical Data
1
Unit, Cairo University. 13C and H NMR spectra were recorded on a
Bruker AC 200 (1H: 200.13 MHz, 13C: 50.32 Mhz), 5 mm dual 1H/13C-VT
probe at 300K; solvent: DMSO-d6 and CDCl3, respectively; values
are given in ppm, internal standard TMS ( = 0 ppm). IR-spectra were
recorded on a Shimadzu 470 Spectrophotometer in KBr pellets.
Diethyl-(4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-
thiosemicarbazide-3,6-dicarboxylate (2)
To a stirred solution of isothiocyanate 1 (0.6 g, 0.0017 mol) in
dichloromethane (10 ml) a solution of hydrazine hydrate (0.07 g,
0.0021 mol) in dichloromethane (10 ml) was added dropwise at room
temperature. The suspension was stirred at room temperature for
2 h and then the solid was collected, washed with dichloromethane,
dried, and recrystallized from ethanol. Yield 0.64 g (70.7%) of com-
pound 2 as colorless crystals, m.p. 172–173 C (found: C, 45.07; H, 5.38;
N, 14.90; S, 17.18. C14H20N4O4S2 requires C, 45.14; H, 5.4; N, 15.04;
S, 17.21%); max/cm 1: 3360,3200 and 3150 (NH, NH2), 1690, 1710
(2 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.30 (t, 3H,
H
COOCH2CH3), 2.80 (t, 2H, H-4), 3.60 (t, 2H, H-5), 4.10 (q, 2H,
COOCH2CH3), 4.30 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7), 5.40
(brs, 2H, NH2), 9.90 (s, 1H, NH), 12.60 (s, 1H, NH); c (DMSO-d6): 14.07
(q, COOCH2CH3), 14.15 (q, COOCH2CH3), 25.94 (t, C-4), 41.23 (t, C-5),
42.17 (t, C-7), 60.25 (t, COOCH2CH3), 60.93 (t, COOCH2CH3), 110.76
(s, C-3), 121.79 (s, C-7a), 128.90 (s, C-3a), 150.20 (s, CO), 154.64 (s, CO),
164.65 (s, C-2), 176.70 (s, CS).
Potassium Salt of Ethyl 3-Amino-4-oxo-2-thioxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4 H)-
carboxylate (3)
To a hot ethanolic solution (5 ml) of potassium hydroxide (0.07 g,
0.0012 mol), compound 2 (0.37 g, 0.001 mol) was added and the re-
sulting mixture was refluxed for 30 min. The hot suspension was
then filtered and the solid was collected, washed with warm dioxane,
and dried to give 0.32 g (88.8% yield) of 3 as pale yellow crys-
tals, m.p. 282–284 C (dec.) (found: C, 39.32; H, 3.74; N, 15.20;
S, 17.40. C12H13N4O3S2K requires C, 39.54; H, 3.59; N, 15.37;
S, 17.59%); max/cm 1: 3240 (NH2), 1710, 1680 (2 CO), 1640 (C N);

1328
E. K. Ahmed
H (DMSO-d6): 1.30 (t, 3H, COOCH2CH3), 2.90 (t, 2H, H-5), 3.70 (t, 2H,
H-6), 4.30 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-8), 6.40 (s, 2H, NH2).
(DMSO-d6): 14.54 (q, COOCH2CH3), 25.24 (t, C-5), 42.74 (t, C-6),
c
46.76 (t, C-8), 60.94 (t, COOCH2CH3), 113.27 (s, C-4a), 128.62 (s, C-4b),
140.92 (s, C-8a), 154.65 (s, C-4), 157.64 (s, C-9a), 161.86 (s, CO), 167.90
(s, C-2).
Ethyl 3-Amino-4-oxo-2-thioxo-1,3,4,5,6,8-
hexahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(2 H)-
carboxylate (4)
Method A (from Compound 1)
A solution of hydrazine hydrate (0.6 g, 0.018 mol) in benzene (5 ml)
was added dropwise at room temperature to a stirred solution of isothio-
cyanate 1 (0.6 g, 0.0017 mol) in benzene (10 ml). The suspension
was refluxed under stirring for 8 h. After cooling, the solid product
was collected by filtration, washed with ethanol, dried, and recrys-
tallized from dioxane. Yield 0.52 g (91.2%) of compound 4 as yellow
crystals, m.p. 232–234 C (dec.) (found: C, 44.07; H, 4.30; N, 17.01;
S, 19.50. C12H14N4O3S2 requires C, 44.15; H, 4.32; N, 17.16; S, 19.64%);
max/cm 1: 3400, 3320, 3180 (NH2, NH), 1710, 1680 (2 CO), 1200 (C S);
H(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H, H-5), 3.60 (t, 2H,
H-6), 4.20 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-8), 6.30–6.50 (br, 2H,
NH2), 13.40 (s, 1H, NH); (DMSO-d6): 14.56 (q, COOCH2CH3), 25.26
c
(t, C-5), 40.74 (t, C-6), 46.75 (t, C-8), 60.95 (t, COOCH2CH3), 113.31 (s,
C-4a), 128.28 (s, C-4b), 141.03 (s, C-8a), 154.64 (s, C-4), 157.64 (s, C-9a),
161.63 (s, CO), 168.83 (s, C-2).
Method B (from Compound 3)
To a stirred solution of potassium salt 3 (3.6 g, 0.01 mol) in water
(50 ml) 37% hydrochloric acid (0.9 ml) was added dropwise, a white
solid separated. The solid product was collected by filtration, washed
with water, dried, and recrystallized from dioxane. Yield 2 g (62.5%) of
compound 4 as yellow crystals. m.p. 231–233 (dec.). The compound is
identical to that obtained according to Method A.
Ethyl 3-Amino-2-(methylthio)-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (5)
A mixture of 3 (0.22 g, 0.0006 mol) and methyl iodide (0.15 ml,
99%, d = 2.27) in water (10 ml) was stired at room temperature. The
methylthio compound 5 started to crystallize almost immediately.

S,N-Heterocycles
1329
After 1 h, it was filtered off, washed with petroleum ether, dried, and
crystallized from 2-propanol. Yield 0.18 g (90%) of compound 5 as white
needles, m.p. 187–188 C (found: C, 45.83; H, 4.67; N, 16.45; S, 18.82.
C13H16N4O3S2 requires C, 45.86; H, 4.73; N, 16.45; S, 18.83%);
/
max
cm 1: 3230 (NH2), 1710, 1680 (2 CO), 1640 (C N); H(DMSO-dd): 1.20
(t, 3H, COOCH2CH3), 2.30 (s, 3H, SCH3), 2.90 (t, 2H, H-5), 3.70 (t, 2H,
H-6), 4.30 (q, 2H, COOCH2CH3), 4.60 (s, 2H, H-8), 5.70 (s, 2H, NH2);
c(DMSO-d6): 14.30 (q, COOCH2CH3), 15.20 (q, SCH3), 25.20 (t, C-5),
40.74 (t, C-6), 46.15 (t, C-8), 60.95 (t, COOCH2CH3), 113.30 (s, C-4a),
127.55 (s, C-4b), 141.03 (s, C-8a), 154.64 (s, C-4), 156.76 (s, C-9a), 161.63
(s, CO), 167.83 (s, C-2).
Ethyl 3-Amino-2-hydrazino-4-oxo-3,5,6,8-tetrahydro-
pyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4 H)-
carboxylate (6)
A mixture of 5 (0.34 g, 0.001 mol), hydrazine hydrate (1.5 ml 98%,
d = 1.032) and 2-propanol (5 ml) was refluxed for 6 h. After cool-
ing, the resulting solid was collected, dried, and crystallized from
ethanol. Yield 0.28 g (87.5%) of compound 6 as colorless needless, m.p.
243–245 C (found: C, 44.60; H, 4.90; N, 25.86; S, 9.80. C12H16N6O3S
requires C, 44.43; H: 4.97; N, 25.90; S, 9.88%); max/cm 1: 3330, 3150
(NH2, NH), 1710, 1680 (2 CO), 1640 (C N);
(DMSO-d6): 1.30
H
(t, 3H, COOCH2CH3), 2.80 (t, 2H, H-5), 3.60 (t, 2H, H-6), 4.10 (q, 2H,
COOCH2CH3), 4.30 (s, 2H, H-8), 4.70 (s, 2H, NH2), 5.30 (s, 2H, NH2),
8.30 (s, 1H, NH).
Ethyl 3-Ethoxymethyleneamino-10-oxo-3,8,9,10-
tetrahydropyrido[40,30:4,5]thieno[3,2-d][1,2,4]-
triazolo[1,5-a]pyrimidine-7(6H)-carboxylate (7) and Ethyl
4-Ethoxymethyleneamino-5-oxo-4,5,6,9-tetrahydropyrido-
[40,30:4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidine-8-
(7H)-carboxylate (8)
A mixture of 6 (0.39 g, 0.001 mol) and triethyl orthoformate (10 ml)
was heated under reflux for 8 h. The precipitate was, after cooling, col-
lected by filtration, dissolved in ethanol (3 ml), and separated by column
chromatography (Kiesegel 60, E. Merk, and chloroform/methanol
(9:1 as solvent) into two fractions. The first fraction gave, after evap-
oration of solvent in vacuo, 0.2 g (42.6% yield) of compound 7 as col-
orless crystals, m.p. 200–202 C (found: C, 48.99; H, 4.48; N, 21.38;
S, 8.18. C16H18N6O4S requires C, 49.22; H, 4.64; N, 21.52; S, 8.21%);
H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.40 (t, 3H, OCH2CH3), 2.95

1330
E. K. Ahmed
(t, 2H, H-9), 3.70 (t, 2H, H-8), 4.10 (q, 2H, COOCH2CH3)), 4.40 (q, 2H,
OCH2CH3), 4.80 (s, 2H, H-6), 8.60 (s, 1H, N CH), 9.30 (s, 1H, H-2).
The second fraction gave, after evaporation of solvent in vacuo,
0.12 g (25.5% yield) of compound 8 as colorless crystals, m.p. 240–
242 C (found: C, 48.95; H, 4.50; N, 21.42; S, 8.10. C16H18N6O4S requires
C, 49.22; H, 4.64; N, 21.52; S, 8.21%);
(DMSO-d6) 1.20 (t, 3H,
H
COOCH2CH3), 1.40 (t, 3H, OCH2CH3), 3.00 (t, 2H H-6), 3.70 (t, 2H,
H-7), 4.20 (q, 2H, COOCH2CH3), 4.40 (q, 2H, OCH2CH3), 4.60 (s, 2H,
H-9), 9.00 (s, 1H, N CH), 9.80 (s, 1H, H-1).
General Procedure for the Synthesis of (9a–e)
To
a solution of the substituted arylamine (0.001 mol) in
dichloromethane (5 ml) a solution of isothiocyanate 1 (0.001 mol) in
dichloromethane (5 ml) was added with stirring. The solution was
stirred at room temperature for 1–3 h and then the solid was filtered
off, washed with ethanol, dried, and recrystallized from an appropriate
solvent.
{
}
Diethyl 2-( [(Phenyl)amino]carbothioyl amino)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate (9a)
Colorless crystals from EtOH. Yield 83.7%, m.p. 178–180 C (found:
C, 55.20; H, 5.38; N, 9.62; S, 14.68. C20H23N3O4S2 requires C, 55.40;
H, 5.34; N, 9.69; S, 14.79%);
(DMSO-d6): 1.10 (t, 3H, COOCH2CH3),
H
1.30 (t, 3H, COOCH2CH3), 2.80 (t, 2H, H-4), 3.60 (t, 2H, H-5), 4.10
(q, 2H, COOCH2CH3), 4.30 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7),
7.30–7.50 (m, 5H, Ar H), 11.10 (s, 1H, NH), 11.90 (s, 1H, NH).
{
}
Diethyl 2-( [(p-Chlorophenyl)amino]carbothioyl amino)-
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate (9b)
Colorless crystals from EtOH. Yield 91.3%, m.p. 186–188 C (found:
C, 51.15; H, 4.79; N, 8.88; S, 13.59. C20H22N3O4S2Cl requires C, 51.33;
H, 4.73; N, 8.97; S, 13.70%); max/cm 1: 3200 (NH), 1710, 1670 (2 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.30 (t, 3H, COOCH2CH3),
H
2.70 (t, 2H, H-4), 3.60 (t, 2H, H-5), 4.10 (q, 2H, COOCH2CH3), 4.30
(q, 2H, COOCH2CH3), 4.55 (s, 2H, H-7), 7.40–7.70 (m, 4H, Ar H), 11.20
(s, 1H, NH), 11.95 (s, 1H, NH); c (DMSO-d6): 14.25 (q, COOCH2CH3),
14.50 (q, COOCH2CH3), 25.91 (t, C-4), 40.74 (t, C-5), 42.13 (t, C-7),
60.56 (t, COOCH2CH3), 61.35 (t, COOCH2CH3), 111.19 (s, C-3), 122.74
(s, C-7a), 128.26 (Ph C-3,5), 129.78 (Ph C-2,6), 137.28 (s, C-3a), 142.12
(Ph C-1), 150.45 (s, CO ester). 154.62 (s, CO ester), 165.39 (s, C-2),
175.50 (s, CS).

S,N-Heterocycles
1331
{
}
Diethyl 2-( [(o-Chlorophenyl)amino]carbothioyl amino)-
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate (9c)
Colorless crystals from EtOH. Yield 74.9%, m.p. 181–183 C (found:
C, 51.20; H, 4.60; N, 8.80; S, 13.61. C20H22N3O4S2Cl requires C, 51.33;
H, 4.73; N, 8.97; S, 13.70%);
(DMSO-d6): 1.10 (t, 3H, COOCH2CH3),
H
1.30 (t, 3H, COOCH2CH3), 2.80 (t, 2H, H-4), 3.60 (t, 2H, H-5), 4.10
(q, 2H, COOCH2CH3), 4.35 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7),
7.40–7.80 (m, 4H, Ar H), 10.90 (s, 1H, NH), 11.80 (s, 1H, NH).
{
}
Diethyl 2-( [(p-Methoxyphenyl)amino]carbothioyl amino)-
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
3,6-dicarboxylate (9d)
Colorless crystals from EtOH. Yield 71.7%, m.p. 188–190 C (found:
C, 54.20; H, 5.35; N, 8.90; S, 13.60. C21H25N3O5S2 requires C, 54.40;
H, 5.43; N, 9.06; S, 13.83%); max/cm 1: 3200 (NH), 1710, 1680 (2 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.30 (t, 3H, COOCH2CH3),
H
2.80 (t, 2H, H-4), 3.60 (t, 2H, H-5), 3.80 (s, 3H, OCH3), 4.10 (q, 2H,
COOCH2CH3), 4.30 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7), 7.15–7.60
(m, 4H, Ar H), 10.60 (s, 1H, NH), 11.50 (s, 1H, NH);
(DMSO-d6):
c
13.92 (q, COOCH2CH3), 14.50 (q, COOCH2CH3), 25.90 (t, C-4), 40.76
(t, C-5), 42.12 (t, C-7), 55.26 (s, OCH3), 60.43 (t, COOCH2CH3), 61.20
(t, COOCH2CH3), 114.87 (s, C-3), 122.20 (s, C-7a), 127.40 (Ph C-3,5),
128.74 (Ph C-2,6), 130.49 (s, C-3a), 142.20 (Ph C-1), 150.80 (s, CO ester),
154.65 (s, CO ester), 165.21 (s, C-2), 175.87 (s, C S).
{
}
Diethyl 2-( [(p-Tolyl)amino]carbothioyl amino)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate (9e)
Colorless crystals from EtOH. Yield 73.9%, m.p. 199–200 C (found:
C, 56.20; H, 5.55; N, 9.30; S, 14.20. C21H25N3O4S2 requires C, 56.35;
H, 5.63; N, 9.38; S, 14.32%); max/cm 1: 3220 (NH), 1710, 1680 (2 CO);
(DMSO-d6): 1.15 (t, 3H, COOCH2CH3), 1.30 (t, 3H, COOCH2CH3),
H
2.30 (s, 3H, CH3), 2.70 (t, 2H, H-4), 3.60 (t, 2H, H-5), 4.10 (q, 2H,
COOCH2CH3), 4.30 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7), 7.20–7.50
(m, 4H, Ar H), 11.00 (s, 1H, NH), 11.90 (s, 1H, NH).
General Procedure for the Synthesis of (10a-e)
To a suspention of the arylthioureas 9a–e (0.001 mol) in ethanol
(10 ml), hydrazine hydrate (0.04 mol) was added. The mixture was
heated under reflux for 3–4 h. After cooling the precipitated was col-
lected, washed with ethanol, dried, and recrystallized from a suitable
solvent.

1332
E. K. Ahmed
Ethyl 3-Amino-2-phenylamino-4-oxo-3,5,6,8-
tetrahydropyrido[4 0,3 0:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (10a)
Colorless crystals from EtOH. Yield 63.1%, m.p. 220–221 C (found:
C, 56.23; H, 5.18; N, 18.42; S, 8.42. C18H19N5O3S requires C, 56.09;
H, 4.96; N, 18.16; S, 8.31%);
(CDCl3): 1.30 (t, 3H, COOCH2CH3),
H
2.90 (t, 2H, H-5), 3.70 (t, 2H, H-6) 4.20 (q, 2H, COOCH2CH3), 4.60
(s, 1H, H-8), 5.40 (s, 2H, NH2), 7.30–7.80 (m, 4H, Ar H), 8.60 (s, 1H,
NH); (CDCl3): 14.62 (q, COOCH2CH3), 25.45 (t, C-5), 41.06 (t, C-6),
c
42.91 (t, C-8), 61.59 (t, COOCH2CH3), 114.46 (s, C-4a), 123.81 (s, C-4b),
128.28 (Ph C-4), 128.57 (Ph C-3,5), 129.90 (Ph C-2,6), 131.40 (Ph C-1),
134.62 (s, C-8a), 147.74 (s, C-9a), 155.49 (s, C-2), 158.08 (s, C-4), 165.46
(s, CO ester).
Ethyl 3-Amino-2-p-chlorophenylamino-4-oxo-3,5,6,8-
tetrahydropyrido[4 0,3 0:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (10b)
Colorless crystals from EtOH. Yield 75.6%, m.p. 204–206 C (found:
C, 51.53; H, 4.42; N, 16.51; S: 7.75. C18H18N5O3SCl requires C, 51.49;
H, 4.32; N, 16.67; S, 7.63%); max/cm 1: 3350, 3200 (NH2, NH), 1710,
1670 (2 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H,
H
H-5), 3.70 (t, 2H, H-6), 4.10 (q, 2H, COOCH2CH3), 4.50 ( s, 2H, H-8),
5.60 (s, 2H, NH2), 7.20–7.70 (m, 4H, Ar H), 9.50 (s, 1H, NH); c (DMSO-
d6): 14.53 (q, COOCH2CH3), 25.17 (t, C-5), 40.75 (t, C-6), 42.65 (t, C-8),
61.02 (t, COOCH2CH3), 114.17 (s, C-4a), 126.93 (s, C-4b), 128.32
(Ph C-3,5), 129.08 (Ph C-2,6), 133.88 (s, C-8a), 148.87 (s, C-9a), 154.74
(s, C-2), 157.66 (s, C-4), 165.78 (s, CO ester).
Ethyl 3-Amino-2-o-chlorophenylamino-4-oxo-3,5,6,8-
tetrahydropyrido[4 0,3 0:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (10c)
Colorless crystals from EtOH. Yield 68.3%, m.p. 210–212 C (found:
C, 51.60; H, 4.40; N, 16.80; S, 7.72. C18H18N5O3SCl requires C, 51.49;
H, 4.32; N, 16.67; S, 7.63%);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3),
H
2.80 (t, 2H, H-5), 3.60 (t, 2H, H-6), 4.20 (q, 2H, COOCH2CH3), 4.60 (s,
2H, H-8), 5.70 (s, 2H, NH2), 7.20–7.70 (m, 4H, Ar H), 9.60 (s, 1H, NH).
Ethyl 3-Amino-2-p-methoxyphenylamino-4-oxo-3,5,6,8-
tetrahydropyrido[4 0,3 0:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (10d)
Colorless crystals from EtOH. Yield 63.4%, m.p. 226–228 C (found:
C, 54.86; H, 5.22; N, 16.44; S, 7.60. C19H21N5O4S requires C, 54.92;

S,N-Heterocycles
1333
H, 5.09; N, 16.85; S, 7.71%); max/cm 1: 3340, 3150 (NH2, NH), 1710,
1670 (2 CO); (CDCl3): 1.30 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-5),
H
3.60 (t, 2H, H-6), 3.85 (s, 3H, OCH3), 4.30 (q, 2H, COOCH2CH3), 4.60
(s, 2H, H-8), 5.40 (s, 2H, NH2), 7.20–7.60 (m, 4H, Ar H), 9.40 (s,
1H, NH);
(CDCl3): 14.62 (q, COOCH2CH3), 25.40 (t, C-5), 40.95 (t,
c
C-6), 42.95 (t, C-8), 55.44 (s, OCH3), 61.58 (t, COOCH2CH3), 115.78 (s,
C-4a), 125.41 (s, C-4b), 129.47 (Ph C-3,5), 129.86 (Ph C-2,6), 130.31 (Ph
C-1), 133.45 (C-8a), 152.10 (s, C-9a), 153.08 (s, C-2), 160.20 (s, C-4),
165.40 (s, CO ester).
Ethyl 3-Amino-2-p-tolylamino-4-oxo-3,5,6,8-
tetrahydropyrido[4 0,3 0:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (10e)
Colorless crystals from EtOH. Yield: 69.2%, m.p. 206–208 C (found:
C, 56.96; H, 5.10; N, 17.35; S, 7.90. C19H21N5O3S requires C, 57.12; H,
5.29; N, 17.53; S, 8.02%); max/cm 1: 3350, 3150 (NH2, NH), 1710, 1675
(2 CO);
(CDCl3): 1.30 (t, 3H, COOCH2CH3), 2.40 (s, 3H, CH3), 2.90
H
(t, 2H, H-5), 3.70 (t, 2H, H-6), 4.20 (q, 2H, COOCH2CH3), 4.65 (s, 2H,
H-8), 5.40 (s, 2H, NH2), 7.20–7.60 (m, 4H, Ar H), 9.50 (s, 1H, NH);
(CDCl3): 14.59 (q, COOCH2CH3), 21.14 (s, CH3), 25.36 (t, C-5), 40.85
c
(t, C-6), 42.92 (t, C-8), 61.57 (t, COOCH2CH3), 115.17 (s, C-4a), 120.20
(s, C-4b), 128.22 (Ph C-3,5), 129.44 (Ph C-2,6), 131.60 (Ph C-1), 134.71
(C-8a), 148.10 (s, C-9a), 151.80 (s, C-2), 158.35 (s, C-4), 164.27 (s, CO
ester).
General Proceedure for the Synthesis of (11a-e)
A
mixture of the 3-amino derivatives 10a–e (0.001 mol),
p-toluenesulfonic acid (p-TSA) (0.0015 mol) and triethyl orthofor-
mate (10 ml) was heated at reflux with stirring for 6–8 h. After cooling,
the solid was filtered off, washed with ethanol, dried, and recrystallized
from a suitable solvent.
Ethyl 3-Phenyl-10-oxo-6,8,9,10-tetrahydropyrido-
[40,30:4,5]thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine-
7-carboxylate (11a)
Yellow crystals from EtOH. Yield 66.8%, m.p. 240–242 C (found:
C, 57.60; H, 4.22; N, 17.59; S, 8.22. C19H17N5O3S requires C, 57.70;
H, 4.33; N, 17.71; S, 8.10%);
(DMSO-dd): 1.20 (t, 3H, COOCH2CH3),
H
2.90 (t, 2H, H-9), 3.60 (t, 2H, H-8), 4.20 (q, 2H, COOCH2CH3), 4.70 (s,
2H, H-6), 7.70–7.90 (m, 4H, Ar H), 9.20 (s, 1H, H-2).

1334
E. K. Ahmed
Ethyl 3-p-Chlorophenyl-10-oxo-6,8,9,10-
tetrahydropyrido[40,30:4,5]thieno[2,3-d][1,2,4]triazolo-
[1,5-a]pyrimidine-7-carboxylate (11b)
Yellow crystals from EtOH. Yield 61.9%, m.p. 232–233 C (found:
C, 53.12; H, 3.82; N, 16.37; S, 7.60. C19H16N5O3SCl requires C, 53.08;
H, 3.75; N, 16.29; S, 7.45%);
(DMSO-dd): 1.20 (t, 3H, COOCH2CH3),
H
2.80 (t, 2H, H-9), 3.40 (t, 2H, H-8), 4.10 (q, 2H, COOCH2CH3), 4.50
(s, 2H, H-6), 7.60–7.90 (m, 4H, Ar H), 9.20 (s, 1H, H-2); (DMSO-d6):
c
14.07 (q, COOCH2CH3), 25.36 (t, C-9), 40.75 (t, C-8), 42.74 (t, C-6), 61.04
(t, COOCH2CH3), 114.59 (s, C-9b), 124.81 (s, C-9a), 128.63 (Ph C-3,5),
128.80 (Ph C-2,6), 129.02 (Ph C-1), 130.43 (s, C-5a), 145.05 (s, C-4a),
151.44 (s, C-3a), 153.27 (s, C-2), 154.73 (s, C-10), 164.10 (s, CO ester).
Ethyl 3-o-Chlorophenyl-10-oxo-6,8,9,10-tetrahydropyrido-
[4 0,3 0:4,5]thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine-
7-carboxylate (11c)
Yellow crystals from EtOH. Yield 59.6%, m.p. 250–252 C (found:
C, 53.20; H, 3.86; N, 16.35; S, 7.66. C19H16N5O3SCl requires C, 53.08;
H, 3.75; N, 16.29; S, 7.45%);
(DMSO-dd): 1.30 (t, 3H, COOCH2CH3),
H
2.90 (t, 2H, H-9), 3.70 (t, 2H, H-8), 4.20 (q, 2H, COOCH2CH3), 4.60
(s, 2H, H-6), 7.70–7.90 (m, 4H, Ar H), 9.20 (s, 1H, H-2).
Ethyl 3-p-Methoxyphenyl-10-oxo-6,8,9,10-
tetrahydropyrido[4 0,3 0:4,5]thieno[2,3-d][1,2,4]triazolo-
[1,5-a]pyrimidin-7-carboxylate (11d)
Yellow crystals from EtOH. Yield 64.4%, m.p. 246–248 C (found:
C, 56.63; H, 4.60; N, 16.95; S, 7.68. C20H19N5O4S requires C, 56.45;
H, 4.50; N, 16.46; S, 7.53%);
(DMSO-dd): 1.20 (t, 3H, COOCH2CH3),
H
2.85 (t, 2H, H-9), 3.60 (t, 2H, H-8), 3.80 (s, 3H, OCH3), 4.20 (q, 2H,
COOCH2CH3), 4.60 (s, 2H, H-6), 7.50–7.80 (m, 4H, Ar H), 9.20 (s, 1H,
H-2).
Ethyl 3-p-Tolyl-10-oxo-6,8,9,10-tetrahydropyrido-
[4 0,3 0:4,5]thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine-
7-carboxylate (11e)
Yellow crystals from EtOh. Yield 73.3%, m.p. 260–262 C (found:
C, 58.8; 1H, 4.77; N, 17.27; S, 7.98. C20H19N5O3S requires C, 58.66;
H, 4.67; N, 17.10; S, 7.83%); max/cm 1: 1710, 1680 (2 CO), 1640 (C N);
(DMSO-dd): 1.30 (t, 3H, COOCH2CH3), 2.40 (s, 3H, CH3), 2.80
H
(t, 2H, H-9), 3.30 (t, 2H, H-8), 4.20 (q, 2H, COOCH2CH3), 4.60 (s, 2H,
H-6), 7.50–7.80 (m, 4H, Ar H), 9.20 (s, 1H, H-2).

S,N-Heterocycles
1335
Ethyl 10-Oxo-8,9-dihydro-10H-pyrido[40,30:4,5]thieno-[2,3-
d]-[1,3,4]thiadiazolo[3,2-a]pyrimidine-7(6H)-
carboxylate (12)
A mixture of 4 (0.32 g, 0.001 mol) and triethyl orthoformate (10 ml)
was refluxed for 2 hours. After cooling, the solid was collected, washed
with warm dioxane, and recrystallized from dioxane. Yield 0.24 g
(72.7%) of compound 12 as white crystals, m.p. 228–230 C (found:
C, 46.20; H, 3.70; N, 16.48; S, 18.97. C13H12N4O3S2 requires C, 46.41;
H, 3.59; N, 16.65; S, 19.06%); max/cm 1: 1710, 1680 (2 CO), 1640 (C N);
H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H, H-9), 3.70 (t, 2H,
H-8), 4.10 (q, 2H, COOCH2CH3), 4.60 (s, 2H, H-6), 9.30 (s, 1H, H-2).
Ethyl 2-Methyl-10-oxo-8,9-dihydro-10H-pyrido[40,30:4,5]-
thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidine-7(6H)-
carboxylate (13)
A mixture of 4 (0.32 g, 0.001 mol), phosphorus pentoxide (0.18 g,
0.0012 mol), acetic acid (0.3 ml, 0.005 mol) and methanesulfonic acid
(1.3 ml, 0.019 mol) was heated at 80 C on an oil bath for 6 h. Af-
ter cooling, the mixture was treated with water and 10% sodium
hydroxide and the resulting solid was collected, washed with wa-
ter, dried, and recrystallized from ethanol. Yield 0.18 g (52.94%) of
compound 13 as colorless crystals, m.p. 194–195 C (found: C, 47.77;
H, 3.90; N, 15.77; S, 18.10. C14H14N4O3S2 requires C, 47.98; H, 4.02;
N, 15.98; S, 18.30%); max/cm 1: 1700, 1680 (2 CO);
(CDCI3): 1.30
H
(t, 3H, COOCH2CH3), 2.70 (s, 3H, CH3), 3.20 (t, 2H, H-9), 3.90 (t, 2H,
H-8), 4.20 (q, 2H, COOCH2CH3), 4.70 (s, 2H, H-6).
Ethyl 2-Phenyl-10-oxo-8,9-dihydro-10H-pyrido[40,30:4,5]-
thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidine-7(6H)-
carboxylate (14)
A mixture of 4 (0.33 g, 0.001 mol), benzoic acid (0.24 g, 0.002 mol) and
phosphorus oxychloride (2 ml, 0.02 mol) was refluxed for 20 min. Af-
ter cooling, phosphorous oxychloride was evaporated under reduced
pressure and the residue was treated with 10% sodium hydroxide.
The resulting solid was collected, washed with water, dried, and re-
crystallized from dioxane. Yield 0.38 g (91.1%) of compound 14 as yel-
low microcrystals, m.p. 248–250 C (found: C, 55.48; H, 3.80; N, 13.39;
S, 15.41. C19H16N4O3S2 requires C, 55.32; H, 3.91; N, 13.58; S, 15.54%);
max/cm 1: 3100 (arom. protons), 1710, 1680 (2 CO);
1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H, H-9), 3.70 (t, 2H, H-8), 4.10
(DMSO-d6):
H

1336
E. K. Ahmed
(q, 2H, COOCH2CH3), 4.60 (s, 2H, H-6), 7.30–7.60 (m, 5H, Ar H);
(DMSO-d6): 14.56 (q, COOCH2CH3), 25.30 (t, C-9), 40.75 (t, C-8),
c
42.79 (t, C-6), 61.13 (t, COOCH2CH3), 117.40 (s, C-9b), 127.20 (s, C-9a),
128.30 (Ph C-4), 128.51 (Ph C-2,6), 128.88 (Ph C-3,5), 131.22 (Ph C-1),
132.80 (C-5a), 152.53 (s, C-4a), 153.60 (s, C-3a), 154.74 (s, C-2), 157.30
(s, C-10), 167.27 (s, CO ester).
REFERENCES
[1] C. G. Dave, P. R. Shah, K. C. Dave, and V. J. Patel, J. Indian Chem. Soc., 66, 48
(1989).
[2] E. Bousquet, G. Romero, F. Guerrera, A. Caruso, and M. A. Roxas, Farmaco Ed. Sci.,
40, 869 (1985).
[3] E. Bousquet, F. Guerrera, N. A. Siracusa, A. Caruso, and M. A. Roxas, Farmaco Ed.
Sci., 39, 110 (1984).
[4] H. Vieweg, S. Leistner, G. Wagner, N. Boehm, U. Krasset, R. Grupe, D. Lohmann,
and G. Loban, East Ger. Pat. DD 257,830 (1988); Chem. Abstr., 110, 95262p (1989).
[5] H. Vieweg, S. Leistner, G. Wagner, N. Boehm, U. Krasset, R. Grupe, D. Lohmann,
and G. Loban; East Ger. Pat. DD 258,234 (1988); Chem. Abstr., 110, 95263p (1989).
[6] E. F. Elslager, P. W. Jacob, and M. Leslio, J. Heterocyclic Chem., 9, 775 (1972).
[7] M. Chaykovsky, M. Lin, A. Rosowsky, and E. J. Modest, J. Med. Chem., 10, 188
(1973).
[8] S. Leistner, G. Wagner, M. Guetscharo, and E. Glusa, Pharmazie, 41, 54 (1986).
[9] G. D. Madding and M. D. Thompson, J. Heterocyclic Chem., 24, 581 (1987).
[10] C. J. Shishoo, M. B. Devani, and V. S. Bhadti, Indian Pat. 151, 456 (1983); Chem.
Abstr, 100, 209858 (1984).
[11] M. Dobosz, A. Pachuta, and J. Rekas, Acta Polon. Pharm., 50, 225 (1993).
[12] M. Dobosz, J. Rekas, and A. Pachuta, Acta Polon. Pharm., 46, 40 (1989).
[13] Lubrizol Corp, U.S. Pat. 4.246.126 (1981); Chem. Abstr., 94, 142505h (1981).
[14] E. Kh. Ahmed, A. M. N. Gohar, and M. A. Ameen, Pharmazie, 55(1), 31 (2000).
[15] E. Kh. Ahmed, U. Sensfuss, and W. D. Habicher, J. Heterocyclic Chem., 36, 1119,
(1999).
[16] E. Kh. Ahmed, J. Frohlich, and F. Sauter, Collect. Czech. Chem. Commun., 61, 147
(1996).
[17] F. Sauter, J. Frohlich, and E. Kh. Ahmed, Monatsh. Chem., 127, 319 (1996).
[18] E. Kh. Ahmed, Monatsh Chem., 126, 953 (1995).
[19] F. Sauter, U. Jordis, J. Frohlich, K. Gewald, F. Grohmann, and E. Kh. Ahmed,
ACH-Models in Chemistry, 131, 489 (1994).