Some reactions of 2-functionalized 3-amino-4-aryl-6-(2′-thienyl)-thieno[2,3-B]-pyridines: Synthesis of new pyridothienopyrimidines, pyridothienotriazines and related fused tetracyclic systems

Article abstract of DOI:10.1080/10426500307820

4-Aryl-3-cyano-6-(2′-thienyl)-pyridine-2(1H)-thiones (2a-c) were prepared and reacted with chloroacetonitrile or chloroacetamide to furnish 3-amino-4-aryl-6-(2′-thienyl)-thieno[2,3-b]pyridine-2-carbonitriles (4a-c) and 2-carboxamide analogs 6a-c respectiv

Full text of DOI:10.1080/10426500307820

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Some Reactions of 2-Functionalized 3-Amino-4-aryl-6-
(2′-thienyl)-thieno[2,3-b]pyridines: Synthesis of New
Pyridothienopyrimidines, Pyridothienotriazines and
Related Fused Tetracyclic Systems
A. E. Abdel-Rahman a , E. A. Bakhite a , O. S. Mohamed a & E. A. Thabet a
a Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
Version of record first published: 27 Oct 2010
To cite this article: A. E. Abdel-Rahman, E. A. Bakhite, O. S. Mohamed & E. A. Thabet (2003): Some Reactions of
2-Functionalized 3-Amino-4-aryl-6-(2′-thienyl)-thieno[2,3-b]pyridines: Synthesis of New Pyridothienopyrimidines,
Pyridothienotriazines and Related Fused Tetracyclic Systems, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:1,
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:89–106
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DOI: 10.1080/10426500390170228
SOME REACTIONS OF 2-FUNCTIONALIZED
3-AMINO-4-ARYL-6-(20-THIENYL)-THIENO[2,3-B]-
PYRIDINES: SYNTHESIS OF NEW
PYRIDOTHIENOPYRIMIDINES,
PYRIDOTHIENOTRIAZINES AND RELATED FUSED
TETRACYCLIC SYSTEMS
A. E. Abdel-Rahman, E. A. Bakhite, O. S. Mohamed,
and E. A. Thabet
Chemistry Department, Faculty of Science, Assiut University,
Assiut, Egypt
(Received June 4, 2002; accepted July 4, 2002)
4-Aryl-3-cyano-6-(20-thienyl)-pyridine-2(1H)-thiones (2a–c) were pre-
pared and reacted with chloroacetonitrile or chloroacetamide to furnish
3-amino-4-aryl-6-(20 -thienyl )-thieno[2,3-b]pyridine-2-carbonitriles
(4a–c) and 2-carboxamide analogs 6a–c respectively. The reaction of
4a and 6a–c with a variety of reagents namely, formamide, carbon
disulfide, phenyl isothiocyanate, ethylene diamine, sodium azide,
triethyl orthoformate, and nitrous acid have been carried out and
their products were identified. Most of these products were subjected to
further reactions to obtain the rest of the title compounds.
Keywords: Fused heterocyclic systems; pyridothienopyrimidines;
pyridothienotriazines
INTRODUCTION
Thieno[2,3-b]pyridine ring system has proved to be an interesting
class of heterocycles. It has been reported that many of its deriva-
tives posses considerable antibaterial,1,2 antiviral,3 antihypertensive,4
and gonadotropin-releasing hormone antagonizing5,6 activity. Pyridoth-
ienopyrimidine derivatives have found applications as analgesics,7
antipyretics,8 and antiinflammatories.9 Also, some pyridothienotri-
azines are reported to exhibit antianaphylactic10 and antiallergic11 ac-
tivity. In view of these benefits and as a continuation of our previous
work on condensed thienopyridines,12 14 we undertook the synthesis of
the title compounds.
Address correspondence to E. A. Bakhite, Chemistry Department, Faculty of Science,
Assiut University, Assiut 71516, Egypt. E-mail: etiafy@aun.eun.eg
89

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A. E. Abdel-Rahman et al.
RESULTS AND DISCUSSION
The starting compounds,4-aryl-3-cyano-6-(20-thienyl)-pyridine-2(1H)-
thiones (2a–c) were synthesized from the reaction of -aryl- -
thiocarbamoylacrylonitriles (1a–c) with 2-acetylthiophene in the pres-
ence of ammonium acetate.
SCHEME 1
The reaction of 2a–c with chloroacetonitrile or chloroacetamide in
the presence of sodium acetate gave 2-substituted methylthio-4-aryl-
3-cyano-6-(20-thienyl)-pyridines (3a–c and 5a–c). Upon treatment of
these compounds with sodium ethoxide in ethanol, they underwent
intramolecular Thorpe-Ziegler cyclization to furnish 2-functionalized
3-amino-4-aryl-6-(20-thienyl)-thieno[2,3-b]pyridines (4a–c and 6a–c re-
spectively). The latter thienopyridines were also prepared via direct
reaction of 2a–c with the appropriate halo compounds in the presence
of sodium ethoxide as a basic catalyst (Scheme 2).
SCHEME 2

Pyridothienopyrimidines
91
Heating 4a with formamide at reflux temperature gave 4-amino-9-
phenyl-7-(20-thienyl)-pyrido[30,20:4,5]thieno[3,2-d]pyrimidine (7). The
interaction of 4a with carbon disulfide in hot pyridine produced
the pyrimidinedithione derivative 8 which in turn was reacted with
methyl iodide or ethyl chloroacetate to furnish 2,4-disubstituted
thiopyrimidines 9a and 9b respectively. When 4a was allowed to react
with phenyl isothiocyanate in hot pyridine, the 4-imino-3,9-diphenyl-
1,2,3,4-tetrahydro-7-(20-thienyl)-2-thioxopyrido[30,20:4,5]thieno[3,2-d]-
pyrimidine (10) was obtained in high yield (Scheme 3).
SCHEME 3
Incorporating the imidazolyl or tetrazolyl moiety into thienopy-
ridine structure was successfully attempted by converting the
nitrile group of 4a into dihydroimidazolyl or tetrazolyl residue fol-
lowed by subsequent reactions. Thus, the reaction of 4a with ethy-
lene diamine in the presence of a catalytic amount of carbon disulfide
gave a good yield of 3-amino-2-(4,5-dihydroimidazol-2-yl)-4-phenyl-6-
(20-thienyl)-thieno[2,3-b]pyridine (11). On treatment of 4a with sodium
azide and ammonium chloride in hot DMF followed by acidification re-
sulted in the formation of the tetrazolyl compound 12 (Scheme 4).
SCHEME 4

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A. E. Abdel-Rahman et al.
The reaction of 11 with triethyl orthoformate, p-chlorobenzal-
dehyde, and/or carbon disulfide gave imidazolo[100,200-c]pyrido[30,20:4,5]-
thieno[2,3-e]pyrimidine derivatives 13, 14 and 15 respectively. On
treatment of 11 with nitrous acid, it underwent diazotization fol-
lowed by self coupling to furnish 7-phenyl-9-(20-thienyl)-2,3-dihydro-
imidazolo[100,200-c]pyrido[30,20:4,5]thieno[3,2-e][1,2,3]triazine (16) in ex-
cellent yield (Scheme 5).
SCHEME 5
In the same manner, the compound 12 was reacted with triethyl or-
thoformate in the presence of acetic anhydride or with carbon disulfide
in hot pyridine to afford the fused tetracyclic compounds 17 and 18
respectively (Scheme 6).
SCHEME 6
Diazotization of 4a using sodium nitrite and HCl-AcOH mix-
ture gave 4-chloro-9-phenyl-7-(20-thienyl)-pyrido[30,2‚:4,5]thieno[3,2-
d][1,2,3]triazine (19). The reaction of 19 with hydrazine hydrate

Pyridothienopyrimidines
93
produced the hydrazino compound 20 which was cyclocondensed
with acetylacetone to furnish the dimethylpyrazolyl derivative 21
(Scheme 7).
SCHEME 7
On the other hand, the interaction of 6a with carbon disulfide
in hot pyridine led to the formation of thioxopyrimidinone deriva-
tive 22. When the latter compound was allowed to react with ethyl
iodide or ethyl chloroacetate in DMF containing anhydrous K2CO3,
the dialkylated products 23a,b were obtained. The compounds 6b,c
were reacted with triethyl orthoformate in the presence of acetic
anhydride to furnish 9-aryl-7-(20-thienyl)-pyrido[30,20:4,5]thieno[3,2-
d]pyrimidine-4(3H)-ones (24b,c). Treatment of compounds 6a–c in
AcOH H2SO4 mixture with sodium nitrite solution at low tempera-
ture resulted in the formation of 1,2,3-triazinone derivatives 25a–c. The
N-alkylation of 25a was achieved upon reaction with some halo com-
pounds viz p-bromophenacy bromide, ethyl chloroacetate and chloroac-
etamide where the N-alkylated triazinone derivatives 26a–c were ob-
tained (Scheme 8).
The structures of all newly synthesized compounds were confirmed
by elemental analyses, IR, 1H NMR, and mass spectral data (cf.
Experimental).
EXPERIMENTAL
All m.p.s are uncorrected and measured on a Gallenkamp apparatus. IR
spectra were recorded on a Shimadzu 470 IR-spectrophotometer (KBr;

94
A. E. Abdel-Rahman et al.
SCHEME 8
Vmax in cm 1); 1H-NMR spectra on a Varian EM-390, 90 MHz spectrom-
eter with TMS as internal standard ( in ppm); MS on a Jeol JMS-600
mass spectrometer and elemental analyses on a Perkin-Elemer 240C
elemental analyser or on an Elementar Analysensystem GmbH VARI-
OEL V2.3 July 1998 CHNS Mode.
4-Aryl-3-cyano-6-(20-thienyl)pyridine-2(1H)-thiones (2a c)
A mixture of -aryl- -thiocarbamoylacrylonitrile (1a–c) (20 mmol), am-
monium acetate (4.0 g) and 2-acetylthiophene (2.18 ml, 20 mmol) in
glacial acetic acid (25 ml) was heated under reflux for 48 h. The reaction
mixture was evaporated under reduced pressure until dried, washed
thorughly with water, and then treated with methanol. The separated
solid was filtered off and crystallized from acetic acid as orange crystals
of 2a–c.
3-Cyano-4-phenyl-6-(20-thienyl)-pyridine-
2(1H)-thione (2a)
Prepared from 1a. Yield: 43%; m.p.: 245 C. Anal. Calcd. for C16H10N2S2
(294.40): C, 65.28; H, 3.42; N, 9.52; S, 21.78%. Found: C, 65.00; H, 3.11;

Pyridothienopyrimidines
95
N, 9.76; S, 21.39%. IR: = 3190–3180 (NH), 2210 (CN) cm 1. 1H NMR
(DMSO): = 8.3 (m, 1H, CH thienyl), 7.6–8.2 (m, 6H: 5 ArH’s and CH
pyridine), 7.3 (m, 1H, CH thienyl), 7.1 (m, 1H, CH thienyl) ppm. MS:
m/z = 294 (M+, 100%), 250 (M+-CS, 37%), 261 (M+-SH, 30%), 77 (C6H+5 ,
7%), 44 (CS+, 3%).
3-Cyano-4-(p-methoxyphenyl)-6-(20-thienyl)-pyridine-
2(1H)-thione (2b)
Prepared from 1b. Yield: 62%; m.p.: 250 C. Anal. Calcd. for
C17H12N2OS2 (324.42): C, 62.94; H, 3.73; N, 8.63; S, 19.77%. Found:
C, 62.53; H, 3.43; N, 8.90; S, 19.65%. IR: = 3190–3180 (NH), 2210
1
(CN) cm 1. H NMR (TFA): = 7.8–8.2 (m, 5H: 2 ArH’s, 2CH thienyl
and CH pyridine), 7.2–7.5 (m, 3H: 2 ArH’s and CH thienyl), 4.0 (s, 3H,
OCH3) ppm.
4-(p-Chlorophenyl)-3-cyano-6-(20-thienyl)-pyridine-
2(1H)-thione (2c)
Prepared from 1c. Yield: 47%; m.p.: 242 C. Anal. Calcd. for
C16H9ClN2S2(329.86): C, 58.44; H, 2.76; N, 8.52; S, 19.50%. Found: C,
58.29; H, 2.90; N, 8.30; S, 19.22; Cl, 10.20%. IR: = 3190–3180 (NH),
2210 (CN) cm 1. 1H NMR (DMSO): = 8.2 (d, 1H, CH thienyl), 7.5–7.8
(m, 6H: 4ArH’s, CH thienyl and CH pyridine), 7.2 (m, 1H, CH thienyl)
ppm.
Reaction of 2a–c with Chloroacetonitrile or
Chloroacetamide: Formation of S-substituted
Thiopyridines 3a–c and 5a–c Respectively
To a suspension of compound 2a–c (20 mmol) and sodium acetate trihy-
drate (3.0 g, 22 mmol) in ethanol (50 ml), chloroacetonitrile or chloroac-
etamide (20 mmol) was added. The resulting mixture was heated under
reflux for 2 h. The precipitate that formed on cooling was collected and
recrystallized from ethanol as pale yellow needles of 3a–c or 5a–c re-
spectively.
(3-Cyano-4-phenyl-6-(20-thienyl)-2-pyridinylthio)-
acetonitrile (3a)
Yield: 87%; m.p.: 225 C. Anal. Calcd. for C18H11N3S2 (333.43): C, 64.84;
H, 3.33; N, 12.60; S, 19.23%. Found: C, 64.65; H, 3.15; N, 12.35; S,
19.39%. IR: = 2220, 2200 (2CN) cm 1. 1H NMR (TFA): = 7.3–8.3 (m,
9H: 5ArH’s, 3CH thienyl and CH pyridine), 4.4 (s, 2H, SCH2) ppm.

96
A. E. Abdel-Rahman et al.
(3-Cyano-4-(p-methoxyphenyl)-6-(20-thienyl)-
2-pyridinylthio)acetonitrile (3b)
Yield: 89%; m.p.: 220 C. Anal. Calcd. for C19H13N3OS2 (363.46): C,
62.79; H, 3.61; N, 11.56; S, 17.64%. Found: C, 62.95; H, 3.82; N, 11.46;
1
S, 17.51%. IR: = 2220, 2200 (2CN) cm
.
4-(p-Chlorophenyl)-3-cyano-6-(20-thienyl)-
2-pyridinylthio)acetonitrile (3c)
Yield: 92%; m.p.: 210 C. Anal. Calcd. for C18H10ClN3S2 (367.89): C,
58.77; H, 2.74; N, 11.42; S, 17.43; Cl, 9.64%. Found: C, 58.69; H, 2.85;
1
N, 11.70; S, 17.50; Cl, 9.43%. IR: = 2220, 2200 (2CN) cm
.
(3-Cyano-4-phenyl-6-(20-thienyl)-2-pyridinylthio)-
acetamide (5a)
Yield: 95%; m.p.: 228 C. Anal. Calcd. for C18H13N3OS2 (351.45): C,
61.51; H, 3.73; N, 11.96; S, 18.25%. Found: C, 61.77; H, 3.85; N, 11.68;
1
S, 18.12%. IR: = 3450, 3320 (NH2); 2200 (CN); 1680 (CO) cm
.
1H NMR (DMSO):
= 8.2 (d, 1H, CH thienyl), 7.3–8.3 (m, 10H:
5ArH’s, 2CH thienyl, CH pyridine and CONH2), 4.1 (s, 2H, SCH2)
ppm.
(3-Cyano-4-(p-methoxyphenyl)-6-(20-thienyl)-
2-pyridinylthio)acetamide (5b)
Yield: 96%; m.p.: 210 C. Anal. Calcd. for C19H15N3O2S2 (381.46): C,
59.82; H, 3.96; N, 11.02; S, 16.81%. Found: C, 59.59; H, 4.08; N, 11.00;
1
S, 16.74%. IR: = 3450, 3320 (NH2); 2200 (CN); 1680 (CO) cm 1. H
NMR (DMSO): = 8.2 (d, 1H, CH thienyl), 7.2–8.0 (m, 9H: 4ArH’s, 2CH
thienyl, CH pyridine and CONH2), 4.2 (s, 2H, SCH2), 3.4 (s, 3H, OCH3)
ppm.
(4-(p-Chlorophenyl)-3-cyano-6-(20-thienyl)-
2-pyridinylthio)acetamide (5c)
Yield: 95%; m.p.: 222 C. Anal. Calcd. for C18H12ClN3OS2 (385.90): C,
56.02; H, 3.13; N, 10.89; S, 16.62; Cl, 9.19%. Found: C, 56.32; H, 3.17;
N, 10.65; S, 16.57; Cl, 9.10%. IR: = 3450, 3320 (NH2); 2200 (CN);
1
1680 (CO) cm 1. H NMR (DMSO): = 8.2 (d, 1H, CH thienyl), 7.3–
8.0 (m, 9H: 4ArH’s, 2CH thienyl, CH pyridine and CONH2), 4.0 (s, 2H,
SCH2).

Pyridothienopyrimidines
97
2-Functionalized 3-amino-4-aryl-6-(20-thienyl)-thieno-
[2,3-b]pyridines 4a c, and 6a c
Method A
Compounds 3a–c or 5a–c (10 mmol) were suspended in sodium ethox-
ide solution (0.12 g sodium in 30 ml abs. ethanol) and heated under
reflux for 5 min. The solid that formed while hot was collected and
recrystallized from ethanol-chloroform mixture to give canary yellow
crystals of 4a–c and 6a–c respectively.
3-Amino-4-phenyl-6-(20-thienyl)-thieno[2,3-b]pyridine-2-carbonitrile
(4a). Yield: 90%; m.p.: 260 C. Anal. Calcd. for C18H11N3S2 (333.43): C,
64.84; H, 3.33; N, 12.60; S, 19.23%. Found: C, 64.93; H, 3.12; N, 12.89;
1
S, 19.00%. IR: = 3450, 3350 (NH2), 2200 (CN) cm
.
3-Amino-4-(p-methoxyphenyl)-6-(20-thienyl)-thieno[2,3-b]pyridine-2-
carbonitrile (4b). Yield: 92%; m.p.: 225 C. Anal. Calcd. for
C19H13N3OS2 (363.46): C, 62.79; H, 3.61; N, 11.56; S, 17.64%.
Found: C, 62.65; H, 3.66; N, 11.71; S, 17.87%. IR: = 3450, 3350 (NH2),
2200 (CN) cm 1. 1H NMR (DMSO-d6): = 7.1–8.1 (m, 8H:4ArH’s, 3CH
thienyl and CH pyridine), 5.7 (s, 2H, NH2), 3.9 (s, 3H, OCH3) ppm.
3-Amino-4-(p-chlorophenyl)-6-(20-thienyl)-thieno[2,3-b]pyridine-2-
carbonitrile (4c). Yield: 89%; m.p.: 261 C. Anal. Calcd. for
C18H10ClN3S2 (367.89): C, 58.77; H, 2.74; N, 11.42; S, 17.43; Cl,
9.64%. Found: C, 58.54; H, 2.67; N, 11.74; S, 17.62; Cl, 9.81%. IR:
=
1
3450, 3350 (NH2), 2200 (CN) cm 1. H NMR (DMSO-d6): = 7.2–8.1
(m, 8H: 4ArH’s, 3CH thienyl and CH pyridine), 5.6 (s, 2H, NH2) ppm.
MS: m/z = 367.5 (M+, 100%), 341 (M+-CN, 1%), 331 (M+-Cl, 9%), 298
(M+-Cl-C4H3S, 1.5%).
3-Amino-4-phenyl-6-(20-thienyl)-thieno[2,3-b]pyridine-2-carboxamide
(6a). Yield: 90%; m.p.: 235–8 C. Anal. Calcd. for C18H13N3OS2
(351.45): C, 61.51; H, 3.73; N, 11.96; S, 18.25%. Found: C, 61.61; H,
3.94; N, 11.75; S, 18.08%. IR: = 3480, 3300, 3150 (NH2), 1640 (CO)
1
cm
.
3-Amino-4-(p-methoxyphenyl)-6-(20-thienyl)-thieno[2,3-b]pyridine-2-
carboxamide (6b). Yield: 95%; m.p.: 231 C. Anal. Calcd. for
C19H15N3O2S2 (381.46): C, 59.82; H, 3.96; N, 11.02; S, 16.81%.
Found: C, 59.65; H, 4.06; N, 11.32; S, 16.79%. IR: = 3480, 3300, 3150
(NH2), 1640 (CO) cm 1. 1H NMR (DMSO): = 7.1–8.1 (m, 10H: 4ArH’s,
3CH thienyl, CH pyridine and CONH2), 5.9 (s, 2H, NH2), 3.5 (s, 3H,
OCH3) ppm.
3-Amino-4-(p-chlorophenyl)-6-(20-thienyl)-thieno[2,3-b]pyridine-2-
carboxamide (6c). Yield: 95%; m.p.: 240–243 C. Anal. Calcd. for

98
A. E. Abdel-Rahman et al.
C18H12ClN3OS2 (385.90): C, 56.02; H, 3.13; N, 10.89; S, 16.62; Cl,
9.19%. Found: C, 56.01; H, 3.14; N, 10.95; S, 16.77; Cl, 9.12%. IR:
=
3480, 3300, 3150 (NH2), 1640 (CO) cm 1. 1H NMR (DMSO): = 8.0 (d,
1H, CH thienyl), 7.5–7.8 (m, 6H: 4ArH’s, CH thienyl and CH pyridine),
7.3 (m, 3H, CH thienyl and CONH2), 5.9 (s, 2H, NH2) ppm.
Method B
To a suspension of compound 2a–c (10 mmol) in sodium ethoxide solu-
tion (0.35 g sodium in 40 ml abs. ethanol), chloroacetonitrile or chloroac-
etamide (10 mmol) was added. The resulting mixture was refluxed for
20 min. The formed precipitate was collected and recrystallized from
ethanol-chloroform mixture to give compounds 4a–c and 6a–c respec-
tively (yield; 76–83%). These products were identical in all aspects to
those described in method A.
4-Amino-9-phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d]pyrimidine (7)
Compound 4a (0.66 g, 0.002 mmol) in formamide (10 ml) was heated
under reflux for 4 h. The solid that formed while hot was collected and
recrystallized from ethanol-chloroform mixture to give white crystals of
7. Yield: 0.62 g (87%); m.p.: 270 C. Anal. Calcd. for C19H12N4S2 (360.46):
C, 63.31; H, 3.36; N, 15.54; S, 17.79%. Found: C, 63.45; H, 3.14; N, 15.72;
S, 17.59%. IR: = 3190, 3100 (NH2), 1640 (C N) cm 1. MS: m/z = 360.48
(M+, 91%), 359 (M+-H, 100%).
2,4-Dithioxo-9-phenyl-1,2,3,4-tetrahydro-7-(20-thienyl)-
pyrido[30,20:4,5]thieno[3,2-d]pyrimidine (8)
A mixture of compound 4a (0.66 g, 0.002 mmol) and carbon disulfide
(1 ml) in pyridine (10 ml) was heated under reflux on a water bath for 6 h.
The solid that formed while hot was collected and recrystallized from
DMF to give orange crystals of 8. Yield: 0.71 g (88%); m.p.: >360 C.
Anal. Calcd. for C19H11N3S4 (409.57): C, 55.72; H, 2.71; N, 10.26; S,
31.31%. Found: C, 55.88; H, 2.82; N, 10.17; S, 31.00%. IR: = 3350,
3100 (2NH) cm 1. MS: m/z = 410.6 (M++1, 21%), 409.7 (M+, 8%), 408.7
(M+-H, 100%), 375.7 (M+-H SH, 14%), 350.8 (M+-1-HNCS, 12%).
2,4-Dimethylthio-9-phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d]pyrimidine (9a)
To a solution of compound 8 (0.81 g, 0.002 mmol) in an ethanolic
sodium hydroxide solution 4% (10 ml, 0.01 mmol), methyl iodide (0.4 ml,

Pyridothienopyrimidines
99
0.006 mmol) was added. The resulting mixture was refluxed for 2 h and
then left to cool. The precipitated solid was collected and recrystallized
from ethanol to give white needles of 9a. Yield: 0.85 g (97%); m.p.:
269 C. Anal. Calcd. for C21H15N3S4 (437.63): C, 57.64; H, 3.45; N, 9.60;
S, 29.31%. Found: C, 57.82; H, 3.75; N, 9.71; S, 29.56%. IR: = 1600
(C N) cm 1. 1H NMR (CDCl3): = 7.2–7.8 (m, 9H: 5ArH’s, 3CH thienyl
and CH pyridine), 2.7 (s, 3H, CH3), 2.0 (s, 3H, CH3) ppm.
2,4-Diethoxycarbonylmethylthio-9-phenyl-7-(20-thienyl)-
pyrido[30,20:4,5]thieno[3,2-d]pyrimidine (9b)
To a suspension of 8 (0.81 g, 0.002 mmol) and sodium acetate trihy-
drate (3.0 g, 22 mmol) in ethanol (50 ml), ethyl chloroacetate (0.5 ml,
0.004 mmol) was added. The resulting mixture was refluxed for 2 h.
The precipitate that formed after cooling was collected and recrystal-
lized from ethanol to give white needles of 9b. Yield: 1.0 g (90%); m.p.:
121 C. Anal. Calcd. for C27H23N3O4S4 (581.75): C, 55.74; H, 3.98; N,
7.22; S, 22.05%. Found: C, 55.97; H, 4.00; N, 9.23; S, 22.16%. IR:
=
1
1730 (CO), 1600 (C N) cm 1. H NMR (CDCl3): d = 7.1–7.8 (m, 9H:
5ArH’s, 3CH thienyl and CH pyridine), 4.0–4.3 (m, 8H, 2XSCH2 and
2XOCH2), 1.2–1.4 (m, 6H, 2XCH3) ppm.
4-Imino-3,9-diphenyl-1,2,3,4-tetrahydro-7-(20-thienyl)-
2-thioxopyrido[30,20:4,5]thieno[3,2-d]pyrimidine (10)
A mixture of compound 4a (0.66 g, 0.002 mmol) and phenyl isothio-
cyanate (0.25 ml, 0.002 mmol) in pyridine (10 ml) was gently heated
under reflux for 6 h. The solid that formed on cooling was collected and
recrystallized from acetic acid to give orange crystals of 10. Yield: 0.88 g
(94%); m.p.: 272 C. Anal. Calcd. for C25H16N4S3 (468.61): C, 64.07; H,
3.44; N, 11.96; S, 20.53%. Found: C, 64.35; H, 3.29; N, 11.80; S, 20.27%.
IR: = 3380, 3200 (2NH) cm 1. MS: m/z = 468 (M+, 100%), 435 (M+-SH,
11%), 410 (M+-1-HNCS, 49%), 77 (C6H+5 , 85%).
3-Amino-2-(4,5-dihydroimidazol-2-yl)-4-phenyl-6-
(20-thienyl)-thieno[2,3-b]pyridine (11)
To a suspension of compound 4a (1.6 g, 0.005 mmol) in ethylene di-
amine (5 ml), carbon disulfide (2 ml) was added dropwise. The reaction
mixture was heated on a water bath for 2 h and then triturated with
ethanol (10 ml). The solid that formed was collected and recrystallized
from ethanol-chloroform mixture to give golden yellow crystals of 11.
Yield: 1.6 g (88%); m.p.: 190 C. Anal. Calcd. for C20H16N4S2 (376.5): C,

100
A. E. Abdel-Rahman et al.
63.80; H, 4.28; N, 14.88; S, 17.03%. Found: C, 63.91; H, 4.43; N, 14.56; S,
17.00%. IR: = 3400, 3250 (NH2), 3100 (NH) cm 1. 1H NMR (DMSO)):
= 7.7–8.2 (m, 8H: 5ArH’s, 2CH thienyl and CH pyridine), 7.3 (m, 1H,
CH thienyl), 6.0 (br, 2H, NH2), 3.6 (s, 4H, 2XCH2) ppm.
3-Amino-4-phenyl-6-(20-thienyl)-2-(1H-tetrazol-20-yl)-
thieno[2,3-b]pyridine (12)
A mixture of compound 4a (1.3 g, 0.004 mmol), sodium azide (0.4 g,
0.006 mmol), and ammonium chloride (0.32 g, 0.006 mmol) in DMF
(15 ml) was heated on a water bath for 5 h. The reaction was cooled,
diluted with water, and acidified with dilute acetic acid. The solid that
formed was collected and crystallized from ethanol to give golden yel-
low crystals of 12. Yield: 1.35 g (92%); m.p.: 279 C. Anal. Calcd. for
C18H12N6S2 (376.46): C, 57.43; H, 3.21; N, 22.32; S, 17.04%. Found: C,
57.49; H, 3.18; N, 22.40; S, 17.32%. IR: = 3490, 3370 (NH2), 3250 (NH)
1
cm
.
7-Phenyl-9-(20-thienyl)-2,3-dihydroimidazolo[100,200-c]-
pyrido[30,20:4,5]thieno[3,2-d]pyrimidine (13)
Compound 11 (0.75 g, 0.002 mmol) in triethyl orthoformate (10 ml) was
heated under reflux for 3 h. The precipitate that formed while hot was
collected and recrystallized from pyridine to give pale yellow needles of
13. Yield: 0.7 g (94%); m.p.: 307 C. Anal. Calcd. for C21H14N4S2 (386.49):
C, 65.26; H, 3.65; N, 14.50; S, 16.30%. Found: C, 65.53; H, 3.88; N, 14.42;
S, 16.30%. IR: = 1640 (C N) cm 1. 1H NMR (TFA): = 8.8 (s, 1H, CH
pyrimidine), 7.5–8.4 (m, 9H: 5ArH’s, 3CH thienyl and CH pyridine), 5.1
(br, 2H, CH2), 4.5 (br, 2H, CH2) ppm.
5-(p-Chlorophenyl)-7-phenyl-9-(20-thienyl)-2,3,5,6-
tetrahydroimidazolo[100,200-c]pyrido[30,20:4,5]thieno-
[3,2-d]pyrimidine (14)
To a mixture of compound 11 (0.75 g, 0.002 mmol) and p-
chlorobenzaldehyde (0.28 g, 0.002 mmol) in ethanol (15 ml), few drops
of piperidine were added. The reaction mixture was heated under reflux
for 4 h. The solid that formed on cooling was collected and recrystal-
lized from dioxane to give yellow crystals of 14. Yield: 0.9 g (90%); m.p.:
286 C. Anal. Calcd. for C27H19N4S2Cl (499.07): C, 64.98; H, 3.84; N,
11.23; S, 12.85; Cl, 7.11%. Found: C, 64.87; H, 3.58; N, 11.11; S, 12.96;
Cl, 7.06%. IR: = 3330 (NH) cm 1. 1H NMR (TFA): = 8.8 (m, 1H, CH
thienyl), 7.3–8.4 (m, 12H: 9ArH’s, 2CH thienyl and CH pyridine), 6.1
(s, 1H, CH), 4.2 (s, 2H, CH2), 3.7 (s, 2H, CH2) ppm.

Pyridothienopyrimidines
101
7-Phenyl-9-(20-thienyl)-5-thioxo-2,3,5,6-tetrahydro-
imidazolo[100,200-c]pyrido[30,20:4,5]thieno[3,2-d]pyrimidine
(15)
A mixture of compound 11 (0.75 g, 0.002 mmol) and carbon disulfide
(1 ml) in pyridine (10 ml) was heated under reflux on a water bath for 8 h.
The solid that formed while hot was collected and recrystallized from
DMF to give orange crystals of 15. Yield: 0.78 g (93%); m.p.: >360 C.
Anal. Calcd. for C21H14N4S3 (418.56): C, 60.26; H, 3.37; N, 13.39; S,
22.94%. Found: C, 60.11; H, 3.42; N, 13.59; S, 22.56%. IR: = 3400
(NH), 1640 (C N) cm 1. MS: m/z = 418 (M+, 100%).
7-Phenyl-9-(20-thienyl)-2,3-dihydroimidazolo[100,200-c]-
pyrido[30,20:4,5]thieno[3,2-d][1,2,3]triazine (16)
Sodium nitrite solution 10% (5 ml) was added to a solution of 11 (0.75 g,
0.002 mmol) in concentrated sulfuric acid (5 ml) and acetic acid (5 ml)
at 0 C during 5 min. with stirring. The reaction mixture was allowed
to stand at room temperature for 30 min. The solid that precipitated on
dilution with water was collected and crystallized from dioxane to give
white needles of 16. Yield: 0.65 g (87%); m.p.: 282 C. Anal. Calcd. for
C20H13N5S2 (387.48): C, 61.99; H, 3.68; N, 18.07; S, 16.55%. Found: C,
1
61.71; H, 3.45; N, 18.30; S, 16.24%. IR: = 1640 (C N) cm
.
7-Phenyl-9-(20-thienyl)-tetrazolo[100,200-c]pyrido-
[30,20:4,5]thieno[2,3-e]pyrimidine (17)
Compound 12 (0.75 g, 0.002 mmol) in triethyl orthoformate (10 ml)
was heated under reflux for 3 h and then left to cool. The precipitate
that formed was collected and recrystallized from dioxane to give pale
yellow needles of 17.Yield: 0.68 g (89%); m.p.: 222 C. Anal. Calcd. for
C19H10N6S2 (386.46): C, 59.05; H, 2.61; N, 21.75; S, 16.59%. Found: C,
1
59.21; H, 2.25; N, 21.43; S, 16.40%. IR: = 1600 (C N) cm
.
7-Phenyl-9-(20-thienyl)-tetrazolo[100,200-c]pyrido-
[30,20:4,5]thieno[2,3-e]pyrimidine-5(6H)-thione (18)
A mixture of compound 12 (0.75 g, 0.002 mmol) and carbon disulfide
(4 ml) in pyridine (15 ml) was heated under reflux on a water bath for
12 h. The solid that formed while hot was collected and recrystallized
from DMF to give yellow crystals of 18. Yield: 0.70 g (84%); m.p.: 317 C.
Anal. Calcd. for C19H10N6S3 (418.52): C, 54.53; H, 2.41; N, 20.08; S,
23.00%. Found: C, 54.22; H, 2.25; N, 20.11; S, 22.70%. IR: = 3330
1
(NH), 1620 (C N) cm
.

102
A. E. Abdel-Rahman et al.
4-Chloro-9-phenyl-7-(20-thienyl)-pyrido-[30,20:4,5]thieno-
[3,2-d][1,2,3]triazine (19)
To a chilled solution of compound 4a (1.7 g, 0.005 mmol) in a mixture of
acetic acid (10 ml) and concentrated hydrochloric acid (7 ml), a sodium
nitrite solution 10% (4 ml, 0.006 mmol) was added with stirring during
5 min. The stirring was continued at 5 C for 3 h. The formed preceiptate
was collected and crystallized from ethanol-chloroform mixture to give
white plates of 19. Yield: 1.7 g (89%); m.p.: 236 C; Anal. Calcd. for
C18H9ClN4S2 (380.88): C, 56.76; H, 2.38; N, 14.71; S, 16.84; Cl, 9.31%.
Found: C, 56.90; H, 2.22; N, 14.91; S, 16.87; Cl, 9.10%. IR: = 1600
1
(C N) cm
.
4-Hydrazino-9-phenyl-7-(20-thienyl)-pyrido[30,20:4,5]-
thieno[3,2-d][1,2,3]triazine (20)
A mixture of 19 (1.5 g, 0.004 mmol) and hydrazine hydrate 99% (4.0 ml
in ethanol (35 ml), was heated under reflux for 4 h. The solid that
formed on cooling was collected and recrystallized from dioxane to give
pale yellow crystals of 20. Yield: 1.35 g (91%); m.p.: 154 C. Anal. Calcd.
for C18H12N6S2 (376.46): C, 57.43; H, 3.21; N, 22.32; S, 17.04%. Found:
C, 57.28; H, 3.19; N, 22.13; S, 17.30%. IR: = 3320–3200 (NHNH2)
1
cm
.
4-(30,50-dimethylpyrazol-10-yl)-9-Phenyl-7-(20-thienyl)-
pyrido[30,20:4,5]thieno[3,2-d][1,2,3]triazine (21)
A mixture of compound 20 (0.75 g, 0.002 mmol) and acetylacetone (2 ml,
0.02 mmol) in ethanol (15 ml) was heated under reflux for 5 h. The
crystalline precipitate that formed while hot was collected and recrys-
tallized from ethanol-chloroform as greenish crystals of 21. Yield: 0.8 g
(91%); m.p.: 310 C. Anal. Calcd. for C23H16N6S2 (440.55): C, 62.71; H,
3.66; N, 19.08; S, 14.56%. Found: C, 62.35; H, 3.32; N, 19.01; S, 14.35%.
IR: = 1600 (C N) cm 1. 1H NMR (TFA): = 7.5–8.5 (m, 9H: 5 ArH’s,
3CH thienyl and CH pyridine), 6.5 (s, 1H, CH pyrazole), 2.9 (s, 3H,
CH3), 2.5 (s, 3H, CH3) ppm.
4-Oxo-9-phenyl-1,2,3,4-tetrahydro-7-(20-thienyl)-
2-thioxopyrido[30,20:4,5]thieno[3,2-d]pyrimidine (22)
A mixture of 6a (1.0 g, 3 mmol) and carbon disulphide (4 ml) in dry
pyridine (30 ml) was heated on a water bath for 48 h. The solid thus
formed while hot was collected and recrystallized from DMF as yellow

Pyridothienopyrimidines
103
crystals of 22. Yield: 88%; m.p.: >360 C. Anal. Calcd. for C19H11N3OS3
(393.51): C, 57.99; H, 2.82; N, 10.68; S, 24.44%. Found: C, 58.04;
H, 2.73; N, 10.39; S, 24.55%. IR: = 3350–3100 (NH), 1680 (C O)
1
cm
.
Reaction of 22 with Halo Compounds; Formation of
Compounds 23a,b: General Procedure
A solution of compound 22 (0.39 g, 1 mmol) in DMF (7 ml) was stirred
for a while with potassium carbonate (0.3 g, 4 mmol) and then alkylat-
ing agent (1 mmol) was added. The reaction mixture was heated on a
water bath for 1 h and then diluted with water. The precipitate that
formed was filtered off, dried and crystallized from ethanol as pale yel-
low crystals of 23a or 23b.
a) 3-Ethyl-2-ethylthio-9-phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d]pyrimidine-4(3 H )-one (23a)
Obtained by using ethyl iodide. Yield: 92%; m.p.: 190 C. Anal. Calcd.
for C23H19N3OS3 (450.22): C, 61.36; H, 4.25; N, 9.47; S, 21.37%. Found:
C, 61.22; H, 4.16; N, 9.39; S, 21.57%. IR: = 1670 (C O) cm 1. 1H NMR
(TFA): = 7.7–8.4 (m, 8H: 5ArH’s, 2CH thienyl and CH pyridine), 7.6
(m, 1H, CH thienyl), 4.4 (q, 2H, NCH2), 2.8 (q, 2H, SCH2), 2.4–2.7 (t,
6H, 2xCH3) ppm.
b) 3-Ethoxycarbonylmethyl-2-ethoxycarbonylmethythio-
7-(20-thienyl)-pyrido[30,20:4,5]thieno[3,2-d]pyrimidine-
4(1 H,3 H )-one (23b)
Obtained by using ethyl chloroacetate. Yield: 90%; m.p.: 151 C. Anal.
Calcd. for C27H23N3O5S3 (479.60): C, 57.60; H, 3.57; N, 8.76; S, 20.06%.
Found: C, 57.79; H, 3.54; N, 8.91; S, 20.32%. IR: = 1720 (C O, ester),
1
1670 (C O, pyrimidinone) cm 1. H NMR (TFA): = 8.2–8.5 (m, 3H:
2CH thienyl and CH pyridine), 7.8–8.1 (m, 5H, ArH), 7.6 (m, 1H, CH
thienyl), 5.6 (s, 2H, NCH2), 4.4–4.7 (q, 4H, 2xOCH2), 4.1 (s, 2H, SCH2),
1.4–1.7 (q, 6H, 2 CH3) ppm.
9-Aryl-7-(20-thienyl)-pyrido[30,20:4,5]thieno-
[3,2-d]pyrimidine-4(3H)-ones (24b,c)
A mixture of compounds 6b,c (5 mmol) and triethyl orthoformate (4 ml)
in acetic anhydride (20 ml) was refluxed for 4 h. The solid that formed
on cooling was filtered off and recrystallized from ethanol-chloroform
mixture as white crystals of 24b,c.

104
A. E. Abdel-Rahman et al.
Compound 24b
Yield: 80%; m.p.: 340 C. Anal. Calcd. for C20H13N3O2S2 (391.47): C,
61.36; H, 3.35; N, 10.73; S, 16.38%. Found: C, 61.11; H, 3.53; N, 10.61; S,
16.22%. IR: = 3200–2000 (NH), 1650 (C O) cm 1. 1H NMR (TFA):
= 9.1 (s, 1H, CH pyrimidine), 8.1–8.4 (m, 3H, 2CH thienyl and CH pyri-
dine), 7.8–8.0 (d, 2H, ArH’s), 7.3–7.7 (m, 3H: 2ArH’s and CH thienyl),
4.1 (s, 3H, OCH3) ppm.
Compound 24c
Yield: 80%; m.p.: 350 C. Anal. Calcd. for C19H10ClN3OS2 (395.89): C,
57.64; H, 2.55; N, 10.61; S, 16.20%. Found: C, 57.89; H, 2.77; N, 10.90;
1
S, 16.53%. IR: = 3200–2000 (NH), 1650 (C O) cm
.
9-Aryl-7-(20-thienyl)-pyrido[30,20:4,5]thieno[3,2-d]-
[1,2,3]triazine-4(3H)-ones (25a c)
To a cold solution of 6a–c (10 mmol) in conc. H2SO4 (5 ml) and glacial
acetic acid (20 ml), sodium nitrite solution 10% (7.7 ml, 11 mmol)
was added dropwise with stirring during 5 min at room temperature.
The formed precipitate was collected dried in air and crystallized from
ethanol-chloroform mixture to give compounds 25a–c.
Compound 25a
Obtained from 6a. Yield: 93%; m.p.: >360 C. Anal. Calcd. for
C18H10N4OS2 (362.43): C, 59.65; H, 2.78; N, 15.46; S, 17.69%. Found:
C, 59.74; H, 2.76; N, 15.41; S, 17.81%. IR: = 3200 (NH), 1650 (C O)
1
cm
.
Compound 25b
Obtained from 6b. Yield: 83%; m.p.: 303 C. Anal. Calcd. for
C19H12N4O2S2 (392.46): C, 58.15; H, 3.08; N, 14.28; S, 16.34%. Found:
C, 58.11; H, 2.98; N, 13.96; S, 16.05%. IR: = 3200 (NH), 1650 (C O)
1
cm 1. H NMR (TFA): = 8.1–8.4 (m, 3H, 2CH thienyl and CH pyri-
dine), 7.8–8.0 (d, 2H, ArH’s), 7.3–7.7 (m, 3H: 2ArH’s and CH thienyl),
4.0 (s, 3H, OCH3) ppm.
Compound 25c
Obtained from 6c. Yield: 87%; m.p.: 235 C. Anal. Calcd. for
C18H9ClN4OS2 (369.88): C, 54.47; H, 2.29; N, 14.12; S, 16.16; Cl, 8.93%.
Found: C, 54.52; H, 2.01; N, 14.30; S, 16.33; Cl, 8.71%. IR: = 3200
1
(NH), 1650 (C O) cm
.

Pyridothienopyrimidines
105
Alkylation of 9-Phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d][1,2,3]triazine-4(3 H)-one
(25a); Formation of 26a c
A solution of triazinone derivative 25a (0.36 g, 1 mmol) in DMF (7 ml)
was stirred for a while with potassium carbonate (0.3 g) and then alky-
lating agent (1 mmol) in DMF (7 ml) was added. The reaction mixture
was stirred for 2 h at room temperature and then diluted with water.
The formed precipitate was filtered off, dried in air and crystallized
from the proper solvent to give 26a–c.
a) 3-p-Bromophenacyl-9-phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d][1,2,3]triazine-4(3H)-one (26a)
Obtained from 25a and p-bromophenacyl bromide (ethanol-
chloroform). Yield: 81%; m.p.: 279 C. Anal. Calcd. for C26H15BrN4O2S2
(559.46): C, 55.82; H, 2.70; N, 10.01; S, 11.46%. Found: C, 55.67; H, 2.65;
1
N, 10.30; S, 11.70%. IR: = 1670 (2C O) cm
.
b) 3-Ethoxycarbonylmethyl-9-phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d][1,2,3]triazine-4(3H)-one (26b)
Obtained from 25a and ethyl chloroacetate (ethanol). Yield: 88%;
m.p.: 245 C. Anal. Calcd. for C22H16N4O3S2 (448.53): C, 58.91; H, 3.60;
N, 12.49; S, 14.30%. Found: C, 58.88; H, 3.57; N, 12.47; S, 14.40%. IR: =
1720 (C O, ester), 1670 (C O, triazinone) cm 1. 1H NMR (CDCl3):
7.8–8.2 (m, 8H: 5ArH’s, 2CH thienyl and CH pyridine), 7.4–7.5 (t, H,
CH thienyl), 5.4 (s, 2H, SCH2), 4.3–4.5 (q, 2H, OCH2), 1.3–1.5 (t, 3H,
CH3) ppm.
=
c) 3-Carbamoylmethyl-9-phenyl-7-(20-thienyl)-pyrido-
[30,20:4,5]thieno[3,2-d][1,2,3]triazine-4(3H)-one (26c)
Obtained from 25a and chloroacetamide (ethanol). Yield: 83%; m.p.:
351 C. Anal. Calcd. for C20H13N5O2S2 (419.49): C, 57.27; H, 3.12; N,
16.70; S, 15.29%. Found: C, 54.42; H, 3.01; N, 16.94; S, 15.12%. IR:
=
1
3400, 3300 cm for (NH2), 1680 (C O, amide), 1670 (C O, triazinone)
1
cm 1. H NMR (DMSOF: 8 = 7.5–8.1 (m, gH; ArHs, 2CH thienyl and
CH pyridine); 7.2 (br, 2H, CONH2), 3.4 (S, 2H, NCH2).
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