Synthesis of novel pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidines, pyrido [3″,2″:4′,5′]thieno[3′,2′:4,5] pyrimido[1,6-a]benzimidazoles and related fused systems

Article abstract of DOI:10.1002/jhet.5570420606

3-Amino-4-aryl-5-ethoxycarbonyl-6-methylthieno[2,3-b]pyridine-2- carboxamides 3a-c were prepared from ethyl 4-aryl-3-cyano-6-methyl-2-thioxo-1,2- dihydropyridine-5-carbonylates 1a-c and reacted with some carbonyl compounds to give tetrahydropyridothienopyrimidine derivatives 6a-c, 7a-c and 8a-c, respectively. Treatment of compound 3c with chloroacetyl chloride led to the formation of a next key compound, ethyl 2-chloromethyl-4-oxo-3,4- dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-8-carboxylate 9. Also, 3-amino-2-benzimidazolylthieno[2,3-b]pyridine-5-carboxylate 5 and 2-(3′-aminothieno [2,3-b]pyridin-2′-yl)-4-oxo-3,4- dihydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-8-carboxylate 17 were prepared from 1c. The compounds 5, 9 and 17 were used as good synthons for other pyridothienopyrimidines and pyridothienopyrimidobenzimidazoles as well as for related fused polyheterocyclic systems.

Full text of DOI:10.1002/jhet.5570420606

Sep-Oct 2005
1069
Synthesis of Novel Pyrido[3',2':4,5]thieno[3,2-d]pyrimidines,
Pyrido [3'',2'':4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazoles
and Related Fused Systems
E. A. Bakhite*
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
A. G. Al-Sehemi
Department of Chemistry, Teachers College at Abha, B.O.Box. 249, Saudi Arabia
Y. Yamada*
Department of Chemistry, Faculty of Education, Utsunomiya University, Utsunomiya 321-8505, Japan
Received December 6, 2004
3-Amino-4-aryl-5-ethoxycarbonyl-6-methylthieno[2,3-b]pyridine-2-carboxamides 3a-c were prepared
from ethyl 4-aryl-3-cyano-6-methyl-2-thioxo-1,2-dihydropyridine-5-carbonylates 1a-c and reacted with
some carbonyl compounds to give tetrahydropyridothienopyrimidine derivatives 6a-c, 7a-c and 8a-c,
respectively. Treatment of compound 3c with chloroacetyl chloride led to the formation of a next key com-
pound, ethyl 2-chloromethyl-4-oxo-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxylate 9.
Also, 3-amino-2-benzimidazolylthieno[2,3-b]pyridine-5-carboxylate 5 and 2-(3'-aminothieno [2,3-
b]pyridin-2'-yl)-4-oxo-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxylate 17 were prepared
from 1c. The compounds 5, 9 and 17 were used as good synthons for other pyridothienopyrimidines and
pyridothienopyrimidobenzimidazoles as well as for related fused polyheterocyclic systems.
J. Heterocyclic Chem., 42, 1069 (2005).
The biological activities of condensed pyrimidines as
derivatives were prepared as antinflammatory agents, par-
ticularly for treating arthritis and bone resorption inhibiting
agents [15]. Pyridothienopyrimidine derivatives have been
found in applications as analgesics [16], antipyretics [17]
and anti-inflammatories [18]. Encouraged by all these facts
and as a continuation of our program directed towards the
synthesis of new condensed thieno[2,3-b]pyridines [19-21],
we undertook the synthesis of the title compounds which
may show good biological and medical applications.
sedatives, antibacterials and antimalarials are well docu-
mented [1,2]. Numerous thieno[2,3-b]pyridines have been
investigated in relation with their biological and pharmaco-
logical activities. Some of them proved to possess antibac-
terial [3,4], antiviral [5], antihypertensive [6] and immunos-
timulating [7] activities. Others are useful as gonadtropin-
releasing hormone antagonists [8-13] and as lipoxygenase
inhibitors [14]. Recently, certain thieno[2,3-b]pyridine

1070
The reaction of ethyl 4-aryl-3-cyano-6-methyl-2-thioxo-
Vol. 42
E. A. Bakhite, A. G. Al-Sehemi, and Y. Yamada
The compounds 3a-c and 5 were used as starting com-
pounds in this investigation. Thus, refluxing of vic-
aminoamides 3a-c with 4-chlorobenzaldehyde in acetic
acid or in ethanol containing a few drops of concentrated
hydrochloric acid afforded the corresponding tetrahdy-
ropyridothienopyrimidines 6a-c. Upon treatment of 3a-c
with cyclopentanone and with cyclohexanone under the
same conditions, the products were respectively identified
as spiro compounds 7a-c and 8a-c, rather than Schiff's
bases [23] (Scheme 2).
1,2-dihydropyridine-5-carbonylates 1a-c [22] with
chloroacetamide in the presence of sodium acetate gave 4-
aryl-3-cyanopyridin-2-ylthioacetamides 2a-c. Upon treat-
ment of these compounds with sodium ethoxide in ethanol,
they underwent intramolecular Thorpe-Ziegler cyclization
to give 3-amino-4-arylthieno[2,3-b]pyridine-2-carboxam-
ides 3a-c. Similarly, the reaction of 1c with 2-chloromethyl-
1H-benzimidazole led to the formation of benzimidazolyl
derivative 4. The latter compound was cyclized into ethyl 3-
amino-2-(1'H-2'-benzimidazolyl)-4-(4'-chlorophenyl)-6-
methylthieno[2,3-b]pyridine-5-carboxylate (5) upon treat-
ment with sodium ethoxide (Scheme 1).
The cyclocondensation of 3c with chloroacetyl chloride
resulted in the formation of ethyl 2-chloromethyl-9-(4'-
chlorophenyl)-7-methyl-4-oxo-3,4-dihydropyrido[3',2':4,5]-

Sep-Oct 2005
Synthesis of Novel Pyrido[3',2':4,5]thieno[3,2-d]pyrimidines
1071
thieno[3,2-d] pyrimidine-8-carboxylate (9) which proved to
be a good synthon for other pyridothienopyrimidine deriva-
tives as well as for related polycyclic systems. Thus, the reac-
tion of 9 with morpholine and with sodium ethoxide gave the
corresponding pyrimidinone derivatives 10 and 11, respec-
tively. The interaction of 9 with thiourea produced an adduct
which upon treatment with sodium hydroxide followed by
acidification with acetic acid furnished the mercap-
tomethylpyrimidinone derivative 12. Heating of compound 9
with an excess amount of phosphorous oxychloride afforded
the dichloro derivative 13 (Scheme 3).
Preferential replacement of a chlorine atom in 13 was
not possible due to the equally mobile nature of both the
chlorine atoms [24]. All such reactions led to the formation
of disubstituted products. Thus, it gave ethyl 9-(4'-chloro-
phenyl)-7-methyl-4-morpholino-2-morpholinomethyl-
pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxylate
(14) with morpholine and ethyl 9-(4'-chlorophenyl)-7-
methyl-2-mercaptomethyl-4-thioxo-3H-pyrido[3',2':4,5]-
thieno[3,2-d]pyrimidine-8-carboxylate (15) upon treat-
ment with thiourea followed by heating the resulting prod-
uct with sodium hydroxide and then acidified with acetic
acid (Scheme 4).
compound underwent intramolecular Thorpe-Zeigler
cyclization upon heating with sodium ethoxide in ethanol
to furnished 2-(thieno[2,3-b]pyridin-2'-yl)-pyrido-
[3',2':4,5]thieno[3',2'-d]pyrimidine-4(3H)-one derivative
17 (Scheme 5).
Furthermore, compound 5, also having the γ-amino-
imine structure, was used as the key intermediate for syn-
thesizing some heterocyclic compounds containing both
theino[2,3-b]pyridine and benzimidazole moieties. Thus,
the reaction of 5 with triethyl orthoformate, acetic anhy-
dride, 4-chlorobenzaldehyde and carbon disulfide led to
the formation of pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrim-
ido[1,6-a]benzimidazoles 22, 23, 24 and 25, respectively.
Treatment of 5 with nitrous acid resulted in diazotisation
followed by the self coupling to give the corresponding
pyrido[3'',2'':4',5']thieno[3',2':4,5][1,2,3]triazino[1,6-
a]benzimidazole derivative 26 (Scheme 7).
In conclusion, 1,3-diamino compound 3 and 3-
aminoimine compound 5, investigated are good starting
materials to construct fused polyheterocyclic system. And
the reactive chloromethyl compound 9, thus obtained, has
the advantage of a building block for complex heterocyclic
compounds. Moreover, 3-aminoimine compound 17, pre-
pared by coupling reaction between 9 and 1, is a good syn-
thon for more complex fused polyheterocyclic systems.
The structural formulae of all compounds prepared were
confirmed by elemental and spectral analyses.
Moreover, treatment of 2-chloromethylpyrimidinone 9
with the pyridine-2(1H)-thione 1c in refluxing ethanol
containing sodium acetate, resulted in nucleophilic dis-
placement reaction and formation of compound 16. This

1072
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E. A. Bakhite, A. G. Al-Sehemi, and Y. Yamada

Sep-Oct 2005
Synthesis of Novel Pyrido[3',2':4,5]thieno[3,2-d]pyrimidines
1073
EXPERIMENTAL
Method A.
Compound 2a-c (0.01 mol) was suspended in sodium ethoxide
solution (0.12 g of sodium in 30 mL of absolute ethanol) and then
heated at reflux for 5 minutes. The solid that formed on cooling
was collected and recrystallized from ethanol.
All melting points were determined on a Gallan-Kamp appara-
tus and are uncorrected. The ir spectra were recorded on a
Shimadzu 470 IR-spectrophotometer (KBr). The H nmr spectra
were taken on a Varian EM-390, 90 MHz spectrometer with TMS
as internal standard. Mass spectra were recorded on either a
JEOL JMS-600 spectrometer (Assiut University) or a JEOL AX-
500 spectrometer (Utsunomiya University). Elemental analyses
were performed on an Elementar Analyses system GmbH VARI-
1
Method B.
To a suspension of compound 1a-c (0.01 mol) in sodium
ethoxide solution (0.35 g sodium in 40 mL absolute ethanol),
chloroacetamide (0.94 g, 0.01 mol) was added. The resulting
mixture was refluxed for 20 minutes. The formed yellow precipi-
tate was collected and recrystallized from ethanol to give yellow
crystals of 3a-c. These products were identical to those described
in method A in all aspects.
OEL V 1998 CHNS Mode.
2.3
Ethyl 4-Aryl-3-cyano-6-methyl-2-thioxo-1,2-dihydropyridine-5-
carbonylates 1a-c.
These compounds were prepared according to a reported
procedure [22].
3-Amino-5-ethoxycarbonyl-6-methyl-4-phenylthieno[2,3-
b]pyridine-2-carboxamide (3a).
This compound was obtained as yellow crystals, mp 219-220
General Procedure for the Preparation of (4-Aryl-3-cyano-5-
ethoxycarbonyl-6-methyl)pyridin-2-ylthioacetamides 2a-c.
°C, yield 93% (Method A), 81% (Method B), ir: 3490, 3450,
-1 1
3300, 3200 (2NH ); 1720, 1650 (2 C=O) cm ; H nmr (DMSO):
2
To a suspension of compound 1a-c (0.02 mol) and sodium
acetate trihydrate (3.0 g, 0.022 mol) in ethanol (50 mL),
chloroacetamide (1.9 g, 0.02 mol) was added. The resulting mix-
ture was heated at reflux for 3 hours. The precipitate that formed
on cooling was collected and recrystallized from ethanol.
δ 7.2-7.7 (m, 7H, CONH and ArH's); 5.7 (s, 2H, NH at C-3);
2
2
3.9-4.2 (q, 2H, OCH ); 2.6 (s, 3H, CH at C-6); 0.7-1.0 (t, 3H,
2
3
+
CH of ester); ms: m/z 355 (M , 100%).
3
Anal. Calcd. for C
H N O S: C, 60.83; H, 4.82; N, 11.83; S,
18 17 3 3
9.00. Found:C, 60.55; H, 4.93; N, 11.61; S, 9.26.
(3-Cyano-5-ethoxycarbonyl-6-methyl-4-phenyl)pyridin-2-ylth-
ioacetamide (2a).
3-Amino-5-ethoxycarbonyl-4-(4'-methoxyphenyl)-6-methylth-
ieno[2,3-b] pyridine-2-carboxamide (3b).
This compound was obtained as colorless needles, mp 160-163
This compound was obtained as yellow crystals, mp 214-215
°C, yield 96%, ir: 3400, 3300 (NH ), 2210(CN); 1720,1670
2
°C, yield 94% (Method A), 78% (Method B), ir: 3490, 3450,
-1 1
(2C=O) cm ; H nmr (CDCl ): δ 7.2-7.5 (m, 5H, ArH's); 6.6 (br,
2H, NH ); 3.8-4.1(m, 4H, OCH and SCH ); 2.6 (s, 3H, CH at
C-6); 0.7-0.9 (t, 3H, CH of ester); ms: m/z 355 (M , 46%).
-1 1
3
3300, 3200 (2NH ); 1720, 1650 (2 C=O) cm ; H nmr (DMSO):
2
2
2
2
3
δ 7.0-7.3 (m, 6H, CONH and ArH's); 5.6 (s, 2H, NH at C-3);
2
2
+
3
3.9-4.2 (m, 5H, OCH and OCH ); 2.6 (s, 3H, CH at C-6); 0.9-
2
3
3
Anal. Calcd. for C
H N O S: C, 60.83; H, 4.82; N, 11.83; S,
+
18 17 3 3
1.1 (t, 3H, CH of ester); ms: m/z 385 (M , 100%).
3
9.00. Found: C, 60.75; H, 4.90; N, 12.03; S, 9.19.
Anal. Calcd. for C
H N O S: C, 59.20; H, 4.97; N, 10.91; S,
19 19 3 4
8.30. Found: C, 59.18; H, 4.98; N, 10.85; S, 8.25.
(3-Cyano-5-ethoxycarbonyl-4-(4'-methoxyphenyl)-6-
methyl)pyridin-2-ylthioacetamide (2b).
3-Amino-4-(4'-chlorophenyl)-5-ethoxycarbonyl-6-methylth-
This compound was obtained as colorless needles, mp 142-
ieno[2,3-b]pyridine-2-carboxamide (3c).
145 °C, yield 95%, ir: 3400, 3300 (NH ), 2210(CN);
2
This compound was obtained as yellow crystals, mp 219-220
-1
1
1720,1670 (2C=O) cm ; H nmr (CDCl ): δ 6.9-7.3 (dd, 4H,
3
°C, yield 93%, (Method A), 83% (Method B), ir: 3490, 3450,
ArH's); 6.7 (br, 2H, NH ); 3.8-4.2 (m, 7H: OCH , SCH and
-1 1
2
2
2
3300, 3200 (2NH ); 1720, 1650 (2 C=O) cm ; H nmr (DMSO):
2
OCH ); 2.7 (s, 3H, CH at C-6); 0.8-1.0 (t, 3H, CH of ester);
3
3
3
δ 7.5-7.8 (dd, 4H, ArH's); 7.3 (s, 2H, CONH ); 5.8 (s, 2H, NH at
2
2
+
ms: m/z 385 (M , 100%).
Anal. Calcd. for C
C-3); 4.0-4.3 (q, 2H, OCH ); 2.7 (s, 3H, CH at C-6); 1.0-1.3 (t,
2
3
H
N O S: C, 59.20; H, 4.97; N, 10.91; S,
+
19 19
3 4
3H, CH of ester); ms: m/z 389 (M , 100%).
3
8.30. Found:C, 59.32; H, 4.91; N, 11.11; S, 8.46.
Anal. Calcd. for C
H ClN O S: C, 55.52; H, 4.14; N, 10.80;
18 16 3 3
S, 8.22; Cl, 8.99. Found: C, 55.51; H, 4.20; N, 10.89; S, 8.55; Cl,
9.32.
(4-(4'-Chlorophenyl)-3-cyano-5-ethoxycarbonyl-6-methyl)-
pyridin-2-ylthioacetamide (2c).
This compound was obtained as colorless needles, mp 161-
Ethyl 2-(1'H-2'-Benzimidazolylmethylthio)-4-(4'-chlorophenyl)-
3-cyano-6-methyl-2-thioxopyridine-5-carbonylate (4).
162 °C, yield 96%, ir: 3400, 3300 (NH ), 2210(CN);
2
-1
1
1720,1670 (2C=O) cm ; H nmr (CDCl ): δ 7.3-7.6 (dd, 4H,
ArH's); 6.8 (br, 2H, NH ); 4.0-4.3 (m, 4H, OCH and SCH );
3
To a suspension of ethyl 4-(4'-chlorophenyl)-3-cyano-6-methyl-
1,2-dihydropyridine-5-carboxylate (1c) (6.66 g, 0.02 mol) and
sodium acetate trihydrate (3.0 g, 0.022 mol) in ethanol (50 mL), 2-
chloromethyl-1H-benzimidazole (3.3 g, 0.02 mol) was added. The
resulting mixture was heated at reflux for 3 hours. The precipitate
that formed was collected and recrystallized from ethanol as color-
less needles of 4, mp 159-160 °C, yield 88%; ir: 3300 (NH); 2200
2
2
2
2.8 (s, 3H, CH at C-6); 0.9-1.2 (t, 3H, CH of ester); ms: m/z
3
3
+
389 (M , 100%).
Anal. Calcd. for C
H ClN O S: C, 55.52; H, 4.14; N, 10.80;
18 16 3 3
S, 8.22; Cl, 8.99. Found:C, 55.29; H, 4.26; N, 10.73; S, 8.35; Cl,
9.18.
-1
1
(CN), 1720 (C=O) cm ; H nmr (CDCl ): δ 7.1-7.6 (m, 8H,
General Procedures for the Preparation of 3-Amino-4-aryl-5-
ethoxycarbonyl-6-methylthieno[2,3-b]pyridine-2-carboxamides
3a-c.
3
ArH's); 4.4 (s, 2H, SCH ); 3.8-4.1 (q, 2H, OCH ); 2.7 (s, 3H, CH
2
2
3
+
at C-6), 0.8-1.1 (t, 3H, CH of ester); ms: m/z 462 (M , 96%).
3

1074
Vol. 42
E. A. Bakhite, A. G. Al-Sehemi, and Y. Yamada
Anal. Calcd. for C
S, 6.92; Cl, 7.57. Found: C, 62.20; H, 4.27; N, 12.21; S, 6.88; Cl,
7.78
H
ClN O S: C, 62.33; H, 4.14; N, 12.12;
General Procedure for the Preparation of Spiro Compounds 7a-c
and 8a-c.
24 19
4 2
A mixture of 3a-c (0.002 mol) and cyclopentanone or cyclo-
hexanone (0.002 mol) in glacial acetic acid (15 mL) or in ethanol
(20 mL) containing a few drops of concentrated hydrochloric
acid was heated at reflux for 3 hours. The product was collected
and recrystallized from ethanol.
Ethyl 3-Amino-2-(1'H-2'-benzimidazolyl)-4-(4'-chlorophenyl)-
6-methylthieno [2,3-b]pyridine-5-carboxylate (5).
Compound 4 (4.63 g, 0.01 mol) was suspended in sodium
ethoxide solution (0.24 g of sodium in 30 mL of absolute ethanol)
and then heated at reflux for 5 minutes. The solid that formed on
cooling and acidification with acetic acid was collected and
recrystallized from ethanol to give yellow crystals of 5, mp 159-
Ethyl 7-Methyl-9-phenyl-2,2-tetramethylene-4-oxo-1,2,3,4-
tetrahydropyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxy-
late (7a).
160°C, yield 88%; ir: 3480, 3300, 3200 (NH, NH ); 1720 (C=O)
2
This compound was obtained as yellow needles, mp 272-273
°C, yield 91%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
-1
1
cm ; H nmr (CDCl ): 7.2-7.7 (m, 8H, ArH's); 6.8 (br, 2H,
-1
3
NH ); 3.9-4.2 (q, 2H, OCH ); 2.7 (s, 3H, CH at C-6), 0.8-1.1 (t,
1
2
2
3
H nmr (CDCl ): δ 7.3-7.7 (m, 5H, ArH's); 6.6 (s, 1H, CONH);
3
+
3H, CH of ester); ms: m/z 462 (M , 100%).
3
4.0-4.3(q, 2H, OCH ); 3.7 (s, 1H, NH); 2.7 (s, 3H, CH at C-7);
2
3
Anal. Calcd. for C
H ClN O S: C, 62.33; H, 4.14; N, 12.12;
24 19 4 2
1.7-2.0 (br, 6H, (CH ) of cyclopentylidene ring); 1.4 (br, 2H,
2 3
S, 6.92; Cl, 7.57. Found: C, 62.39; H, 4.20; N, 12.41; S, 7.14; Cl,
7.70.
CH of cyclopentylidene ring); 1.1-1.3 (t, 3H, CH of ester); ms:
2
3
+
m/z 421 (M , 70%).
Anal. Calcd. for C
7.59. Found: C, 65.48; H, 5.69; N, 10.15; S, 7.76.
H
N O S: C, 65.54; H, 5.50; N, 9.97; S,
General Procedure for the Preparation of Ethyl 9-Aryl-2-(4'-
chlorophenyl)-7-methyl-4-oxo-1,2,3,4-tetrahydropyrido-
[3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxylates 6a-c.
23 23
3 3
Ethyl 9-(4'-Methoxyphenyl)-7-methyl-2,2-tetramethylene-4-
oxo-1,2,3,4-tetrahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-
8-carboxylate (7b).
A mixture of 3a-c (0.002 mol) and the respective aldehyde
(0.002 mol) in glacial acetic acid (15 mL) or in ethanol (20 mL)
containing few drops of concentrated hydrochloric acid was
heated at reflux for 3 hours. The product was collected and
recrystallized from acetic acid.
This compound was obtained as yellow needles, mp 278-279
°C, yield 88%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
-1
1
H nmr (CDCl ): δ 7.3-7.6 (m, 5H, ArH's); 6.8 (s, 1H, CONH );
3
Ethyl 2-(4'-Chlorophenyl)-7-methyl-9-phenyl-4-oxo-1,2,3,4-
tetrahydropyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-car-
boxylate (6a).
4.0-4.3 (q, 2H, OCH ); 3.5 (s, 1H, NH); 2.7 (s, 3H, CH at C-7);
2
3
1.9-2.2 (m, 4H, (CH ) of cyclohexylidene ring); 1.3-1.6 ( m, 4H,
2 2
(CH ) of cyclohexylidene ring); 1.1-1.3 (t, 3H, CH of ester);
2 2
3
+
0.6-0.9 (m, 2H, CH of cyclohexylidene ring); ms: m/z 435 (M ,
2
This compound was obtained as yellow needles, mp 248-250
31%).
-1
°C, yield 87%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
Anal. Calcd. for C
H N O S: C, 66.18; H, 5.79; N, 9.65; S,
1
24 25 3 3
H nmr (CF CO D): δ 7.2-7.6 (m, 9H, ArH's); 6.0 (s, 1H, CH at
3
2
7.35. Found: C, 66.25; H, 5.98; N, 9.51; S, 7.53.
C-2); 4.1-4.4 (q, 2H, OCH ); 2.9 (s, 3H, CH at C-7); 9.0-1.2 (t,
3H, CH of ester); ms: m/z 477 (M , 67%).
2
3
+
3
Ethyl 9-(4'-Chlorophenyl)-7-methyl-2,2-tetramethylene-4-oxo-
1,2,3,4-tetrahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (7c).
Anal. Calcd. for C
H ClN O S: C, 62.88; H, 4.22; N, 8.81;
25 20 3 3
S, 6.70; Cl, 7.33. Found: C, 62.69; H, 4.30; N, 8.74; S, 6.65; Cl,
7.55.
This compound was obtained as yellow needles, mp 250-252
°C, yield 92%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
-1
Ethyl 2-(4'-Chlorophenyl)-9-(4'-methoxyphenyl)-7-methyl-4-
oxo-1,2,3,4-tetrahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-
8-carboxylate (6b).
1
H nmr (CDCl ): δ 7.1-7.4 (dd, 4H, ArH's); 6.7 (s, 1H, CONH );
3
4.0-4.2 (q, 2H, OCH ); 3.9 (s, 3H, OCH ); 3.6 (s, 1H, NH); 2.7
2
3
(s, 3H, CH at C-7); 1.8-2.0 (br, 6H, (CH ) of cyclopentylidene
This compound was obtained as yellow needles, mp 242-243
°C, yield 90%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
3
2 3
-1
ring); 1.4 (br, 2H, CH of cyclopentylidene ring); 1.1-1.3 (t, 3H,
2
+
1
CH of ester); ms: m/z 451 (M , 42%).
H nmr (CF CO D): δ 7.0-7.5 (m, 8H, ArH's); 6.0 (s, 1H, CH at
3
3
2
Anal. Calcd. for C
H N O S: C, 63.84; H, 5.58; N, 9.31; S,
C-2); 4.1-4.4 (q, 2H, OCH ); 3.9 (s, 3H, OCH ); 3.1 (s, 3H, CH
24 25 3 4
2
3
3
+
7.09. Found: C, 63.67; H, 5.64; N, 9.18; S, 7.38.
at C-7); 1.0-1.3 (t, 3H, CH of ester); ms: m/z 507 (M , 70%).
3
Anal. Calcd. for C
S, 6.30; Cl, 6.90. Found: C, 61.81; H, 4.44; N, 8.26; S, 6.19; Cl,
7.20.
H ClN O S: C, 61.53; H, 4.37; N, 8.28;
26 22 3 4
Ethyl 7-Methyl-9-phenyl-2,2-pentamethylene-4-oxo-1,2,3,4-
tetrahydropyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxy-
late (8a).
Ethyl 2,9-Di(4'-chlorophenyl)-7-methyl-4-oxo-1,2,3,4-tetrahy-
dropyrido[3',2':4,5] thieno[3,2-d]pyrimidine-8-carboxylate (6c).
This compound was obtained as yellow needles, mp 247-248
°C, yield 80%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
-1
1
H nmr (CDCl ): δ 7.0-7.4 (dd, 4H, ArH's); 6.8 (s, 1H, CONH);
This compound was obtained as yellow needles, mp 260-262
3
-1
4.0-4.3 (q, 2H, OCH ); 3.9 (s, 3H, OCH ); 3.6(s, 1H, NH); 2.8 (s,
°C, yield 88%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
2
3
1
3H, CH at C-7); 1.9-2.2 (m, 4H, (CH ) of cyclohexylidene
H nmr (CF CO D): δ 7.3-7.7 (m, 8H, ArH's); 6.1 (s, 1H, CH at
3
2 2
3
2
ring); 1.3-1.8 (m, 4H, (CH ) of cyclohexylidene ring) 0.9-1.2 (t,
C-2); 4.2-4.5 (q, 2H, OCH ); 3.0 (s, 3H, CH at C-7); 1.0-1.3 (t,
3H, CH of ester); ms: m/z 511 (M , 100%).
2 2
2
3
+
3H, CH of ester); 0.6-0.9(m, 2H, CH of cyclohexylidene ring);
3
2
3
+
ms: m/z 465 (M , 40%).
Anal. Calcd. for C
Anal. Calcd. for C
H Cl N O S: C, 58.70; H, 3.75; N, 8.22;
25 19 2 3 3
H
N O S: C, 64.49; H, 5.85; N, 9.03; S,
S, 6.26: Cl, 13.69. Found: C, 58.66; H, 3.70; N, 8.25; S, 6.17: Cl,
3.90.
25 27
3 4
6.87. Found: C, 64.28; H, 5.88; N, 9.11; S, 6.84.

Sep-Oct 2005
Synthesis of Novel Pyrido[3',2':4,5]thieno[3,2-d]pyrimidines
1075
Ethyl 9-(4-Chlorophenyl)-7-methyl-2,2-pentamethylene-4-oxo-
1,2,3,4-tetrahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-8-car-
boxylate (8b).
Ethyl 9-(4'-Chlorophenyl)-2-ethoxymethyl-7-methyl-4-oxo-3,4-
dihydropyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxylate (11).
Compound 9 (0.9 g, 0.002 mol) in sodium ethoxide solution
(0.35 g of sodium in 40 mL of absolute ethanol) was heated at
reflux for 1 hour. The precipitate that formed on cooling was col-
lected and recrystallized from ethanol as colorless crystals of 11,
mp 275-276 °C, yield 90%, ir: 3200-3000 (NH); 1720, 1660 (2
This compound was obtained as yellow needles, mp 258-259
-1
C, yield 85%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
1
H nmr (CDCl ): δ 7.4-7.7 (dd, 4H, ArH's); 6.7 (s, 1H, CONH);
3
4.1-4.4 (q, 2H, OCH ); 3.8 (s, 1H, NH); 2.9 (s, 3H, CH at C-7);
2
3
-1
1
C=O) cm ; H nmr (CF CO D): δ 7.5-7.9 (dd, 4H, ArH's); 4.8
1.8-2.1 (br, 6H, (CH ) of cyclopentylidene ring); 1.5 (br, 2H,
3
2
2 3
(s, 2H, CH O); 4.3-4.6 (q, 2H, OCH ); 3.7-4.0 (q, 2H, OCH );
CH of cyclopentylidene ring); 1.1-1.3 (t, 3H, CH of ester); ms:
2
2
2
2
3
+
3.2 (s, 3H, CH at C-7); 1.1-1.6 (m, 6H, two CH groups); ms:
m/z 455 (M , 32%).
3
3
+
m/z 457 (M , 19 %).
Anal. Calcd. for C
H ClN O S: C, 60.64; H, 4.87; N, 9.23;
23 22 3 3
Anal. Calcd. for C
H
ClN O S: C, 57.76; H, 4.41; N, 9.19;
S, 7.03; Cl, 7.68. Found: C, 60.53; H, 4.81; N, 9.31;S, 7.00; Cl,
7.50.
22 20
3 4
S, 6.99; Cl,7.65. Found: C, 57.96; H, 4.21; N, 9.25; S, 7.17; Cl,
8.00.
Ethyl 9-(4-Chlorophenyl)-7-methyl-4-oxo-2,2-pentamethylene-
1,2,3,4-tetrahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine-8-car-
boxylate (8c).
Ethyl 9-(4'-Chlorophenyl)-2-mercaptomethyl-7-methyl-4-oxo-
3,4-dihydropyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-car-
boxylate (12).
This compound was obtained as yellow needles, mp 271-272
A mixture of 9 (0.9 g, 0.002 mol) and thiourea (0.15 g, 0.002
mol) in ethanol (20 mL) was refluxed for 3 hours. The product
that formed while hot was collected and dissolved in aqueous
sodium hydroxide solution 10% (10 mL) and then heated on a
water bath for 1 hour. The reaction mixture was filtered and the
clear filtrate was acidified with acetic acid. The formed yellow
precipitate was collected and recrystallized from ethanol-chloro-
form as yellow crystals of 12, mp 270-271 °C, yield 91%, ir:
-1
°C, yield 90%, ir: 3400, 3200 (2NH); 1720, 1650 (2 C=O) cm ;
1
H nmr (CDCl ): δ 7.3-7.7 (dd, 4H, ArH's); 6.9 (s, 1H, CONH);
3
4.0-4.3 (q, 2H, OCH ); 3.8 (s, 1H, NH); 2.8 (s, 3H, CH at C-7);
2
3
1.8-2.1 (m, 4H, (CH ) of cyclohexylidene ring); 1.3-1.7 ( m, 4H,
2 2
(CH ) of cyclohexylidene ring); 1.0-1.2 (t, 3H, CH of ester);
2 2
3
+
0.6-0.9 (m, 2H, CH of cyclohexylidene ring); ms: m/z 469 (M ,
2
30%).
Anal. Calcd. for C
H ClN O S: C, 61.39; H, 5.16; N, 8.95;
24 24 3 3
-1
1
3200-3000 (NH); 2760 (SH); 1720, 1650 (2 C=O) cm ; H nmr
S, 6.82; Cl, 7.45. Found: C, 61.25; H, 5.31; N, 8.98; S, 6.70; Cl,
7.76.
(CF CO D): δ 7.5-7.8 (dd, 4H, ArH's); 4.8 (s, 2H, CH S); 4.2-
3
2
2
4.5 (q, 2H, OCH ); 3.1 (s, 3H, CH at C-7); 1.0-1.2 (t, 3H, CH
2
3
3
+
Ethyl 2-Chloromethyl-9-(4'-chlorophenyl)-7-methyl-4-oxo-3,4-
dihydropyrido [3',2':4,5]thieno[3,2-d] pyrimidine-8-carboxylate
(9).
of ester); ms: m/z 445 (M , 100%).
Anal. Calcd. for C ClN O S : C, 53.93; H, 3.62; N, 9.44;
H
20 16
3 3 2
S, 14.37; Cl, 7.86. Found: C, 53.86; H, 3.58; N, 9.69; S, 14.45;
Cl, 7.70.
Compound 3c (1.95 g, 0.005 mol) in chloroacetyl chloride (15
mL) was heated on a water bath for 3 hours. The product that
formed on cooling was collected and recrystallized from ethanol
to give 9 in the form of colorless crystals, mp 279-280 °C, yield
Ethyl 4-Chloro-2-chloromethyl-9-(4'-chlorophenyl)-7-
methylpyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-carboxylate
(13).
-1
1
87%, ir: 3320-3000 (NH); 1710, 1650 (2 C=O) cm ; H nmr
Compound 9 (1.8 g, 0.004 mol) in an excess amount of phos-
phorus oxychloride (20 mL) was refluxed for 4 hours. The cooled
reaction mixture was poured into ice-water with vigorous stir-
ring. The separated product was collected and recrystallized from
ethanol as yellowish needles of 13, mp 139-140 °C, yield 90%, ir:
(CF CO D): δ 7.4-7.8 (dd, 4H, ArH's); 4.2-4.5 (m, 4H, CH Cl
3
2
2
and OCH ); 3.1 (s, 3H, CH at C-7); 1.1-1.4 (t, 3H, CH of ester);
2
3
3
+
ms: m/z 447 (M , 100%).
Anal. Calcd. for C
H
Cl N O S: C, 53.69; H, 3.38; N, 9.40;
2 3 3
20 15
S, 7.15; Cl, 15.65. Found: C, 53.42; H, 3.33; N, 9.68; S, 7.18; Cl,
16.11.
-1
1
1720 (C=O) cm ; H nmr (CDCl ): δ 7.2-7.6 (dd, 4H, ArH's);
3
4.2 (s, 2H, CH at C-2); 3.8-4.1 (q, 2H, OCH ); 2.9 (s, 3H, CH
at C-7); 1.0-1.2 (t, 3H, CH of ester) ); ms: m/z 465 (M , 96%).
2
2
3
+
Ethyl 9-(4'-Chlorophenyl)-7-methyl-2-morpholinomethyl-4-
oxo-3,4-dihydropyrido[3',2':4,5]thieno[3,2-d] pyrimidine-8-
carboxylate (10).
3
Anal. Calcd. for C
H Cl N O S: C,51.61; H, 3.03; N, 9.03;
20 14 3 3 2
S, 6.88; Cl, 22.56. Found: C, 51.57; H, 3.11; N, 9.17; S, 6.80; Cl,
22.55.
Compound 9 (2.24 g, 0.005 mol) in morpholine (5 mL) was
heated on a water bath for 3 hours. The reaction mixture was
then triturated with ethanol (15 mL) and left to cool. The pre-
cipitate was collected and recrystallized from ethanol to give
colorless crystals of 10, mp 275-276 °C, yield 90%, ir: 3200-
Ethyl 9-(4'-Chlorophenyl)-7-methyl-4-morpholino-2-mor-
pholinomethylpyrido [3',2':4,5] thieno[3,2-d]pyrimidine-8-car-
boxylate (14).
Compound 13 (0.93 g, 0.002 mol) in morpholine (6 mL) was
heated on a water bath for 3 hours. The reaction mixture was then
triturated with ethanol (10 mL) and then left to cool. The precipi-
tate was collected and recrystallized from ethanol to give 14 in the
form of colorless crystals, mp 157-158 °C, yield 82%, ir: 1720
-1
1
3000 (NH); 1720, 1660 (2 C=O) cm ; H nmr (DMSO): δ 7.3-
7.6 (dd, 4H, ArH's); 4.0-4.3 (q, 2H, OCH ); 3.6-3.8 (t, 4H,
2
CH OCH ); 3.3 (s, 2H, CH N); 2.7 (s, 3H, CH at C-7); 2.3-2.5
2
2
2
3
(t, 4H, CH NCH ); 0.9-1.2 (t, 3H, CH of ester); ms: m/z 498
2
2
3
+
-1
1
(M , 15%).
(C=O) cm ; H nmr (DMSO): δ 7.3-7.6 (dd, 4H, ArH's); 4.1-4.3
Anal. Calcd. for C
H
ClN O S: C, 57.77; H, 4.65; N,11.23;
(q, 2H, OCH ); 3.6-3.8 (t, 8H, two CH OCH ); 3.5 (s, 2H,
24 23
4 4
2
2
2
S, 6.43; Cl, 7.10. Found: C, 57.70; H, 4.72; N, 11.35; S, 6.50; Cl,
7.26.
CH N); 2.7 (s, 3H, CH at C-7); 2.2-2.4 (t, 8H, two CH NCH );
2
3
2
2
+
0.9-1.2 (t, 3H, CH of ester); ms: m/z 567 (M , 23 %).
3

1076
Vol. 42
E. A. Bakhite, A. G. Al-Sehemi, and Y. Yamada
Anal. Calcd. for C
S, 5.64; Cl, 6.17. Found: C, 58.97; H, 5.25; N, 12.40; S, 5.91; Cl,
6.10.
H
ClN O S: C, 59.24; H, 5.33; N,12.34;
Compound 17 (0.75 g, 0.001 mol) in triethyl orthoformate (15
mL) was refluxed for 4 hours. The solid that formed on cooling
was collected and recrystallized from ethanol-chloroform mix-
ture as colorless crystals of 18, mp 318-319 C, yield 73%, ir:
28 30
5 4
Ethyl 9-(4'-Chlorophenyl)-7-methyl-2-mercaptomethyl-4-
thioxo-3,4-dihydropyrido[3',2': 4,5]thieno[3,2-d]pyrimidine-8-
carboxylate (15).
-1
1
1720 (2C=O); 1650 (C=O) cm ; H nmr (CF CO D): δ 9.7 (s,
3
2
1H, CH pyrimidinone); 7.4-8.0 (m, 8H, ArH's); 4.2-4.6 (q, 4H,
two OCH ); 3.1 (s, 6H, two CH attached to the pyridine rings );
2
3
+
A mixture of 13 (0.93 g, 0.002 mol) and thiourea (0.3 g, 0.004
mol) in ethanol (20 mL) was refluxed for 3 hours. The product
that formed while hot was collected and dissolved in aqueous
sodium hydroxide solution 10% (15 mL). The reaction mixture
was heated on a water bath for 1 hour and then filtered. The clear
filtrate was acidified with acetic acid whereby a yellow precipi-
tate formed. It was collected and recrystallized from ethanol-
chloroform as yellow crystals of 15, mp 254-255 °C, yield 87%,
1.0-1.3 (t, 6H, two CH of esters); ms: m/z 753 (M , 25 %).
3
Anal. Calcd. for C
H Cl N O S : C, 58.96; H, 3.35; N,
37 25 2 5 5 2
9.30; S, 8.49; Cl, 9.29. Found: C, 59.10; H, 3.17; N, 9.03; S, 8.78;
Cl, 9.67.
Diethyl 4,13-Di(4'-chlorophenyl)-2,6,11-trimethyl -8-oxo-8H-
bis(pyrido[3',2':4,5] thieno)[2,3-b:3',2'-h]pyrimido[1,6-a]pyrimi-
dine-3,12-dicarboxylate (19).
-1
1
ir: 3200-3000 (NH); 2760 (SH); 1720 (C=O) cm ; H nmr
Compound 17 (0.75 g , 0.001 mol) in acetic anhydride (15 mL)
was refluxed for 4 hours. The solid that formed on cooling was col-
lected and recrystallized from ethanol-chloroform mixture as col-
orless crystals of 19, mp 289-290° C, yield 92%, ir: 1720 (2C=O);
(CF CO D): δ 7.4-7.8 (dd, 4H, ArH's); 4.7 (s, 2H, CH S); 4.1-
3
2
2
4.4 (q, 2H, OCH ); 3.0 (s, 3H, CH at C-7); 1.0-1.3 (t, 3H, CH
2
3
3
+
of ester); ms: m/z 461 (M , 80%).
Anal. Calcd. for C ClN O S : C, 52.06; H, 3.50; N, 9.11;
-1
1
H
1650 (C=O) cm ; H nmr(CF CO D): δ 7.5-8.0 (m, 8H, ArH's);
20 16
3 2 3
3
2
S, 20.81; Cl, 7.59. Found: C, 51.88; H, 3.56; N, 9.43; S, 20.65;
Cl, 7.49.
Ethyl 9-(4'-Chlorophenyl)-7-methyl-2-(4'-(4''-chlorophenyl)-
3'-cyano-5'-ethoxycarbonyl-6'-methylpyridin-2'-ylthiomethyl)-4-
oxo-3,4-dihydropyrido [3',2':4,5]thieno[3,2-d]pyrimidine-8-car-
boxylate (16).
4.4-4.7(q, 4H, two OCH ); 3.3 (s, 3H, CH attached to the pyridine
2
3
ring); 3.2 (s, 3H, CH attached to the pyridine ring); 1.9 (s, 3H,
3
+
CH )1.3-1.5 (t, 6H, two CH of esters); ms: m/z 767 (M , 100 %).
3
3
Anal. Calcd. for C
H Cl N O S : C, 59.44; H, 3.55; N,
38 27 2 5 5 2
9.13; S, 8.34; Cl, 9.12. Found: C, 59.12; H, 3.49; N, 9.24; S, 8.12;
Cl, 9.13.
To a suspension of compound 1c (6.66 g, 0.02 mol) and
sodium acetate trihydrate (3.0 g, 0.022 mmol) in ethanol (50
mL), compound 9 (9.0 g, 0.02 mol) was added. The resulting
mixture was refluxed for 3 hours. The precipitate that formed on
cooling was collected and recrystallized from ethanol as colorless
needles of 16, mp 261-262 °C, yield 82%, ir: 3200-3000 (NH);
Diethyl 4,13-Di(4'-chlorophenyl)-2,11-dimethyl-8-oxo-6-thioxo-
5,6-dihydro-8H-bis(pyrido[3',2':4,5]thieno)[2,3-b:3',2'-h]-
pyrimido[1,6-a]pyrimidine-3,12-dicarboxylate (20).
A mixture of compound 17 (0.75 g, 0.001 mol) and carbon
disulfide (5 mL) in pyridine (15 mL) was refluxed for 4 hours.
The solid that formed on cooling was collected and recrystallized
from dimethyl formamide as yellow crystals of 20, mp 297-298
-1
1
2200(CN); 1720 (2 C=O); 1650 (C=O) cm
; H nmr
(CF CO D): δ 7.3-7.7(m, 8H, ArH's);; 4.2-4.6 (m, 6H, SCH and
3
2
2
-1
°C, yield 76%, ir: 3250 (NH); 1720 (2C=O); 1650 (C=O) cm ;
two OCH ); 3.2 (s, 3H, CH attached to thienopyridine moiety);
2
3
1
H nmr (CF CO D): δ 7.5-7.9 (m, 8H, ArH's); 4.4-4.7(q, 4H, two
2.8 (s, 3H, CH attached to pyridine ring ); 1.1-1.4 (m, 6H, two
3
2
3
+
OCH ); 3.2 (s, 6H, two CH attached to the pyridine rings); 1.1-
1.4 (t, 6H, two CH of esters); ms: m/z 785 (M , 21 %).
CH of esters); ms: m/z 743 (M ,12 %).
2
3
3
+
Anal. Calcd. for C
H Cl N O S : C,58.14; H, 3.66; N, 9.42;
3
36 27 2 5 5 2
Anal. Calcd. for C
H Cl N O S : C, 56.56; H, 3.20; N,
S, 8.61; Cl, 9.41. Found: C, 57.78; H, 3.69; N, 9.32; S, 8.38; Cl,
9.29.
37 25 2 5 5 3
8.92; S, 12.22; Cl, 8.91. Found: C, 56.77; H, 3.22; N, 9.21; S,
12.50; Cl, 9.19.
Ethyl 9-(4'-Chlorophenyl)-7-methyl-2-(3'-amino-4'-(4''-
chlorophenyl)-5'-ethoxycarbonyl-6'-methylthieno[2,3-b]pyridin-
2'-yl)-4-oxo-3,4-dihydropyrido [3',2':4,5]thieno[3,2-d]pyrimi-
dine-8-carboxylate (17).
Diethyl 4,13-Di(4'-chlorophenyl)-2,11-dimethyl-8-oxo-8H-
bis(pyrido[3',2':4,5] thieno)[3,2-c:3',2'-g]pyrimido[1,2-
c][1,2,3]triazine-3,12-dicarboxylate (21).
To a solution of 17 (0.75 g , 0.001 mol) in concentrated sulfu-
ric acid (5 mL) and glacial acetic acid (5 mL), sodium nitrite
solution 10% (5 mL) was added at 0 °C over a period of 5 min-
utes with stirring. The reaction mixture was allowed to stand at
room temperature for 30 minutes. The solid that precipitated on
dilution with water was collected and recrystallized from 1,4-
dioxane to give colorless needles of 21, mp 268-269 °C, yield
Compound 16 (3.72 g, 0.005 mol) was suspended in sodium
ethoxide solution (0.24 g of sodium in 35 mL of absolute ethanol)
and then heated at reflux for 5 minutes. The solid that formed on
cooling and acidification with acetic acid was collected and
recrystallized from ethanol to give yellow crystals of 17, mp
>360 °C, yield 77%, ir: 3490, 3380 (NH ); 1720 (2C=O); 1650
2
-1
1
(C=O) cm ; H nmr (DMSO): δ 7.2-7.7 (m, 8H, ArH's); 5.6 (s,
2H, NH ); 4.1-4.4(q, 4H, two OCH ); 2.7 (s, 6H, two CH
-1 1
79%, ir: 1720 (2C=O); 1650 (C=O) cm ; H nmr (CF CO D): δ
3
2
2
2
3
7.5-7.9 (m, 8H, ArH's); 4.3-4.6(q, 4H, two OCH ); 3.1 (s, 6H,
attached to the pyridine rings); 1.0-1.2 (t, 6H, two CH of esters);
2
3
+
two CH attached to the pyridine rings); 1.1-1.3 (t, 6H, two CH
ms: m/z 743 (M , 28 %).
3
3
+
of esters) ms: m/z 754 (M , 6 %).
Anal. Calcd. for C Cl N O S : C, 57.29; H, 3.21; N,
Anal. Calcd. for C
H Cl N O S : C,58.14; H, 3.66; N, 9.42;
36 27 2 5 5 2
H
S, 8.61; Cl, 9.41. Found: C, 58.12; H, 3.82; N, 9.67; S, 8.51; Cl,
9.29.
36 24
2 6 5 2
11.14; S, 8.48; Cl, 9.27. Found: C, 57.18; H, 3.25; N,11.23; S,
8.31; Cl, 9.54.
Diethyl 4,13-Di(4'-chlorophenyl)-2,11-dimethyl-8-oxo-8H-
bis(pyrido[3',2':4,5] thieno)[2,3-b:3',2'-h]pyrimido[1,6-a]pyrimi-
dine-3,12-dicarboxylate (18).
Ethyl 10-(4'-Chlorophenyl)-12-methyl-7H-pyrido[3'',2'':4',5']-
thieno[3',2':4,5] pyrimido[1,6-a]benzimidazole-11-carboxylate (22).

Sep-Oct 2005
Synthesis of Novel Pyrido[3',2':4,5]thieno[3,2-d]pyrimidines
1077
To a suspension of compound 5 (0.92 g, 0.002 mol) in triethyl
orthoformate (15 mL), few drops of glacial acetic acid was
added. The reaction mixture was refluxed for 4 hours and then
left to cool. The precipitated solid was collected and recrystal-
lized from ethanol-chloroform mixture as colorless crystals of 22,
To a solution of 5 (0.92 g, 0.002 mol) in concentrated sulfuric
acid (5 mL) and glacial acetic acid (5 mL), sodium nitrite solu-
tion 10% (10 mL) was added at 0 °C over a period of 5 minutes
with stirring. The reaction mixture was allowed to stand at room
temperature for 30 minutes. The solid that precipitated on dilu-
tion with water was collected and crystallized from 1,4-dioxane
to give colorless needles of 26, mp 307 °C, yield 85%, ir: 1720
-1
1
mp >360 °C, yield 91%, ir: 1720 (C=O) cm
; H nmr
(CD CO D): δ 9.0 (s, 1H, CH pyrimidine); 7.8-8.4 (m, 4H,
3
2
-1 1
ArH's); 7.4-7.7 (dd, 4H, ArH's); 4.1-4.4 (q, 2H, OCH ); 3.0 (s,
(C=O) cm ; H nmr (CD CO D): δ 7.8-8.4 (m, 4H, ArH's); 7.4-
2
3
2
3H, CH at C-11); 1.1-1.3 (t, 3H, CH of ester); ms: m/z 472
7.7 (dd, 4H, ArH's); 4.0-4.3 (q, 2H, OCH ); 3.0 (s, 3H, CH at C-
3
3
2 3
+
+
(M , 100 %).
11); 1.0-1.2 (t, 3H, CH of ester) ); ms: m/z 473 (M , 100%).
3
Anal. Calcd. for C
H
ClN O S: C, 63.55; H, 3.63; N,11.87;
Anal. Calcd. for C H ClN O S: C, 60.89; H, 3.39; N,14.80;
25 17
4
2
24 16 5 2
S, 6.77; Cl, 7.41. Found: C, 63.40; H, 3.65; N, 11.81; S, 6.90; Cl,
7.66.
S, 6.76; Cl, 7.40. Found: C, 60.97; H, 3.68; N, 14.85; S, 6.93; Cl,
7.53.
Ethyl 10-(4'-Chlorophenyl)-8,12-dimethyl-7H-pyrido[3'',2'':4',5']-
thieno [3',2':4,5]pyrimido[1,6-a]benzimidazole-11-carboxylate
(23).
REFERENCES AND NOTES
[1] K. Eichenberger, E. Schweizer and P. Schmidt, U.S. Patent,
2,627,76614; Chem. Abstr., 74, 88638w (1971).
Compound 5 (0.92 g, 0.002 mol) in acetic anhydride (15 mL)
was refluxed for 4 hours. The solid that formed on cooling was
collected and recrystallized from ethanol-chloroform mixture as
colorless crystals of 23, mp >360 °C, yield 91%, ir: 1720 (C=O)
[2] A. Burger, Wiley-Inter. Sciences, 3rd ed., Medicinal
Chemistry, New York (N.Y.), 72, 544, 719 (1970).
[3] Z. Shraideh and A.-K.Sallal, Biomed. Lett., 54, 233 (1997).
[4] J. Bompart, L. Giral, G. Malicorne and M. Puygrenier, Eur. J.
Med. Chem., 22, 139 (1987).
[5] M. E. Schnute, M. M. Cudahy and A. Scott, PCT Int. Appl.
WO, 00,53,610; Chem. Abstr., 133, 222607g (2000).
[6] I. Adachi and Y. Hiramatsu, Jap. Pat., 03,52,890; Chem.
Abstr., 115, 71573 (1991).
[7] T. Ooe, M. Sano, H. Kobayashi and M. Kudome Jpn. Kokai
Tokkyo Koho JP, 07 53, 562; Chem. Abstr., 123, 256681k (1995).
[8] S. Furuya, N. Choh, K. Kato and S. Hinuma, PCT Int. Appl.
WO, 95, 28, 405; Chem. Abstr., 124, 202226t (1996).
[9] N. Cho, M. Harada, T. Imaeda, T. Imada, H. Matsumoto, Y.
Hayase, S. Sasaki, S. Furuya, N. Suzuki, S. Okubo, K. Ogi, S. Endo, H.
Onda and M. Fujino, J. Med. Chem., 41, 4190(1998).
[10] S. Miki, K. Fukuoka, M. Akita, J. Kawakami, S. Furuya and
Y. Ishimaru, PCT Int, Appl. WO, 99, 09, 033; Chem. Abstr., 130,
196644h (1999).
-1 1
cm ; H nmr (CD CO D): δ 7.8-8.4 (m, 4H, ArH's); 7.4-7.7 (dd,
3
2
4H, ArH's); 4.1-4.4 (q, 2H, OCH ); 3.2 (s, 3H, CH attached to
2
3
pyrimidine ring); 3.0 (s, 3H, CH attached to pyridine ring); 1.1-
3
+
1.3 (t, 3H, CH of ester); ms: m/z 486 (M , 100 %).
3
Anal. Calcd. for C
H ClN O S: C, 64.19; H, 3.94; N, 11.52;
26 19 4 2
S, 6.58; Cl, 7.19. Found: C, 64.20; H, 3.88; N, 11.45; S, 6.65; Cl,
7.41.
Ethyl 8,10-Di(4'-chlorophenyl)-12-methyl-8,9-dihydro-7H-
pyrido[3'',2'':4',5'] thieno[3',2':4,5]pyrimido[1,6-a]benzimida-
zole-11-carboxylate (24).
A mixture of compound 5 (0.92 g, 0.002 mol) and 4-
chlorobenzaldehyde (0.28 g, 0.002 mol) in ethanol (15 mL) con-
taining few drops of glacial acetic acid was refluxed for 4 hours.
The solid that formed on cooling was collected and recrystallized
from dimethyl formamide as yellow crystals of 24, mp 268-269
[11] N. Suzuki, H. Matsumoto and S. Furuya, Eur. Pat. Appl. EP,
781,774; Chem. Abstr., 127, 135807e (1997).
-1
1
°C, yield 82%, ir: 3400 (NH); 1720 (C=O) cm ; H nmr
[12] S. Furuya, N. Choh, N. Suzuki and T. Imada, PCT Int. Appl.
WO, 00,00,493 ; Chem. Abstr., 132, 64179s (2000).
[13] S. Furuya, H. Matsumoto, Y. Hayase, N. Suzuki and T. Imada,
PCT Int. Appl. WO, 97,41,126; Chem. Abstr., 128, 13211f (1998).
[14] H. Vieweg, S. Leistner, J. Prantz, N. Bohm and G. Wagner,
Pharmazie, 47, 841 (1992).
[15] T. Sohda, H. Makino and A. Baba, PCT Int. Appl. WO,
96,14,319; Chem. Abstr., 125, 114583x (1996).
[16] C. G. Dave, P. R. Shah, K.C. Dave and V. J. Patel, J. Indian
Chem. Soc., 66, 48 (1989).
[17] E. Bousquent, G. Romero F. Guerrera, A. Caruso and M. A.
Roxas, Farmaco Ed. Sci., 40, 869 (1985).
[18] S. Leistner, G. Wagener, M. Guestscharo and E. Glusa,
Pharmazie, 41, 54 (1986).
[19] E. A. Bakhite, A. E. Abdel-Rahman, O. S. Mohamed and E.
A. Thabet, Pharmazie, 55, 577 (2000)..
[20] A. E. Abdel-Rahman, E. A. Bakhite, O. S. Mohamed and E.
A. Thabet, Phosphorus, Sulfur and Silicon, 166, 149 (2000).
[21] A. E. Abdel-Rahman, E. A. Bakhite and E. A. Al-Taifi, J.
Chin. Chem. Soc., 49, 223 (2002).
(CDCl ): δ 6.9-7.8 (m, 12H, ArH's); 5.4 (d, 1H, CH at C-7); 4.0-
3
4.3 (q, 2H, OCH ); 3.6 (d, 1H, NH); 2.9 (s, 3H, CH3 at C-11);
2
+
0.9-1.1 (t, 3H, CH of ester); ms: m/z 584 (M , 18%).
3
Anal. Calcd. for C
H Cl N O S: C, 63.69; H,3.80; N, 9.59;
31 22 2 4 2
S, 5.47; Cl,11.97. Found: C, 63.91; H, 3.96; N, 9.68; S, 5.33; Cl,
12.32.
Ethyl 10-(4'-Chlorophenyl)-12-methyl-8-thioxo-8,9-dihydro-7H-
pyrido [3'',2'':4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimida-
zole-11-carboxylate (25).
A mixture of compound 5 (0.92 g, 0.002 mol) and carbon
disulfide (5 mL) in pyridine (15 mL) was heated at reflux for 4
hours. The solid that formed on cooling was collected and recrys-
tallized from dimethyl formamide as yellow crystals of 25, mp
-1 1
350-351 °C, yield 80%, ir: 3380 (NH); 1720 (C=O) cm ; H nmr
(CD CO D): δ 7.7-8.3 (m, 4H, ArH's); 7.2-7.6 (dd, 4H, ArH's);
3
2
4.1-4.4 (q, 2H, OCH ); 2.9 (s, 3H, CH at C-11); 1.1-1.3 (t, 3H,
2
3
+
CH of ester); ms: m/z 504 (M , 100%).
3
[22] A. M. Abd El-Fattah; Phosphorus, Sulfur Silicon Relat. Elem.,
156, 53 (2000).
[23] E. A. Bakhite, J. Chem. Res. Synop., (M): 500 (2000); (S):
1201 (2000).
Anal. Calcd. for C
S, 12.69; Cl, 6.94. Found: C, 59.54; H, 3.44; N, 11.21; S, 12.36;
Cl, 7.16.
H ClN O S : C, 59.51; H, 3.40; N,11.11;
25 17 4 2 2
Ethyl 10-(4'-Chlorophenyl)-12-methyl-7H-pyrido[3'',2'':4',5']-
thieno[3',2':4,5] [1,2,3]triazino[1,6-a]benzimidazole (26).
[24] V. F. Vaidya and Y. S. Agasimundin, Indian J. Chem., 20B,
780 (1981).