Synthesis of 3-substituted pyrido[4′,3′: 4,5]thieno[2,3-d]pyrimidines and related fused thiazolo derivatives

Article abstract of DOI:10.1080/10426500307796

New ethyl 3-(substituted)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8- octahydropyrido[4′,3′:4,5]thieno-[2,3-d]pyrimidine-7- carboxylates (3a,b), (6), (11-13), ethyl 3-methyl-5-oxo-2,3,6,9-tetrahydro 5H-pyrido[4′,3′:4,5]-thieno[2,3-d][1,3]thiazolo[3,2-a] pyrimidine-8(7H)-carboxylate (4), and ethyl 2-methyl-5-oxo-2,3,6,9-tetrahydro-5H-pyrido[4′,3′:4,5]thieno- [2,3-d][1,3]thiazolo[3,2-a]-pyrimidine-8(7H)-carboxylate (8) have been synthesized from diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine-3,6-dicarboxylate 1. The structure of these compounds as well as their intermediates have been established by their spectral data.

Full text of DOI:10.1080/10426500307796

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of 3-Substituted Pyrido[4′,3′:4,5]thieno[2,3-
d]pyrimidines and Related Fused Thiazolo Derivatives
a
Essam Kh. Ahmed
a
El-Minia University , El-Minia, Egypt
Published online: 27 Oct 2010.
To cite this article: Essam Kh. Ahmed (2003) Synthesis of 3-Substituted Pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines and
Related Fused Thiazolo Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:4, 667-679, DOI:
10.1080/10426500307796
To link to this article: http://dx.doi.org/10.1080/10426500307796
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:667–679
Copyright �C 2003 Taylor & Francis
1
042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390197940
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0
SYNTHESIS OF 3-SUBSTITUTED PYRIDO[4 ,3 :
4
,5]THIENO[2,3-D]PYRIMIDINES AND RELATED
FUSED THIAZOLO DERIVATIVES
Essam Kh. Ahmed
El-Minia University, El-Minia, Egypt
New ethyl 3-(substituted)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydro-
0
0
pyrido[4 ,3 :4,5]thieno-[2,3-d]pyrimidine-7-carboxylates (3a,b), (6),
0
0
(
11–13), ethyl 3-methyl-5-oxo-2,3,6,9-tetrahydro 5H-pyrido[4 ,3 :4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-carboxylate (4), and
0
0
ethyl
2,3-d][1,3]thiazolo[3,2-a]-pyrimidine-8(7H)-carboxylate (8) have been
synthesized from diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno-
2,3-c]pyridine-3,6-dicarboxylate 1. The structure of these compounds
2-methyl-5-oxo-2,3,6,9-tetrahydro-5H-pyrido[4 ,3 :4,5]thieno-
[
[
as well as their intermediates have been established by their spectral
data.
0
0
0
0
Keywords: Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines; pyrido[4 ,3 :4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines; synthesis; thieno[2,3-c]-
pyridines
Compounds containing a fused pyrimidine ring represent a broad class
of compounds which have received considerable attention over the past
years due to their wide range of biological activity. As an example,
1
� 3
pyridothienopyrimidines long have been used as antiinflammatory,
antipyretic,4 analgesic, and antianaphylactic activity. On the other
hand, thiazoles represent a very interesting class of compounds due
to their wide applications in pharmaceutical, phytosanitary, analyt-
ical, and industrial aspects, such as fungicides, anthelmintics, and
herbicides.9 Because of these findings, our interest was focused on
investigating efficient and convenient routes to construct the titled
novel ring systems. In continuation of our interest in the synthe-
sis of pharmacologically interesting new heterocyclic systems con-
,5
6
7,8
1
0� 16
taining the thienopyrimidine moiety.
We have succeeded in the
synthesis of new derivatives of pyrido[4 ,3 :4,5]thieno-[2,3-d]pyrimidine
0
0
Address correspondence to Essam Kh. Ahmed, Department of Chemistry, Faculty of
Science, El-Minia University, El-Minia 61519, Egypt. E-mail: essamkhalaf24@yahoo.com
6
67

6
68
E. Kh. Ahmed
0
0
and pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine with
expected potential biological activity.
In the syntheses presented in this paper, the conveniently avail-
able diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
1
1
3
,6-dicarboxylate 1 was employed as the starting material. Reac-
tion of compound 1 with aminoalcohols under mild reaction conditions
provided the corresponding thioureido derivatives 2a,b. Compound 2b
could be cyclized into the corresponding ethyl 3-methyl-5-oxo-2,3, 6,9-
0
0
tetrahydro-5H-pyrido[4 ,3 : 4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimi-
dine-8 (7H)-carboxylate (4) by heating in methanolic hydrogen chlo-
ride at reflux temperature in good yield. During this reaction course
0
0
no intermediate pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine derivative was
0
0
isolated, although in a separate reaction, pyrido[4 ,3 :4,5]thieno[2,3-
d]pyrimidine derivatives 3a,b were synthesized by heating correspond-
ing thiourea derivatives 2a,b in ethanolic potassium hydroxide solu-
tion. Structures 4 and 3a,b were confirmed by the results of elemental
analysis and spectral data (Scheme 1 and see Experimental).
SCHEME 1
For the synthesis of ethyl 2-methyl-5-oxo-2,3,6,9-tetrahydro-5H-
0
0
pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)car-
boxylate (8), compound 1 was reacted with allylamine to give ethyl
2
-{[(2-propenyl)aminothioxomethyl]amino}-4,5,6,7-tetrahydrothieno-
2,3-c]pyridine-3,6-dicarboxylate (5), which could be cyclized into
ethyl 3-(2-propenyl)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido-
4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-carboxylate (6) through heating
[
0
0
[

0
0
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines
669
under reflux in potassium hydroxide solution. The structure of 6 was
substantiated by elemental analysis and spectroscopic data. Thus, IR
�
1
spectrum revealed absorption band at � = 3180, 1710, and 1680 cm
due to the NH, CO ester, and CO of the pyrimidine ring respectively.
Moreover, the 1H NMR spectrum gave strong evidence for the for-
mation of 6, which revealed the presence of signals at � = 4.90–5.12
assignable to two allylic proton CH2 CH CH2. It also gave two
multiplets at � 5.80–6.10 (1H) and at � 5.18–5.30 (2H), the former
assigned to one vinylic protons CH CH2 and CH CH2. A singlet at �
1
3.7 attributable to pyrimidine NH. Other analytical and spectroscopic
data are given in the experimental section. Treatment of 6 with methyl
iodide under basic conditions afforded the S-methylated compound
(
7) in excellent yield. The target product (8) was prepared in 68%
yield by ring closure of 6 in a mixture of hydrochloric acid and acetic
acid. Compound 8 was alternatively obtained from isothiocyanate 1
by initial conversion to ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-hexa-
0
0
16
hydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7(2H)-carboxylate (9),
followed by deamination with nitrous acid to yield ethyl 4-Oxo-2-thioxo-
0
0
1
,2,3,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (10). Compound 10 proved to be a key intermediate for
subsequent conversion leading to (8) when was allowed to react with
1
,2-dibromopropane (Scheme 2).
Our interest in developing synthetic approches with a view to synthe-
size new derivatives of intersting heterocyclic pyridothienopyrimidine
ring system led us to investigate the reaction of isothiocyanate 1
0
0
with amino acid derivatives in which pyrido[4 ,3 :4,5]thieno[2,3-d]-
pyrimidine derivatives with the nitrogen of the amino acid component
being incorporated into the fused pyrimidine ring at position 3. When
isothiocyanate 1 was reacted with glycine, L-alanine, and �-alanine in
a mixture of dioxane and water in slightly alkaline media (pH = 8–9)
under mild conditions, it gave ethyl 3-carboxymethyl-4-oxo-2-thioxo-
0
0
1
,2,3,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]-thieno[2,3-d]pyrimidine7-car-
boxylate (11), ethyl 3-[(S )-1-carboxyethyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
0
0
octahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7carboxylate (12),
and ethyl 3-(2-carboxyethyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydro-
0
0
pyrido-[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-carboxylate (13), respec-
tively, with the amino acid residue attached to nitrogen at position 3 in
pyrimidine part of the tricyclic system. The structures of 11–13 were
established on the basis of their elemental and spectral data (Scheme 3
and see Experimental).
0
0
Ethyl 2,5-dioxo-2,3,6,9-tetrahydro-5H-pyrido[4 ,3 :4,5]thieno[2,3-d]-
1,3]thiazolo-[3,2-a]pyrimidine-8 (7H )-carboxylate (14) could be
[
obtained either by fusion of compound 11 over its melting point

6
70
E. Kh. Ahmed
SCHEME 2
SCHEME 3

0
0
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines
671
or by the reaction of compound 10 with chloroacetyl chloride in
DMF.
EXPERIMENTAL
All m.p.s were recorded on a GallenKamp apparatus and are uncor-
rected. Microanalyses were performed at the Microanalytical Data
1
3
1
Unit, Cairo University. C and H NMR spectra were measured in
1
deuterated dimethyl sulfoxide on a Bruker AC 300 ( H:300.13 MHz,
C:75.5 Mhz) spectrometer using TMS as an internal standered; chem-
1
3
ical shifts are expressed as �-values (ppm). IR-spectra were recorded on
a Shimadzu 470 spectrophotometer in KBr pellets.
Diethyl 2-({[(2-Hydroxyethyl)amino]carbothioyl}amino)-
4
,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate (2a)
To a stirred solution of diethyl 2-isothiocyanato-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-3,6-dicarboxylate 1 (0.34 g, 0.001 mmol) in 8 ml
dichloromethane, 2-amino-ethanol (0.07 g, 0.0011 mmol) was added,
and stirred at room temperature for 20 min. After evaporation of the
solvent at reduced pressure the solid product was collected and crys-
tallized from ethanol. Yield 0.28 g (70%) of compound 2a as color-
�
less crystals, m.p. 158–160 C; (found: C, 47.65; H, 5.83; N, 10.59; S,
1
1
5.87. C16H23N3O5S2 (401.51) requires C, 47.86; H, 5.77; N, 10.46; S,
5.97%); �max/cm :3500 (OH), 3200 (NH), 2990 (aliph. CH), 1720, 1690
�
1
(
2 CO ester); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.30 (t, 3H,
COOCH2CH3), 2.80 (t, 2H, H-4), 3.60 (t, 2H, H-5), 3.70 (q, 2H, NCH2),
3
4
.90 (t, 2H, CH2OH), 4.10 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7),
.80–4.90(t, 1H, CH2OH), 9.60 (s, 1H, NH), 11.40 (broad s, 1H, NH); �c
(
DMSO-d6): 14.11 (q, COOCH2CH3), 14.41 (q, COOCH2CH3), 25.87 (t,
C-4), 41.04 (t, C-5), 42.57 (t, C-7), 46.94 (t, NHCH2), 58.56 (t, CH2OH),
0.26 (t, COOCH2CH3), 60.86 (t, COOCH2CH3), 110.02 (s, C-3), 121.30
s, C-7a), 129.98 (s, C-3a), 154.78 (s, CO ester), 165.65 (s, CO ester),
75.12 (s, C-2), 177.42 (s, CS).
6
(
1
Diethyl 2-({[(2-Hydroxy-1-methylethyl)amino]-
carbothioyl}amino)-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine-3,6-dicarboxylate (2b)
This compound was obtained from diethyl 2-isothiocyanato-
4
,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1 (0.34 g,

6
72
E. Kh. Ahmed
0
.001 mmol), 2-aminopropanol (0.08 g, 0011 mmol) at room tempera-
ture for 30 min. After evaporation of the solvent at reduced pressure the
solid product was collected and crystallized from ethanol. Yield 0.37 g
�
(
89.1%) of compound 2b as pale yellow crystals, m.p. 166–168 C; (found:
C, 49.32; H, 6.18; N, 10.30; S, 15.29. C17H25N3O5S2 (415.54) requires C,
�
1
4
2
9.13; H, 6.06; N, 10.11; S, 15.43%); �max/cm : 3500 (OH), 3220 (NH),
980 (CH aliph.), 1710, 1690 (2 CO ester); �H (DMSO-d6): 1.10 (d, 3H,
CH3CH-), 1.20 (t, 3H, COOCH2CH3), 1.35 (t, 3H, COOCH2CH3), 2.80
t, 2H, H-4), 3.40–3.55 (m, 2H, CH2OH), 3.65 (t, 2H, H-5), 4.10 (q, 2H,
COOCH2CH3), 4.20–4.35 (m, 3H, COOCH2CH3, NHCH(CH3)CH2OH),
.40 (s, 2H, H-7), 4.70–4.85 (t, 1H, CH2OH ), 9.40–9.50 (broad s, 1H,
NH), 11.40 (s, 1H, NH); �c (DMSO-d6): 14.11 (q, COOCH2CH3), 14.43
q, COOCH2CH3), 16.19 (q, CH3), 25.79 (t, C-4), 40.69 (t, C-5), 42.10 (t,
C-7), 51.89 (d, CH), 60.24 (t, COOCH2CH3), 60.85 (t, COOCH2CH3),
(
4
(
63.32 (t, CH2OH), 109.91 (s, C-3), 121.29 (s, C-7a), 128.33 (s, C-
3a), 154.54 (s, CO ester), 165.25 (s, CO ester), 176.49 (s, C-2),
179.33 (s, CS).
Ethyl 3-(2-Hydroxyethyl)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
0
0
octahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-
-carboxylate (3a)
7
Compound 2a (0.4 g, 0.001 mmol) was added to a solution of potassium
hydroxide (0.06 g, 0.0011 mmol) in absolute ethanol (10 ml), and the
mixture was refluxed with stirring for 15 min. The potassium salt of
compound 3a was collected by filtration then dissolved in water and
acidified (to pH = 6.6) with hydrochloric acid, the product was col-
lected by filtration, washed with water, dried, and recrystallized from
ethanol. Yield 0.27 g (77.1%) of compound 3a as colorless crystals, m.p.
�
1
(
77–179 C; (found: C, 47.18; H, 4.89; N, 11.60; S, 18.26. C14H17N3O4S2
�
1
355.44) requires C, 47.31; H, 4.81; N, 11.82; S, 18.04%); �max/cm :
3
550 (OH), 3180 (NH), 2800 (aliph. CH), 1720 (CO ester), 1680 (CO
pyrimidine ring); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H,
H-5), 3.60–3.80 (m, 4H, H-6, NCH2CH2OH), 4.10 (q, 2H, COOCH2CH3),
4
1
.40 (s, 2H, H-8), 4.65 (t, 2H, NCH2CH2OH), 4.70 (t, 1H, CH2OH ),
1.85 (br, 1H, NH); �c (DMSO-d6): 14.45 (q, COOCH2CH3), 25.31
(
t, C-5), 40.20 (t, C-6), 42.64 (t, C-8), 46.68 (t, NCH2), 58.36 (t,
CH2OH), 60.84 (t, COOCH2CH3), 113.55 (s, C-4a), 120.30 (s, C-4b),
1
1
28.68 (s, C-8a), 152.67 (s, C-9a), 154.67 (s, C-4), 164.68 (s, CO ester),
75.81 (s, C-2).

0
0
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines
673
Ethyl 3-(2-Hydroxy-1-methylethyl)-4-oxo-2-thioxo-
0
0
1
[
,2,3,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]thieno-
2,3-d]pyrimidine-7-carboxylate (3b)
Compound 2b (0.41 g, 0.001 mmol) was added to a solution of potas-
sium hydroxide (0.06 g, 0.0011 mmol) in absolute ethanol (10 ml),
and the mixture was refluxed with stirring for 1 h. The potassium
salt of compound 3b was collected by filtration then dissolved in wa-
ter and acidified (to pH = 6.6) with hydrochloric acid, the product
was collected by filtration, washed with water, dried, and recrystal-
lized from ethanol. Yield 0.25 g (69.4%) of compound 3b as colorless
�
crystals, m.p. 188–190 C; (found: C, 48.89; H, 5.10; N, 11.50; S, 17.22.
C15H19N3O4S2 (369.47) requires C, 48.76; H, 5.18; N, 11.37; S, 17.35%);
�
H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.40 (d, 3H, CH3CH ), 2.90
t, 2H, H-5), 3.55 (t, 2H, H-6), 3.80–3.95 (m, 2H, CH2OH), 4.20 (q, 2H,
COOCH2CH3), 4.55 (s, 2H, H-8), 4.80–4.90 (br, 1H, CH2OH ); 5.80–6.04
m, 1H, CH(CH3)CH2OH)), 11.80 (s, 1H, NH); �c (DMSO-d6): 14.56 (q,
(
(
COOCH2CH3), 18.72 (q, CH3), 25.51 (t, C-5), 40.68 (t, C-6), 42.72 (t,
C-8), 61.84 (t, COOCH2CH3), 64.41 (d, CH), 68.94 (t, CH2OH), 116.60
(
s, C-4a), 121.40 (s, C-4b), 128.70 (s, C-8a), 151.6 (s, C-9a), 155.71 (s,
C-4), 165.60 (s, CO ester), 174.82 (s, C-2).
Ethyl 3-Methyl-5-oxo-2,3,6,9-tetrahydro-5 H-pyrido-
0
0
[
8
4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-
(7H)-carboxylate (4)
Compound 2b (0.4 g, 0.001 mmol) was dissolved in 10 ml of methano-
lic hydrogen chloride and stirred at reflux temperature for 10 h, and
after evaporation of the solvent under reduced pressure the yellow
residue was dissolved in 10 ml of water and neutralized to pH = 7.5
with ammonium hydroxide and extracted with chloroform. The organic
layer was dried (magnesium sulfate) and evaporated to yield the solid
which was recrystallized from ethanol. Yield 0.21 g (62.1%) of com-
�
pound 4 as yellow crystals, m.p. 136–138 C; (found: C, 51.10; H, 4.79;
N, 11.80; S, 18.36. C15H17N3O3S2 (351.45) requires C, 51.26; H, 4.87;
�
1
N, 11.95; S, 18.24%); �max/cm : 2990 ( aliph. CH), 1720 ( CO ester),
1
1
700 (CO pyrimidine ring); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3),
.45 (d, 3H, CH3CH ), 2.90 (t, 2H, H-6), 3.20–3.30 (d, 2H, H-2), 3.65
(
(
t, 2H, H-7), 4.15 (q, 2H, COOCH2CH3), 4.60 (s, 2H, H-9), 5.10–5.20
m, 1H, H-3); �c (DMSO-d6): 14.15 (q, COOCH2CH3), 21.83 (q, CH3),
2
5.12 (t, C-6), 31.81 (t, C-2), 40.71 (t, C-7), 42.70 (s, C-9), 58.86 (d,
C-3), 61.08 (t, COOCH2CH3), 117.48 (s, C-5a), 127.03 (s, C-5b), 128.92

6
74
E. Kh. Ahmed
(
s, C-9a), 154.72 (s, C-10a), 156.19 (s, C-11a), 160.77 (s, C-5), 163.43 (s,
CO ester).
Ethyl 2-{[(2-Propenyl)-aminothioxomethyl]-amino}-
4
,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate (5)
A solution of isothiocyanate 1 (0.34 g, 0.001 mmol) in dichloromethane
(
10 ml) was added with stirring to a solution of an equimolar amount
of allylamine (0.06 g, 0.001 mmol) in dichloromethane (10 ml), and the
mixture was stirred at room temperature for 1 h. The solvent was re-
moved under reduced pressure and the solid product was collected by
filtration, washed with dichloromethane, dried, and recrystallized from
ethanol. Yield 0.36 g (90.6%) of compound 5 as pale yellow crystals, m.p.
�
1
48–150 C; (found: C, 51.18; H, 5.92; N, 10.41; S, 15.95. C17H23N3O4S2
�
1
(
(
(
(
397.52) requires C, 51.36; H, 5.83; N, 10.57; S, 16.13%); �max/cm : 3290
NH), 2982 (aliph. CH), 1720, 1690 (2 CO ester) ; �H (DMSO-d6): 1.20
t, 3H, COOCH2CH3), 1.35 (t, 3H, COOCH2CH3), 2.80 (t, 2H, H-4), 3.65
t, 2H, H-5), 3.85 (d, 2H, CH2 CH CH2), 4.20 (q, 2H, COOCH2CH3),
4
.55 (s, 2H, H-7), 4.95–5.40 (m, 2H, CH2 CH CH2), 5.70–5.90 (m, 1H,
CH CH2), 6.55–6.65 (br, 1H, NH), 11.90 (s, 1H, NH); �c (DMSO-d6):
4.20 (q, COOCH2CH3), 14.63 (q, COOCH2CH3), 26.28 (t, C-4), 41.10 (t,
1
C-5), 42.53 (t, C-7), 46.69 (t, NHCH2), 60.84 (t, COOCH2CH3), 61.60 (t,
COOCH2CH3), 111.22 (s, C-3), 115.91 (t, CH CH2),122.20 (s, C-7a),
1
31.78 (s, C-3a), 133.96 (d, CH CH2), 153.56 ( s, CO ester), 166.52
(
s, CO ester), 169.98 (s, C-2), 177.73 (s, CS).
Ethyl 3-(2-Propenyl)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
0
0
octahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-
-carboxylate (6)
7
Compound 5 (0.4 g, 0.001 mmol) was added to a solution of potassium
hydroxide (0.07 g, 0.0012 mmol) in absolute ethanol (10 ml), and the
mixture was refluxed with stirring for 10 min. The potassium salt of
compound 6 was collected by filtration then dissolved in water and acidi-
fied (to pH = 6.6) with hydrochloric acid, the product was collected by fil-
tration, washed with water dried, and recrystallized from ethanol. Yield
�
0
.3 g (85.7%) of compound 6 as pale yellow crystals, m.p. 178–180 C;
(
found: C, 51.39; H, 4.95; N, 12.11; S, 18.38. C15H17N3O3S2 (351.45)
�
1
requires C, 51.26; H, 4.87; N, 11.95; S, 18.24%); �max/cm 3180 (NH),
990 (aliph. CH), 1710 (CO ester), 1680 (CO pyrimidine ring), 1620
2
(
(
C N); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-5), 3.65
t, 2H, H-6), 4.10 ( q, 2H, COOCH2CH3), 4.55 (s, 2H, H-8), 4.90–5.12

0
0
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines
675
(
6
d, 2H, CH2 CH CH2), 5.18–5.30 (m, 2H, CH2 CH CH2), 5.80–
.10 (m, 1H, CH CH2), 13.70 (s, 1H, NH); �c (DMSO-d6): 14.43 (q,
COOCH2CH3), 24.87 (t, C-5), 40.21 (t, C-6), 42.39 (t, C-8), 47.12 (t,
NCH2), 60.99 (t, COOCH2CH3),114.88 (t, CH CH2), 116.94 (s, C-4a),
1
1
24.51 (s, C-4b), 129.57 (s, C-8a), 134.51 (d, CH CH2), 149.52 (s, C-9a),
54.59 (s, C-4), 159.96 (s, CO ester), 173.45 (s, C-2).
Ethyl 3-(2-Propenyl)-2-(methylsulfanyl)-4-oxo-,
0
0
3
,4,5,6,7,8-hexahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
pyrimidine-7-carboxylate (7)
A solution of 6 (0.35 g, 0.001 mmol) in 1 M aqueous sodium hydroxide
(
1.5 ml) was treated with methyl iodide (0.16 g, 0.0011 mmol) and the
mixture was stirred at room temperature. The methylthio compound 7
started to crystallize almost immediately. After 30 min, it was filtered,
washed with water, dried, and recrystallized from ethanol. Yield 0.32 g
�
(
88.8%) of compound 7 as colorless crystals, m.p. 130–132 C; (found:
C, 52.47; H, 5.18; N, 11.40; S, 17.41. C16H19N3O3S2 (365.48) requires
�
1
C, 52.58; H, 5.23; N, 11.49; S, 17.54%); �max/cm 2990 (aliph. CH),
1
1
710 (CO ester), 1670 (CO pyrimidine ring), 1620 (C N); �H (DMSO-d6):
.20 (t, 3H, COOCH2CH3), 2.65 (s, 3H, SCH3), 2.80 (t, 2H, H-5), 3.60
(t, 2H, H-6), 4.20 (q, 2H, COOCH2CH3), 4.60 (s, 2H, H-8), 4.80–5.10
(d, 2H, CH2 CH CH2), 5.25–5.55 (m, 2H, CH2 CH CH2), 5.80–6.10
(m, 1H, CH CH2); �c (DMSO-d6): 14.41 (q, COOCH2CH3), 15.66 (q,
SCH3), 25.09 (t, C-5), 40.20 (t, C-6), 42.64 (t, C-8), 45.16 (t, NCH2), 60.96
t, COOCH2CH3), 114.30 (t, CH CH2), 116.80 (s, C-4a), 126.99 (s, C-
b), 129.11 (s, C-8a), 134.30 (d, CH CH2), 151.20 (s, C-9a), 154.61 (s,
(
4
C-4), 158.10 (s, C-2), 161.90 (s, CO ester).
Ethyl 2-Methyl-5-oxo-2,3,6,9-tetrahydro-5 H-
0
0
pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-
pyrimidine-8(7H)-carboxylate (8)
Method A
A mixture of 6 (0.35 g, 0.001 mmol) in acetic acid (1 ml) and con-
centrated hydrochloric acid (2 ml) was refluxed for 1 h. After cooling to
room temperature, the solid formed by neutralizing the mixture with
1
0% sodium hydroxide was collected by filtration and washed with wa-
ter (20 ml), affording 0.32 g of crude product which was recrystallized
from 15% aqueous ethanol. Yield 0.24 g (68.5%) of compound 8 as yellow
�
crystals, m.p. 138–140 C; (found: C, 51.17; H, 4.95; N, 11.82; S, 18.13.
C15H17N3O3S2 (351.45) requires C, 51.26; H, 4.87; N, 11.95; S, 18.24%);
�
1
�max/cm
2980 (aliph. CH), 1720 (CO ester), 1680 (CO pyrimidine

6
76
E. Kh. Ahmed
ring); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.60 (d, 3H, CH3),
.90 (t, 2H, H-6), 3.60 (t, 2H, H-7), 3.95–4.10 (d, 2H, H-3), 4.20 (q, 2H,
2
COOCH2CH3), 4.40–4.55 (m, 1H, H-2), 4.65 (s, 2H, H-9).
Method B
1
,2-Dibromopropane (0.22 g, 0.0011 mmol) in DMF (5 ml) was added
to a stirred solution containing 10 (0.31 g, 0.001 mmol), water (5 ml),
�
and sodium hydroxide (0.05 g). The mixture was heated at 90 C for
1
h and then stirred at room temperature for an additional 1 h. The
reaction mixture was poured into cold water, the precipitated product
was collected by filtration, dried, and recrystallized from 15% aqueous
ethanol. Yield 0.24 g (68.7% ) of compound 8 as yellow crystals. m.p.
�
1
39–140 C. The compound is identical to that obtained according to
method A.
Ethyl 3-Amino-4-oxo-2-thioxo-1,3,4,5,6,8-
0
0
hexahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7(2 H)-
carboxylate (9)
A solution of diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothieno[2,3-
c]pyridine-3,6-dicarboxylate 1 (0.6 g, 0.0017 mmol) in benzene (10 ml)
was added dropwise at room temperature to a stirred solution of hy-
drazine hydrate (0.6 g, 0.018 mmol) in benzene (5 ml). The suspen-
sion was refluxed with stirring for 8 h. After cooling, the solid prod-
uct was collected, by filtration washed with ethanol, dried, and recrys-
tallized from dioxane. Yield 0.57 g (91.2%) of compound 9 as yellow
�
crystals, m.p. 232–234 C (dec.); (found: C, 44.07; H, 4.30; N, 17.01; S,
1
1
9.50. C12H14N4O3S2 (326.40) requires C, 44.15; H, 4.32; N, 17.16; S,
9.64%); �max/cm 3400, 3320, 3180 (NH2, NH), 1710 (CO ester), 1680
�
1
(
CO pyrimidine ring), 1200 (C S); �H (DMSO-d6): 1.20 (t, J 7 Hz, 3H,
COOCH2CH3), 2.90 (t, J 5.6 Hz, 2H, H-5), 3.60 (t, J 5.6 Hz, 2H, H-6),
.20 (q, J 7 Hz, 2H, COOCH2CH3), 4.50 (s, 2H, H-8), 6.30–6.50 (br, 2H,
NH2); 13.40 (s, 1H, NH); �c (DMSO-d6): 14.56 (q, COOCH2CH3), 25.26
t, C-5), 40.74 (t, C-6), 46.75 (t, C-8), 60.95 (t, COOCH2CH3), 113.31 (s,
4
(
C-4a), 128.28 (s, C-4b), 141.03 (s, C-8a), 154.76 (s, C-4), 157.64 (s, C-9a)
+
1
61.63 (s, CO), 168.83 (s, C-2). MS: m/z = 326 (M ).
Ethyl 4-Oxo-2-thioxo-1,2,3,4,5,6,7,8-
0
0
octahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (10)
To a suspention of 9 (0.32 g, 0.001 mmol) in 2 ml of acetic acid and 10 ml
of water, a solution of sodium nitrite (0.27 g, 0.0039 mmol) in 1 ml of

0
0
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines
677
water was added, After 15 min stirring at room temperature, 5 ml of a
0% sodium hydroxide solution was added and warmed to obtain a clear
4
solution. After cooling it was acidified with a 50% solution of sulfuric
acid to give colorless crystals. The crystals were washed with cold water,
dried, and recrystallized from ethanol. Yield 0.2 g (65.5%) of compound
�
1
1
1
0 as colorless crystals, m.p. 287–289 C; (found: C, 46.18; H, 3.15; N,
3.32; S, 20.52. C12H13N3O3S2 (311.38) requires C, 46.28; H, 4.20; N,
3.49; S, 20.59%); �max/cm 3300 (NH), 2980 (aliph. CH), 1700 (CO
�
1
ester), 1670 (CO pyrimidine ring); �H (DMSO-d6) 1.20 (t, J 7 Hz, 3H,
COOCH2CH3), 2.90 (t, J 5.6 Hz, 2H, H-5), 3.70 (t, J 5.6 Hz, 2H, H-6),
4
1
4
.10 (q, J 7 Hz, 2H, COOCH2CH3), 4.60 (s, 2H, H-8), 12.40 (s, 1H, NH),
3.40 (s, 1H, NH); �c (DMSO-d6): 14.3 ( q, COOCH2CH3), 24.7 (t, C-5),
0.2 (t, C-6), 42.3 (s, C-8), 60.9 ( t, COOCH2CH3), 115.7 (s, C-4a), 124.5
(
s, C-4b), 129.4 (s, C-8a), 150.7 (s, C-9a), 154.8 (s, C-4), 156.6 (s, CO),
72.9 (s, C-2).
1
Ethyl 3-Carboxymethyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
0
0
octahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
pyrimidine-7-carboxylate (11)
To a solution of glycine (0.08 g, 0.001 mmol) in a mixture of water (5 ml),
dioxane (5 ml) and sodium hydroxide (1M, 5 ml) 1 (0.34 g, 0.001 mmol)
�
was added and the mixture was stirred at 50 C for 5 h. The volatile com-
ponents were evaporated in vacuo, water was added to the solid residue
and acidified with hydrochloric acid (18%) to pH = 3. The precipitate
was collected by filtration, dried, and recrystallized from DMF/water.
�
Yield 0.26 g (70.6%) of compound 11 as yellow crystals, m.p. 280–282 C;
(
found: C, 45.39; H, 4.19; N, 11.24; S, 17.48. C14H15N3O5S2 (369.43) re-
quires C, 45.51; H, 4.09; N, 11.37; S, 17.35%); �H (DMSO-d6): 1.20 (t,
H, COOCH2CH3), 2.80 (t, 2H, H-5), 3.70 (t, 2H, H-6), 4.10 (q, 2H,
3
COOCH2CH3), 4.60 (s, 2H, H-8), 5.10 (s, 2H, NCH2), 13.40 (s, 1H,
NH). �c (DMSO-d6): 14.45 (q, COOCH2CH3), 24.73 (t, C-5), 40. 43 (t,
C-6), 42.43 (t, C-8), 45.99 (t, NCH2), 60.83 (t, COOCH2CH3), 115.76
(
s, C-4a), 125.06 (s, C-4b), 129.53 (s, C-8a), 150.06 (s, C- 9a), 154.61 (s,
C-4), 166.44 (s, CO ester), 169.29 (s, C-2), 173.75 (s, COOH).
Ethyl 3-[(S)-1-Carboxyethyl-4-oxo-2-thioxo-
0
0
1
,2,3,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
pyrimidine-7-carboxylate (12)
To a stirred solution of L-alanine (0.09 g, 0.001 mmol) in a mixture of
water (5 ml), dioxane (5 ml) and sodium hydroxide (1 M, 5 ml) 1 (0.34 g,
�
0
.001 mmol) was added and the mixture was stirred at 50 C for 10 h.

6
78
E. Kh. Ahmed
The volatile components were evaporated in vacuo, water was added to
the solid residue, and acidified with hydrochloric acid (18%) to pH = 3.
The precipitate was collected by filtration dried and recrystallized from
DMF/water. Yield 0.24 g (63.1%) of compound 12 as yellow crystals,
�
m.p. 290–292 C; (found: C, 46.91; H, 4.39; N, 10.82; S, 16.61.
C15H17N3O5S2 (383.45) requires C, 46.98; H, 4.46; N, 10.95; S,
1
6.72%); �H (DMSO-d6): 1.10 (t, 3H, COOCH2CH3), 1.52 ( d, 3H,
CH(CH3)COOH), 2.80 (t, 2H, H-5), 3.60 (t, 2H, H-6), 4.10 (q, 2H,
COOCH2CH3), 4.60 (s, 2H, H-8), 6.20 (q, 1H, CH(CH3)COOH), 13.20
s, 1H, NH). �c (DMSO-d6): 14.54 (q, COOCH2CH3), 17.44 (q, CH3),
4.89 (t, C-5), 40.75 (t, C-6), 42.55 (t, C-8), 49.95 (d, CH), 61.12 (t,
COOCH2CH3), 115.43 (s, C-4a), 125.48 (s, C-4b), 129.60 (s, C-8a), 150.48
s, C-9a), 155.66 (s, C-4), 161.67, 170.51 (s, C-2), 174.47 (s, COOH).
(
2
(
Ethyl 3-(2-Carboxyethyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
0
0
octahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (13)
To a solution of �-alanine (0.09 g, 0.001 mmol) in water (5 ml), dioxane
(
5 ml) and sodium hydroxide (1M, 5 ml) 1 (0.34 g, 0.001 mmol) was
�
added and the mixture was stirred at 50 C for 3 h, and then at room
temperature for 4 h. The volatile components were evaporated in vacuo,
water (10 ml) was added to the residue and the mixture was acidified
with hydrochloric acid (18%) to pH = 3. The precipitate was collected by
filtration, dried, and recystallized from DMF/water. Yield 0.26 g (68.4%)
�
of compound 13 as yellow crystals, m.p. > 300 C; (found: C, 46.84; H,
4
4
2
.39; N, 10.82; S, 16.59. C15H17N3O5S2 (383.45) requires C, 46.98; H,
.46; N, 10.95; S, 16.72%); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3),
.65 (t, 2H, CH2COOH), 2.85 (t, 2H, H-5), 3.60 (t, 2H, H-6), 4.10
(q, 2H, COOCH2CH3), 4.60–4.80 (m, 4H, H-8, CH2CH2COOH), 13.60
(br, 1H, NH); �c (DMSO-d6): 14.40 (q, COOCH2CH3), 24.77 (t, C-5), 30.55
(t, NCH2), 36.65 (t, CH2COOH), 40.23 (t, C-6), 42.41 (t, C-8), 60.99 (t,
COOCH2CH3), 115.80 (s, C-4a), 124.81 (s, C-4b), 129.54 (s, C-8a), 149.45
s, C-9a), 154.61 (s, C-4), 163.55 (s, CO ester), 170.12 (C-2), 173.22 (s,
(
COOH).
Ethyl 2,5-Dioxo-2,3,6,9-tetrahydro-5 H-
0
0
pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-
pyrimidine-8 (7H)-carboxylate (14)
Method A
Compound 11 (0.5 g, 0.0013 mmol) was heated over its melting point
for 15 min, then the residue was cooled and crystallized from DMF.

0
0
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines
679
�
Yield 0.28 g (58.9%) of compound 14 as brown crystals, m.p 260–262 C;
(
found: C, 47.76; H, 3.64; N, 11.81; S, 18.33. C14H13N3O4S2 (351.41) re-
�
1
quires C, 47.85; H, 3.72; N, 11.95; S, 18.24%); %); �max/cm : 1740, 1720,
1
2
680, (3 CO), 1640 (C N); �H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3),
.85 (t, 2H, H-6), 3.60 (t, 2H, H-7), 3.90 (s, 2H, H-3), 4.20 (q, 2H,
COOCH2CH3), 4.60 (s, 2H, H-9).
Method B (from Compound 10)
To a solution of 10 (0.31 g, 0.001 mmol) in 10 ml dimethylformamide
was added chloroacetyl chloride (0.14 g, 0.0012 mmol) dropwise under
stirring. The reaction mixture was then heated on a water-bath for
2
h and, after cooling, poured into 100 ml of cold water with vigorous
stirring. The precipitate was collected by filtration, washed with water,
dried, and recrystallized from DMF. Yield 0.21 g (62.1%) of compound 14
�
as yellow crystals, m.p. 260–261 C, The compound is identical to that
obtained according to method A.
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[
[
1] S. Leistner, G. Wagner, M. Guetscharo, and E. Glusa, Pharmazie, 41, 54 (1986).
2] M. Chaykovsky, M. Lin, A. Rosowsky, and E. J. Modest, J. Med. Chem., 10, 188
(1973).
[
[
3] E. F. Elslager, P. W. Jacob, and M. Leslic, J. Heterocyclic Chem., 9, 775 (1972).
4] E. Bousquet, G. Romero, F. Guerrera, A. Caruso, and M. A. Roxas, Farmaco Ed. Sci.,
4
0, 869 (1985).
[
[
[
[
[
5] E. Bousquet, F. Guerrera, N. A. Siracusa, A. Caruso, and M. A. Roxas, Farmaco Ed.
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(1989).
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and G. Loban, East Ger. Pat. DD 257, 830 (1988); C.A., 110, 95262p (1989).
8] H. Vieweg, S. Leistner, G. Wagner, N. Boehm, U. Krasset, R. Grupe, D. Lohmann,
and G. Loban, East Ger. Pat. DD 258, 234 (1988); C.A., 110, 95263q (1989).
9] J. V. Metzger, Comprehensive Heterocyclic Chemistry, edited by A. R. Katritzky,
W. Rees, and K. T. Potts (Pergamon Press, Oxford, 1984), vol. 6 (4b), p. 328.
[
[
10] E. Kh. Ahmed, A. M. N. Gohar, and M. A. Ameen, Pharmazie, 55(1), 31 (2000).
11] E. Kh. Ahmed, U. Sensfuss, and W. D. Habicher, J. Heterocyclic Chem., 36, 1119
(1999).
[
[
12] F. Sauter, J. Frohlich, and E. Kh. Ahmed, Monatsh. Chem., 127, 319 (1996).
13] E. Kh. Ahmed, J. Frohlich, and F. Sauter, Collect. Czech. Chem. Commun., 61, 147
(1996).
[
[
14] E. Kh. Ahmed, Monatsh. Chem., 126, 953 (1995).
15] F. Sauter, U. Jordis, J. Frohlich, K. Gewald, F. Grohmann, and E. Kh. Ahmed, ACH
Models in Chemistry, 131(3–4), 489 (1994).
[
16] E. Kh. Ahmed, Phosphorous, Sulfur, and Silicon (in press).