Synthesis of some new pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines and related fused heterocycles

Article abstract of DOI:10.1080/10426500307772

A highly efficient and versatile synthetic approach to the synthesis of pyrido[4′,3′:4,5]thieno[2,3-d]pyrimidines (3, 7a-c), pyrido[4′,3′:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines (8, 10-12), (15, 16), pyrido[4″,3″:4′,5′]thieno[2′,3′:4,5] pyrimido[2,1-b][1,3]thiazine (9), and polymethylene condensed (e.g., pyrrolo-, piperidino-, azepino-)pyridothienopyrimidines (18a-c) is described utilizing diethyl 2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1 as the starting material.

Full text of DOI:10.1080/10426500307772

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Synthesis of Some New Pyrido[4′,3′:4,5]thieno[2,3-
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Essam Kh. Ahmed a
a Minia University, El-Minia, Egypt
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:1–16
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DOI: 10.1080/10426500390170110
SYNTHESIS OF SOME
NEW PYRIDO[40,30:4,5]THIENO[2,3-d]PYRIMIDINES
AND RELATED FUSED HETEROCYCLES
Essam Kh. Ahmed
Minia University, El-Minia, Egypt
(Received May 30, 2002; accepted July 11, 2002)
A highly efficient and versatile synthetic approach to the synthesis of
pyrido[40,30:4,5]thieno[2,3-d]pyrimidines (3, 7a–c), pyrido[40,30:4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines (8, 10–12), (15, 16),
pyrido [400,300:40,50] thieno [ 20,30:4,5 ] pyrimido [2,1-b ] [1,3] thiazine (9),
and polymethylene condensed (e.g., pyrrolo-, piperidino-, azepino-)-
pyridothienopyrimidines (18a–c) is described utilizing diethyl 2-
amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1 as
the starting material.
Keywords: BMMA reagents; fused S,N-heterocycles; pyrimidine
annelations
Work in our laboratories recently has been concerned with the discov-
ery and development of synthesis of new tetracyclic systems containing
pyrimidine moiety in order to search for new pharmacological or biolog-
ical active compounds. We have reported previously on the synthesis of
novel tetracyclic ring systems, containing the thienopyrimidine skele-
ton with potential pharmaceutical activity.1 6 Pyridothienopyrimidines
represent an important class of heterocyclic compounds owing to their
medicinal interest. A number of syntheses for substituted derivatives
of this triheterocyclic ring system, which feature a variety of phar-
macological activities have been reported in a number of articles.
Such derivatives have analgesic,7 antipyretic,8,9 antianaphylactic,10,11
14
and antiinflammatory12
activity. Also, some of these compounds
are clinically effective antiallergic15 and a few possess signifficant
hypocholesterolenic16 activity. As a part of our continuing study on the
synthesis of such system,1 here we report on efficient syntheses of
3
some fused pyridothienopyrimidines utilizing diethyl 2-amino-4,5,6,
Accepted Essam Kh. Ahmed, Department of Chemistry, Faculty of Science, Minia
University, El-Minia, 61510 Egypt. E-mail: essamkhalaf24@yahoo.com
1

2
E. Kh. Ahmed
7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 117 as the starting
material.
Diethyl 2({[(benzoyl)amino]carbothioyl}amino)-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-3,6-dicarboxylate 2 was obtained from diethyl
2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1 by
treatment with ammonium thiocyanate and benzoyl chloride in acetone
at reflux. This was subjected to cyclization reactions under different re-
action conditions to afford pyrido[40,30:4,5]thieno[2,3-d]pyrimidine
or pyrido[40,30:4,5]thieno[2,3-d][1,3]thiazine derivatives. Thus, trea-
tment of 2 in alkaline medium, resulted in the formation of
ethyl
4-Oxo-2-thioxo-1,2,3,4,5,6,7,8-octahyropyrido[40,30:4,5]thieno-
[2,3-d]pyrimidine-7-carboxylate 3 through cyclization and debenzoy-
lation, while in acidic medium 2 yield ethyl 2-amino-4-oxo-5,6,7,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d][1,3]thiazine-7-carboxylate 4.
The N3-substituted pyrido[40,30:4,5]thieno[2,3-d]pyrimidines 7a–c
were synthesized from the isothiocyanate 52 and methylamine,
propylamine and cyclohexylamine in dichloromethane at room temper-
ature, with subsequent heating of the (hydrazinothioxomethyl)amino
derivatives 6a–c with an ethanolic potassium hydroxide solution.
Acidification of an aqueous solution of the 3-substituted pyridoth-
ienopyrimidine potassium salts gave the thioxo compounds 7a–c.
Whose structures were substantiated by elemental analysis and
spectral data which were found to be in good agreement with the
assigned structures (Scheme 1).
Our interest in developing synthetic approaches with a view to syn-
thesize new derivatives of interesting heterocycles pyrido[40,30:4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines, compound 3 was thus
investigated as a good precursor for this purpose. Reaction of 3 with
1,2-dibromoethane afforded ethyl 5-Oxo-2,3,6,9-tetrahydro-5H-pyrido
[40,30:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-pyrimidine-8(7H)-carboxyl-
ate 8. Similary, the condensation of 3 with 1,3-dibromopropane and
1,2-dibromoethylene in dimethyl formamide yielded the correspond-
ing ethyl 6-Oxo-3,4,7,10-tetrahydro-2H,6Hpyrido[400,300:40,50]thieno
[20,30:4,5]pyrimido[2,1-b][1,3]thiazine-9(8H)-carboxylate (9) and ethyl
5-Oxo-6,9-dihydro-5H-pyrido[40,30:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-
pyrimidine-8(7H)-carboxylate (10), respectively. Condensation of com-
pound 3 with dimethylacetylene dicarboxylate provided ethyl 2-
methoxycarbonylmethylidene-3,5-dioxo-2,3,6,9-tetrahydro-5H-pyrido-
[40,30:4,5]thieno[2,3-d][1,3]thiazolo[3,2a]pyrimidine 8(7H)-carboxylate
11. The reaction of 3 with benzaldehyde and chloroacetic acid, in the
presence of acetic acid and acetic anhydride gave ethyl 2-benzylidene-3,
5-dioxo-2,3,6,9-tetrahydro-5H-pyrido[40,30:4,5]thieno[2,3-d][1,3]thiazolo
[3,2-a]-pyrimidine-8(7H)-carboxylate 12 (Scheme 2).

Fused Heterocycles
3
SCHEME 1
The ethyl (3-substituted)-5-oxo-6,9-dihydro-5H-pyrido[40,30:4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-carboxylates 15, 16
were prepared by a simple acid cyclodehydration in 98% sul-
phuric acid of the ethyl 2-[(2-substituted) sulfanyl]-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4H)-carboxylates
13, 14 at room temperature for 2–3 days. The intermediates 13, 14
were prepared by stirring the compound 3 with -haloketone, in
anhydrous acetone/ potassium carbonate.
As the preparation of novel tetracyclic systems is the main tar-
get of this synthetic program, the diethyl 2-amino-4,5,6,7-tetra-
hydrothieno[2,3-c]pyridine-3,6-dicarboxylate 1 was selected as a model
compound for studying all the reactions leading to the construc-
tion of various heterocyclic systems incorporating a pyrimidine, thia-
zolopyrimidine, pyrimidothiazine, and polymethylene condensed (e.g.,
pyrrolo-, piperidino-, azepino-)pyrimidine in addition to the thienopy-
ridine moiety.

4
E. Kh. Ahmed
SCHEME 2
It is worth mentioning that ethyl N-[bis(methylthio) methylene]-
glycinate (BMMA)18 is known as a reagent for the synthesis
of a variety of heterocycles.19 To the best of our knowledge,
its utility in the synthesis of pyridothienopyrimidines derivati-
ves is unknown. We recently5 reported on the use of ethyl N-
[bis(methylthio)methylene]-glycinate for the direct one-pot annelation

Fused Heterocycles
5
of a fused pyrimidine moiety when starting from 2-amino-4,7-
dihydro-5H-thieno[2,3-c]thiopyran-3-carboxylic acid ethyl ester. In
order to shed further light on the synthetic ability of this reagent,
we report herin its reaction with the aminoester 1. Thus it has been
found that in an one-pot reaction of 1 with ethyl N-[bis(methyl-
thio)methylene]-glycinate (BMMA), ethyl 3-(2-ethoxy-2-oxoethyl)-
2-(methylsulfanyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[40,30:4,5]thieno-
[2,3-d]pyrimidine-7-carboxylate 17 is formed. A variety of novel,
structurally related linear tetracyclic systems, were approached either
by reacting 1 with the cyclic BMMA reagents such as 2-(methylthio)-
2-thiazoline20 and 2-methylthio-dihydro-1,3-thiazine21 to yield 8 and
9 (both of which are products of a one-pot double annelation at a
thiazolopyrimido- or a thiazinopyrimido moiety respectively) or by
reacting 1 with 5-, 6-, and 7-membered lactams to obtain 18a–c (both
of which are products of a double annelation at a pyrrolopyrimido-,
a pyridopyrimido-, and an azepinopyrimido-moiety respectively). The
incorporation of lactams into our annelation studies was done with
the intention to compare the results thus obtained with those realized
by BMMA reagents and to access via these means the novel target
compounds 18a–c (Scheme 3).
SCHEME 3

6
E. Kh. Ahmed
EXPERIMENTAL
All m.p.s were recorded on a Gallenkamp melting point apparatus and
are uncorrected. Microanalyses were performed at the Microanalytical
1
Data Unit, Cairo University. 13C and H NMR spectra were recorded
on a Bruker AC 300 (1H: 300.13 MHz, 13C: 75.5 MHz). The solvent were
deuterated dimethyl sulfoxide and chloroform respectively; -values are
given in ppm, the internal standard TMS ( = 0 ppm). IR spectra were
recorded on a Shimadzu 470 Spectrophotometer in KBr pellets.
Diethyl 2({[(Benzoyl)amino]carbothioyl}amino)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate (2)
To a solution of ammonium thiocyanate (0.76 g, 0.01 mmol) in anhy-
drous acetone (15 ml) was added benzoyl chloride (1.40 g, 0.01 mmol).
To the resulting suspension, after being refluxed for 15 min, was added
a solution of amino ester 1 (2.98 g, 0.01 mmol) in anhydrous ace-
tone (50 ml). The mixture was refluxed for another 15 min and fil-
tered while hot. After cooling, the solid product was collected by fil-
tration, poured into water, and filtered to give by recrystallization from
ethanol. Yield 3.7 g (80.4%) of compound 2 as yellow microcrystals, m.p.
222–224 C; (found: C, 54.55; H, 5.10; N, 9.26; S, 13.97. C21H23N3O5S2
1
(461.56) requires C, 54.64; H, 5.02; N, 9.10; S, 13.89%); max/cm
:
3240 (NH), 3110–3045 (Ar-CH), 2980 (aliph. CH), 1720, 1685, 1675
(3 CO), 1250 (CS); (DMSO-d6): 1.15 (t, 3H, COOCH2CH3), 1.30 (t,
H
3H, COOCH2CH3), 2.85 (t, 2H, H-4), 3.65 (t, 2H, H-5), 4.10 (q, 2H,
COOCH2CH3), 4.35 (q, 2H, COOCH2CH3), 4.60 (s, 2H, H-7), 7.40–7.90
(m, 5H, Ar-H), 11.90 (s, 1H, NH), 13.80 (s, 1H, NH).
Ethyl 4-Oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido-
[40,30:4,5]thieno[2,3-d]pyrimidine-7-carboxylate (3)
A solution of compound 2 (0.92 g, 0.002 mmol) dissolved in 2N methano-
lic sodium hydroxide (10 ml) was refluxed for 6 h then filtered. The
clear solution was acidified (pH = 5.6) with 10% hydrochloric acid, and
the mixture was stirred at room temperature for 30 min. The solid
was collected by filtration, washed with water, dried, and recrystal-
lized from DMF/water. Yield 0.48 g (77.4%) of compound 3 as color-
less crystals, m.p. 288–290 C; (found: C, 46.20; H, 4.11; N, 13.38; S,
20.50. C12H13N3O3S2 (311.38) requires: C, 46.28; H, 4.20; N, 13.49; S,
20.59%); max/cm 1: 3150 (NH), 1710, 1685 (2 CO);
(DMSO-d6): 1.20
H
(t, 3H, COOCH2CH3), 2.90 (t, 2H, H-5), 3.70 (t, 2H, H-6), 4.10 (q, 2H,
COOCH2CH3), 4.60 (s, 2H, H-8), 12.40 (s, 1H, NH), 13.60 (s, 1H, NH);

Fused Heterocycles
7
(DMSO-d6): 14.20 (q, COOCH2CH3), 24.75 (t, C-5), 40.20 (t, C-6),
c
42.35 (s, C-8), 60.95 (t, COOCH2CH3), 115.85 (s, C-4a), 124.60 (s, C-4b),
129.45 (s, C-8a), 150.80 (s, C-9a), 154.85 (s, C-4), 156.68 (s, CO), 172.90
(s, C-2).
Ethyl 2-Amino-4-oxo-5,6,7,8-tetrahydropyrido-
[40,30:4,5]thieno[2,3-d][1,3]thiazine-7-carboxylate (4)
A suspension of compound 2 (0.6 g, 0.0013 mmol) in 98% sulphuric
acid (5 ml) was left at room temperature for 2 days. The resultant
clear solution was slowly added to ice water (30 ml) and the solid
residue was collected, washed with 5% sodium bicarbonate solution
and cold water, dried and recrystallized from ethanol. Yield 0.33 g
(81.6%) of compound 4 as pale yellow crystals, m.p. 250–252 C; (found:
C, 46.40; H, 4.21; N, 13.43; S, 20.66. C12H13N3O3S2 (311.38) requires: C,
46.28; H, 4.20; N, 13.49; S, 20.59%); max/cm 1: 3340 (NH2), 1720, 1660
(2 CO), 1630 (C N);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.85
H
(t, 2H, H-5), 3.65 (t, 2H, H-6), 4.10 (q, 2H, COOCH2CH3), 4.50 (s, 2H,
H-8), 8.35 (s, 2H, NH2). (DMSO-6): 14.42 (q, COOCH2CH3), 25.80
c
(t, C-5), 40.20 (t, C-6), 42.21 (t, C-8), 60.90 (t, COOCH2CH3), 112.45
(s, C-4a), 121.04 (s, C-4b), 128.38 (s, C-8a), 154.59 (s, C-9a), 163.01
(s, C-2), 170.13 (s, C-4), 174.86 (s, CO ester).
General Procedure for the Synthesis of 6a---c
A solution of isothiocyanate 5 (0.34 g, 0.001 mmol) in dichloromethane
(5 ml) was added under stirring to a solution of an equimolar amount
of respective amine (0.001 mmol) in dichloromethane (5 ml) and the
mixture was stirred at room temperature for 1–2 h. The solvent was
removed under reduced pressure and the solid collected by filtration,
washed with dichloromethane, dried, and recrystallized from an appro-
priate solvent.
Diethyl 2({[(Methyl)amino]carbothioyl}amino)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate (6a)
Colorless crystals from EtOH. Yield 86.4%, m.p. 178–180 C; (found:
C, 46.40; H, 4.21; N, 13.43; S, 20.66. C15H21N3O4S2 (371.49) requires:
C, 48.49; H, 5.69; N, 11.31; S, 17.26%); max/cm 1: 3340–3240 (NH),
2995 (aliph. CH), 1710, 1680 (2 CO), 1220 (CS);
(CDCl3): 1.20
H
(t, 3H, COOCH2CH3), 1.30 (t, 3H, COOCH2CH3), 2.80 (t, 2H, H-4),
3.10 (d, 3H, CH3), 3.60 (t, 2H, H-5), 4.15 (q, 2H, COOCH2CH3), 4.25
(q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7), 5.30 (s, 1H, NH), 6.55 (s, 1H,
NH).
(DMSO-d6): 4.22 (q, COOCH2CH3), 14.64 (q, COOCH2CH3),
c
26.36 (t, C-4), 30.83 (q, CH3), 41.09 (t, C-5), 42.53 (t, C-7), 60.85

8
E. Kh. Ahmed
(t, COOCH2CH3), 61.60 (t, COOCH2CH3), 111.30 (s, C-3), 122.25 (s,
C-7a), 129.23 (s, C-3a), 155.12 (s, CO), 155.51 (s, CO), 167.11 (s, C-2),
177.89 (s, CS).
Diethyl 2({[(Propyl)amino]carbothioyl}amino)-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate (6b)
Colorless crystals from EtOH. Yield 87.7%, m.p. 148–150 C; (found:
C, 51.21; H, 6.39; N, 10.43; S, 15.92. C17H25N3O4S2 (399.54) requires:
C, 51.10; H, 6.30; N, 10.51; S, 16.05%);
(CDCl3): 0.93 (t, 3H,
H
CH3), 1.20 (t, 3H, COOCH2CH3), 1.35 (t, 3H, COOCH2CH3), 1.60–176
(m, 2H, CH2), 2.85 (t, 2H, H-4), 3.45 (t, 2H, CH2), 3.60 (t, 2H, H-5),
4.15 (q, 2H, COOCH2CH3), 4.25 (q, 2H, COOCH2CH3), 4.50 (s, 2H,
H-7), 6.50 (br s, 1H, NH), 1.90 (br s, 1H, NH).
(DMSO-d6): 11.35
c
(q, CH2CH2CH3), 14.19 (q, COOCH2CH3), 14.61 (q, COOCH2CH3),
21.90 (t, CH2CH2CH3), 26.23 (t, C-4), 41.08 (t, C-5), 42.51 (t, C-7), 46.01
(t, NHCH2), 60.79 (t, COOCH2CH3), 61.57 (t, COOCH2CH3), 115.30
(s, C-3), 122.19 (s, C-7a), 129.08 (s, C-3a), 154.45 (s, CO), 155.55 (s, CO),
167.01 (s, C-2), 177.01 (s, CS).
Diethyl 2({[(Cyclohexyl)amino]carbothioyl}amino)-
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate (6c)
Colorless crystals from EtOH. Yield 79.7%, m.p. 206–208 C; (found:
C, 54.74; H, 6.73; N, 9.43; S, 14.69. C20H29N3O4S2 (439.60) re-
quires: C, 54.64; H, 6.64; N, 9.55; S, 14.58%);
(CDCl3): 1.20
H
(t, 3H, COOCH2CH3), 1.35 (t, 3H, COOCH2CH3), 1.45–1.95 (m, 11H,
cyclohexane-H), 2.80 (t, 2H, H-4), 3.60 (t, 2H, H-5), 4.10 (q, 2H,
COOCH2CH3), 4.30 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-7), 6.30 (br s,
1H, NH), 11.95 (br s, 1H, NH).
Ethyl 3-Methyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
octahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (7a)
Compound 6a (0.37 g, 0.001 mmol) was added to a solution of potas-
sium hydroxide (0.07 g, 0.0012 mmol) in absolute ethanol (10 ml), and
the mixture was refluxed under stirring for 10–30 min. The potassium
salt of compound 7a was collected by filtration then dissolved in wa-
ter and neutralized (to pH = 4) with hydrochloric acid. The product
was collected by filtration, washed with water and recrystallized from
ethanol. Yield 0.26 g (80.2%) of compound 7a as colorless crystals, m.p.
304–306 C; (found: C, 47.91; H, 4.60; N, 12.84; S, 19.59. C13H15N3O3S2
1
(325.41) requires: C, 47.98; H, 4.64; N, 12.91; S, 19.70%); max/cm
:

Fused Heterocycles
9
3240 (NH), 2980 (aliph. CH), 1710, 1680 (2 CO);
(DMSO-d6): 1.20
H
(t, 3H, COOCH2CH3), 2.85 (t, 2H, H-5), 3.60 (t, 2H, H-6), 3.70 (s, 3H,
CH3), 4.10 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-8), 13.40 (s, 1H, NH).
(DMSO-d6): 14.47 (q, COOCH2CH3), 25.73 (t, C-5), 40.78 (t, C-6),
c
42.65 (t, C-8), 55.93 (q, CH3), 60.87 (t, COOCH2CH3), 113.17 (s, C-4a),
120.04 (s, C-4b), 128.67 (s, C-8a), 154.68 (s, C-9a), 159.63 (s, C-4), 164.71
(s, CO), 176.11 (s, C-2).
In a similar manner the following compounds were obtained.
Ethyl 3-Propyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
octahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (7b)
Colorless crystals from EtOH. Yield 85.7%, m.p. 220–222 C; (found:
C, 50.89; H, 5.49; N, 11.80; S, 18.25. C15H19N3O3S2 (353.47) requires:
C, 50.97; H, 5.41; N, 11.88; S, 18.14%); H (DMSO-d6): 0.95 (t, 3H, CH3),
1.25 (t, 3H, COOCH2CH3), 1.60–1.76 (m, 2H, CH2), 2.90 (t, 2H, H-5),
3.60 (t, 2H, H-6), 4.10 (q, 2H, COOCH2CH3), 4.30 (t, 2H, CH2), 4.60
(t, 2H, H-8), 13.45 (s, 1H, NH).
Ethyl 3-Cyclohexyl-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-
octahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (7c)
Colorless crystals from EtOH. Yield 78.9%, m.p. 228–230 C; (found: C,
54.88; H, 5.83; N, 10.77; S, 16.38. C18H23N3O3S2 (393.53) requires:
C, 54.93; H, 5.89; N, 10.67; S, 16.29%);
(DMSO-d6): 1.20 (t, 3H,
H
COOCH2CH3), 1.45–1.97 (m, 11H, cylohexane-H), 2.85 (t, 2H, H-5),
3.65 (t, 2H, H-6), 4.10 (q, 2H, COOCH2CH3), 4.55 (s, 2H, H-8), 13.50 (s,
1H, NH).
Ethyl 5-Oxo-2,3,6,9-tetrahydro-5H-pyrido[40,30:4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-
carboxylate (8)
Method A (from Compound 3)
1,2-Dibromoethane (0.19 g, 0.001 mmol) in DMF (5 ml) was added
dropwise to a stirred solution containing 3 (0.31 g, 0.001 mmol), water
(10 ml), and sodium hyroxide (0.05 g). The mixture was heated at 80 C
for 1 h and then stirred at room temperature for an additional 1 h.
The solid product was washed with water and then triturated with
ethanol to give a colorless solid which was crystallized from ethanol.
Yield 0.24 g (71.6%) of compound 8 as colorless crystals, m.p. 174–176 C;

10
E. Kh. Ahmed
(found: C, 49.78; H, 4.42; N, 12.36; S, 19.13. C14H15N3O3S2 (337.43)
requires: C, 49.83; H, 4.48; N, 12.45; S, 19.00%); (DMSO-d6): 1.20 (t,
H
3H, COOCH2CH3), 2.80 (t, 2H, H-6), 3.55–3.70 (m, 4H, H-7, H-2), 4.10
(q, 2H, COOCH2CH3), 4.30 (t, 2H, H-3), 4.60 (s, 2H, H-9). c (DMSO-d6):
14.15 (q, COOCH2CH3), 25.12 (t, C-6), 26.80 (t, C-2), 40.70 (t, C-7), 42.70
(s, C-9), 48.16 (t, C-3), 61.06 (t, COOCH2CH3), 117.48 (s, C-5a), 127.03
(s, C-5b), 128.92 (s, C-9a), 154.70 (s, C-10a), 156.18 (s, C-11a), 160.76
(s, C-5), 163.43 (S, CO ester).
Method B (from Compound 1)
A mixture of 1 (0.6 g, 0.002 mmol) and 2-methylthio-2-thiazoline
(0.28 g, 0.0021 mmol) in dry AcOH (3 ml) was heated at 80 C for
4 h. After cooling the separated solid product was collected by filtra-
tion, washed with ethanol, dried, and recrystallized from ethanol. Yield
0.44 g (64.8%) of compound 8 as colorless crystals, m.p. 175–176 C. The
compound is identical to that obtained according to method A.
Ethyl 6-Oxo-3,4,7,10-tetrahydro-2H,6H-pyrido-
[400,300:40,50]thieno[20,30:4,5]pyrimido[2,1-b][1,3]-
thiazine-9(8H)-carboxylate (9)
Method A (from Compound 3)
1,3-Dibromopropane (0.22 g, 0.0011 mmol) in DMF (10 ml) was
added dropwise to a stirred solution containing compound 3 (0.31 g,
0.001 mmol), water (10 ml), and sodium hydroxide (0.05 g). The mix-
ture was heated at 80–90 C for 2.5 h and then stirred at room temper-
ature for an additional 1 h. The solid product was washed with water
and then triturated with ethanol to give a yellow solid which was crys-
tallized from ethanol. Yield 0.23 g (65.9%) of compound 9 as yellow
crystals, m.p. 148–150 C; (found: C, 51.19; H, 4.81; N, 11.86; S, 18.13.
C15H17N3O3S2 (351.45) requires: C, 51.26; H, 4.87; N, 11.95; S 18.24%);
H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.20 (m, 2H, H-3), 2.80 (t, 2H,
H-7), 3.30 (t, 2H, H-2), 3.60 (t, 2H, H-8), 4.10 (q, 2H, COOCH2CH3), 4.35
(t, 2H, H-4), 4.60 (s, 2H, H-10).
Method B (from Compound 1)
A mixture of 1 (0.6 g, 0.002 mmol) and 2-methylthio-dihydro-1,3-
thiazine (0.31 g, 0.0021 mmol) in dry AcOH (4 ml) was heated at at
80 C for 3 h. After cooling the separated solid product was collected by
filtration, washed with ethanol, dried, and recrystallized from ethanol.
Yield 0.45 g (63.7%) of compound 9 as yellow crystals, m.p. 149–150 C.
The compound is identical to that obtained according to method A.

Fused Heterocycles
11
Ethyl 5-Oxo-6,9-dihydro-5H-pyrido[40,30:4,5]thieno-
[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-
carboxylate (10)
1,2-Dibromoethylene (0.19 g, 0.001 mmol) in DMF (10 ml) was
added dropwise to a stirred solution containing compound 3 (0.31 g,
0.001 mmol), water (10 ml), and sodium hydroxide (0.04 g). The mixture
was heated at 80 C for 1 h and then stirred at room temperature for an
additional 1 h. The solid product was washed with water and then trit-
urated with ethanol to give a yellow solid which was crystallized from
ethanol. Yield 0.26 g (78.7%) of compound 10 as yellow crystals, m.p.
230–232 C; (found: C, 50.25; H, 3.98; N, 12.69; S, 19.21. C14H13N3O3S2
(335.41) requires: C, 50.13; H, 3.90; N, 12.52; S, 19.11%); H (DMSO-d6):
1.20 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-6), 3.60 (t, 2H, H-7), 4.10 (q,
2H, COOCH2CH3), 4.60 (s, 2H, H-9), 7.55 (d, 1H, H-3), 8.10 (d, 2H, H-2).
Ethyl 2-Methoxycarbonylmethylidene-3,5-dioxo-2,3,6,9-
tetrahydro-5H-pyrido[40,30:4,5]thieno[2,3-d][1,3]thiazolo-
[3,2-a]pyrimidine-8(7H)-carboxylate (11)
A mixture of 3 (0.31 g, 0.001 mmol) and dimethyl acetylenedicarboxy-
late (0.16 g, 0.0011 mmol) in 15 ml of toluene was refluxed for 2 h. After
cooling, the reaction mixture was filtered and the resulting solid was
recrystallized from ethyl acetate. Yield 0.28 g (66.8%) of compound 11
as orange crystals, m.p. 224–226 C; (found: C, 48.36; H, 3.52; N, 9.86;
S, 15.12. C17H15N3O6S2 (421.46) requires: C, 48.44; H, 3.58; N, 9.97;
S, 15.21%); max/cm 1: 1720, 1710, 1700, 1685, (4 CO), 1620 (C N);
H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.85 (t, 2H, H-6), 3.65 (t, 2H,
H-7), 3.88 (s, 3H, OCH3), 4.10 (q, 2H, COOCH2CH3), 4.65 (s, 2H, H-9),
7.10 (s, 1H, C CH).
Ethyl 2-Benzylidene-3,5-dioxo-2,3,6,9-tetrahydro-
5H-pyrido[40,30:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-
pyrimidine-8(7H)-carboxylate (12)
A mixture of 3 (3.1 g, 0.01 mmol), chloroacetic acid (0.94 g, 0.01 mmol),
benzaldehyde (1.1 g, 0.01 mmol), anhydrous sodium acetate (0.82 g,
0.01 mmol), acetic anhydride (6 ml), and acetic acid (8 ml) was refluxed
for 5 h. The mixture was poured into ice-water. The precipitate was
separated and dissolved in dichloromethane. The organic layer was
washed using 6% sodium bicarbonate solution, then was evaporated
under reduced pressure. The crude product was recrystallized from
ethanol. Yield 3.3 g (75.5%) of compound 12 as yellow crystals, m.p.

12
E. Kh. Ahmed
248–250 C; (found: C, 57.29; H, 3.81; N, 9.45; S, 14.48. C21H17N3O4S2
1
(439.51) requires: C, 57.38; H, 3.89; N, 9.56; S, 14.59%); max/cm
:
3060–3000 (Ar-CH), 1720, 170, 1685 (3 CO), 1620 (C N), (DMSO-
H
d6): 1.20 (t, 3H, COOCH2CH3), 2.90 (t, 2H, H-6), 3.65 (t, 2H, H-7), 4.20
(q, 2H, COOCH2CH3), 4.65 (s, 2H, H-9), 7.1–7.5 (m, 5H, Ar-H), 8.15 (s,
1H, C H). c (DMSO-d6): 14.10 (q, COOCH2CH3), 25.72 (t, C-6), 40.16
(t, C-7), 42.22 (t, C-9), 61.63 (t, COOCH2CH3), 115.60 (s, C-5a), 117.48
(s, C-2), 127.13 (s, C-5b), 128.30 (Ph, C-4), 128.83 (Ph C-2,6), 128.88
(Ph C-3,5), 131.22 (Ph C-1), 132.80 (s, C-9a), 140.27 (s, C Ph), 152.93
(s, C-10a), 160.72 (s, C-5), 161.62 (s, C-11a), 164.64 (s, CO ester), 165.49
(s, CO thiazole).
Ethyl 2-[(2-Oxopropyl)sulfanyl]-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-
7(4H)-carboxylate (13)
A mixture of compound 3 (0.31 g, 0.001 mmol), chloroacetone (0.11 g,
0.0012 mmol) and potassium carbonate (0.14 g, 0.001 mmol) in anhy-
drous acetone (10 ml) was gently warmed under stirring for 2 h. The
mixture was then poured into water (50 ml) and the resulting solid was
collected by filtration, dried, and crystallized from ethanol/water. Yield
0.26 g (71.2%) of compound 13 as colorless crystals, m.p. 158–160 C;
(found: C, 49.12; H, 4.75; N, 11.52; S, 17.56. C15H17N3O4S2 (367.45) re-
quires: C, 49.03; H, 4.66; N, 11.43; S, 17.45%); max/cm 1: 3180 (NH),
2900 (aliph. CH), 1720, 1690, 1680 (3 CO);
(DMSO-d6): 1.20 (t, 3H,
H
COOCH2CH3), 2.25 (s, 3H, CH3), 2.90 (t, 2H, H-5), 3.60 (t, 2H, H-6),
3.85 (s, 2H, SCH2), 4.10 (q, 2H, COOCH2CH3), 4.50 (s, 2H, H-8), 12.25
(s, 1H, NH).
Ethyl 2-[(2-Phenyl-2-oxoethyl)sulfanyl]-4-oxo-3,5,6,8-
tetrahydropyrido[40,30:4,5]thieno[2,3-d]pyrimidine-7(4H)-
carboxylate (14)
To a stirred suspension of compound 3 (0.31 g, 0.001 mmol) and potas-
sium carbonate (0.14 g, 0.001 mmol) in anhydrous acetone (15 ml) a
saturated phenacylbromide solution (0.2 g, 0.001 mmol) was slowly
added for 2 h. The mixture was then stirred for an additional 20 h
and the solid was collected by filtration, washed with water, dried,
and recrystallized from acetic acid. Yield 0.29 g (67.9%) of compound
14 as colorless crystals, m.p. 216–218 C; (found: C, 55.85; H, 4.38;
N, 9.67; S, 14.82. C20H19N3O4S2 (429.52 ) requires: C, 55.92; H, 4.45;
N, 9.78; S, 14.93%); max/cm 1: 3160 (NH), 3018–3000 (Ar-CH), 1720,
1695, 1685 (3 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.85
H

Fused Heterocycles
13
(t, 2H, H-5), 3.65 (t, 2H, H-6), 4.10 (q, 2H, COOCH2CH3), 4.60 (s, 2H,
H-8), 4.85 (s, 2H, SCH2), 7.40–7.80 (m, 3H, Ar-H), 7.90–8.10 (m, 2H,
Ar-H), 12.70 (br s, 1H, NH).
Ethyl 3-Methyl-5-oxo-6,9-dihydro-5 H-pyrido[40,30:4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-
carboxylate (15)
A suspension of compound 13 (0.36 g, 0.001 mmol) in 98% sulphuric acid
(3 ml) was stirred for 1 h, then left at room temperature for 2 days. The
clear solution was then poured into water (100 ml) and the resulting
solid was collected, dried, and recrystallized from ethanol/water. Yield
0.22 g, (64.7%) of compound 15 as yellow crystals, m.p. 168–170 C;
(found: C, 51.42; H, 4.27; N, 12.12; S, 18.26. C15H15N3O3S2 (349.44) re-
quires: C, 51.55; H, 4.32; N, 12.02; S, 18.35%); max/cm 1: 2980 (aliph.
CH), 1720, 1680 (2 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3),
H
2.65 (s, 3H, CH3), 2.80 (t, 2H, H-6), 3.65 (t, 2H, H-7), 4.10 (q, 2H,
COOCH2CH3), 4.60 (s, 2H, H-9), 6.90 (s, 1H, H-2).
Ethyl 3-Phenyl-5-oxo-6,9-dihydro-5 H-pyrido[40,30:4,5]-
thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidine-8(7H)-
carboxylate (16)
A suspension of compound 14 (0.52 g, 0.0012 mmol) in 98% sulphuric
acid (4 ml) was stirred for 1 h, then left at room temperature for 3 days.
The clear solution was then poured into water (50 ml) and the result-
ing solid was collected, dried, and recystallized from DMF/water. Yield
0.29 g (58.2%) of compound 16 as colorless crystals, m.p. 198–200 C;
(found: C, 58.49; H, 4.21; N, 10.29; S, 15.69. C20H17N3O3S2 (411.50) re-
quires: C, 58.37; H, 4.16; N, 10.21; S, 15.58%); max/cm 1: 3055–3006
(Ar-CH), 1720, 1680 (2 CO);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3),
H
2.90 (t, 2H, H-6), 3.60 (t, 2H, H-7), 4.10 (q, 2H, COOCH2CH3), 4.65 (s,
2H, H-9), 6.80 (s, 1H, H-2), 7.30–7.50 (m, 3H, Ar-H), 7.60–7.75 (m, 2H,
Ar-H).
Ethyl 3-(2-Ethoxy-2-oxoethyl)-2-methylsulfanyl)-4-
oxo-3,4,5,6,7,8-hexahydropyrido[40,30:4,5]thieno-
[2,3-d]pyrimidine-7-carboxylate (17)
A mixture of 1 (0.72 g, 0.0024 mmol), N-(bis-(methylthio)-methylene)-
glycine ethyl ester (0.51 g, 0.0024 mmol) in dry acetic acid (5 ml) was
heated at 60–70 C for 5 h under nitrogen. On cooling, the separated
solid product was filtered, washed with ethanol, dried, and recrystal-
lized from ethanol. Yield 0.62 g (62.6%) of compound 17 as colorless

14
E. Kh. Ahmed
crystals, m.p. 133–134 C; (found: C, 49.75; H, 5.19; N, 10.08; S, 15. 64.
C17H21N3O5S2 (411.51) requires: C, 49.61; H, 5.14; N, 10.21; S, 15.58%);
1
max/cm : 2985 (aliph. CH), 1720, 1700, 1680 (3 CO); 1620 (C N);
(DMSO-d6): 1.2 (t, 3H, CO2CH2CH3), 1.25 (t, 3H, CO2CH2CH3),
H
2.60 (s, 3H, SCH3), 2.90 (t, 2H, H-5), 3.70 (t, 2H, H-6), 4.20 (q, 2H,
CO2CH2CH3, 4.35 (q, 2H, CO2CH2CH3), 4.60 (s, 2H, H-8), 4.85 (s, 2H,
CH2CO2Et); c (DMSO-d6): 13.7 (q, SCH3), 13.9 (q, CO2CH2CH3), 14.3
(q, CO2CH2CH3), 24.9 (t, C-5), 40.2 (t, C-6), 42.6 (t, C-8), 44.3 (t, NCH2),
60.9 (t, CO2CH2CH3), 61.3 (t, CO2CH2CH3), 116.7 (s, C-4a), 127.5 (s,
C-4b), 129.0 (s, C-8a), 154.5 (s, C-2), 156.0 ( s, C-9a), 158.0 (s, C-4), 162.0
(s, CO), 166.6 ( s, CO); ms: m/z 411 (M+).
Ethyl 1,3,4,7,8,9-Hexahydro-5-oxo-5 H,10H-
pyrido[40,30:4,5]thieno[2,3-d]pyrrolo[1,2-a]pyrimidine-
2-carboxylate (18a)
To a mixture of 1 (0.3 g, 0.001 mmol) and 2-pyrrolidone (0.094 g,
0.0011 mmol) in 1,2-dichloromethane (5 ml) was added 5 drops of phos-
phorous oxychloride and refluxed for 1 h. After evaporation of the
solvent under reduced pressure, the residue was dissolved in water,
alkalinized with dilute potassium hydroxide solution, and extracted
with chloroform. The extract was evaporated and the residue was crys-
tallized from ethanol. Yield 0.22 g (68.7%) of compound 18a as pale
yellow crystals, m.p. 129–130 C; (found: C, 56.49; H, 5.43; N, 13.23; S,
10.13. C15H17N3O3S (319.38) requires: C, 56.41; H, 5.36; N, 13.15; S,
10.03%); max/cm 1: 2990 (aliph. CH), 1720, 1685 (2 CO), 1630 (C N);
H (DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 2.25 (m, 2H, H-8), 2.85 (t, 2H,
H-4), 3.15 (t, 2H, H-9), 3.65 (t, 2H, H-3), 4.02 (t, 2H, H-7), 4.10 (q, 2H,
COOCH2CH3), 4.65 (s, 2H, H-1). c (DMSO-d6): 14.20 (q, COOCH2CH3),
18.86 (t, C-8), 25.55 (t, C-4), 31.42 (t, C-9), 40.22 (t, C-3), 42.51 (t, C-
1), 45.96 (t, C-7), 60.83 (t, COOCH2CH3), 118.92 (s, C-4b), 127.22 (s,
C-11a), 128.74 (s, C-4a), 154.54 (s, C-5), 156.55 (s, C-10a), 160.75 (s,
C-9a), 163.65 (s, CO ester).
Ethyl 3,4,7,8,9,10-Octahydro-5-oxo-1 H,5H-pyrido-
[40,30:4,5]thieno[2,3-d]pyrido[1,2-a]pyrimidine-
2-carboxylate (18b)
Molar portions of amino ester 1 and valerolactam were treated as de-
scribed for the preparation of 18a. The yield of the crystallized com-
pound was 62.6%, m.p. 194–195 C; yellow crystals; (found: C, 57.56;
H, 5.68; N, 12.51; S, 9.53. C16H19N3O3S (333.41) requires: C, 57.64;
H, 5.74; N, 12.60; S, 9.61%);
(DMSO-d6): 1.09 (t, 2H, H-10), 1.20
H

Fused Heterocycles
15
(t, 3H, COOCH2CH3), 1.95–2.10 (m, 4H, H-8, H-9), 2.85 (t, 2H, H-4), 3.65
(t, 2H, H-3), 3.95 (t, 2H, H-7), 4.20 (q, 2H, COOCH2CH3), 4.65 (s,
2H, H-1). (DMSO-d6): 14.15 (q, COOCH2CH3), 18.43 (t, C-9), 21.32
c
(t, C-8), 25.53 (t, C-4), 31.33 (t, C-10), 40.50 (t, C-3), 42.40 (t, C-1), 44.55
(t, C-7), 60.95 (t, COOCH2CH3), 119.42 (s, C-4b), 127.15 (s, C-4a), 130.13
(s, C-12a), 156.03 (s, C-11a), 157.66 (s, C-10a), 160.65 (s, C-5), 164.55
(s, CO).
Ethyl 1,3,4,7,8,9,10,11-Octahydro-5-oxo-5 H-pyrido-
[40,30:4,5]thieno[2,3-d]azepino[1,2-a]pyrimidine-
2-carboxylate (18c)
Upon treatment of amino ester 1 with caprolactam as described for the
preparation of 18a, 57.3% yield of recrystallized 18c was obtained; m.p.
260–262 C, yellow crystals; (found: C, 58.69; H, 5.99; N, 12.21; S, 9.34.
C17H21N3O3S (347.44) requires: C, 58.76; H, 6.09; N, 12.09; S, 9.22%);
(DMSO-d6): 1.20 (t, 3H, COOCH2CH3), 1.55–1.88 (m, 6H, H-8,
H
H-9, H-10), 2.85 (t, 2H, H-4), 3.10 (t, 2H, H-11), 3.65 (t, 2H, H-3), 4.20
(q, 2H, COOH2CH3), 4.36 (t, 2H, H-7), 4.65 (s, 2H, H-1).
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E. Kh. Ahmed
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