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

Article abstract of DOI:10.1002/hc.10131

The synthesis of 3-substituted pyrido [4′,3′:4,5]-thieno [2,3-d] pyrimidines and related fused thiazolo derivative was discussed. The absorption band due to NH, ester CO and pyrimidine ring CO was elaborated. The reaction of diethyl 2-isothiocyanato-4,5,6,7-tetrahydrothienol[2,3-c] pyridine-3,6-dicarboxylate with amino acids glycine, L-alanine and β-alanine in a mixture of dioxane and water under mild conditions was investigated for the synthesis of pyridothienopyrimidine derivatives.

Full text of DOI:10.1002/hc.10131

Heteroatom Chemistry
Volume 14, Number 3, 2003
ꢀ ꢀ
ynthesis of 3-Substituted Pyrido[4 ,3 :4,5]-
S
thieno[2,3-d]pyrimidines and Related Fused
Thiazolo Derivatives
Essam Kh. Ahmed
Chemistry Department, Faculty of Science, El-Minia University, El-Minia, A.R. Egypt
Received 10 April 2002; revised 4 June 2002
focused on investigating efficient and convenient
ABSTRACT: Convenient syntheses of 3-substituted
routes to construct the titled novel ring systems. In
ethyl 4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido-
continuation of our interest in the synthesis of phar-
macologically interesting new heterocyclic systems
containing the thienopyrimidine moiety [10–16],
we now succeeded in the synthesis of new de-
ꢀ
ꢀ
[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-
ꢀ
ꢀ
5
H-pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]-
pyrimidine-8(7H)-carboxylate (4), and ethyl 2-methyl-
ꢀ
ꢀ
rivatives of pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine
ꢀ
ꢀ
5
-oxo-2,3,6,9-tetrahydro-5H-pyrido[4 ,3:4,5]thieno-
ꢀ
ꢀ
and pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo[3,2-
a]pyrimidine with expected potential biological
activity.
[2, 3-d][1,3]thiazolo[3,2-a]pyrimidine-8[7 H]carboxy-
late (8) from diethyl 2-isothiocyanato-4,5,6,7-tetrahy-
drothieno[2,3-c]pyridine-3,6-dicarboxylate (1) are re-
ported. ꢁC 2003 Wiley Periodicals, Inc. Heteroatom Chem
1
4:201–207, 2003; Published online in Wiley InterScience
RESULTS AND DISCUSSION
(
www.interscience.wiley.com). DOI 10.1002/hc.10131
In the syntheses presented in this paper, the con-
veniently available diethyl 2-isothiocyanato-4,5,6,7-
tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate
INTRODUCTION
(1) [11] was employed as the starting material.
Compounds containing a fused pyrimidine ring
have received considerable attention over the past
years because of their wide range of biological
activity. As an example, pyridothienopyrimidines
have long been used for their antiinflammatory
Reaction of compound 1 with aminoalcohols under
mild conditions provided the thioureido deriva-
tives 2a,b. Compound 2b could be cyclized to
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]pyrimidi-
[1–3], antipyretic [4,5], analgesic [6], and antiana-
ne-8(7H)-carboxylate (4) in good yield by heating
phylactic [7,8] activity. On the other hand, thiazoles
represent a very intersting class of compounds be-
cause of their wide applications in pharmaceutical,
phytosanitary, analytical, and industrial aspects,
e.g. as fungicides, anthelmintics, and herbicides
in methanolic hydrogen chloride to reflux. No in-
termediate pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine
ꢀ
ꢀ
derivative was isolated. In a separate reaction,
ꢀ
ꢀ
pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine derivatives
a,b were synthesized by heating 2a,b in ethanolic
potassium hydroxide solution. Structures 4 and
a,b were confirmed by the results of elemental
3
[9]. Because of these findings, our interest was
3
analysis and spectroscopic data (Scheme 1).
For the synthesis of ethyl 2-methyl-5-oxo-2,3,6,
9-tetrahydro-5H-pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]-
Correspondence to: Essam Kh. Ahmed; e-mail: essamkhalaf24@
yahoo.com.
c 2003 Wiley Periodicals, Inc.
ꢀ
ꢀ
ꢁ
2
01

2
02 Ahmed
spectrum showed signals assignable to the allyl
substituent and to pyrimidine NH (Experimental
section). Treatment of 6 with methyl iodide under
basic conditions afforded the S-methylated com-
pound 7 in excellent yield. The target product 8
was prepared in 68% yield by ring closure of 6 in a
mixture of hydrochloric and acetic acid. Compound
8
was alternatively obtained from 1 by initial con-
version to ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-
ꢀ
ꢀ
hexahydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-
( 2H)-carboxylate (9) [16], followed by deamination
with nitrous acid to yield ethyl 4-oxo-2-thioxo-
7
ꢀ
ꢀ
1
,2,3,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-
d]pyrimidine-7-carboxylate (10) and the subsequent
reaction with 1,2-dibromopropane (Scheme 2).
For the synthesis of more pyridothienopyrimi-
dine derivatives, we investigated the reaction of 1
SCHEME 1
thiazolo[3,2-a]pyrimidine-8(7H)-carboxylate
(8),
with amino acids glycine, -alanine, and ꢀ-alanine
L
compound 1 was reacted with allylamine to give
ethyl 2-{[(2-propenyl)aminothioxomethyl]amino}-
in a mixture of dioxane and water (pH 8–9) under
mild conditions, which gave ethyl 3-carboxymethyl,
3-[(S)-1-carboxyethyl], and 3-(2-carboxyethyl-4-oxo-
4
,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarbo-
ꢀ
ꢀ
xylate (5), which could be cyclized to ethyl 3-(2-
2-thioxo-1,2,3,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]-
thieno[2,3-d]pyrimidine-7-carboxylate 11,12,13, re-
spectively. The structures of 11–13 were estab-
lished on the basis of their elemental and spectral
data.
propenyl)-4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydro-
ꢀ
ꢀ
pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-carboxy-
late (6) by heating to reflux in potassium hydroxide
solution. The structure of 6 was substantiated by
elemental analysis and spectroscopic data. The IR
spectrum showed absorption bands due to NH,
ꢀ
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-
ꢀ
1
ester CO, and pyrimidine ring CO. The H NMR
8(7H)-carboxylate (14) could be obtained either by
SCHEME 2

ꢀ
ꢀ
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines and Related Fused Thiazolo Derivatives 203
1
(
(
21.3 (s, C-7a), 130.0 (s, C-3a), 154.8 (s, CO), 165.7
s, CO), 175.1 (s, C-2), 177.4 (s, CS). C16
401.51) calcd.: C, 47.86; H, 5.77; N, 10.46; S, 15.97.
H
23
N
3
O
5
S
2
Found: C, 47.65; H, 5.83; N, 10.59; S, 15.87.
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 1 (0.34 g, 0.001
mol) and 2-aminopropanol (0.08 g, 0.0011 mol) in
dichloromethane (5 ml) and stirred at room tem-
perature for 30 min. After evaporation of the sol-
vent at reduced pressure the solid product was col-
lected and crystallized from ethanol. Yield: 0.37 g,
◦
(
89%) 2b as pale yellow crystals, m.p. 166–168 C.
SCHEME 3
IR: ꢁ = 3500 (OH), 3220 (NH), 2980 (aliph. CH),
710, 1690 (2CO), 1620 cm . H NMR (DMSO-d ):
CH ), 1.20 (t, 3H, CH CH ), 1.35
), 2.80 (t, 2H, H-4), 3.40–3.55 (m, 2H,
−
1
1
1
6
δ = 1.10 (d, 3H, CH
3
2
3
thermal fusion of compound 11 or by reaction of
compound 10 with chloroacetyl chloride in DMF
(
t, 3H, CH
CH OH), 3.65 (t, 2H, H-5), 4.10 (q, 2H, CH
.20–4.35 (m, 3H, CH CH , NHCH(CH OH)CH
.40 (s, 2H, H-7), 4.70–4.85 (t, 1H, CH
.50 (br s, 1H, NH), 11.40 (s, 1H, NH). C NMR
): δ = 14.1 (q, CH CH ), 14.4 (q, CH CH ),
6.2 (q, CH ), 25.8 (t, C-4), 40.7 (t, C-5), 42.1 (t, C-
), 51.9 (d, CH), 60.2 (t, CH CH ), 60.9 (t, CH CH ),
3.3 (t, CH OH), 109.9 (s, C-3), 121.3 (s, C-7a), 128.3
2
CH
3
CH
3
),
),
(Scheme 3).
2
2
4
4
9
2
3
2
3
2
OH), 9.40–
EXPERIMENTAL
13
(
DMSO-d
6
2
3
2
3
Melting points were recorded on a GallenKamp ap-
paratus and are uncorrected. Microanalyses were
performed at the microanalytical Data Unit, Cairo
University. C and H NMR spectra were recorded
on a Bruker AC 300 ( H: 300.13 MHz, C: 75.5 MHz;
solvent: DMSO-d and CDCl , respectively). Chemi-
1
7
6
(
1
3
2
3
2
3
1
3
1
2
1
13
s, C-3a), 154.5 (s, CO), 165.3 (s, CO), 176.5 (s, C-2),
79.3 (s, CS), C17 (415.54) calcd.: C, 49.13;
H
25
N
3
O
5
S
2
6
3
H, 6.06; N, 10.11; S, 15.43. Found: C, 49.32; H, 6.18;
N, 10.30; S, 15.29.
cal shifts δ are given relative to the internal standard
TMS. IR spectra were recorded on a Shimadzu 470
spectrophotometer in KBr pellets.
Ethyl 3-(2-hydroxyethyl)-4-oxo-2-thioxo-1,2,3,4,
5,6,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
pyrimidine-7-carboxylate (3a)
ꢀ
ꢀ
Diethyl 2-({[(2-hydroxyethyl)amino]carbothioyl}-
amino)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
3,6-dicarboxylate (2a)
Compound 2a (0.4 g, 0.001 mol) was added to a so-
lution of potassium hydroxide (0.06 g, 0.0011 mol)
in absolute ethanol (10 ml), and the mixture was re-
fluxed with stirring for 15 min. The potassium salt
of compound 3a was collected by filtration and then
dissolved in water and neutralized (to pH 4) with
hydrochloric acid. The product was collected by fil-
tration, washed with water, dried, and recrystallized
from ethanol. Yield: 0.27 g (77%) 3a as colorless crys-
To a stirred solution of 1 (0.34 g, 0.001 mol) in
dichloromethane (8 ml), 2-aminoethanol (0.07 g,
0.0011 mol) was added and stirred at room temper-
ature for 20 min. After evaporation of the solvent
at reduced pressure, the solid product was collected
and crystallized from ethanol. Yield: 0.28 g (70%)
◦
2
3
a as colorless crystals, m.p. 158–160 C. IR: ꢁ =
500 (OH), 3200 (NH), 2990 (aliph. CH), 1720, 1690
−1
1
◦
(2CO, 1620 cm . H NMR (DMSO-d
6
): δ = 1.20 (t,
), 2.80 (t, 2H, H-
), 3.60 (t, 2H, H-5), 3.70 (q, 2H, NCH ), 3.90 (t,
H, CH OH), 4.10 (q, 2H, CH CH ), 4.50 (s, 2H,
OH), 9.60 (s, 1H, NH),
1.40 (br s, 1H, NH). C NMR (DMSO-d
): δ = 14.1
q, CH CH ), 14.4 (q, CH CH ), 25.9 (t, C-4), 41.0 (t,
C-5), 42.6 (t, C-7), 46.9 (t, NHCH ), 58.6 (t, CH OH),
0.3 (t, CH CH ), 60.9 (t, CH CH ), 110.0 (s, C-3),
tals, m.p. 177–179 C. IR: ꢁ = 3550 (OH), 3180 (NH),
3
4
2
H, CH
2
CH
3
), 1.30 (t, 3H, CH
2
CH
3
2850 (aliph. CH), 1720 (CO ester), 1680 (CO pyrimi-
−
1 1
2
dine ring), 1620 cm . H NMR (DMSO-d
(t, 3H, CH CH ), 2.90 (t, 2H, H-5), 3.60–3.80 (m, 4H,
H-6, NCH CH OH), 4.10 (q, 2H, CH CH ), 4.40 (s,
2H, H-8), 4.65 (t, 2H, NCH CH OH), 4.70 (t, 1H,
CH OH), 11.85 (br, 1H, NH). C NMR (DMSO-
): δ = 14.5 (q, CH CH ), 25.3 (t, C-5), 40.2 (t, C-6),
42.6 (t, C-8), 46.7 (t, NCH ), 58.4 (t, CH OH), 60.8
6
): δ = 1.20
2
2
3
2
3
H-7), 4.80–4.90 (t, 1H, CH
1
(
2
2
2
2
3
1
3
6
2
2
1
3
2
3
2
3
2
2
2
d
6
2
3
6
2
3
2
3
2
2

2
04 Ahmed
(
(
1
t, CH
s, C-8a), 152.7 (s, C-9a), 154.7 (s, C-4), 164.7 (s, CO),
75.8 (s, C-2). C14 (355.44) calcd.: C, 47.31;
2
CH
3
), 113.6 (s, C-4a), 120.3 (s, C-4b), 128.7
Ethyl 2-{[(2-propenyl)-aminothioxomethyl]-
amino}-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-
3,6-dicarboxylate (5)
H
17
N
3
O
4
S
2
H, 4.81; N, 11.82; S, 18.04. Found: C, 47.18; H, 4.89;
N, 11.60; S, 18.26.
A
solution of
1
(0.34 g, 0.001 mol) in
dichloromethane (10 ml) was added under stir-
ring to a solution of an equimolar amount of
allylamine (0.06 g, 0.001 mol) in dichloromethane
(10 ml), and the mixture was stirred at room tem-
perature for 1 h. The solvent was removed under
reduced pressure and the solid product collected by
filtration, washed with dichloromethane, dried, and
recrystallized from ethanol. Yield: 0.36 g (91%) 5 as
Ethyl 3-(2-hydroxy-1-methylethyl)-4-oxo-2-thioxo-
ꢀ
ꢀ
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 mol) was added to a so-
lution of potassium hydroxide (0.06 g, 0.0011 mol)
in absolute ethanol (10 ml), and the mixture was re-
fluxed under stirring for 1 h. The potassium salt of
compound 3b was collected by filtration and then
dissolved in water and neutralized (to pH 4) with
hydrochloric acid. The product was collected by fil-
tration, washed with water, dried, and recrystallized
from ethanol. Yield: 0.25 g (69%) 3b as colorless crys-
◦
pale yellow crystals, m.p. 148–150 C. IR: ꢁ = 3190
(
NH), 2982 (aliph. CH), 1720 (CO), 1690 (CO),
−
1
1
1
610 cm . H NMR (DMSO-d
CH ), 1.35 (t, 3H, CH CH ), 2.80 (t, 2H, H-4),
.65 (t, 2H, H-5), 3.85 (d, 2H, CH CH CH ), 4.20
q, 2H, CH CH ), 4.55 (s, 2H, H-7), 4.95–5.40 (m,
CH CH ), 5.70–5.90 (m, 1H, CH CH ),
.55–6.65 (br, 1H, NH), 11.90 (s, 1H, NH). C NMR
): δ = 14.2 (q, CH CH ), 14.6 (q, CH CH ),
6.3 (t, C-4), 41.1 (t, C-5), 42.5 (t, C-7), 46.7 (t,
), 60.8 (t, CH CH ), 61.6 (t, CH CH ), 111.2
s, C-3), 115.9 (t, CH CH ), 122.20 (s, C-7a), 131.8
s, C-3a), 134.0 (d, CH CH ), 153.6 (s, CO), 166.5
s, CO), 170.0 (s, C-2), 177.7 (s, CS). C17
397.52) calcd.: C, 51.36; H, 5.83; N, 10.57; S, 16.13.
6
): δ = 1.20 (t, 3H,
CH
3
(
2
6
(
2
2
3
2
3
2
2
2
3
H, CH
2
2
2
◦
1
tals, m.p. 188–190 C. H NMR (DMSO-d
t, 3H, CH CH ), 1.40 (d, 3H, CH CH ), 2.90 (t, 2H,
H-5), 3.55 (t, 2H, H-6), 3.80–3.95 (m, 2H, CH OH),
.10–4.20 (m, 6H, CH CH , CH(CH )CH OH), 4.55
s, 2H, H-8), 4.80–4.90 (br, 1H, CH OH), 11.80 (s,
): δ = 14.6 (q, CH CH ),
), 25.5 (t, C-5), 40.7 (t, C-6), 42.7 (t, C-
), 61.8 (t, CH CH ), 64.4 (d, CH), 68.9 (t, CH OH),
16.6 (s, C-4a), 121.4 (s, C-4b), 128.7 (s, C-8a), 151.6
6
): δ = 1.20
1
3
(
2
3
3
DMSO-d
6
2
3
2
3
2
4
(
1
1
8
1
2
3
3
2
NHCH
2
2
3
2
3
2
(
(
(
(
2
1
3
H, NH). C NMR (DMSO-d
6
2
3
2
8.7 (q, CH
3
H
23
N
3
O
4
S
2
2
3
2
Found: C, 51.18; H, 5.92; N, 10.41; S, 15.95.
(s, C-9a), 155.7 (s, C-4), 165.6 (s, CO), 174.8 (s, C-2).
C
15
H
19
N
3
O
4
S
2
(369.47) calcd.: C, 48.76; H, 5.18; N,
1
1
1.37; S, 17.35. Found: C, 48.89; H, 5.10; N, 11.50; S,
7.22.
Ethyl 3-(2-propenyl)-4-oxo-2-thioxo-1,2,3,4,5,
ꢀ ꢀ
,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
6
pyrimidine-7-carboxylate (6)
Ethyl 3-methyl-5-oxo-2,3,6,9-tetrahydro-5H-
Compound 5 (0.4 g, 0.001 mol) was added to a so-
lution of potassium hydroxide (0.07 g, 0.0012 mol)
in absolute ethanol (10 ml), and the mixture was
refluxed under stirring for 10 min. The potassium
salt of compound 6 was collected by filtration and
then dissolved in water and neutralized (to pH 4)
with hydrochloric acid. The product was collected
by filtration, washed with water dried, and recrys-
tallized from ethanol. Yield: 0.3 g (86%) 6 as pale
ꢀ
ꢀ
pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]-thiazolo-
3,2-a]pyrimidine-8(7H)-carboxylate (4)
[
Compound 2b (0.4 g, 0.001 mol) was dissolved in
0 ml of methanolic hydrogen chloride and stirred
1
at reflux temperature for 10 h. After evaporation
of the solvent under reduced pressure the yellow
residue was dissolved in 10 ml of water and neutral-
ized to pH 7.5 with aqueous ammonia and extracted
with chloroform. The organic layer was dried (mag-
nesium sulfate) and evaporated to yield the solid,
◦
yellow crystals, m.p. 178–180 C. IR: ꢁ = 3150 (NH),
2990 (aliph. CH), 1710 (CO ester), 1680 (CO pyrim-
−
1
1
which was recrystallized from ethanol. Yield: 0.21 g
idine ring), 1620 cm . H NMR (DMSO-d
1.20 (t, 3H, CH CH ), 2.85 (t, 2H, H-5), 3.65 (t,
2H, H-6), 4.10 (q, 2H, CH CH ), 4.55 (s, 2H, H-8),
4.90–5.12 (m, 2H, CH CH CH ), 5.15–5.30 (m,
2H, CH CH CH ), 5.80–6.10 (m, 1H, CH CH ),
13.70 (s, 1H, NH). C NMR (DMSO-d
): δ = 14.4 (q,
CH CH ), 24.9 (t, C-5), 40.2 (t, C-6), 42.4 (t, C-8),
47.1 (t, NCH ), 61.0 (t, CH CH ), 114.9 (t, CH CH ),
116.9 (s, C-4a), 124.5 (s, C-4b), 129.6 (s, C-8a), 134.5
(d, CH CH ), 149.5 (s, C-9a), 154.6 (s, C-4), 160.0
6
): δ =
◦
(
2
62%) 4 as yellow crystals, m.p. 136–138 C. IR: ꢁ =
2
3
955 (aliph. CH), 1720 (CO ester), 1680 (CO pyrimi-
2
3
−1 1
dine ring), 1590 cm . H NMR (DMSO-d
t, 3H, CH CH ), 1.45 (d, 3H, CH CH ), 2.90 (t, 2H,
H-6), 3.20–3.30 (d, 2H, H-2), 3.65 (t, 2H, H-7), 4.15
q, 2H, CH CH ), 4.60 (s, 2H, H-9), 5.10–5.20 (m, 1H,
H-3). C15 (351.45) calcd.: C, 51.26; H, 4.87;
6
): δ = 1.20
2
2
(
2
3
3
2
2
2
1
3
6
(
2
3
2
3
H
17
N
3
O
3
S
2
2
2
3
2
N, 11.95; S, 18.24. Found: C, 51.10; H, 4.79; N, 11.80;
S, 18.36.
2

ꢀ
ꢀ
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines and Related Fused Thiazolo Derivatives 205
(s, CO), 173.5 (s, C-2). C15
H
17
N
3
O
3
S
2
(351.45) calcd.:
containing 10 (0.31 g, 0.001 mol), water (5 ml), and
C, 51.26; H, 4.87; N, 11.95; S, 18.24. Found: C, 51.39;
H, 4.95; N, 12.11; S, 18.38.
sodium hydroxide (0.05 g). The mixture was heated
to 90 C for 1 h and then stirred at room tempera-
◦
ture for an additional hour. The reaction mixture was
poured into cold water; the precipitated product was
collected by filtration, dried, and recrystallized from
Ethyl 3-(2-propenyl)-2-(methylsulfanyl)-4-oxo-
ꢀ
ꢀ
3
,4,5,6,7,8-hexahydropyrido[4 ,3 :4,5]thieno-
2,3-d]pyrimidine-7-carboxylate (7)
1
5% aqueous ethanol. Yield: 0.24 g (69%) 8 as yellow
[
◦
crystals, m.p. 139–140 C. The product is identical to
A solution of 6 (0.35 g, 0.001 mol) in 1 M aqueous
sodium hydroxide (1.5 ml) was treated with methyl
iodide (0.16 g, 0.0011 mol) and the mixture was
stirred at room temperature. Compound 7 started
to crystallize almost immediately. After 30 min, it
was filtered, washed with water, dried, and recrys-
tallized from ethanol. Yield: 0.32 g (89%) 7 as col-
that obtained according to Method A.
Ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-hexa-
ꢀ
ꢀ
hydropyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-
(2H)-carboxylate (9)
7
A solution of 1 (0.6 g, 0.0017 mol) in benzene (10
ml) was added dropwise at room temperature to a
stirred solution of hydrazine hydrate (0.6 g, 0.0018
mol) in benzene (5 ml). The suspension was refluxed
under stirring for 8 h. After cooling, the solid prod-
uct was collected by filtration, washed with ethanol,
dried, and recrystallized from dioxane. Yield: 0.57 g
◦
orless crystals, m.p. 130–132 C. IR: ꢁ = 2990 (aliph.
CH), 1710 (CO ester), 1680 (CO pyrimidine ring),
−
1
1
1
600 cm . H NMR (DMSO-d
CH CH ), 2.65 (s, 3H, SCH ), 2.80 (t, 2H, H-5), 3.60
t, 2H, H-6), 4.20 (q, 2H, CH CH ), 4.60 (s, 2H, H-
CH CH ), 5.25–5.55 (m,
), 5.80–6.10 (m, 1H, CH CH ).
): δ = 14.4 (q, CH CH ), 15.7 (q,
), 25.1 (t, C-5), 40.2 (t, C-6), 42.6 (t, C-8), 45.2 (t,
), 61.0 (t, CH CH ), 114.3 (t, CH CH ), 116.8
s, C-4a), 127.0 (s, C-4b), 129.1 (s, C-8a), 134.3 (d,
CH CH ), 151.2 (s, C-9a), 154.6 (s, C-4), 158.1 (s,
C-2), 161.9 (s, CO). C16 (365.48) calcd.: C,
2.58; H, 5.23; N, 11.49; S, 17.54. Found: C, 52.47; H,
.18; N, 11.40; S, 17.41.
6
): δ = 1.20 (t, 3H,
2
3
3
(
8
2
3
), 4.80–5.10 (d, 2H, CH
H, CH CH CH
C NMR (DMSO-d
2
2
◦
2
2
2
2
(91%) 9 as yellow crystals, m.p. 232–234 C (dec). IR:
1
3
6
2
3
ꢁ = 3400, 3320, 3180 (NH
1680 (CO pyrimidine ring), 1200 (C S). H NMR
(DMSO-d CH ), 2.90
): δ = 1.20 (t, J = 7 Hz, 3H, CH
(t, J = 5.6 Hz, 2H, H-5), 3.60 (t, J = 5.6 Hz, 2H, H-
6), 4.20 (q, J = 7 Hz, 2H, CH CH ), 4.50 (s, 2H, H-
8), 6.30–6.50 (br, 2H, NH ), 13.40 (s, 1H, NH).
NMR (DMSO-d CH ), 25.3 (t, C-
): δ = 14.6 (q, CH
5), 40.7 (t, C-6), 46.8 (t, C-8), 61.0 (t, CH CH ), 113.3
s, C-4a), 128.3 (s, C-4b), 141.0 (s, C-8a), 154.8 (s,
C-4), 157.6 (s, C-9a), 161.6 (s, CO), 168.8 (s, C-2).
(326.40) calcd.: C, 44.15; H, 4.32; N,
2
, NH), 1720 (CO ester),
1
SCH
NCH
(
3
2
2
3
2
6
2
3
2
2
3
1
3
H
19
N
3
O
3
S
2
2
C
5
5
6
2
3
2
3
(
Ethyl 2-methyl-5-oxo-2,3,6,9-tetrahydro-
C
12
H
14
N
4
O
3
S
2
ꢀ ꢀ
H-pyrido[4 ,3 :4,5]thieno[2,3-d][1,3]thiazolo-
5
1
1
7.16; S, 19.64. Found: C, 44.07; H, 4.30; N, 17.01; S,
9.50. MS: m/z = 326 (M ).
[3,2-a]pyrimidine-8(7H)-carboxylate (8)
+
Method A. A mixture of 6 (0.35 g, 0.001 mol)
in acetic acid (1 ml) and concentrated hydrochlo-
ric acid (2 ml) was refluxed for 1 h. After cooling
to room temperature, the solid formed by neutraliz-
ing the mixture with 10% sodium hydroxide was col-
lected by filtration and washed with water (20 ml), af-
fording 0.32 g of crude product, which was recrystal-
Ethyl 4-oxo-2-thioxo-1,2,3,4,5,6,7,8-octahydro-
pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidine-7-
carboxylate (10)
ꢀ
ꢀ
To a suspention of 9 (0.32 g, 0.001 mol) in acetic
acid (2 ml) and water (10 ml), a solution of sodium
nitrite (0.27 g, 0.0039 mol) in 1 ml of water was
added. After stirring for 15 min at room tempera-
ture, 5 ml of a 40% sodium hydroxide solution was
added and warmed to obtain a clear solution. Af-
ter cooling it was acidified with a 50% solution of
sulfuric acid to give colorless crystals. The crystals
were washed with cold water, dried, and recrystal-
lized from ethanol. Yield: 0.2 g (66%) 10 as colorless
lized from 15% aqueous ethanol. Yield: 0.24 g (69%)
◦
8
(
as yellow crystals, m.p. 138–140 C. IR: ꢁ = 2980
aliph. CH), 1700 (CO ester), 1670 (CO pyrimidine
−
1
1
ring), 1610 cm . H NMR (DMSO-d
6
): δ = 1.20 (t,
), 2.90 (t, 2H, H-6),
.60 (t, 2H, H-7), 3.95–4.10 (d, 2H, H-3), 4.20 (q, 2H,
3H, CH
2
CH
3
), 1.60 (d, 3H, CH
3
3
CH
2
CH
3
), 4.40–4.55 (m, 1H, H-2), 4.65 (s, 2H, H-9).
(351.45) calcd.: C, 51.26; H, 4.87; N,
C
15
H
17
N
3
O
3
S
2
◦
1
1
1.95; S, 18.24. Found: C, 51.17; H, 4.95; N, 11.82; S,
8.13.
crystals, m.p. 287–289 C. IR: ꢁ = 3200 (NH), 2980
(aliph. CH), 1720 (CO ester), 1680 (CO pyrimidine
−
1
1
ring), 1620 cm . H NMR (DMSO-d
J = 7 Hz, 3H, CH CH ), 2.90 (t, J = 5.6 Hz, 2H, H-
5), 3.70 (t, J = 5.6 Hz, 2H, H-6), 4.10 (q, J = 7 Hz,
6
): δ = 1.20 (t,
Method B. 1,2-Dibromopropane (0.22 g, 0.0011
mol) in DMF (5 ml) was added to a stirred solution
2
3

2
06 Ahmed
2
1
CH
(
H, CH
3.40 (s, 1H, NH). C NMR (DMSO-d
CH ), 24.7 (t, C-5), 40.2 (t, C-6), 42.3 (s, C-8), 60.9
t, CH CH ), 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). C12 (311.38) calcd.: C, 46.28,
2
CH
3
), 4.60 (s, 2H, H-8), 12.40 (s, 1H, NH),
(s, C-8a), 150.5 (s, C-9a), 155.7 (s, C-4), 161.7, 170.5
(s, C-2), 174.5 (s, COOH). C15 (383.45)
calcd.: C, 46.98; H, 4.46; N, 10.95; S, 16.72. Found:
C, 46.91; H, 4.39; N, 10.82; S, 16.61.
1
3
6
): δ = 14.3 (q,
H
17
N
3
O
5
S
2
2
3
2
3
1
H
13
N
3
O
3
S
2
Ethyl 3-(2-carboxyethyl)-4-oxo-2-thioxo-1,2,3,4,
H, 4.20; N, 13.49; S, 20.59. Found: C, 46.18; H, 3.15;
N, 13.32; S, 20.52.
ꢀ ꢀ
,6,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
5
pyrimidine-7-carboxylate (13)
To a solution of ꢀ-alanine (0.09 g, 0.001 mol) in wa-
ter (5 ml), dioxane (5 ml), and sodium hydroxide
Ethyl 3-carboxymethyl-4-oxo-2-thioxo-1,2,3,4,5,
ꢀ ꢀ
,7,8-octahydropyrido[4 ,3 :4,5]thieno[2,3-d]-
6
(
1 M, 5 ml), 1 (0.34 g, 0.001 mol) was added and
pyrimidine-7-carboxylate (11)
◦
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 hy-
drochloric acid (18%) to pH 3. The precipitate was
collected by filtration, dried, and recrystallized from
DMF/water. Yield: 0.26 g (68%) 13 as yellow crys-
To a solution of glycine (0.08 g, 0.001 mol) in a mix-
ture of water (5 ml), dioxane (5 ml), and sodium hy-
droxide (1 M, 5 ml), 1 (0.34 g, 0.001 mol) was added
◦
and the mixture was stirred at 50 C for 5 h. The
volatile components were evaporated in vacuo, water
was added to the solid residue, and the mixture was
acidified with hydrochloric acid (18%) to pH 3. The
precipitate was collected by filtration, dried, and re-
crystallized from DMF/water. Yield: 0.26 g (71%) 11
◦
1
tals, m.p. >300 C. H NMR (DMSO-d
6
): δ = 1.20 (t,
COOH), 2.85 (t,
H, H-5), 3.60 (t, 2H, H-6), 4.10 (q, 2H, CH CH ),
.60–4.80 (m, 4H, H-8, CH CH COOH), 13.60 (br,
): δ = 14.4 (q, CH CH ),
), 36.7 (t, CH COOH),
CH ), 115.8
3
2
4
1
2
4
H, CH
2
CH
3
), 2.65 (t, 2H, CH
2
CH
2
2
3
◦
1
as yellow crystals, m.p. 280–282 C. H NMR (DMSO-
): δ = 1.20 (t, 3H, CH CH ), 2.80 (t, 2H, H-5), 3.70 (t,
H, H-6), 4.10 (q, 2H, CH CH ), 4.60 (s, 2H, H-8), 5.10
s, 2H, NCH ), 13.40 (s, 1H, NH). C NMR (DMSO-
): δ = 14.5 (q, CH CH ), 24.7 (t, C-5), 40.4 (t, C-
), 42.43 (t, C-8), 46.0 (t, NCH ), 60.8 (t, CH CH ),
15.8 (s, C-4a), 125.1 (s, C-4b), 129.5 (s, C-8a), 150.1
2
2
d
6
2
3
13
H, NH). C NMR (DMSO-d
4.8 (t, C-5), 30.6 (t, NCH
6
2
3
2
(
2
3
2
2
1
3
2
0.2 (t, C-6), 42.4 (t, C-8), 61.0 (t, CH
2
3
d
6
1
6
2
3
(
9
(
s, C-4a), 124.8 (s, C-4b), 129.5 (s, C-8a), 149.5 (s, C-
a), 154.6 (s, C-4), 163.6 (s, CO), 170.1 (C-2), 173.2
s, COOH). C15 (383.45) calcd.: C, 46.98;
2
2
3
H
17
N
3
O
5
S
2
(s, C-9a), 154.6 (s, C-4), 166.4 (s, CO), 169.3 (s, C-
H, 4.46; N, 10.95; S, 16.72. Found: C, 46.84; H, 4.39;
N, 10.82; S, 16.59.
2
), 173.8 (s, COOH). C14 (369.43) calcd.:
H
15
N
3
O
5
S
2
C, 45.51; H, 4.09; N, 11.37; S, 17.35. Found: C, 45.39;
H, 4.19; N, 11.24; S, 17.48.
ꢀ
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]pyrimi-
Ethyl 3-[(S)-1-carboxyethyl]-4-oxo-2-thioxo-1,2,
ꢀ
ꢀ
dine-8 (7H)-carboxylate (14)
3
,4,5,6,7,8-octahydropyrido[4 ,3 :4,5]thieno-
[2,3-d]pyrimidine-7-carboxylate (12)
Method A. Compound 11 (0.5 g, 0.0013 mol)
was heated above its melting point for 15 min; the
residue was cooled and crystallized from DMF. Yield:
To a stirred solution of -alanine (0.09 g, 0.001 mol) in
a mixture of water (5 ml), dioxane (5 ml), and sodium
L
◦
0
.28 g (59%) 14 as yellow crystals, m.p. 260–262 C.
hydroxide (1 M, 5 ml), 1 (0.34 g, 0.001 mol) was
1
◦
IR: ꢁ = 1740, 1710, 1680 (3CO), 1640 (C N).
NMR (DMSO-d CH ), 2.85 (t,
): δ = 1.20 (t, 3H, CH
H, H-6), 3.60 (t, 2H, H-7), 3.90 (s, 2H, H-3), 4.20
q, 2H, CH CH ), 4.60 (s, 2H, H-9). C14
351.41) calcd.: C, 47.85; H, 3.72; N, 11.95; S, 18.24.
H
added and the mixture was stirred at 50 C for 10 h.
6
2
3
The volatile components were evaporated in vacuo,
water was added to the solid residue, and the mixture
was acidified with hydrochloric acid (18%) to pH
2
(
(
2
3
H
13
N
3
O
4
S
2
3. The precipitate was collected by filtration, dried,
Found: C, 47.76; H, 3.64; N, 11.81; S, 18.33.
and recrystallized from DMF/water. Yield: 0.24 g
◦
1
(
(
63%) 12 as yellow crystals, m.p. 290–292 C. H NMR
DMSO-d CH ), 1.52 (d, 3H,
): δ = 1.10 (t, 3H, CH
)COOH), 2.80 (t, 2H, H-5), 3.60 (t, 2H, H-
), 4.10 (q, 2H, CH CH ), 4.60 (s, 2H, H-8), 6.20 (q,
H, CH(CH )COOH), 13.20 (s, 1H, NH). C NMR
): δ = 14.5 (q, CH CH ), 17.4 (q, CH ), 24.9
t, C-5), 40.8 (t, C-6), 42.6 (t, C-8), 50.0 (d, CH), 61.1
t, CH CH ), 115.4 (s, C-4a), 125.5 (s, C-4b), 129.6
6
2
3
Method B. To a solution of 10 (0.31 g, 0.001
mol) in DMF (10 ml) was added chloroacetyl chlo-
ride (0.14 g, 0.0012 mol) 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,
CH(CH
6
1
(
(
(
3
2
3
1
3
3
DMSO-d
6
2
3
3
2
3

ꢀ
ꢀ
Synthesis of 3-Substituted Pyrido[4 ,3 :4,5]thieno[2,3-d]pyrimidines and Related Fused Thiazolo Derivatives 207
and recrystallized from DMF. Yield: 0.21 g (62%) 14
as yellow crystals, m.p. 260–261 C. The product is
identical to that obtained by Method A.
German Patent DD 257,830, 1988; Chem Abstr 1989,
110, 95262p.
8] Vieweg, H.; Leistner, S.; Wagner, G.; Boehm, N.;
Krasset, U.; Grupe, R.; Lohmann, D.; Loban, G. East
German Patent DD 258,234, 1988; Chem Abstr 1989,
◦
[
[
1
10, 95263q.
9] Metzger, J. V.; Katritzky, A. R.; Rees, W.; Potts, K.
T. (Eds.). Comprehensive Heterocyclic Chemistry,
Pergamon: Oxford, 1984; Vol. 6(4b), p. 328.
[10] Ahmed, E. Kh.; Gohar, A. M. N.; Ameen, M. A. Phar-
mazie 2000, 55(1), 31.
[11] Ahmed, E. Kh.; Sensfuss, U.; Habicher, W. D. J Hete-
rocycl Chem 1999, 36, 1119.
[12] Sauter, F.; Frohlich, J.; Ahmed, E. Kh. Monatsh Chem
1996, 127, 319.
[13] Ahmed, E. Kh.; Frohlich, J.; Sauter, F. Collect Czech
Chem Commun 1996, 61, 147.
[14] Ahmed, E. Kh. Monatsh Chem 1995, 126, 953.
[15] Sauter, F.; Jordis, U.; Frohlich, J.; Gewald, K.;
Grohmann, F.; Ahmed, E. Kh. ACH Models Chem
1994, 131(3/4), 489.
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[
[
[
[
[
[
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