Synthesis and transformations of 2-substituted tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,3]oxazines and 2,3-disubstituted hexahydrobenzo [4,5]thieno[2,3-d]pyrimidines

Article abstract of DOI:10.1080/10426500307943

3-(4-Oxo-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,3]oxazin-2-yl) propanoic acid and its ethyl ester 6a,b have been prepared via succinoylation of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1, followed by ester hydrolysis, selective esterification, and acetic anhydride induced cyclization of the thiophenecarboxylic acid derivatives 3, 5. Reaction of 1 with diethyl malonate gave the malonic acid diamide 7, which on ester hydrolysis followed by acetic anhydride induced water elimination furnished the 2-substituted 4H-benzo[4,5]thieno[2,3-d][1,3]oxazine derivative 10 in high yield. A series of new benzo[4,5]thieno[2,3-d]pyrimidines 11-19, which bear a propanoic acid substituent in the 2-position and an amino, aryl, aminosugar, and arylmethylideneamino-substituents in the 3-position have been prepared via the reaction of 6a,b with hydrazine hydrate or aromatic amines followed by treatment with aromatic aldehydes, isatin, or aldoses. The aldimines 18a-d underwent unprecedented acid catalyzed tandem cyclization-transannular aldehyde extrusion into octahydro-1H-benzo[4′5′]thieno[2′,3′:4,5]pyrimido [1,2-b]pyridazines 21. Two other unequivocal approaches for 21 also have been explored, either by treatment of the amino acid derivative 11 with thionyl chloride or by thermal cyclization of the amino ester derivative 12.

Full text of DOI:10.1080/10426500307943

This article was downloaded by: [University of Auckland Library]
On: 02 November 2014, At: 17:31
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis and Transformations of 2-Substituted
Tetrahydro-4 H -benzo[4,5]thieno[2,3-d][1,3]oxazines
and 2,3-Disubstituted Hexahydrobenzo[4,5]thieno[2,3-
d]pyrimidines
a
a
a
A.-A. S. El-Ahl , M. A. Ismail & F. A. Amer
a
Chemistry Department, Faculty of Science , Mansoura University , Mansoura, Egypt
Published online: 27 Oct 2010.
To cite this article: A.-A. S. El-Ahl , M. A. Ismail & F. A. Amer (2003) Synthesis and Transformations of 2-Substituted
Tetrahydro-4 H -benzo[4,5]thieno[2,3-d][1,3]oxazines and 2,3-Disubstituted Hexahydrobenzo[4,5]thieno[2,3-d]pyrimidines,
Phosphorus, Sulfur, and Silicon and the Related Elements, 178:2, 245-259, DOI: 10.1080/10426500307943
To link to this article: http://dx.doi.org/10.1080/10426500307943
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur and Silicon, 2003, Vol. 178:245–259
Copyright �C 2003 Taylor & Francis
1
042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390170372
SYNTHESIS AND TRANSFORMATIONS
OF 2-SUBSTITUTED TETRAHYDRO-4H-
BENZO[4,5]THIENO[2,3-d][1,3]OXAZINES
AND 2,3-DISUBSTITUTED
HEXAHYDROBENZO[4,5]THIENO[2,3-d]PYRIMIDINES
A.-A. S. El-Ahl, M. A. Ismail, and F. A. Amer
Chemistry Department, Faculty of Science,
Mansoura University, Mansoura, Egypt
(Received May 10, 2002; accepted May 30, 2002)
3
-(4-Oxo-5,6,7,8-tetrahydro-4H-benzo[4,5]thieno[2,3-d][1,3]oxazin-2-
yl)propanoic acid and its ethyl ester 6a,b have been prepared via
succinoylation of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-
3
-carboxylate 1, followed by ester hydrolysis, selective esterification,
and acetic anhydride induced cyclization of the thiophenecarboxylic
acid derivatives 3, 5. Reaction of 1 with diethyl malonate gave the
malonic acid diamide 7, which on ester hydrolysis followed by acetic
anhydride induced water elimination furnished the 2-substituted
4
H-benzo[4,5]thieno[2,3-d][1,3]oxazine derivative 10 in high yield. A
series of new benzo[4,5]thieno[2,3-d]pyrimidines 11–19, which bear
a propanoic acid substituent in the 2-position and an amino, aryl,
aminosugar, and arylmethylideneamino-substituents in the 3-position
have been prepared via the reaction of 6a,b with hydrazine hydrate
or aromatic amines followed by treatment with aromatic aldehydes,
isatin, or aldoses. The aldimines 18a–d underwent unprecedented acid
catalyzed tandem cyclization-transannular aldehyde extrusion into
0
0
0
0
octahydro-1H-benzo[4 ,5 ]thieno[2 ,3 :4,5]pyrimido[1,2-b]pyridazines
2
1. Two other unequivocal approaches for 21 also have been explored,
either by treatment of the amino acid derivative 11 with thionyl
chloride or by thermal cyclization of the amino ester derivative 12.
0
0
0
0
Keywords:
Octahydro-1H-benzo[4 ,5 ]thieno[2 ,3 :4,5]pyrimido[1,2-
b]pyridazines; synthesis; thieno[2,3-d][1,3]oxazines; thieno[2,3-
d]pyrimidines
INTRODUCTION
Several thieno[2,3-d][1,3]oxazines have been reported to exhibit a wide
spectrum of biological activity, for example, as antiviral agents,1
–4
Address correspondence to M. A. Ismail, Chemistry Department, Georgia State
University, Atlanta, GA 30303. E-mail: ismail 158@yahoo.com
2
45

2
46
A.-A. S. El-Ahl et al.
5
6
inhibitors of human leukocyte elastase, and as antitumor agents. An-
nulated 1,3-oxazine-4-ones can be considered as semi-acid anhydrides,
which undergo many of the reactions of true acid anhydrides but at a
slower rate. This special reactivity allows this class of compounds to be
7
quite useful as serine protease inhibitors. The chemical stability and
potency of oxazinones can be tuned by choosing substituents, which
influence the reactivity of the carbonyl group by electronic and steric
effects. Besides, thieno[2,3-d]pyrimidine derivatives are useful as gluta-
mate receptor antagonists in the treatment of neurodegenerative, psy-
chotropic, induced central and peripheral nervous system disorders;8
as prophylactic or therapeutic agents for the treatment of hormone de-
pendent diseases, for example, a sex hormone dependent cancer.10
In view of the general interest in the biological activities of
thieno[2,3-d][1,3]oxazine and thieno[2,3-d]pyrimidine derivatives and
,9
1
1
in continuation of our work in this area, we report herein the synthe-
ses of some hitherto unreported thieno[2,3-d][1,3]oxazine-2-propanoic
acid and thieno[2,3-d]pyrimidine-2-propanoic acid derivatives for bio-
logical evaluation. In this study, we also demonstrate the versatility
of ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene carboxylate 1 as
a synthetic entry into several thieno[2,3-d][1,3]oxazine and thieno[2,3-
d]pyrimidine derivatives.
RESULTS AND DISCUSSION
The thieno[2,3-d][1,3]oxazine-2-propanoic acid derivative 6a was pre-
pared through acetic anhydride induced cyclization of the dicarbox-
lyic acid derivative 3, which has been synthesized by respective N-
succinoylation of the aminothiophene derivative 1, to give the monoacid
derivative 2, followed by selective ester hydrolysis (5% aqueous-
alcoholic sodium hydroxide, Scheme 1). The synthesis of the thieno[2,3-
d][1,3]oxazine-2-propanoic acid ester 6b required the monoacid es-
ter 5. All attempts to synthesize 5 in reasonable yield, via selective
hydrolysis of the diester derivative 4, gave a mixture of products
(
TLC). Interestingly, selective acid-catalyzed esterfication of the dicar-
boxylic acid derivative 3 afforded the monoacid ester 5. A subsequent
acetic anhydride induced cyclodehydration of 5 furnished thieno[2,3-
d][1,3]oxazine-2-propanoic acid ester 6b in good yield.
Successive treatment of the amino thiophene derivative 1 with
diethyl malonate in refluxing xylene, followed by ester hydrolysis
yielded the amidoester and amidoacid derivatives 7, 8 respectively. A
subsequent acetic anhydride induced cyclodehydration of 8 afforded
the thieno[2,3-d][1,3]oxazine derivative 10 rather than the expected

Synthesis and Transformations
247
SCHEME 1
bis-oxazine derivative 9 (Scheme 1). A plausible mechanism for the for-
mation of 10 is depicted in Scheme 2. It is believed that 10 is formed
through the formation of the enaminic mixed acid anhydride interme-
diate A, which underwent interamolecular enamine acid anhydride cy-
clization, to give the intermediate B, followed by water elimination.
This mechanism is consistent with our previously reported work.11

2
48
A.-A. S. El-Ahl et al.
SCHEME 2
The structures of the condensed oxazine heterocycles 6a,b and 10
were established through elemental and spectral analyses. The IR spec-
tra of compounds 6a,b and 10 showed a characteristic strong absorption
�
1
band at 1750–1780 cm attributable to the oxazinone carbonyl group.
1
In particular, the H-NMR of 6b displayed three multiplets at � 1.8,
2
.75, and 2.92 integrated for eight protons and two triplets at � 2.78
and 3.06 corresponding to two methylene groups.
With these functionalized thieno[2,3-d][1,3]oxazine derivatives 6a,b
and 10, and the succinoylaminothiophene derivative 2 in hand,
the possible synthesis of several 2,3-disubstituted and annulated
thieno[2,3-d]pyrimidine derivatives was investigated. Thus, treat-
ment of compound 2 with hydrazine hydrate under reflux yielded
3
-aminothieno[2,3-d]pyrimidine derivative 11 in high yield. The struc-
ture of 11 was based on analytical and spectral data. Furthermore,
the structure of 11 was supported by an unequivocal synthesis via hy-
drazinolysis of thieno[2,3-d][1,3]oxazine 6a. Treatment of thieno[2,3-
d][1,3]oxazine 6b with hydrazine hydrate furnished the acid hydrazide
derivative 13. The structure of 13 was confirmed by unequivocal syn-
thesis through esterfication of 11 to give the amino ester derivative 12,
followed by hydrazinolysis of 12 in refluxing ethanol.
The reaction of thieno[2,3-d][1,3]oxazine 6b with aromatic amines
viz. p-anisidine and p-toluidine) in acetic acid afforded the thieno[2,3-
(
d]pyrimidine derivatives 14a,b (Scheme 3). The structure of 14a,b was
assigned on the basis of spectral and analytical data. The IR spectra
showed the disappearance of the absorption band which is correspond-
1
ing to the oxazinone carbonyl group and the H-NMR spectrum of 14a

Synthesis and Transformations
249
SCHEME 3
displayed, in addition to the aliphatic hydrogen resonance, an AB sys-
tem at � 7.24 and 7.39 corresponding to p-substituted phenyl ring.
The introduction of sugar moieties to the thieno[2,3-d]pyrimidine
derivatives is expected to affect their pharmacological activity, since
the sugar would render the molecules more hydrophilic and, accord-
ingly, ensure better pervasion into biological systems.12 Thus, reaction
of 3-aminotheino[2,3-d]pyrimidine 11 with the aldoses, D-arabinose,
D-glucose and D-galactose gave the respective saccharide hydrzone in-
termediates A and B, which underwent self-acid catalyzed cyclization
to give the nucleotides 15, 16, and 17 in good yields (Scheme 4). The
1
given structures of 15, 16, and 17 were established unequivocally by H
and 13C-NMR. One of the diagnostic features of the C-NMR spectra
of the reaction products is the lack of any absorption peaks correspond-
ing to azomethine carbon in the intermediates A and B. Instead peaks
13
0
at � 91.17–91.45 were observed, being assigned to the 1 -carbon atoms
1
3
of the glycosyl amines 15–17. The antiperiplanar coupling constant
8 Hz) of the proton 1 -H and 2 -H in 16 shows that a �-glucoside is
involved. The presence of compound 15 in the arabinofuranose form
was depicted on the basis of comparing its C-data with those reported
0
0
(
14
1
3
1
3,15
in the literature for similar structures.
The treatment of 3-aminothieno[2,3-d]pyrimidine 11 with aromatic
aldehydes (4-methoxy, 2-hydroxy, 4-chloro and 4-bromobenzaldehyde)
and isatin in refluxing ethanol afforded the aldimines 18a–d and 19,

2
50
A.-A. S. El-Ahl et al.
SCHEME 4
respectively, in good yields. The aldimines 18a–d underwent unprece-
dented consecutive acid catalyzed cyclization and transannular alde-
hyde extrusion, in refluxing chloroform containing a catalytic amount of
4
-toluenesulphonic acid, to furnish the tetracyclic structure 21 through
the formation of the oxadiazocine intermediate 20 (Scheme 4). The
structure of 21 was assigned on the basis of spectral and analytical
1
data. The H-NMR of 21 showed three multiplets at � 1.78, 2.72, and
2
.87 integrated for eight protons and two triplets, two protons each,
at � 2.63 and 3.11. Two other unequivocal approaches for 21 have been

Synthesis and Transformations
251
investigated, either by treatment of the amino acid 11 with thionyl chlo-
ride and absolute ethanol in a stoppered flask at room temperature or
�
by heating the aminoester 12 at 120 C.
In summary, we have described a multi step procedure to synthesize
thieno[2,3-d][1,3]oxazine subsystems of 6a,b. Several synthetically use-
ful transformations of substrates 6a,b are also given in Schemes 3 and
4
. Specific attention was given to the aldimines 18a–d, which under-
went unprecedented acid-catalyzed tandem cyclization-transannular
aldehyde extrusion to afford the tetracyclic compound 21 (Scheme 4). It
is important to note that no chromatography was involved and analyti-
cally pure products were obtained by crystallization in all cases studied.
Experimental
Melting points (Pyrex capillary) are not corrected. IR spectra were
1
13
recorded on MATTSON 5000 FT-IR Spectrometer. H-NMR and C-
NMR spectra were recorded on a Varian-Gemini 300 MHz instrument
at 300 and 75 MHz, respectively. The NMR spectra were taken in CDCl3
or DMSO-d6 as solvents, with TMS as an internal standard. Mass spec-
tra were recorded on GC-MS GP-1000 EX. Shimadzu machine. Ele-
mental analyses were carried out at the Microanalytical Unit, Faculty
of Science, Mansoura University.
4
-{[3-(Ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]-
thiophen-2-yl]amino}-4-oxobutanoic Acid (2)
A mixture of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate 1 (50 mmol, 11.25 g) and succinic anhydride (50 mmol,
5
.0 g) in toluene (150 mL), containing a catalytic amount of triethy-
lamine, was refluxed for 3 h. After cooling, the formed precipitate was
filtered and recrystallized from ethanol. Yield (95%); m.p. 155–158 C;
�
IR (KBr) 3383, 2937, 2852, 1685, 1660, 1543, 1437, 1410, 1330, 1285,
�
1 1
1
252, 1212, 1169, 1137, 926 cm ; H-NMR (DMSO-d6): � 1.49 (t, 3H,
J = 7 Hz), 1.88 (m, 4H), 2.73 (m, 4H), 2.89 (m, 4H), 3.60 (br s, 1H), 4.45
1
3
(
2
1
q, 2H, J = 7 Hz), 11.2 (s, 1H); C-NMR (DMSO-d6): � 14.08, 22.29,
2.48, 23.67, 25.80, 28.70, 30.75, 60.30, 111.06, 125.82, 130.32, 146.03,
64.96, 169.08, 173.46. Anal. Calcd. for C15H19NO5S (325.379): C, 55.37;
H, 5.89. Found: C, 55.19; H, 6.02.
2
-[3-(Carboxypropanoyl)amino]-4,5,6,7-tetrahydrobenzo-
[
b]thiophene-3-carboxylic Acid (3)
To a suspension of the monoacid-ester 2 (50 mmol, 16.25 g) in
ethanol (100 mL) was added a 10% sodium hydroxide solution (100 mL).
�
The reaction mixture was refluxed for 3 h, cooled (0 C), and acidified
with dilute hydrochloric acid (pH = 4). The formed precipitate was

2
52
A.-A. S. El-Ahl et al.
filtered, washed with excess water, and recrystallized from ethanol.
�
Yield (69%); m.p. 204–206 C; IR (KBr) 3383, 3026, 2937, 2852, 1685,
�
1
1
650, 1543, 1437, 1410, 1330, 1285, 1252, 1212, 1169, 1137, 926 cm ;
1
H-NMR (DMSO-d6): � 1.77 (m, 4H), 2.64 (m, 4H), 2.76 (m, 4H), 3.46
(
br s, 1H, NH), 11.28 (s, 1H), 12.63 (br s, 1H); 13C-NMR (DMSO-d6):
�
22.28, 22.54, 23.66, 25.83, 28.61, 30.73, 111.64, 125.31, 130.78, 148.06,
1
66.89, 168.77, 173.42. Anal. Calcd. for C13H15NO5S (297.325): C, 52.52;
H, 5.09. Found: C, 52.84; H, 5.27.
Ethyl 2-[(4-Ethoxy-4-oxobutanoyl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (4)
A suspension of compound 2 (5 mmol, 1.63 g) in absolute ethanol
(
1
50 mL) containing a few drops of conc. sulfuric acid was refluxed for
h. The reaction mixture was cooled and poured onto ice (80 g). The
formed colorless precipitate was filtered, washed with water, and recrys-
�
tallized from ethyl acetate/pet. ether (60–80 C) (1:3). Yield (71%); m.p.
�
9
5–97 C; IR (KBr) 3291, 2983, 2937, 2859, 1736, 1687, 1669, 1562, 1535,
440, 1329, 1277, 1231, 1163, 1033 cm ; H-NMR (DMSO-d6): � 1.57
�
1 1
1
(
(
7
2
1
t, 3H, J = 7 Hz), 1.70 (t, 3H, J = 7 Hz), 2.09 (m, 4H), 2.95 (m, 2H), 3.05
m, 4H), 3.17 (t, 2H, J = 7 Hz), 4.45 (q, 2H, J = 7 Hz), 4.65 (q, 2H, J =
1
3
Hz), 11.42 (s, 1H, NH); C-NMR (DMSO-d6): � 14.02 (2C), 22.29,
2.47, 23.67, 25.81, 28.57, 30.58, 60.05, 60.29, 111.05, 125.80, 130.27,
46.07, 165.0, 168.73, 171.92; Anal. Calcd. for C17H23NO5S (353.433):
C, 57.77; H, 6.56. Found: C, 57.36; H, 6.43.
2
-[(4-Ethoxy-4-oxobutanoyl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylic Acid (5)
A suspension of 2-[3-(carboxypropanoyl)amino]-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylic acid 3 (5 mmol, 1.49 g) in absolute
ethanol (50 mL) containing a few drops of conc. sulfuric acid was left
overnight, then poured onto ice (80 g). The formed colorless precipitate
was filtered, washed with water, and recrystallized from ethyl acetate.
�
Yield (63%); m.p. 165–166 C; IR (KBr) 3279, 3134, 2942, 1737, 1701,
1
�
1
641, 1543, 1531, 1454, 1238, 1210, 1026, 905, 702 cm ; Anal. Calcd.
for C15H19NO5S (325.379): C, 55.37; H, 5.89. Found: C, 55.58; H, 5.63.
3
-(4-Oxo-5,6,7,8-tetrahydro-4 H-benzo[4,5]thieno[2,3-d]-
[
1,3]oxazin-2-yl)propanoic Acid (6a)
The dicarboxylic acid 3 (25 mmol, 7.43 g) was refluxed for 4 h in a mix-
ture of acetic anhydride and acetic acid (3:1, 75 mL). The solvent was
distilled off under reduced pressure and the residue was recrystallized
�
from chloroform/ether (1:1). Yield (81%); m.p. 214–216 C; IR (KBr)
3
030, 2940, 2860, 1765, 1676, 1490, 1442, 1354, 1273, 1239, 1163,

Synthesis and Transformations
253
17, 660 cm 1; H-NMR (DMSO-d6): � 2.00 (m, 4H), 2.80 (m, 4H), 2.85
�
1
7
(
+
m, 4H), 12.60 (s, 1H, CO2H); MS (m/z, %): 279.16 (M , 38), 261.15 (60),
2
35.18 (50), 221.16 (80), 193.13 (58), 179.14 (100) 151.03 (80), 135.02
(
84), 125.04 (86), 108 (50), 91.13 (48), 69.04 (58), 55.04 (70); Anal. Calcd.
for C13H13NO4S (279.31): C, 55.90; H, 4.69. Found: C, 55.63; H, 5.02.
Ethyl 3-(4-Oxo-5,6,7,8-tetrahydro-4 H-benzo[4,5]thieno-
[
2,3-d][1,3]oxazin-2-yl)propanoate (6b)
The monoacid ester 5 (25 mmol, 8.13 g) was refluxed for 2 h in a
mixture of acetic anhydride, and acetic acid (3:1, 75 mL). The solvent
was distilled off under reduced pressure and the residue was recrys-
�
tallized from ethyl acetate/pet. ether (60–80 C) (2:3). Yield (74%); m.p.
�
1
15–117 C; IR (KBr) 2929, 1780, 1730, 1601, 1421, 1314, 1310, 1209,
166, 1165, 1021, 1019, 909, 645 cm ; H-NMR (CDCl3): � 1.23 (t, 3H,
�
1 1
1
J = 7 Hz), 1.86 (m, 4H), 2.75 (m, 2H), 2.78 (t, 2H, J = 7 Hz), 2.92 (m,
H), 3.06 (t, 2H, J = 7 Hz), 4.16 (q, 2H). Anal. Calcd. for C15H17NO4S
307.364): C, 58.62; H, 5.58. Found: C, 58.86; H, 5.73.
2
(
Ethyl-2-[(3-{[3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo-
[
b]thiophen-2-yl]-amino}-3-oxopropanoyl)amino]-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (7)
A mixture of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (1) (50 mmol, 11.25 g) and diethyl malonate (50 mmol, 8 g)
in xylene (100 mL) was refluxed for 5 h. After cooling, the formed pre-
cipitate was filtered and recrystallized from ethanol. Yield (90%); m.p.
�
2
1
10–212 C; IR (KBr) 3219, 3163, 2937, 2859, 1705, 1669, 1561, 1522,
�
1
1
443, 1404, 1330, 1277, 1229, 1173, 1136, 1024, 779 cm ; H-NMR
(
(
DMSO-d6): � 1.31 (dt, 6H, 2 � CH3), 1.72 (m, 8H), 2.61 (m, 4H), 2.71
m, 4H), 3.97 (s, 2H), 4.30 (dq, 4H, 2 � CH2), 11.38 (s, 2H, 2 � NH);
Anal. Calcd. for C25H30N2O6S2 (518.643): C, 57.90; H, 5.83. Found:
C, 57.58; H, 6.00.
2
2
-({3-[(3-Carboxy-4,5,6,7-tetrahydrobenzo[b]thiophen-
-yl)amino]-3-oxopropanoyl}-amino)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylic Acid (8)
To a suspension of the dicarboxylic acid ester 7 (50 mmol, 25.9 g) in
ethanol (100 mL) was added a 10% sodium hydroxide solution (100 mL).
�
The reaction mixture was refluxed for 2 h, cooled (0 C) and acidified
with dilute hydrochloric acid (pH = 4). The formed precipitate was fil-
tered, washed with excess water and recrystallized from ethanol. Yield
�
(
59%); m.p. 197–199 C; IR (KBr) 3472, 3320, 3215, 3131, 3075, 3040,
3
7
020, 2932, 2850, 1707, 1644, 1537, 1445, 1365, 1328, 1277, 1226, 787,
10 cm . Anal. Calcd. for C21H22N2O6S2 (462.535): C, 54.53; H, 4.79.
�
1
Found: C, 54.92; H, 4.52.

2
54
A.-A. S. El-Ahl et al.
2
-Hydroxy-3-(4-oxo-5,6,7,8-tetrahydro-4 H-benzo[4,5]-
thieno[2,3-d][1,3]oxazin-2-yl)-5,6,7,8-tetrahydrobenzo-
[4,5]thieno[2,3-b]pyridin-4-yl Acetate (10)
The dicarboxylic acid 8 (25 mmol, 11.55 g) was refluxed for 3 h in a
mixture of acetic anhydride and acetic acid (3:1, 75 mL). The solvent was
distilled off under reduced pressure and the residue was recrystallized
�
from ether. Yield (81%); m.p. 216–218 C; IR (KBr): 2937, 2860, 2830,
1
1
2
750, 1735, 1600, 1553, 1478, 1420, 1373, 1334, 1283, 1227, 1160, 1095,
016, 895, 767 cm ; H-NMR (DMSO-d6): � 1.72 (m, 8H), 2.22 (s, 3H),
.59 (m, 4H), 2.71 (m, 4H), 11.18 (s, 1H). Anal. Calcd. for C23H20N2O5S2
�
1 1
(
468.542): C, 58.96; H, 4.30. Found: C, 58.63; H, 4.01.
3
-(3-Amino-4-oxo-3,4,5,6,7,8-hexahydro-4 H-benzo[4,5]-
thieno[2,3-d]pyrimidin-2-yl)propanoic Acid (11)
Method A. A mixture of the monoacid-ester 2 (50 mmol, 16.25 g)
and hydrazine hydrate (25 mL) was heated under reflux for 2 h. After
cooling, the formed precipitate was filtered and washed with ether and
recrystallized from chloroform/ethanol (1:1) to afford 11 in 87% yield.
Method B. A mixture of thieno[2,3-d][1,3]-oxazine-2-propanoic acid
a (10 mmol, 2.79 g) and hydrazine hydrate (4 mL) was heated at 40 C
�
6
for 1 h. The reaction mixture was poured onto ice water. The formed
precipitate was filtered, washed with water, and recrystallized from
�
chloroform/ethanol (1:1). Yield (72%); m.p. 214–215 C; IR: 3309, 3215,
3
1
173, 2932, 2852, 1671, 1644, 1538, 1489, 1436, 1391, 1342, 1287, 1184,
003 cm ; H-NMR (DMSO-d6): � 1.75 (m, 4H) 2.46 (m, 2H), 2.68
�
1
1
(
9
m, 2H), 2.84 (m, 2H), 3.12 (t, 2H, J = 7.5 Hz), 4.10 (br s, 2H, NH2),
1
3
.00 (s, 1H, CO2H); C-NMR (DMSO-d6): � 21.75, 22.46, 24.48, 25.14,
8.96, 29.47, 119.2, 130.28, 131.86, 156.43, 156.93, 160.21, 170.66; Anal.
2
Calcd. for C13H15N3O3S (293.341): C, 53.23; H, 5.15. Found: C, 52.86;
H, 5.41.
Ethyl-3-(3-amino-4-oxo-3,4,5,6,7,8-hexahydro-4 H-
benzo[4,5]thieno[2,3-d]pyrimidin-2-yl)propanoate (12)
A suspension of compound 11 (5 mmol, 1.47 g) in absolute ethanol
(
25 mL) containing a few drops of conc. sulfuric was refluxed for 2 h.
The reaction mixture was cooled and poured onto ice (80 g). The formed
colorless precipitate was filtered, washed with water, and recrystallized
from ethyl acetate/pet. ether (60–80 C) (1:2). Yield (74%); m.p. 125 C;
IR (KBr) 3304, 3247, 3212, 2977, 2934, 2860, 1731, 1669, 1562, 1463,
�
�
�
1
1
1
416, 1352, 1280, 1182, 1161 cm ; H-NMR (CDCl3): �: 1.26 (t, 3H,
J = 7 Hz), 1.85 (m, 4H), 2.75 (m, 2H), 2.85 (t, 2H, J = 7 Hz), 2.98 (m,
H), 3.30 (t, 2H, J = 7 Hz), 4.14 (q, 2H, J = 7 Hz), 5.00 (br s, 2H, NH2);
2

Synthesis and Transformations
255
13C-NMR (CDCl3): � 14.21, 22.19, 22.89, 25.14, 25.34, 28.46, 30.65,
0.63, 119.98, 130.95, 133.23, 155.17, 158.0, 161.2, 172.79; Anal. Calcd.
for C15H19N3O3S (321.395): C, 56.06; H, 5.96. Found: C, 56.28; H, 6.07.
6
3
-(3-Amino-4-oxo-3,4,5,6,7,8-hexahydrobenzo-
[
4,5]thieno[2,3-d]pyrimidin-2yl)propanehydrazide (13)
Method A. A mixture of 6b (10 mmol, 3.07 g) and hydrazine hydrate
(
2 mL, 80%) in absolute ethanol (25 mL) was refluxed for 3 h. The
solvent and excess hydrazine hydrate was distilled off and the residue
was recrystallized from ethanol to furnish 13 in 68% yield.
Method B. A mixture of the thieno[2,3-d]pyrimidine derivative 12
10 mmol, 3.21 g) and hydrazine hydrate (2 mL, 80%) in absolute
(
ethanol (25 mL) was refluxed for 3 h. The solvent and excess hy-
drazine hydrate was distilled off and the residue was recrystallized from
�
ethanol. Yield (85%); m.p. 225–226 C; IR (KBr) 3303, 3200, 3160, 2933,
2
1
5
852, 1662, 1652, 1600, 1536, 1488, 1486, 1441, 1341, 1207, 1183, 1101,
029, 1003 cm ; Anal. Calcd. for C13H17N5O2S (307.372): C, 50.80; H,
.58. Found: C, 50.97; H, 5.27.
�
1
Reaction of Thieno[1,3]oxazine Derivative (6b) with
Aromatic Amines
A mixture of compound 6b (5 mmol, 1.54 g) and the respective aro-
matic amine (p-toluidine or p-anisidine) (5 mmol) was refluxed in glacial
acetic acid (10 mL) for 3–4 h. The solvent was distilled off and the
residue was poured onto ice-water. The formed precipitate was filtered
and recrystallized from ethanol to afford 14a,b.
Ethyl-3-[3-(4-methylphenyl)-4-oxo-3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-
propanoate (14a)
�
Yield (84%); m.p. 125–127 C; IR (KBr) 2924, 2851, 1732, 1682, 1636,
�
1 1
1
�
600, 1549, 1512, 1283, 1220, 1165, 1017 cm ; H-NMR (DMSO-d6):
1.19 (t, 3H, J = 7 Hz), 1.77 (m, 4H), 2.29 (s, 3H), 2.65–2.83 (m, 6H),
4
.05 (q, 2H, J = 7 Hz), 7.24 (d, 2H, J = 8 Hz), 7.39 (d, 2H, J = 8 Hz).
Anal. Calcd. for C22H24N2O3S (396.505): C, 66.64; H, 6.10. Found:
C, 66.93; H, 5.75.
Ethyl-3-[3-(4-methoxyphenyl)-4-oxo-3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-
propanoate (14b)
�
Yield (81%); m.p. 138–140 C; IR (KBr) 3070, 2927, 2837, 1729,
�
1
1
655, 1604, 1514, 1243, 1175, 1029, 830, 770 cm ; Anal. Calcd.

2
56
A.-A. S. El-Ahl et al.
for C22H24N2O4S (412.504): C, 64.06; H, 5.86. Found: C, 64.47; H,
.63.
5
Reaction of 3-(3-Amino-4-oxo-3,4,5,6,7,8-tetrahydro-4 H-
benzo[4,5]thieno[2,3-d]pyrimidin-2-yl)propanoic Acid (11)
with Aldopentoses and Aldohexoses
To
benzo[4,5]thieno[2,3-d]pyrimidin-2-yl)propanoic acid 11 (10 mmol,
.93 g) in ethanol (50 mL) was added the appropriate aldose (10 mmol).
The reaction mixture was heated under reflux on a water bath for
–3 h. The formed precipitate was filtered off and recrystallized from
aqueous/ethanol to afford 15–17.
a
solution of 3-(3-amino-4-oxo-3,4,5,6,7,8-tetrahydro-4H-
2
2
3
-(3-{[�-D-Arabinofuranosyl]amino}-4-oxo-3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-
propanoic Acid (15)
�
Yield (76%); m.p. 205–207 C; IR (KBr) 3491, 3433, 3398, 3367, 2928,
�
1 1
2
2
856, 1655, 1543, 1090, 1082 cm ; H-NMR (DMSO-d6): � 1.58 (m, 4H),
.43 (m, 2H), 2.65 (m, 2H), 2.94 (m, 2H), 3.34 (m, 5H), 4.28 (m, 1H), 4.58
(
m, 1H), 4.77 (br s, 1H), 5.43 (br, 3H), 9.32 (s, 1H); 13C-NMR (DMSO-
d6): � 21.71, 22.42, 24.45, 25.09, 28.38, 29.35, 66.09, 67.73, 68.34, 72.41,
1.45, 119.18, 130.22, 131.82, 156.33, 156.95, 160.16, 170.48; Anal.
9
Calcd. for C18H23N3O7S (425.456): C, 50.82; H, 5.45. Found: C, 50.61;
H, 5.73.
3
-(3-{[�-D-Glucopyranosyl]amino}-4-oxo-3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-
propanoic Acid (16)
�
1 1
Yield (71%); m.p. 132–133 C; IR (KBr) 3482, 2938, 2848, 1658, 1620,
�
1
546, 1431, 1347, 1290 cm ; H-NMR (DMSO-d6): � 1.70 (m, 4H), 2.62
(
(
9
2
1
m, 2H), 2.77 (m, 2H), 2.97 (m, 2H), 3.08 (m, 4H), 3.39 (m, 2H), 3.62
m, 2H), 4.35 (m, 1H), 4.57 (m, 2H), 5.55 (m, 1H) 5.66 (d, 1H, J = 8 Hz),
.44 (s, 1H); 13C-NMR (DMSO-d6): � 21.92, 22.64, 24.68, 25.30, 29.17,
9.61, 61.54, 70.38, 70.57, 76.79, 78.09, 91.17, 119.26, 130.44, 132.18,
56.43, 157.21, 160.37, 171.25; Anal. Calcd. for C19H25N3O8S (455.479):
C, 50.10; H, 5.53. Found: C, 50.48; H, 5.86.
3
-(3-{[�-D-Galactopyranosyl]amino}-4-oxo-3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)-
propanoic Acid (17)
�
Yield (88%); m.p. 255–257 C; IR (KBr) 3429, 3316, 3057, 2938,
�
1
1
677, 1647, 1552, 1440, 1153, 1097, 1065, 1041 cm ; Anal. Calcd.

Synthesis and Transformations
257
for C19H25N3O8S (455.479): C, 50.10; H, 5.53. Found: C, 50.41; H,
.26.
5
3
-{3-[1-(Arylmethylidene)amino]-4-oxo-3,4,5,6,7,8-
hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl}-
propanoic Acid (18a–d)
A mixture of 2-aminothieno[2,3-d]pyrimidine-2-propanoic acid 11
(
5 mmol, 1.47 g) and the appropriate aromatic aldehyde (5 mmol)
was taken in ethanol (25 mL). The reaction mixture was refluxed for
–3 h. The formed precipitate was filtered and recrystallized from chlo-
roform/ethanol (1:1) to furnish the aldimines 18a–d.
2
3
3
2
-{3-[1-(4-Methoxyphenylmethylidene)amino]-4-oxo-
,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-yl}propanoic Acid (18a)
�
Yield (85%); m.p. 260–261 C; IR (KBr) 3441, 2935, 2879, 2831, 1709,
1
1
673, 1626, 1601, 1570, 1489, 1464, 1431, 1373, 1354, 1318, 1300, 1279,
251, 1213, 1163, 1109, 1023, 936, 831, 768 cm ; H-NMR (DMSO-d6):
�
1 1
�
1.80 (m, 4H), 2.65 (t, 2H, J = 7 Hz), 2.88 (m, 2H), 3.13 (t, 2H, J = 7 Hz),
3
1
.82 (s, 3H), 7.04 (d, 2H, J = 8 Hz), 7.79 (d, 2H, J = 8 Hz), 8.60 (s, 1H),
+
1.10 (s, 1H); MS (m/z, %): 276 (M -135, 100), 260 (10), 248 (25), 231
(
(
50), 218 (12), 204 (5), 191 (5), 55 (25); Anal. Calcd. for C21H21N3O4S
411.476): C, 61.30; H, 5.14. Found: C, 61.48; H, 5.36.
3
3
2
-{3-[1-(2-Hydroxyphenylmethylidene)amino]-4-oxo-
,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-yl}propanoic Acid (18b)
�
Yield (74%); m.p. 240–241 C; IR (KBr) 3454, 3253, 3045, 2935, 2861,
1
1
702, 1641, 1618, 1549, 1483, 1433, 1407, 1381, 1355, 1273, 1194, 1174,
157, 748 cm ; H-NMR (DMSO-d6): � 1.76 (m, 4H), 2.74 (m, 4H), 2.86
�
1 1
(
(
m, 2H), 3.28 (m, 2H), 6.93 (m, 3H), 7.41 (m, 1H), 8.37 (s, 1H), 8.97
s, 1H), 11.12 (s, 1H); Anal. Calcd. for C20H19N3O4S (397.449): C, 60.44;
H, 4.82. Found: C, 60.84; H, 5.05.
3
3
2
-{3-[1-(4-Chlorophenylmethylidene)amino]-4-oxo-
,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-yl}propanoic Acid (18c)
�
Yield (82%); m.p. 207–209 C; IR (KBr) 3390, 2932, 1712, 1671, 1629,
1
8
591, 1569, 1545, 1486, 1422, 1373, 1354, 1283, 1175, 1152, 1089, 1013,
22, 510 cm ; H-NMR (DMSO-d6): � 1.86 (m, 4H), 2.77 (m, 4H), 3.00
�
1 1
(
8
5
m, 2H), 3.24 (m, 2H), 7.43 (d, 2H, J = 7.5 Hz), 7.78 (d, 2H, J = 7.5 Hz),
.61 (s, 1H), 9.72 (s, 1H); Anal. Calcd. for C20H18ClN3O3S (415.895): C,
7.76; H, 4.36. Found: C, 57.38; H, 4.71.

2
58
A.-A. S. El-Ahl et al.
3
3
2
-{3-[1-(4-Bromophenylmethylidene)amino]-4-oxo-
,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-yl}propanoic Acid (18d)
�
Yield (70%); m.p. 225–226 C; IR (KBr) 3285, 3194, 3132, 3109, 2982,
2
1
932, 2843, 1708, 1661, 1607, 1541, 1483, 1443, 1392, 1345, 1285, 1261,
�
1 1
211, 1172, 1137, 1065, 1006, 933, 809, 773 cm ; H-NMR (DMSO-d6):
1.56 (m, 4H), 2.62 (m, 4H), 3.05 (m, 4H), 7.71 (d, 2H, J = 7.5 Hz)
.83 (d, 2H, J = 7.5 Hz), 8.70 (s, 1H), 11.08 (s, 1H). Anal. Calcd. for
C20H18BrN3O3S (460.346): C, 52.18; H, 3.94. Found: C, 52.42; H, 4.25.
�
7
3
3
2
-{4-Oxo-3-[(2-oxo-2,3-dihydro-1H-3-indolylidene)amino]-
,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-
-yl}propanoic Acid (19)
A mixture of 2-aminothieno[2,3-d]pyrimidine-2-propionic acid 11
(
5 mmol, 1.47 g) and isatin (5 mmol, 0.74 g) in ethanol (25 mL) was
refluxed for 5 h. The formed precipitate was filtered and recrystallized
from DMF/ethanol (1:5). Yield (51%); m.p. 251–252 C; IR (KBr) 3184,
�
3
1
124, 2934, 1721, 1690, 1654, 1603, 1541, 1479, 1441, 1345, 1177, 1159,
120, 1000 cm ; H-NMR (DMSO-d6): � 1.77 (m, 4H), 2.69 (m, 2H), 2.87
�
1 1
(
m, 2H), 3.18 (m, 2H), 3.28 (m, 2H), 6.88 (d, 1H, J = 8 Hz), 7.01 (t, 1H,
J = 8 Hz), 7.36 (t, 1H, J = 8 Hz), 8.05 (d, 1H, J = 8 Hz), 10.67 (s, 1H),
1.0 (s, 1H). Anal. Calcd. for C21H18N4O4S (422.459): C, 59.71; H, 4.29.
Found: C, 59.47; H, 4.52.
1
0
0
0
0
2
,3,4,7,8,9,10,11-Octahydro-1H-benzo[4 ,5 ]thieno[2 ,3 :
,5]pyrimido[1,2-b]pyridazin-2,11-dione (21)
Method A. A solution of the aldimines 18a–d (5 mmol) in chloroform
30 mL), containing a catalytic amount of 4-toluenesulphonic acid, was
4
(
refluxed for 3–4 h. After cooling the formed precipitate was filtered and
recrystallized from ethanol. Yield (65–77%).
Method B. To a solution of the amino acid 11 (5 mmol, 1.47 g) in
ethanol (25 mL) was added thionyl chloride (20 mmol, 2.38 g). The
reaction mixture was kept in a stoppered flask at room temperature for
2
4 h, the solvent was distilled off and the residue was recrystallized
from ethanol in 92% yield.
�
Method C. Compound 12 (5 mmol, 1.47 g) was heated at 120 C in
an oil bath for 1 h to give a molten sticky mass, which was triturated
with ethanol and cooled to room temperature. The separated solid was
�
filtered and recrystallized from ethanol. Yield (74%); m.p. 294 C; IR
(
1
KBr) 3161, 2935, 2864, 2830, 1707, 1673, 1568, 1486, 1466, 1430, 1374,
353, 1317, 1279, 1212, 1175, 1155 cm ; H-NMR (DMSO-d6): � 1.78
�
1 1
(
m, 4H), 2.63 (t, 2H, J = 7 Hz), 2.72 (m, 2H), 2.87 (m, 2H), 3.11 (t, 2H,

Synthesis and Transformations
259
J = 7 Hz), 11.08 (s, 1H, NH); Anal. Calcd. for C13H13N3O2S (275.326):
C, 56.71; H, 4.76. Found: C, 56.95; H, 4.53.
REFERENCES
[
[
1] D. Haigh, D. G. Smith, and R. W. Ward, PCT Int. Appl. WO 98 54,192 (Cl. C07D
98/04) (December 1998); C. A. 130: 38389z (1999).
2] D. J. McNair, A. N. Shaw, A. D. Gribble, L. J. A. Jennings, M. J. Parratt, and R. L.
4
Jarvest, PCT Int. Appl. WO 97 48,707 (Cl. C07D 498/04) (December 1997); C. A.
1
29: 16093a (1998).
[
[
3] R. L. Jarvest, L. J. A. Jennings, and I. L. Pinto, PCT Int. Appl. WO 97 27, 200 (Cl.
C07D 498/04) (July 1997); C. A. 127: 190744g (1997).
4] R. L. Jarvest, I. L. Pinto, S. M. Ashman, C. E. Dabrowski, A. V. Fernndez, L. J. A.
Jennings, P. Lavery, and D. G. Tew, Bioorg. Med. Chem. Lett., 9(3), 443 (1999).
5] M. Guetschow and U. Neumann, J. Med. Chem., 41(10), 1729 (1998).
6] M. R. Player and J. W. Sr. Sowell, J. Heterocycl. Chem., 32(5), 1537 (1995).
7] I. L. Pinto, R. L. Jarvest, B. Clarke, C. E. Dabrowski, A. Fenwick, M. M. Gorczyca,
L. J. Jennings, P. Larvey, E. J. Sternberg, D. G. Tew, and A. West, Bioorg. Med. Chem.
Lett., 9(3), 449 (1999).
[
[
[
[
[
8] B. L. Chenard and W. M. Welch, Jr., Eur. Pat. Appl. EP 900, 799 (Cl. C07D495/04)
(
March 1999); C. A. 130: 209718n (1999).
9] N. Suzuki and S. Furuya, PCT Int. Appl. WO 97 40,846 (Cl.A61K38/09) (November
997). C. A. 128: 16433r (1998).
1
[
10] S. Furuya, N. Coho, K. Kato, and S. Hinuma, PCT Int. Appl. WO 96 24,597 (Cl.
C07D495/04) (August 1996); C. A. 125: 247795q (1996).
[
[
[
11] A.-A. S. El-Ahl, Phosphorus, Sulfur and Silicon, 156, 189 (2000).
12] S. Hanessian and A. G. Parnet, Adv. Carbohydr. Chem. Biochem., 33, 111 (1976).
13] G. Ah-Kow, F. Terrier, M.-J. Pouet, and M.-P. Simonnin, J. Org. Chem., 45, 4399
(1980).
[
14] E. Breitmaier, Structure Elucidation By NMR in Organic Chemistry: A Practical
Guide (New York: John Wiley and Sons, 1993), p. 46.
[
15] F.-L. Chung, R. A. Earl, and L. B. Townsend, J. Org. Chem., 45, 2532 (1980).