Heterocyclization of orthoaminoester and orthoamino-nitrile-thieno[2,3-c] pyridine: The facile synthesis of fused pyridothienopyrimidines

Article abstract of DOI:10.1080/10426500500263748

A highly efficient and versatile synthetic approach to the synthesis of pyrido-[4′,3′:4,5]thieno[2,3-d]pyrimidines (4, 14, 15, 21) and their heterofused (e.g., triazolo-, triazino-, imidazo-, and tetrazolo-,) pyridothienopyrimidines (5-9, 16, 17, 22-24) i

Full text of DOI:10.1080/10426500500263748

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Heterocyclization of
Orthoaminoester and
Orthoamino-nitrile-
thieno[2, 3-c]pyridine: The
Facile Synthesis of Fused
Pyridothienopyrimidines
E. Kh. Ahmed a , M. A. Ameen a & F. F. Abdel-latif a
a Chemistry Department , El-Minia University , El-
Minia, Egypt
Published online: 01 Feb 2007.
To cite this article: E. Kh. Ahmed , M. A. Ameen & F. F. Abdel-latif (2006)
Heterocyclization of Orthoaminoester and Orthoamino-nitrile-thieno[2, 3-c]pyridine:
The Facile Synthesis of Fused Pyridothienopyrimidines, Phosphorus, Sulfur, and Silicon
and the Related Elements, 181:3, 497-510, DOI: 10.1080/10426500500263748
To link to this article: http://dx.doi.org/10.1080/10426500500263748
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Phosphorus, Sulfur, and Silicon, 181:497–510, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500263748
Heterocyclization of Orthoaminoester and
Orthoamino-nitrile-thieno[2,3-c]pyridine:
The Facile Synthesis of Fused Pyridothienopyrimidines
E. Kh. Ahmed
M. A. Ameen
F. F. Abdel-latif
Chemistry Department, El-Minia University, El-Minia, Egypt
A highly efficient and versatile synthetic approach to the synthesis of pyrido-
[4 ꢀ,3 ꢀ:4,5]thieno[2,3-d]pyrimidines (4, 14, 15, 21) and their heterofused (e.g.,
triazolo-, triazino-, imidazo-, and tetrazolo-,) pyridothienopyrimidines (5–
9, 16, 17, 22–24) is described utilizing 2-amino-3-cyano-4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine-6-carboxylic acid ethyl ester (2) and diethyl 2-isothio-
cyanate-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-dicarboxylate (10) as starting
materials.
Keywords Cyclization; heterofused; hydrazine hydrate; orthoaminoester; orthoaminon-
itrile
Orthomino, o-isothiocyanate, -ester, and orthoaminocyano thiophene
derivatives have been found to be important intermediates in the chem-
istry of pyrimidine. Therefore, they have attracted much attention dur-
ing recent years.1−9 The resulting pyrimidine derivatives have found
a wide application in a variety of synthetic transformations. Various
heterocycles have been built to produce the corresponding fused pyrim-
idines, which show marked biological activities,10−13 and these interest-
ing activities have driven our work during the last few years, for which
we have been interested in the synthesis of fused pyrimidines.14−19
The present article follows that line of research by reporting on a
new series of reactions leading the formation of fused pyridothieno-
pyrimidines starting from the bi-functional o-amino-ester and -nitrile
compounds.
Received January 12, 2005; accepted May 1, 2005.
Address correspondence to M. A. Ameen, El-Minia University, Chemistry Department,
Faculty of Science, El-Minia, 61519 Egypt. E-mail: m ameen10@yahoo.com
497

498
E. Kh. Ahmed et al.
RESULTS AND DISCUSSION
In connection with our interest to study the chemistry of pyrimidines,
we have devised the following route for the efficient synthesis of het-
erofused, 1,2,4-triazoles and 1,2,4-triazine by novel methods. The key
compound 2-amino-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-6-
carboxylic acid ethyl ester (2) was synthesized by the condensation of
N-carbethoxy-4-piperidone (1), sulfer, and malononitrile following the
Gewald synthesis.20
The synthesis of model compounds pyridothienopyrimidine 4 and
heterofused triazino- and triazolo-derivatives 5–9 required the conden-
sation of compound 2 with triethylorthoformate in the presence of a cat-
alytic amount of acetic anhydride to give 2-ethoxymethyleneamino-3-
cyano-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-6-carboxylic acid ethyl
ester (3). The treatment of compound 3 with hydrazine hydrate
in ethanol at r.t. afforded the target 3-amino-4-imino-3,4,5,6,7,8-
hexahydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d]pyrimidine-7-carboxylic
ethyl ester (4) in an 85% yield (Scheme 1).
acid
SCHEME 1
The structure of compound 4 was established by 1H, 13C-NMR, and
IR spectra as well as elemental analysis. The elemental analysis was
consistent with a molecular formula of C12H15N5O2S. The IR spec-
troscopy of 4 showed absorption bands at 3300–3200 and 1680 cm−1
related to the NH2, NH, and carbonyl group, respectively. The 1H-
NMR showed two broad singlets at δH = 5.60 and 7.93 ppm, assigned
to the NH2 and NH-imino protons, respectively. The 13C-NMR sup-
1
ported the H-NMR spectroscopy by the appearance of three signals
at δC = 151.31, 154.62, and 156.09 ppm, corresponding to C-2, C NH,
and C O present in compound 4.

Orthoaminoester and Orthoamino-nitrile-thieno[2,3-c]pyridine
499
Interestingly, on condensation of 4 with triethylorthoformate, the cor-
responding 9,10-dihydropyrido[4ꢀ3ꢀ,4,5]thieno[2,3-d]-1,2,4-triazolo[3,2-
f ]pyrimidine-8(7H)-carboxylic acid ethyl ester (5) was obtained in an
84% yield. Similarly, the triazolo derivatives 6, 7, and 8 were pre-
pared by the interaction of 4 with p-chloro-benzaldehyde, acetic anhy-
dride, and phenyl isothiocyanate, respectively. On the other hand, the
1,2,4-triazino moiety was built in compound 9 by the treatment 4 with
chloroacetyl chloride in DMF catalyzed by triethylamine (Scheme 2).
SCHEME 2 Reagents and conditions: i: CH2(CN)2, S, morpholine, EtOH. r.t.;
ii: CH(OEt)3, Ac2O, reflux 8 h; iii: N2H4·H2O, EtOH, stirring 2 h; iv: CH(OEt)3,
Ac2O, reflux 3 h; v: P-chlorobenzaldehyde, AcOH, reflux 3 h; vi: Ac2O, reflux
3 h; vii: PhNCS, pyridine, reflux 4 h; viii: ClCH2COCl, DMF, Et3N, stirring
5 h.
1
The H-NMR and IR were used to identify the 1,2,4-triazolo com-
1
pounds 5–8; neither IR or H-NMR spectra supported the presence of
1
the NH and NH2 group protons that existed in 4. Moreover, the H
NMR spectra revealed two singlet signals at δH = 9.42 and 2.68 ppm,
which were assigned to the triazolo proton in compound 5 and CH3-
protons in compound 7, respectively. The 1H-NMR spectra showed two

500
E. Kh. Ahmed et al.
double-doublets and a multiplet at δH = 7.63, 7.95, and 7.11–7.52 ppm,
corresponding to aromatic protons related to compounds 6 and 8, re-
spectively.
Promoted by the presence of the bifunctional ortho-amino and
-ester groups, which is considered as a precursor for the prepa-
ration of the thioxopyrimidinone derivative 12 by the reaction of
diethyl 2-isothiocyanate-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3,6-
dicarboxylate (10)14 with aniline in dichloromethane to give the open-
form 11. The latter was subjected to ensuing cyclization in sodium
ethoxide solution, yielding the target compound 12. S-methylation of
compound 12 with methyl iodide afforded the target product 3-phenyl-2-
thiomethyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d]-
pyrimidine-7-carboxylic acid ethyl ester (13) (Scheme 3).
SCHEME 3 Reagents and conditions: i: PhNH2; CH2Cl2, stirring 2 h;
ii: EtONa, reflux 1 h; iii: CH3I, 1N NaOH, stirring 2 h; iv: N2H4·H2O, EtOH, re-
flux 15 h; v: HOCH2CH2NH2, 15 h; vi: NaNO2, HCl, AcOH, stirring; vii: POCl3,
reflux 14 h.

Orthoaminoester and Orthoamino-nitrile-thieno[2,3-c]pyridine
501
Treating the S-methylated pyridothienopyrimidine 13 with excess
hydrazine hydrate afforded the 2-hydrazino compound 14, which is
considered a good starting material for the synthesis of the tetracyclic
ring system 16 via a diazotization reaction. The same approach to ob-
taining 3-phenyl-2-[1-hydroxyethan]-4-oxo-3,4,5,6,7,8-hexahydropyri-
do[4ꢀ,3ꢀ:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl ester (15)
can be achieved by the treatment of compound 13 with ethanolamine.
The open structure 15 underwent direct cylization to build the imidazo
moiety 17 (Scheme 3).
The structure of compound 13 was proved by the help of the
1H-NMR, 13C-NMR, and IR spectra as well as elemental analy-
sis. Elemental analysis of 13 was in accordance to its molecular
formula as C19H19N3O3S2. The 1H-NMR spectrum of 13 showed a
triplet and quartet corresponding to ester protons. The methyl pro-
tons were found to resonate as a singlet at δH = 2.49 ppm, whereas
the aromatic protons appeared at δH = 7.27–7.55 ppm. The 13C-
1
NMR supported the H-NMR spectrum by showing three signals at
δC = 15.21, 127.11, 128.11, 129.87, and 130.98 ppm corresponding
to SCH3 and (Ar-C) present in compound 13 (see the Experimen-
tal section). The IR spectrum of 13 showed the absorption of the
CH-arom. and the carbonyl groups at 3000 and 1710–1680 cm−1, re-
spectively. Combining these spectral and analytical data, compound
13 was identified as 3-phenyl-2-thiomethyl-4-oxo-3,4,5,6,7,8-hexa-
hydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid ethyl
ester.
Analogously, compound 2 was proved to be a key intermediate
for other subsequent conversions. Thus, when it was allowed to re-
act with carbon disulfide in alcoholic KOH, the reaction produced
compound 18. This was triturated with methyl iodide to yield ethyl-
2,4-bithiomethyl-5,8-dihydropyrido[4ꢀ,3ꢀ :4,5]thieno[2,3-d]pyrimidine-
7(6H)-carboxylate (19), which was confirmed easily by the 1H-NMR
spectrum that exhibited a singlet for the two CH3-protons at δH = 2.61
ppm (Scheme 4).
Surprisingly, on reacting 19 with excess hydrazine hydrate
in the presence of pyridine as a solvent to synthesize the 2,4-
dihydrazino compound, the process removed only one –SCH3 by
–NHNH2 in ethyl-4-hydrazino-2-thiomethyl-5,8-dihydropyrido[4ꢀ,3ꢀ
:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate (21). The structure of
21 was synthetically proved by its cyclization using triethylortho-
formate and carbon disulfide to give 22 and 23. On reducing 22 by
Raney Ni in ethanol, we isolated our known compound ethyl-7,10-
dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d]-1,2,4-triazolo[2,1- f ]pyrimidine-
8(9H)-carboxylate (24).13 The aforementioned synthetic proof indicated

502
E. Kh. Ahmed et al.
the prevalence of SCH3 group in position 2 without change in compound
21 (Scheme 4).
In conclusion and by the results in hand, we might serve in the
synthesis new classes of fused pyridothienopyrimidines using efficient,
facile, and elegant methods of preparation.
SCHEME 4 Reagents and conditions: i: CS2, alc. KOH, reflux 5 h; ii: CH3I,
1N NaOH, stirring 1 h; iii: N2H4·H2O, pyridine, reflux 4 h; iv: CH(OEt)3, re-
flux 4 h; v, iv: CS2, KOH, CH3OH, reflux 3 h; vi: raney Ni, ethanol, reflux
2 h.

Orthoaminoester and Orthoamino-nitrile-thieno[2,3-c]pyridine
503
EXPERIMENTAL
Melting points were determined on a Boetius melting point apparatus
and are uncorrected. Elemental analyses were performed on a Carol
1
Erba CHN-S Elemental Analyzer 1108. The 13C and H NMR spec-
tra were obtained using sa Bruker AC 300 (1H: 300.13 MHz, 13C :75.5
MHz). The solvents were deuterated dimethyl sulfoxide and chloro-
form. The δ-values are given in ppm and the internal standard was
tetra-methylsilane. The IR spectra were recorded on a Nicolet 250 FT-
IR spectrophotometer as potassium bromide pellets.
2-Ethoxymethyleneamino-3-cyano-4,5,6,7-tetrahydro-
thieno[2,3-c ]pyridine-6-carboxylic Acid Ethyl Ester (3)
A mixture of 2 (2.51 g, 10 mmol) with a few drops of acetic anhydride
in triethylorthoformate (20 mL) was refluxed for 8 h. The separated
crystalline product was obtained on cooling at r.t. Yield: 2.4 g (80%),
colorless plates (ethanol), m.p. 90–92◦C, IR (KBr): υ· = 2210 (CN), 1715
1
(ester C O), 1618 (C N) cm−1, H NMR (DMSO-d6): δ = 1.21 (t, 3H,
COOCH2CH3), 1.35 (t, 3H, OCH2CH3), 2.85 (t, 2H, H-4), 3.65 (t, 2H,
H-5), 4.11 (q, 2H, COOCH2CH3), 4.35 (q, 2H, OCH2CH3), 4.55 (s, 2H,
H-7), 8.55 (s, 1H, CH), 13C NMR (DMSO-d6): δ = 14.38 (CH3), 14.38
(CH3), 23.39 (C-4), 40.93 (C-5), 42.02 (C-7), 60.86 (CH2), 60.97 (CH2),
113.38 (CN), 123.99 (C-3), 129.60 (C-7a), 146.09 (C-3a), 154.55 (C O),
159.07 (CH N), 163.58 (C-2).
3-Amino-4-imino-3,4,5,6,7,8-hexahydropyrido[4ꢀ,3ꢀ:4,5]
thieno[2,3-d ]pyrimidine-7-carboxylic Acid Ethyl Ester (4)
To a stirred suspension of 3 (6.1 g, 20 mmol) in absolute ethanol (40 mL),
hydrazine hydrate (1.5 g, 30 mmol) was added. The reaction mixture
was stirred at r.t. for 2 h. The precipitate that formed was filtered off,
washed with cold ethanol, and recrystalized from dioxane to produce
white needles. Yield: 4.9 g (85%), m.p. 152–154◦C, (Found: C, 49.02; H,
5.01; N, 23.63; S, 10.91. Calc. for C12H15N5O2S (293.35): C, 49.13; H,
5.15; N, 23.87; S, 10.73), IR (KBr): υ = 3360–3280 (NH2, NH), 1708
(ester C O), 1615 (C N) cm−1, 1H NMR (DMSO-d6): δ = 1.21 (t, J = 7
Hz, 3H, COOCH2CH3), 3.00 (t, J = 5.6 Hz, 2H, H-5), 3.65 (t, J = 5.6
Hz, 2H, H-6), 4.11 (q, J = 7 Hz, 2H, COOCH2CH3), 4.55 (s, 2H, H-8),
5.60 (b, 2H, NH2), 7.93 (b, 1H, NH), 8.35 (s, 1H, CH), 13C NMR (DMSO-
d6): δ = 14.42 (CH3), 26.09 (C-5), 40.87 (C-6), 42.79 (C-8), 60.92 (CH2),
119.68 (C-4a), 127.95 (C-4b), 129.84 (C-8a), 148.22 (C-2), 151.31 (C-9a),
154.62 (C NH), 156.09 (C O).

504
E. Kh. Ahmed et al.
9,10-Dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d]-1,2,4-triazolo
[3,2-f ]pyrimidine-8(7H )-carboxylic Acid Ethyl Ester (5)
Compound 4 (0.59 g, 2 mmol) in triethylorthoformate (5 mL) was heated
under reflux for 3 h. The solid product that formed was collected and re-
crystalized from methanol to produce white needles. Yield: 0.5 g (84%),
m.p. 160–161◦C, IR (KBr): υ = 1700 (ester C O), 1610 (C N) cm−1, 1H
NMR (DMSO-d6): δ = 1.24 (t, 3H, COOCH2CH3), 3.17 (t, 2H, H-10),
3.69 (t, 2H, H-9), 4.18 (q, 2H, COOCH2CH3), 4.68 (s, 2H, H-7), 9.12 (s,
1H, H-4), 9.42 (s, 1H, H-2).
2-(4-Chlorophenyl)-9,10-dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-
1,2,4-triazolo[3,2-f ]pyrimidine-8(7H )-carboxylic Acid Ethyl
Ester (6)
A mixture of 4 (1.47 g, 5 mmol) and p-chlorobenzaldehyde (0.7 g, 5 mmol)
in 15 mL of acetic acid was heated under reflux for 3 h. The resulting
precipitate was collected and crystallized from dioxane to produce pale
yellow needles. Yield: 1.8 g (90%), m.p. 175–176◦C, IR (KBr): υ = 3090
(arom. CH), 1705 (ester C O), 1605 (C N) cm−1, 1H NMR (DMSO-d6):
δ = 1.29 (t, 3H, COOCH2CH3), 3.15 (t, 2H, H-10), 3.85 (t, 2H, H-9), 4.18
(q, 2H, COOCH2CH3), 4.75 (s, 2H, H-7), 7.63 (d, 2 ArH), 7.95 (d, 2 ArH),
9.12 (s, 1H, H-4).
2-Methyl-9,10-dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-1,2,4-
triazolo[3,2-f ]pyrimidine-8(7H )-carboxylic Acid Ethyl Ester (7)
A solution of 4 (0.59 g, 2 mmol) in acetic anhydride (5 mL) was re-
fluxed for 3 h. The reaction mixture was allowed to cool and poured
in ice water. The precipitate that formed was filtered off, washed
with cold water, and recrystalized from ethanol to produce white nee-
dles. Yield: 0.56 g (88%), m.p. 181–182◦C, IR (KBr): υ = 2950 (aliph.
1
CH), 1705 (ester C O), 1610 (C N) cm−1, H NMR (DMSO-d6): δ =
1.30 (t, 3H, COOCH2CH3), 2.68 (s, 3H, CH3), 3.27 (t, 2H, H-10),
3.87 (t, 2H, H-9), 4.20 (q, 2H, COOCH2CH3), 4.83 (s, 2H, H-7), 9.09
(s, 1H, H-4).
2-(Phenylamino)-9,10-dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-
1,2,4-triazolo[3,2-f ]pyrimidine-8(7H )-carboxylic Acid Ethyl
Ester (8)
A mixture of 4 (0.59 g, 2 mmol) and phenyl isothiocyanate (0.27 g,
2 mmol) in pyridine (10 mL) was refluxed for 4 h. On cooling, the

Orthoaminoester and Orthoamino-nitrile-thieno[2,3-c]pyridine
505
formed solid product was collected by filtration. Yield: 0.57 g (72%),
yellow crystals (ethanol), m.p. 200–202◦C, IR: (KBr) υ = 3075 (arom.
CH), 1708 (ester C O), 1620 (C N) cm−1, 1H NMR (DMSO-d6): δ = 1.18
(t, 3H, COOCH2CH3), 3.05 (t, 2H, H-10), 3.65 (t, 2H, H-9), 4.16 (q, 2H,
COOCH2CH3), 4.64 (s, 2H, H-7), 7.11–7.52 (m, 5ArH), 9.18 (s, 1H, H-4),
10.45 (s, 1H, NH).
4-Oxo-2,3,4,8,10,11-hexahydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-
1,2,4-triazolo[3,2-f ]pyrimidine-9-carboxylic Acid Ethyl
Ester (9)
To a mixture of 4 (0.293 g, 1 mmol) and chloroacetyl chloride (0.17 g,
1.5 mmol) in DMF (5 mL), triethylamine (0.101 g, 1 mmol) was added.
The reaction mixture was stirred at r.t. for 5 h and then poured into
ice water. The precipitate that formed was filtered off, washed with
water, and recrystalized from ethanol to produce pale yellow needles,
0.25 g (75%), m.p. 139–140◦C, IR (KBr): υ = 3280 (NH), 1710 (ester
C O), 1665 (C O), 1615 (C N) cm−1, 1H NMR (DMSO-d6): δ = 1.18 (t,
3H, COOCH2CH3), 3.14 (t, 2H, H-11), 3.65 (t, 2H, H-10), 4.14 (q, 2H,
COOCH2CH3), 4.30 (s, 2H, C-2), 4.67 (s, 2H, H-8), 9.15 (s, 1H, H-5),
10.83 (s, 1H, NH).
Diethyl-2-(3-phenyl-thioureido)-4,7-dihydro-5H-thieno[2,3-c ]-
pyridine-3,6-dicarboxylate (11)
Isothiocyanate compound 10 (3.4 g, 10 mmol) was dissolved in
dichloromethane (30 mL) and then an equivalent amount of aniline was
added. The mixture was stirred at r.t. for 2 h. The solid product that
precipitated was filtered off and recrystalized from methanol to produce
white crystals, 3.9 g (90%), m.p. 179–181◦C, IR (KBr): υ = 3270 (NH),
1
3080 (arom. CH), 1705 (ester C O), 1680 (ester C O) cm−1, H NMR
(DMSO-d6): δ = 1.26 (t, 6H, 2COOCH2CH3), 2.85 (t, 2H, H-4), 3.65 (t,
2H, H-5), 4.11 (q, 4H, 2COOCH2CH3), 4.55 (s, 2H, H-7), 7.26–7.56 (m,
5H, ArH), 9.55 (s, 1H, NH), 11.02 (s, 1H, NH).
Ethyl-4-oxo-3-phenyl-2-thioxo-1,2,3,4,5,,8-hexahydropyrido-
[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]pyrimidine-7(6H )-carboxylate (12)
A mixture of 11 (4.3 g, 10 mmol) and a solution of sodium ethoxide (0.3 g
sodium in 30 mL absolute ethanol) was refluxed for 1 h. After removing
the solvent, the residue was diluted with water and acidified with HCl.
The product was collected by filtration, washed with water, dried and
recrystallized from DMF/n hexane to produce white crystals. Yield: 3.6 g
(92%), m.p. 273–275◦C, IR (KBr): υ = 3250 (NH), 3040 (arom. CH), 1708

506
E. Kh. Ahmed et al.
(ester C O) cm−1, 1H NMR (DMSO-d6): δ = 1.21 (t, 3H, COOCH2CH3),
2.95 (t, 2H, H-5), 3.72 (t, 2H, H-6), 4.14 (q, 2H, COOCH2CH3), 4.63 (s,
2H, H-8), 7.22–7.54 (m, ArH), 10.50 (s, H, NH).
Ethyl-4-oxo-3-phenyl-2-thiomethyl-3,4,5,8-tetrahydropyrido-
[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]pyrimidine-7(6H )-carboxylate (13)
To a suspension of 12 (1.16 g, 3 mmol) in 1N sodium hydroxide (12 mL),
methyl iodide (0.72 g, 5 mmol) was added. The reaction mixture was
stirred at r.t. for 2 h. The solid was precipitated, collected, washed
with water, and dried. Yield: 1.14 g (95%), colorless crystals (methanol),
m.p. 160–161◦C, (Found: C, 56.64; H, 4.59; N, 10.31; S, 15.94. Calc. for
C19H19N3O3S2 (401.51): C, 56.84; H, 4.77; N, 10.47; S, 15.81), IR (KBr):
1
υ = 3060 (arom. CH), 1710 (ester C O), 1680 (C O) cm−1, H NMR
(DMSO-d6): δ = 1.30 (t, 3H, COOCH2CH3), 2.49 (s, 3H, SCH3), 3.05 (t,
2H, H-5), 3.75 (t, 2H, H-6), 4.21 (q, 2H, COOCH2CH3), 4.68 (s, 2H, H-
8), 7.27–7.55 (m, 5ArH), 13C NMR (DMSO-d6): δ = 14.23 (CH3), 15.21
(SCH3), 24.87 (C-5), 40.21 (C-6), 41.20 (C-8), 60.79 (CH2), 110.94 (C-
4a), 114.63 (C-4b), 121.45 (C-8a), 127.11, 128.11, 129.87, 130.98 (Ar-C),
131.69 (C-9a), 155.22 (C-2), 157.12 (C O), 164.86 (C O).
Synthesis of 14 and 15
To a stirred suspension of 13 (10 mmol) in absolute ethanol (10 mL),
hydrazine hydrate 80% or amino ethanol (5 mL) was added. The re-
action mixture was heated under reflux for 15 h. Excess solvent was
removed and the residue was poured into water. The precipitates that
formed were filtered off, washed with cold ethanol, and recrystalized
from methanol.
Ethyl-2-hydrazino-4-oxo-3-phenyl-3,4,5,,8-tetrahydropyrido-
[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]pyrimidine-7(6H )-carboxylate (14)
Yield: 2.1 g (55%), m.p. 112–113◦C, IR (KBr): υ = 3370–3280 (NH2,
1
NH), 3070 (arom. CH), 1710 (ester C O), 1680 (C O) cm−1, H NMR
(DMSO-d6): δ = 1.28 (t, 3H, COOCH2CH3), 2.65 (b, 2H, NH2), 3.07 (t,
2H, H-5), 3.52 (t, 2H, H-6), 4.17 (q, 2H, COOCH2CH3), 4.64 (s, 2H, H-8),
5.26 (b, H, NH), 7.25–7.54 (m, 5H, ArH).
Ethyl-2-(hydroxyethylamino)-4-oxo-3-phenyl-3,4,5,,8-
tetrahydro-pyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]pyrimidine-
7(6H )-carboxylate (15)
Yield: 1.6 g (40%), m.p. 88–90◦C, IR (KBr): υ = 3430–3300 (OH), 3230
(NH), 3080 (arom. CH), 2920 (aliph. CH), 1709 (ester C O) cm−1,1H

Orthoaminoester and Orthoamino-nitrile-thieno[2,3-c]pyridine
507
NMR (DMSO-d6): δ = 1.29 (t, 3H, COOCH2CH3), 2.51 (b, H, OH), 2.97
(t, 2H, H-5), 3.47 (t, 2H, H-6), 3.54–3.71 (m, 4H, 2CH2), 4.16 (q, 2H,
COOCH2CH3), 4.58 (s, 2H, H-8), 4.63 (s, H, NH), 7.26–7.58 (m, 5H,
ArH).
Ethyl-5-oxo-4-phenyl-4,5,,6,9-tetrahydropyrido[4ꢀ,3ꢀ:4,5]
thieno[2,3-d ]tetrazolo[5,1-b ]pyrimidine-8(7H )- carboxylate
(16)
To a solution of 14 (0.39 g, 1 mmol) in conc. HCl (5 mL) and glacial
acetic acid (5 ml) at 0◦C, a cold solution of (10%) sodium nitrite (7 mL,
10 mmol) was added with stirring for 10 min. The formed precipi-
tate was filtered, washed with water, and recrystalized from ethanol
to produce buff crystals. Yield: 0.25 g (62%), m.p. 205–207◦C, IR (KBr):
υ = 3065 (arom. CH), 1712 (ester C O), 1675 (C O) cm−1,1H NMR
(DMSO-d6): δ = 1.21 (t, 3H, COOCH2CH3), 2.89 (t, 2H, H-6), 3.53
(t, 2H, H-7), 4.13 (q, 2H, COOCH2CH3), 4.55 (s, 2H, H-9), 7.25–7.51
(m, 5H, ArH).
Ethyl-5-oxo-4-phenyl-1,2,4,5,,6,9-hexahydropyrido[4ꢀ,3ꢀ:4,5]
thieno[2,3-d ]imidazo[2,1-b ]pyrimidine-8(7H )-
carboxylate (17)
A mixture of compound 15 (0.42 g, 1 mmol) and phosphoryl chloride
(10 mL) was refluxed for 14 h. Excess solvent was removed and the
residue was poured into water. After extraction with chloroform, the
organic layer was washed with sodium bicarbonate and water, and then
dried over anhydrous sodium sulfate. The solvent was evaporated under
vacuum. Yield: 0.14 g (35%), yellow crystals (methanol/n-hexane), m.p.
132–133◦C, IR (KBr): υ = 3085 (arom. CH), 1707 (ester C O) cm−1, 1H
NMR (DMSO-d6): δ = 1.24 (t, 3H, COOCH2CH3), 2.86 (t, 2H, H-6), 3.65
(t, 2H, H-7), 3.85–4.05 (m, 4H, 2CH2), 4.17 (q, 2H, COOCH2CH3), 4.55
(s, 2H, H-9), 7.28–7.59 (m, 5H, ArH).
Ethyl-2,4-dithioxo-1,2,3,4,5,8-hexahydropyrido[4ꢀ,3ꢀ:4,5]thieno
[2,3-d ]pyrimidine-7(6H )-carboxylate (18)
To suspension of 2 (2.5 g, 10 mmol) in 10 % alcoholic potassium hy-
droxide (15 mL), 5 mL of carbon disulfide was added. The mixture was
refluxed for 5 h. Excess solvent was removed. The residue diluted with
water and acidified with HCl. The product was filtered off, washed with
water, dried and recrystallized from DMF/water to produce yellow crys-
tals, 3 g (93%), m.p. 251–252◦C, IR (KBr): υ = 3270 (NH), 1710 (ester

508
E. Kh. Ahmed et al.
C O), 1612 (C N) cm−1,1H NMR (DMSO-d6): δ = 1.21 (t, J = 7 Hz, 3H,
COOCH2CH3), 3.07 (t, J = 5.6 Hz, 2H, H-5), 3.62 (t, J = 5.6 Hz, 2H, H-
6), 4.06 (q, J = 7 Hz, 2H, COOCH2CH3), 4.53 (s, 2H, H-8), 13.25 (bs,
2H, 2NH), 13C NMR (DMSO): δ = 14.37 (CH3), 27.22 (C-5), 40.92 (C-6),
42.58 (C-8), 60.93 (CH2), 115.33 (C-4a), 126.19 (C-4b), 130.73 (C-8a),
148.70 (C-9a), 154.70 (C O) 169.21 (C S), 181.27 (C S)
Ethyl-2,4-dithiomethyl-5,8-dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-
d ]pyrimidine-7(6H )-carboxylate (19)
To a suspension of 18 (0.98 g, 3 mmol) in 1N sodium hydroxide (12 mL),
methyl iodide (1.44 g, 10 mmol) was added. The reaction mixture was
stirred at r.t. for 1 h. The solid was precipitated, filtered off, washed
with water, and dried. Yield: 0.92 g (86%), orange crystals (methanol).
m.p. 134–135◦C, IR (KBr): υ = 1710 (ester C O), 1615 (C N) cm−1, 1H
NMR (DMSO-d6): δ = 1.21 (t, 3H, COOCH2CH3), 2.61 (s, 6H, 2CH3),
2.96 (t, 2H, H-5), 3.68 (t, 2H, H-6), 4.06 (q, 2H, COOCH2CH3), 4.64 (s,
2H, H-8).
Ethyl-4-hydrazino-2-thiomethyl-5,8-dihydropyrido[4ꢀ,3ꢀ:4,5]
thieno[2,3-d ]pyrimidine-7(6H )-carboxylate (21)
To a stirred suspension of 19 (3.5 g, 10 mmol) in pyridine (30 mL),
hydrazine hydrate 80% (2 mL) was added. The reaction mixture was
heated under reflux for 4 h. The precipitate that formed after cool-
ing was filtered off, washed with cold ethanol, and recrystalized from
methanol to produce gray needles. Yield: 2.2 g (65%), m.p. 176–177◦C,
(Found: C, 44.38; H, 5.17; N, 30.19; S, 9.89. Calc. for C12H17N7O2S
(323.38): C, 44.57; H, 5.30; N, 30.32; S, 9.68), IR (KBr): υ = 3380–3270
(NH2, NH), 1702 (ester C O), 1630 (C N) cm−1,1H NMR (DMSO-d6):
δ 1.21 (t, 3H, COOCH2CH3), 2.56 (s, 3H, SCH3), 2.61 (b, 2H, NH2),
=
2.85 (b, 1H, NH), 3.08 (t, 2H, H-5), 3.78 (t, 2H, H-6), 4.21 (q, 2H,
COOCH2CH3), 4.85 (s, 2H, H-8).
Ethyl-4-thiomethyl-7,10-dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-
1,2,4-triazolo[2,1-f ]pyrimidine-8(9H )-carboxylate (22)
A mixture of compound 21 (0.65 g, 2 mmol) and triethylorthoformate
(10 mL) was refluxed for 4 h. After cooling at r.t., the formed product
was filtered off, dried, and recrystallized from ethanol to produce color-
less crystals. Yield: 0.50 g (72%). m.p. 192–194◦C, IR (KBr): υ = 1706
1
(ester C O), 1613 (C N) cm−1, H NMR (DMSO-d6): δ = 1.30 (t, 3H,

Orthoaminoester and Orthoamino-nitrile-thieno[2,3-c]pyridine
509
COOCH2CH3), 2.81 (s, 3H, SCH3), 3.29 (t, 2H, H-10), 3.85 (t, 2H, H-9),
4.22 (q, 2H, COOCH2CH3), 4.77 (s, 2H, H-7), 8.79 (s, H, CH).
Ethyl-3-thioxo-4-thiomethyl-2,3,7,10-
tetrahydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-1,2,4-triazolo[2,1-
f]pyrimidine-8(9H )-carboxylate (23)
To a mixture of 21 (0.65 g, 2 mmol) and KOH (0.112 g, 2 mmol ) in
methanol (10 mL), carbon disulfide (1 mL) was added. The mixture was
refluxed for 3 h. After removing the solvent on vacuum, the residue was
diluted with water and acidified with HCl. The solid product was filtered
off, washed with water, dried, and recrystalized from DMF/water to
produce yellow crystals. Yield: 0.47 g (62%), m.p. 285–287◦C, IR (KBr):
υ = 3220 (NH), 1705 (ester C O), 1610 (C N) cm−1,1H NMR (DMSO-
d6): δ = 1.28 (t, 3H, COOCH2CH3), 2.71 (s, 3H, SCH3), 3.24 (t, 2H, H-10),
3.82 (t, 2H, H-9), 4.20 (q, 2H, COOCH2CH3), 4.73 (s, 2H, H-7), 9.86 (b,
1H, NH).
Ethyl–7,10-dihydropyrido[4ꢀ,3ꢀ:4,5]thieno[2,3-d ]-1,2,4-
triazolo[2,1-f ]pyrimidine-8(9H )-carboxylate (24)
To a solution of compound 22 (0.7 g, 2 mmol) in ethanol (10 mL), Raney
nickel catalyst (0.2 g) was added. The mixture was gently refluxed under
a hydrogen atmosphere for 2 h. The catalyst was removed by filtration.
The solvent was removed under vacuum to give white needles in a 61%
yield. (M.p. 212–214◦C Lit.13)
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