Utility of a 2-Aminothiophene-3-carboxamide in the synthesis of thienopyridines and thienopyrimidines

Article abstract of DOI:10.1002/hc.10179

The article discussed about the utility of a 2-aminothiophene-3-carboxamide in the synthesis of Theinopyridines and theinopyrimidines. The reactivity of the compound toward a variety of chemical reagents was studied. The reaction mixture was evaporated in vacuo and triturated with cold water, whereby the resulting solid product was collected by filtration and crystallized from the proper solvent.

Full text of DOI:10.1002/hc.10179

Heteroatom Chemistry
Volume 14, Number 5, 2003
Utility of a 2-Aminothiophene-3-carboxamide
in the Synthesis of Thienopyridines
and Thienopyrimidines
Rafat M. Mohareb,1 Sherif M. Sherif,1 Hatem M. Gaber,2
Sami S. Ghabrial,2 and Susan I. Aziz1
1Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
2National Organization for Drug Control and Research (NODCAR), P.O. Box 29, Cairo, Egypt
Received 17 March 2003
RESULTS AND DISCUSSION
ABSTRACT: 2-Amino-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxamide (1) was prepared according
to Gewald procedure. Its reactivity toward a variety
of chemical reagents was studied to give thienopy-
Compound 1 was prepared in a one-pot facile high-
yield reaction by the alkaline condensation of cyclo-
hexanone, elemental sulfur, and cyanoacetamide in
ethanolic triethylamine solution following Gewald
synthesis. The reactivity of compound 1 toward a
variety of chemical reagents was investigated. It was
found that the reaction of compound 1 with triethyl
orthoformate, in the presence of acetic anhydride,
gave the 4-hydroxybenzo[b]thieno[2,3-d]pyrimidine
derivative 3 and not the keto form 2 (Scheme 1).
Structure 3 was established on the basis of analyt-
ical and spectral data. Thus, the IR spectrum of the
reaction product showed the OH group stretching at
ꢀ
C
ridines and -pyrimidines. 2003 Wiley Periodicals, Inc.
Heteroatom Chem 14:459–467, 2003; Published online
in Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.10179
INTRODUCTION
Benzo[b]thiophene derivatives have been found to
possess good medicinal and biological activities
[1–3]. Recently, we were involved in a program us-
ing these derivatives in heterocyclic and fused het-
erocyclic synthesis to afford pyrazole, pyrimidine,
and pyridazine derivatives [4–6]. In view of these ver-
satile benefits and in connection with our program,
we aimed to extend this route using 2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxamide (1) [7]
as a key precursor for the synthesis of some new hete-
rocycles with an expected wide spectrum of potential
applications.
1
3517–3246 cm−1. Also, its H NMR spectrum exhib-
ited a singlet at δ 7.12 ppm for pyrimidine H-2 proton
and a broad D2O-exchangeable singlet at δ 11.59 ppm
for the OH group.
Compound 1 reacted with phenyl isothiocyanate
in refluxing ethanol containing a catalytic amount
of triethylamine, to afford the 2-mercapto-3-
phenylbenzo[b]thieno[2,3-d]pyrimid-4-one deriva-
tive 4 via ammonia liberation (Scheme 1). The
IR spectrum (KBr) of 4 revealed the SH group
stretching at 2558 cm−1 and the cyclic C O group
stretching at 1695 cm−1. Moreover, its 1H NMR
spectrum exhibited a singlet at δ 3.89 ppm (D2O-
exchangeable) corresponding to SH.
Correspondence to: Rafat M. Mohareb; e-mail: rmmohareb@
With halides, 1 formed the acyl derivatives 5a,b
(Scheme 1). The IR spectrum of 5a showed an
hotmail.com.
c
ꢀ
2003 Wiley Periodicals, Inc.
459

460 Mohareb et al.
SCHEME 1
absorption peak at ν 3445–3230 cm−1 due to the
stretching vibrations of the NH2 and NH functions
as well as two C O stretching absorption peaks at
and spectral data. As an example, the IR spectrum
of compound 10a (X = CN; Ar = C6H5) showed ab-
sorption peaks at ν 3520–3203 and 2220 cm−1 corre-
sponding to OH and CN functions, respectively. Also,
1
1669 and 1660 cm−1. Also, its H NMR spectrum
1
its H NMR spectrum showed a D2O-exchangeable
revealed two D2O-exchangeable singlets at δ 5.95
(2H) and δ 8.63 (1H) ppm corresponding to NH2
and NH protons, respectively. As expected, com-
pounds 5a,b underwent cyclization, in concentrated
sulfuric acid at 160◦C, to give the corresponding
4-hydroxybenzo[b]thieno[2,3-d]pyrimidine deriva-
tives 6a,b.
The behavior of 1 toward ꢀ-addition was also
examined. It reacted with equimolar amounts of
ꢁ-substituted cinnamonitrile derivatives 7a–d, in
ethanol containing a catalytic amount of piperi-
dine, to yield the corresponding 4-hydroxybenzo-
[b]thieno[2,3-b]pyridine derivatives 10a–d (Scheme
1). The reaction took place via the intermediacy of
8a–d and 9a–d through a Michael-type addition, sub-
sequent intramolecular cyclization via loss of ammo-
nia, followed by elimination of hydrogen cyanide.
Similar reactions of cinnamonitrile derivatives have
been reported in the literature [8,9]. The structures
of 10a–d were confirmed on the basis of analytical
singlet at δ 9.92 ppm corresponding to a OH moi-
ety. The reactions open a facile and convenient route
to fused pyrimidines and fused pyridines, which are
otherwise difficult to access.
As an extension of this synthetic route, the be-
havior of 1 toward some cyanomethylene reagents
11a–c was investigated. Thus, compound 1 re-
acted with equimolar amounts of malononitrile
(11a), in refluxing ethanol containing a catalytic
amount of triethylamine, to yield the correspon-
ding 4-hydroxybenzo[b]thieno[2,3-d]pyrimidine-2-
acetonitrile derivative 13a (Scheme 2). Formation
of 13a was assumed to proceed through the inter-
mediate formation of 12a, followed by intramolec-
ular cyclization via ammonia elimination. Both ele-
mental and spectral data of 13a were consistent with
the assigned structure. Thus, its IR spectrum showed
the OH group stretching at 3550–3335 cm−1 and one
1
CN group stretching at 2220 cm−1. Moreover, its H

Utility of a 2-Aminothiophene-3-carboxamide in the Synthesis of Thienopyridines and Thienopyrimidines 461
SCHEME 2
NMR spectrum (DMSO-d6) revealed, in addition to
the expected agreeable signals, the presence of a sin-
glet signal at δ 4.34 ppm (s, 2H, CH2) and a D2O-
exchangeable singlet at δ 11.00 ppm (s, 1H, OH).
On the other hand, the reaction of 1 with equimo-
lar amounts of ethyl cyanoacetate (11b), under the
same experimental conditions, surprisingly yielded
a product containing a methyleneamide moiety in-
stead of the expected ester moiety. The IR spectrum
of this product exhibited absorption bands at 3520–
3188 (OH, NH2) and 1665 cm−1 (C O). Addition-
ally, its 1H NMR spectrum showed the complete ab-
sence of both triplet and quartet signals related to
the presence of the expected ester group, while the
spectrum showed only the presence of a singlet sig-
nal at δ 4.29 ppm attributed to the side chain CH2
group and two types of D2O-exchangeable protons
at δ 5.32 (s, 2H, NH2) and 10.22 ppm (s, 1H, OH), be-
sides the expected signals for the tetrahydrobenzene
moiety. Collecting the above data led to the conclu-
sion that the reaction product could be formulated
as the 4-hydroxybenzo[b]thieno[2,3-d]pyrimidine-2-
acetamide structure 13b. Formation of 13b, in this
reaction, was assumed to proceed via the intermedi-
acy of the initial noneisolable ester 12b, which un-
derwent cyclization followed by ammonolysis, un-
der the applied reaction conditions, with the ammo-
nia eliminated during the cyclization step affording
the final isolable acetamide derivative 13b via loss of
ethanol. A similar observation has been reported pre-
viously [10,11]. A conclusive evidence for the struc-
ture of 13b was achieved by its independent synthe-
sis via an alternative route. Thus, compound 1 re-
acted with equimolar amounts of cyanoacetamide
(11c) to afford a single product that was found to
be identical in all respects (m.p., mixed m.p., and
IR data) with 13b. Compound 13b, in this case, was
believed to be formed through the intermediacy of
12c, followed by intramolecular cyclization via loss
of ammonia molecule.

462 Mohareb et al.
Further proof of the structures 13a,b was ob-
tained by studying their behavior toward various
chemical reagents. Their reactivity was attributed to
the electron-withdrawing cyano or amide group at-
tached to the methylene moiety. Thus, compounds
13a and 13b could be easily coupled with aryldia-
zonium chloride in ethanolic sodium acetate solu-
tions at 0–5◦C, to afford the arylhydrazone deriva-
tives 14a–f (Scheme 2). Their structures were con-
firmed on the basis of their correct elemental analy-
ses as well as compatible spectral data. Thus, the IR
spectra (KBr) of 14a–c showed the presence of CN
function in the 2221–2216 cm−1 region. The arylhy-
drazone derivative 14a, as an example, revealed in its
1H NMR spectrum two D2O-exchangeable singlets at
δ 8.29 (1H) and δ 11.54 (1H) ppm corresponding to
NH and OH groups, respectively. On the other hand,
involved initial addition of the active methylene
in 11a to the cyano moiety in 13a, followed by
intramolecular cyclization to give the stable product
18a. Its IR spectrum revealed absorption bands
at 3525–3205 cm−1 due to one OH and two NH2
functions, and at 2217 cm−1 due to CN function.
Moreover, its 1H NMR spectrum showed three
singlets (D2O-exchangeable) at δ 6.31 (2H), δ 7.51
(2H), and δ 11.25 (1H) ppm corresponding to two
NH2 and one OH protons, respectively. Analogously,
the reaction of 13a with ethyl cyanoacetate (11b)
and elemental sulfur, under the same experimental
conditions, yielded the 4-amino-3-cyano-2-hydroxy-
thiophen-5-yl derivative 18b via ethanol elimination.
Its IR spectrum showed an absorption peak at 3545–
3216 cm−1 due to the stretching vibrations of the
two OH and one NH2 functions as well as one
CN stretching absorption peak at 2220 cm−1. Also,
its 1H NMR spectrum (DMSO-d6) revealed three
D2O-exchangeable protons at δ 5.95 (s, 2H, NH2),
9.52 (s, 1H, OH), and 11.61 ppm (s, 1H, OH).
the IR spectra of 14d–f showed the presence of C
O
function in the 1666–1662 cm−1 region. The arylhy-
drazone derivative 14d revealed in its 1H NMR spec-
trum three D2O-exchangeable singlets at δ 5.51 (2H),
δ 8.92 (1H), and δ 9.88 (1H) ppm corresponding to
NH2, NH, and OH protons, respectively.
EXPERIMENTAL
As expected, the methylene moiety in 13a,b
proved to be highly reactive toward aldehydes.
Thus, the condensation of 13a,b with benzalde-
hyde (15a), 4-methoxybenzaldehyde (15b), 4-hydro-
xybenzaldehyde (15c), or 3,4-dichlorobenzaldehyde
(15d), in boiling ethanol containing a catalytic
amount of piperidine, yielded the corresponding
arylidene derivatives 16a–h in reasonable yields
(Scheme 2). As an example, the structure 16d was es-
tablished on the basis of IR spectrum, which revealed
a broad peak at ν 3520–3315 cm−1 characteristic for
OH function and a peak at ν 2215 cm−1 characteristic
of CN function. Also, its 1H NMR spectrum exhibited
a singlet at δ 6.68 (1H) ppm, a multiplet at δ 7.22–7.41
(3H) ppm, and a D2O-exchangeable singlet at δ 11.31
(1H) ppm corresponding to CH ylidene, C6H3, and
OH moieties, respectively.
All melting points are uncorrected. IR spectra were
recorded (KBr) on a Pye Unicam Sp-1000 spec-
trophotometer. H NMR spectra were obtained on
a Varian EM-390 90 MHz spectrometer in DMSO-d6
as solvent and TMS as internal reference. Chemical
shifts δ are expressed in ppm. Compound 1 was pre-
pared as reported previously [7].
1
4-Hydroxy-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (3)
Equimolar amounts (0.01 mol) of 1 and triethyl or-
thoformate, in acetic acid (20 ml) containing acetic
anhydride (10 ml), were heated under reflux for 5 h.
The reaction mixture was allowed to stand overnight
at room temperature. The formed solid product was
collected by filtration.
The condensation of 13a,b with N,N-dimethyl-
4-nitrosoaniline gave the imino derivatives 17a,b
(Scheme 2). Compound 17b, as an example, exhib-
3: Pale yellow crystals (from AcOH–H2O), yield
68% (1.40 g), m.p. 82–84◦C. IR (ν/cm−1) = 3517–3246
1
1
ited in its H NMR spectrum two singlets at δ 2.79
(OH), 2925, 2853 (CH2), 1630 (C N). H NMR δ =
and 2.88 ppm for the two CH3 groups and a multiplet
at δ 7.12–7.34 ppm attributed to C6H4 moiety.
1.63–2.04 (m, 4H, 2H-6, 2H-7), 2.27–2.83 (m, 4H, 2H-
5, 2H-8), 7.12 (s, 1H, pyrimidine H-2), 11.59 (s, br,
1H, OH, D2O-exchangeable). C10H10N2OS (206.25):
Calcd: C, 58.23; H, 4.88; N, 13.58; S, 15.54; Found:
C, 58.0; H, 4.7; N, 13.5; S, 15.3.
The reactivity of 2-acetonitrile derivative 13a
toward the formation of thiophenes via Gewald re-
action [6,12,13] was studied. Thus, when compound
13a was allowed to react with equimolar amounts
of each of malononitrile (11a) and elemental sulfur,
upon boiling under reflux in ethanol–triethylamine
solution, it yielded the corresponding 3-cyano-2,4-
diaminothiophen-5-yl derivative 18a (Scheme 2).
A proposed mechanism for the formation of 18a
2-Mercapto-3-phenyl-5,6,7,8-tetrahydrobenzo-
[b]thieno[2,3-d]pyrimid-4(3H)-one (4)
A mixture of 1 (0.01 mol) and phenyl isothio-
cyanate (0.01 mol) in ethanol (30 ml) containing a

Utility of a 2-Aminothiophene-3-carboxamide in the Synthesis of Thienopyridines and Thienopyrimidines 463
catalytic amount of Et3N (0.5 ml) was heated, un-
4-Hydroxy-2-methyl-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine (6a) and 4-Hydroxy-2-
phenyl-5,6,7,8-tetrahydrobenzo[b]thieno-
[2,3-d]pyrimidine (6b)
der reflux, for 6 h. The reaction mixture was then
poured onto ice/water and neutralized with dilute
HCl. The solid product, so formed, was collected by
filtration.
General Procedure. A suspension of dry solid of
each of 5a or 5b (0.02 mol) in concentrated sulfuric
acid (10 ml) was heated in an oil bath (160◦C) for
6 h and then left to cool. The reaction mixture was
poured over water and neutralized with sodium hy-
droxide (10%), and then left aside overnight at room
temperature. The formed solid product, in each case,
was collected by filtration and crystallized from the
proper solvent.
4: Buff crystals (from 1,4–dioxane), yield 71%
(2.23 g), m.p. 73◦C. IR (ν/cm−1) = 3035 (CH aro-
matic), 2926, 2852 (CH2), 2558 (SH), 1695 (C O),
1
1628 (C N). H NMR δ = 1.61–2.05 (m, 4H, 2H-6,
2H-7), 2.22–2.61 (m, 4H, 2H-5, 2H-8), 3.89 (s, 1H,
SH, D2O-exchangeable), 7.09–7.29 (m, 5H, C6H5).
C16H14N2OS2 (314.41): Calcd: C, 61.12; H, 4.48; N,
8.90; S, 20.39; Found: C, 61.0; H, 4.5; N, 8.7; S,
20.0.
6a: Yellow crystals (from EtOH), yield 61%
(2.68 g), m.p. 220◦C. IR (ν/cm−1) = 3552–3335
(OH), 2960–2862 (CH3, CH2), 1625 (C N). 1H NMR
δ = 1.61–2.02 (m, 4H, 2CH2), 2.25–2.77 (m, 7H,
2CH2, CH3), 9.68 (s, 1H, OH, D2O-exchangeable).
C11H12N2OS (220.28): Calcd: C, 59.97; H, 5.48; N,
12.71; S,14.55; Found: C, 60.0; H, 5.3; N, 12.7; S, 14.4.
6b: Yellow crystals (from 1,4–dioxane), yield 58%
(3.27 g), m.p. 199◦C. IR (ν/cm−1) = 3560–3350 (OH),
3030 (CH aromatic), 2927, 2855 (CH2), 1625 (C N).
1H NMR δ = 1.61–2.08 (m, 4H, 2CH2), 2.24–2.68 (m,
4H, 2CH2), 7.12–7.33 (m, 5H, C6H5), 10.20 (s, 1H, OH,
D2O-exchangeable). C16H14N2OS (282.35): Calcd: C,
68.06; H, 4.99; N, 9.92; S, 11.35; Found: C, 67.9; H,
4.7; N, 9.9; S, 11.2.
2-Acetamido-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxamide (5a)
A mixture of 1 (0.01 mol) and acetyl chloride
(0.01 mol) in glacial acetic acid (15 ml) was heated,
under reflux, for 5 h. The reaction mixture was
cooled at room temperature and poured onto ice,
whereby the resulting solid product was collected by
filtration.
5a: Pale yellow crystals (from AcOH–H2O), yield
69% (1.64 g), m.p. 180◦C. IR (ν/cm−1) = 3445–
3230 (NH2, NH), 2959–2865 (CH3, CH2), 1669, 1660,
(2C O). 1H NMR δ = 1.55–1.79 (m, 4H, 2CH2), 2.03–
2.39 (m, 4H, 2CH2), 2.59 (s, 3H, CH3CO), 5.95
(s, 2H, NH2, D2O-exchangeable), 8.63 (s, 1H, NH,
D2O-exchangeable). C11H14N2O2S (238.29): Calcd: C,
55.44; H, 5.91; N, 11.75; S, 13.45; Found: C, 55.4; H,
5.7; N, 11.5; S, 13.4.
4-Hydroxy-2-phenyl-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-b]pyridine-3-carbonitrile (10a),
4-Hydroxy-2-(4-methoxyphenyl)-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-b]pyridine-
3-carbonitrile (10b), Ethyl 4-hydroxy-2-
(4-methoxyphenyl)-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-b]pyridine-3-carboxylate (10c), and
Ethyl 2-(4-chlorophenyl)-4-hydroxy-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-b]-pyridine-
3-carboxylate (10d)
2-Benzamido-4,5,6,7-tetrahydrobenzo[b]-
thiophene-3-carboxamide (5b)
To a cold solution (0–5◦C) of 1 (0.01 mol) in pyridine
(15 ml), benzoyl chloride (0.01 mol) was added drop-
wise with continuous stirring for 1 h. The reaction
mixture was heated, under reflux, for 3 h and then
evaporated in vacuo. The remaining product was trit-
urated with ethanol and the formed solid product
was isolated by filtration.
General Procedure. To
a suspension of 1
(0.01 mol), in ethanol (30 ml) containing a cat-
alytic amount of piperidine (0.5 ml), the appro-
priate ꢁ-substituted cinnamonitrile derivative 7a–d
(0.01 mol) was added. The reaction mixture was re-
fluxed for 6 h and then evaporated in vacuo. The re-
action mixture was triturated with cold water and
neutralized with HCl. The resulting solid product, in
each case, was collected by filtration and crystallized
from the proper solvent.
5b: Pale brown crystals (from EtOH), yield
58% (1.74 g), m.p. 238◦C. IR (ν/cm−1) = 3450–
3240 (NH2, NH), 3033 (CH aromatic), 2923, 2855
1
(CH2), 1675, 1660 (2C O). H NMR δ = 1.58–2.05
(m, 4H, 2CH2), 2.22–2.51 (m, 4H, 2CH2), 6.13
(s, 2H, NH2, D2O-exchangeable), 7.21–7.39 (m,
5H, C6H5), 9.14 (s, 1H, NH, D2O-exchangeable).
C16H16N2O2S (300.36): Calcd: C, 63.98; H, 5.36; N,
9.32; S, 10.67; Found: C, 63.7; H, 5.2; N, 9.3; S,
10.7.
10a: Buff crystals (from 1,4–dioxane-H2O), yield
70% (2.14 g), m.p. 97◦C. IR (ν/cm−1) = 3520–
3203 (OH), 3031 (CH aromatic), 2928, 2853 (CH2),
1
2220 (CN), 1630 (C N). H NMR δ = 1.65–2.01 (m,

464 Mohareb et al.
4H, 2CH2), 2.25–2.71 (m, 4H, 2CH2), 7.52–7.81 (m,
5H, C6H5), 9.92 (s, 1H, OH, D2O-exchangeable).
C18H14N2OS (306.37): Calcd: C, 70.56; H, 4.60; N,
9.14; S, 10.46; Found: C, 70.2; H, 4.5; N, 9.0; S, 10.4.
10b: Brown crystals (from 1,4–dioxane-H2O),
yield 74% (2.49 g), m.p. 77◦C. IR (ν/cm−1) = 3525–
3203 (OH), 3025 (CH aromatic), 2960–2857 (CH3,
CH2), 2216 (CN), 1627 (C N). C19H16N2O2S (336.39):
Calcd: C, 67.83; H, 4.78; N, 8.32; S, 9.53; Found: C,
67.5; H, 4.9; N, 8.1; S, 9.4.
ture was then cooled, poured onto cold water, neu-
tralized with dilute HCl, whereby the resulting solid
product was collected by filtration.
Method B. The same experimental procedure
described before for the synthesis of 13b was fol-
lowed up except for using cyanoacetamide (11c)
(0.01 mol) instead of ethyl cyanoacetate. The prod-
uct was found to be identical in all respects (m.p.,
mixed m.p., and IR spectrum) with authentic sam-
ple prepared according to method A.
13b: Buff crystals (from DMF–H2O), yield 61%
(1.60 g), m.p. 129◦C. IR (ν/cm−1) = 3520–3188
(OH, NH2), 2927, 2852 (CH2), 1665 (C O), 1630
(C N). 1H NMR δ = 1.63–2.03 (m, 4H, 2CH2), 2.20–
2.61 (m, 4H, 2CH2), 4.29 (s, 2H, CH2), 5.32 (s,
br, 2H, NH2, D2O-exchangeable), 10.22 (s, 1H, OH,
D2O-exchangeable). C12H13N3O2S (263.30): Calcd: C,
54.73; H, 4.97; N, 15.95; S, 12.17; Found: C, 54.7; H,
4.9; N, 16.0; S, 11.9.
10c: Yellowish brown crystals (from EtOH-H2O),
yield 69% (2.64 g), m.p. 62◦C. IR (ν/cm−1) = 3550–
3340 (OH), 3026 (CH aromatic), 2962–2871 (CH3,
1
CH2), 1716 (C O), 1630 (C N). H NMR δ = 1.31
(t, 3H, CH3), 1.59–2.12 (m, 4H, 2CH2), 2.23–2.59 (m,
4H, 2CH2), 3.72 (s, 3H, OCH3), 4.15 (q, 2H, CH2),
7.01–7.17 (m, 4H, C6H4), 10.72 (s, 1H, OH, D2O-
exchangeable). C21H21NO4S (383.44): Calcd: C, 65.78;
H, 5.51; N, 3.65; S, 8.36; Found: C, 65.8; H, 5.2; N,
3.5; S, 8.1.
10d: Pale brown crystals (from EtOH), yield 65%
(2.52 g), m.p. 68◦C. IR (ν/cm−1) = 3540–3331 (OH),
3028 (CH aromatic), 2966–2855 (CH3, CH2), 1720
(C O), 1625 (C N). 1H NMR δ = 1.39 (t, 3H, CH3),
1.61–2.04 (m, 4H, 2CH2), 2.21–2.60 (m, 4H, 2CH2),
4.23 (q, 2H, CH2), 7.11–7.31 (m, 4H, C6H4), 10.12 (s,
1H, OH, D2O-exchangeable). C20H18ClNO3S (387.87):
Calcd: C, 61.93; H, 4.67; N, 3.61; S, 8.26; Found: C,
61.9; H, 4.5; N, 3.3; S, 8.0.
4-Hydroxy-ꢁ-(phenylhydrazono)-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidine-
2-acetonitrile (14a), ꢁ-(4-Chlorophenylhydra-
zono)-4-hydroxy-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine-2-acetonitrile (14b),
and 4-Hydroxy-ꢁ-(4-methylphenylhydrazono)-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidine-2-acetonitrile (14c)
General Procedure. A solution of compound 13a
(0.005 mol) in ethanol (30 ml) containing sodium ac-
etate (1.0 g) was cooled to 0–5◦C with stirring. The
reaction mixture was then treated gradually with
a cold solution of the appropriate aryldiazonium
chloride salt [prepared from the corresponding ary-
lamine (0.005 mol) and the appropriate quantities
of concentrated HCl and NaNO2]. After the addi-
tion of the diazonium salts was completed, the re-
action mixture was stirred at room temperature for
an additional 30 min. The precipitated product, in
each case, separated upon dilution with cold water
(30 ml), was filtered off, washed with water several
times, dried, and crystallized from the appropriate
solvent.
14a: Orange crystals (from 1,4–dioxane–H2O),
yield 80% (1.40 g), m.p. 120◦C. IR (ν/cm−1) =
3508–3212 (OH, NH), 3033 (CH aromatic), 2935,
2858 (CH2), 2221 (CN), 1640 (C N). 1H NMR
δ = 1.58–2.00 (m, 4H, 2CH2), 2.25–2.83 (m, 4H,
2CH2), 7.13–7.29 (m, 5H, C6H5), 8.29 (s, 1H,
NH, D2O-exchangeable), 11.54 (s, 1H, OH, D2O-
exchangeable). C18H15N5OS (349.40): Calcd: C, 61.87;
H, 4.32; N, 20.04; S, 9.17; Found: C, 61.9; H, 4.3; N,
19.9; S, 9.0.
4-Hydroxy-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine-2-acetonitrile (13a)
Equimolar amounts (0.01 mol) of 1 and malononi-
trile (11a), in ethanol (30 ml) containing a catalytic
amount of Et3N (0.5 ml), were heated under reflux for
6 h. The reaction mixture was then cooled, poured
onto cold water, neutralized with HCl, whereby the
solid product, so formed, was collected by filtration.
13a: Yellowish brown crystals (from DMF–H2O),
yield 58% (1.42 g), m.p. 139◦C. IR (ν/cm−1) = 3550–
3335 (OH), 2927, 2852 (CH2), 2220 (CN), 1630
(C N). 1H NMR δ = 1.61–2.00 (m, 4H, 2CH2), 2.25–
2.71 (m, 4H, 2CH2), 4.34 (s, 2H, CH2), 11.00 (s,
1H, OH, D2O-exchangeable). C12H11N3OS (245.29):
Calcd: C, 58.75; H, 4.51; N, 17.12; S, 13.07; Found:
C, 58.6; H, 4.4; N, 17.1; S, 12.9.
4-Hydroxy-5,6,7,8-tetrahydrobenzo[b]-
thieno[2,3-d]pyrimidine-2-acetamide (13b)
Method A. A mixture of equimolar amounts
(0.01 mol) of 1 and ethyl cyanoacetate (11b) was
heated, under reflux, in ethanol (30 ml) containing a
catalytic amount of Et3N for 8 h. The reaction mix-

Utility of a 2-Aminothiophene-3-carboxamide in the Synthesis of Thienopyridines and Thienopyrimidines 465
14b: Reddish brown crystals (from 1,4–dioxane–
(s, 1H, NH, D2O-exchangeable), 10.41 (s, 1H, OH,
D2O-exchangeable). C19H19N5O2S (381.43): Calcd: C,
59.82; H, 5.01; N, 18.35; S, 8.40; Found: C, 59.8; H,
4.8; N, 18.3; S, 8.2.
H2O), yield 75% (1.44 g), m.p. 107◦C. IR (ν/cm−1) =
3510–3194 (OH, NH), 3031 (CH aromatic), 2935,
2860 (CH2), 2216 (CN), 1635 (C N). 1H NMR
δ = 1.61–2.00 (m, 4H, 2CH2), 2.23–2.72 (m, 4H,
2CH2), 7.12–7.30 (m, 4H, C6H4), 8.41 (s, 1H,
NH, D2O-exchangeable), 10.81 (s, 1H, OH, D2O-
exchangeable). C18H14ClN5OS (383.84): Calcd: C,
56.32; H, 3.67; N, 18.24; S, 8.35; Found: C, 56.3; H,
3.5; N, 18.0; S, 8.3.
ꢁ-(Benzylidene)-4-hydroxy-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidine-
2-acetonitrile (16a), 4-Hydroxy-ꢁ-
(4-methoxybenzylidene)-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidine-
2-acetonitrile (16b), 4-Hydroxy-ꢁ-(4-
hydroxybenzylidene)-5,6,7,8-tetrahydrobenzo-
[b]thieno [2,3-d]pyrimidine-2-acetonitrile (16c),
and ꢁ-(3,4-Dichlorobenzylidene)-4-hydroxy-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidine-2-acetonitrile (16d)
14c: Yellow crystals (from 1,4–dioxane), yield
67% (1.22 g), m.p. 160◦C. IR (ν/cm−1) = 3520–3199
(OH, NH), 3033 (CH aromatic), 2970–2862 (CH3,
CH2), 2220 (CN), 1632 (C N). C19H17N5OS (363.42):
Calcd: C, 62.79; H, 4.71; N, 19.26; S, 8.82; Found: C,
62.5; H, 4.7; N, 19.1; S, 8.8.
General Procedure. A mixture of equimolar
amounts (0.005 mol) of 13a and the appropriate aro-
matic aldehyde 15a–d, in ethanol (30 ml) containing
a catalytic amount of piperidine (0.5 ml), was heated
under reflux for 5 h. The solution was then poured
over iced water and neutralized with dilute HCl to
precipitate the solid product. The formed product,
in each case, was isolated by suction filtration and
crystallized from the appropriate solvent.
4-Hydroxy-ꢁ-(phenylhydrazono)-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidine-2-
acetamide (14d), ꢁ-(4-Chlorophenylhydrazono)-
4-hydroxy-5,6,7,8-tetrahydrobenzo[b]thieno-
[2,3-d]pyrimidine-2-acetamide (14e), and
4-Hydroxy-ꢁ-(4-methylphenylhydrazono)-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidine-2-acetamide (14f)
16a: Buff crystals (from DMF–H2O), yield 74%
(1.23 g), m.p. 92◦C. IR (ν/cm−1) = 3565–3351 (OH),
3030 (CH aromatic), 2931, 2854 (CH2), 2221 (CN),
General Procedure. The same experimental pro-
cedure as described before for the synthesis of
14a–c was carried out except that 2-acetamide
derivative 13b (0.005 mol) was used in place of
13a.
14d: Red crystals (from 1,4–dioxane–H2O), yield
66% (1.21 g), m.p. 214◦C. IR (ν/cm−1) = 3530–3193
(OH, NH2, NH), 3033 (CH aromatic), 2933, 2858
(CH2), 1666 (C O), 1635 (C N). 1H NMR δ = 1.52–
2.00 (m, 4H, 2CH2), 2.19–2.40 (m, 4H, 2CH2), 5.51 (s,
br, 2H, NH2, D2O-exchangeable), 7.14–7.28 (m, 5H,
C6H5), 8.92 (s, 1H, NH, D2O-exchangeable), 9.88 (s,
1H, OH, D2O-exchangeable). C18H17N5O2S (367.41):
Calcd: C, 58.84; H, 4.65; N, 19.06; S, 8.72; Found: C,
58.7; H, 4.4; N, 18.8; S, 8.7.
14e: Orange crystals (from EtOH), yield 62%
(1.24 g), m.p. 102◦C. IR (ν/cm−1) = 3552–3207 (OH,
NH2, NH), 3035 (CH aromatic), 2933, 2858 (CH2),
1662 (C O), 1635 (C N). C18H16ClN5O2S (401.85):
Calcd: C, 53.80; H, 4.00; N, 17.42; S, 7.97; Found: C,
53.8; H, 3.9; N, 17.1; S, 8.0.
14f: Reddish brown crystals (from 1,4–dioxane–
H2O), yield 59% (1.12 g), m.p. 150◦C. IR (ν/cm−1) =
3560–3210 (OH, NH2, NH), 3033 (CH aromatic),
2975–2860 (CH3, CH2), 1664 (C O), 1633 (C N).
1H NMR δ = 1.57–1.91 (m, 4H, 2CH2), 2.00–2.31 (m,
4H, 2CH2), 2.59 (s, 3H, CH3), 4.93 (s, br, 2H, NH2,
D2O-exchangeable), 7.12–7.29 (m, 4H, C6H4), 8.61
1
1630 (C N). H NMR δ = 1.58–2.06 (m, 4H, 2CH2),
2.26–2.51 (m, 4H, 2CH2), 6.59 (s, 1H, CH ylidene),
7.17–7.32 (m, 5H, C6H5), 11.17 (s, 1H, OH, D2O-
exchangeable). C19H15N3OS (333.39): Calcd: C, 68.45;
H, 4.53; N, 12.60; S, 9.61; Found: C, 68.5; H, 4.2; N,
12.5; S, 9.5.
16b: Brown crystals (from DMF–H2O), yield 72%
(1.31 g), m.p. 247◦C. IR (ν/cm−1) = 3552–3340 (OH),
3031 (CH aromatic), 2962–2858 (CH3, CH2), 2220
1
(CN), 1631 (C N). H NMR δ = 1.63–2.03 (m, 4H,
2CH2), 2.27–2.81 (m, 4H, 2CH2), 3.82 (s, 3H, OCH3),
6.76 (s, 1H, CH ylidene), 7.03–7.22 (m, 4H, C6H4),
10.83 (s, 1H, OH, D2O-exchangeable). C20H17N3O2S
(363.42): Calcd: C, 66.10; H, 4.71; N, 11.56; S, 8.82;
Found: C, 66.0; H, 4.4; N, 11.5; S, 8.8.
16c: Pale brown crystals (from EtOH), yield 60%
(1.05 g), m.p. 165◦C. IR (ν/cm−1) = 3580–3365 (2OH),
3033 (CH aromatic), 2933, 2856 (CH2), 2225 (CN),
1629 (C N). C19H15N3O2S (349.39): Calcd: C, 65.31;
H, 4.32; N, 12.02; S, 9.17; Found: C, 65.1; H, 4.3; N,
11.9; S, 9.0.
16d: Yellow crystals (from DMF), yield 63%
(1.27 g), m.p. 155◦C. IR (ν/cm−1) = 3520–3315 (OH),
3034 (CH aromatic), 2933, 2856 (CH2), 2215 (CN),
1630 (C N). 1H NMR δ = 1.63–2.10 (m, 4H, 2CH2),
2.19–2.43 (m, 4H, 2CH2), 6.68 (s, 1H, CH ylidene),

466 Mohareb et al.
(C O), 1630 (C N). 1H NMR δ = 1.60–2.04 (m, 4H,
2CH2), 2.23–2.82 (m, 4H, 2CH2), 4.99 (s, br, 2H,
NH2, D2O-exchangeable), 6.72 (s, 1H, CH, ylidene),
7.15–7.33 (m, 3H, C6H3), 9.97 (s, 1H, OH, D2O-
exchangeable). C19H15Cl2N3O2S (420.30): Calcd: C,
54.29; H, 3.59; N, 9.99; S, 7.62; Found: C, 54.0; H,
3.5; N, 9.8; S, 7.5.
7.22–7.41 (m, 3H, C6H3), 11.31 (s, 1H, OH, D2O-
exchangeable). C19H13Cl2N3OS (402.29): Calcd: C,
56.72; H, 3.25; N, 10.44; S, 7.97; Found: C, 56.7; H,
3.2; N, 10.2; S, 7.8.
ꢁ-(Benzylidene)-4-hydroxy-5,6,7,8-tetrahydro-
benzo[b]thieno[2,3-d]pyrimidine-2-acetamide
(16e), 4-Hydroxy-ꢁ-(4-methoxybenzylidene)-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidine-2-acetamide (16f), 4-Hydroxy-ꢁ-
(4-hydroxybenzylidene)-5,6,7,8-tetrahydrobe-
nzo[b]thieno[2,3-d]pyrimidine-2-acetamide
(16g), and ꢁ-(3,4-Dichlorobenzylidene)-4-
hydroxy-5,6,7,8-tetrahydrobenzo[b]thieno-
[2,3-d]pyrimidine-2-acetamide (16h)
ꢁ-[4-(N,N-Dimethylamino)phenylimino]-4-
hydroxy-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidine-2-acetonitrile (17a) and ꢁ-[4-(N,N-
Dimethylamino)phenylimino]-4-hydroxy-5,6,
7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidine-
2-acetamide (17b)
General Procedure. To a mixture of each of
13a or 13b (0.005 mol) and N,N-dimethyl-4-
nitrosoaniline (0.005 mol), in ethanol (30 ml), a
catalytic amount of piperidine (0.5 ml) was added.
The reaction mixture was heated, under reflux, for
5 h and then left aside to cool and poured onto
ice/water containing few drops of HCl. The solid
product so formed, in each case, was collected by
filtration.
General
Procedure. Equimolar
amounts
(0.005 mol) of 13b and the appropriate aro-
matic aldehyde 15a–d, in ethanol (30 ml) containing
a catalytic amount of piperidine (0.5 ml), were
heated under reflux for 4 h. The reaction mixture
was evaporated in vacuo and triturated with cold
water, whereby the resulting solid product, in each
case, was collected by filtration and crystallized
from the proper solvent.
16e: Buff crystals (from 1,4–dioxane), yield 73%
(1.28 g), m.p. 229◦C. IR (ν/cm−1) = 3520–3197 (OH,
NH2), 3028 (CH aromatic), 2927, 2852 (CH2), 1666
(C O), 1635 (C N). 1H NMR δ = 1.60–1.82 (m,
4H, 2CH2), 2.01–2.43 (m, 4H, 2CH2), 5.13 (s, br,
2H, NH2, D2O-exchangeable), 6.64 (s, 1H, CH yli-
dene), 7.16–7.32 (m, 5H, C6H5), 10.55 (s, 1H, OH,
D2O-exchangeable). C19H17N3O2S (351.41): Calcd: C,
64.94; H, 4.87; N, 11.95; S, 9.12; Found: C, 65.0; H,
4.6; N, 11.9; S, 8.9.
16f: Pale yellow crystals (from DMF–H2O), yield
79% (1.50 g), m.p. 188◦C. IR (ν/cm−1) = 3530–
3204 (OH, NH2), 3033 (CH aromatic), 2962–2859
(CH3, CH2), 1664 (C O), 1635 (C N). C20H19N3O3S
(381.43): Calcd: C, 62.97; H, 5.01; N, 11.01; S, 8.40;
Found: C, 62.9; H, 4.8; N, 10.9; S, 8.1.
16g: Pale yellow crystals (from 1,4–dioxane),
yield 66% (1.21 g), m.p. 203◦C. IR (ν/cm−1) = 3560–
3224 (2OH, NH2), 3022 (CH aromatic), 2933, 2857
(CH2), 1668 (C O), 1630 (C N). 1H NMR δ =
1.61–1.83 (m, 4H, 2CH2), 2.00–2.33 (m, 4H, 2CH2),
4.82 (s, br, 2H, NH2, D2O-exchangeable), 6.79 (s,
1H, CH ylidene), 7.37–7.45 (m, 4H, C6H4), 9.79
(s, 1H, OH, D2O-exchangeable), 12.00 (s, 1H, OH,
D2O-exchangeable). C19H17N3O3S (367.41): Calcd: C,
62.11; H, 4.65; N, 11.43; S, 8.72; Found: C, 61.9; H,
4.6; N, 11.4; S, 8.4.
17a: Brown crystals (from DMF), yield 77% (1.45
g), m.p. 208◦C. IR (ν/cm−1) = 3530–3293 (OH), 3030
(CH aromatic), 2966–2856 (CH3, CH2), 2221 (CN),
1
1630 (C N). H NMR δ = 1.57–2.04 (m, 4H, 2CH2),
2.26–2.51 (m, 4H, 2CH2), 2.77, 2.85 (2s, 6H, 2NCH3),
7.15–7.35 (m, 4H, C6H4), 11.35 (s, 1H, OH, D2O-
exchangeable). C20H19N5OS (377.45): Calcd: C, 63.64;
H, 5.06; N, 18.55; S, 8.49; Found: C, 63.6; H, 4.9; N,
18.5; S, 8.3.
17b: Brown crystals (from DMF), yield 58%
(1.15 g), m.p. 170◦C. IR (ν/cm−1) = 3528–3224 (OH,
NH2), 3030 (CH aromatic), 2968–2857 (CH3, CH2),
1
1665 (C O), 1630 (C N). H NMR δ = 1.61–1.83
(m, 4H, 2CH2), 2.00–2.33 (m, 4H, 2CH2), 2.79,
2.88 (2s, 6H, 2NCH3), 5.12 (s, br, 2H, NH2, D2O-
exchangeable), 7.12–7.34 (m, 4H, C6H4), 10.45 (s,
1H, OH, D2O-exchangeable). C20H21N5O2S (395.46):
Calcd: C, 60.74; H, 5.34; N, 17.70; S, 8.10; Found: C,
60.7; H, 5.0; N, 17.8; S, 8.0.
2-(3-Cyano-2,4-diaminothiophen-5-yl)-4-
hydroxy-5,6,7,8-tetrahydrobenzo[b]thieno-
[2,3-d]pyrimidine (18a) and 2-(4-Amino-
3-cyano-2-hydroxythiophen-5-yl)-4-hydroxy-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidine (18b)
General
Procedure. Equimolar
amounts
16h: Yellow crystals (from DMF–H2O), yield 82%
(1.72 g), m.p. 174◦C. IR (ν/cm−1) = 3540–3209 (OH,
NH2), 3035 (CH aromatic), 2933, 2857 (CH2), 1665
(0.005 mol) of 13a, elemental sulfur, and mal-
ononitrile (11a) or ethyl cyanoacetate (11b), in
ethanol (30 ml) containing a catalytic amount of

Utility of a 2-Aminothiophene-3-carboxamide in the Synthesis of Thienopyridines and Thienopyrimidines 467
Et3N, were heated under reflux for 5 h and, after
REFERENCES
being allowed to cool, poured onto iced water.
The solutions were then neutralized with dilute
HCl and the formed products were collected by
suction filtration and crystallized from the proper
solvents.
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18a: Brown crystals (from 1,4–dioxane), yield
79% (1.35 g), m.p. 195◦C. IR (ν/cm−1) = 3525–
3205 (OH, 2NH2), 2931, 2854 (CH2), 2217 (CN),
1
1635 (C N). H NMR δ = 1.60–2.05 (m, 4H, 2CH2),
2.24–2.83 (m, 4H, 2CH2), 6.31 (s, 2H, NH2, D2O-
exchangeable), 7.51 (s, 2H, NH2, D2O-exchangeable);
11.25 (s, 1H, OH, D2O-exchangeable). C15H13N5OS2
(343.41): Calcd: C, 52.46; H, 3.81; N, 20.39; S, 18.67;
Found: C, 52.5; H, 3.5; N, 20.4; S, 18.6.
18b: Grey crystals (from EtOH), yield 75%
(1.29 g), m.p. 225◦C. IR (ν/cm−1) = 3545–3216 (2OH,
NH2), 2933, 2854 (CH2), 2220 (CN), 1630 (C N). 1H
NMR δ = 1.63–2.04 (m, 4H, 2CH2), 2.27–2.83 (m, 4H,
2CH2), 5.95 (s, 2H, NH2, D2O-exchangeable), 9.52
(s, 1H, OH, D2O-exchangeable), 11.61 (s, 1H, OH,
D2O-exchangeable). C15H12N4O2S2 (344.40): Calcd:
C, 52.31; H, 3.50; N, 16.26; S, 18.62; Found: C, 52.3;
H, 3.4; N, 16.0; S, 18.5.
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