New regio-selective method of combinatorial synthesis of substituted thiophenes, thieno[3,2-b]pyridines and other heterocycles via combination of 'domino'-type reactions

Article abstract of DOI:10.1016/j.tet.2013.09.025

We present a novel combinatorial multicomponent regio-selective approach towards the synthesis of thieno[3,2-b]pyridines and pyridine pyrans. The methodology is based on the 'domino'-type reaction. The high regio-selectivity in this reaction is gained by the in situ generation of the mono-potassium salt of 2-cyano-1-mercaptoethenethiolate. We also demonstrate that the use of ethyl 2-cyanoacetate in this reaction as a CH-acid leads to the termination of the domino sequence at the Dieckmann condensation step and yields novel ethyl 3-(4-cyano-3-hydroxy-5-(alkylthio)thiophen-2-yl)-3-oxopropanoate.

Full text of DOI:10.1016/j.tet.2013.09.025

Accepted Manuscript
New Regio-selective Method of Combinatorial Synthesis of Substituted Thiophenes,
Thieno[3,2-b]pyridines and other Heterocycles via Combination of “Domino”-type
Reactions
Andrey A. Zubarev, Anatoliy M. Shestopalov, Natalia A. Larionova, Lyudmila A.
Rodinovskaya, Alexander A. Shestopalov
PII:
S0040-4020(13)01421-X
10.1016/j.tet.2013.09.025
TET 24800
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 June 2013
Revised Date: 28 August 2013
Accepted Date: 9 September 2013
Please cite this article as: Zubarev AA, Shestopalov AM, Larionova NA, Rodinovskaya LA,
Shestopalov AA, New Regio-selective Method of Combinatorial Synthesis of Substituted Thiophenes,
Thieno[3,2-b]pyridines and other Heterocycles via Combination of “Domino”-type Reactions,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.09.025.
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ACCEPTED MANUSCRIPT
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New Regio-selective Method of
Leave this area blank for abstract info.
Combinatorial Synthesis of Substituted
Thiophenes, Thieno[3,2-b]pyridines and
other Heterocycles via Combination of
“Domino”-type Reactions.
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Andrey A. Zubarev, Anatoliy M. Shestopalov*, Natalia A. Larionova, Lyudmila A. Rodinovskaya,
Alexander A. Shestopalov.
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., Moscow,
119991, Russian Federation. Fax: +7 (499) 135 53 28.

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Tetrahedron
journal homepage: www.elsevier.com
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New Regio-selective Method of Combinatorial Synthesis of Substituted Thiophenes,
Thieno[3,2-b]pyridines and other Heterocycles via Combination of “Domino”-type
Reactions.
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Andrey A. Zubarev, Anatoliy M. Shestopalov*, Natalia A. Larionova, Lyudmila A. Rodinovskaya,
Alexander A. Shestopalov.
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., Moscow, 119991, Russian Federation. Fax: +7 (499) 135 53 28.
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ABSTRACT
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Article history:
Received
Received in revised form
We present a novel combinatorial multicomponent regio-selective approach towards the
synthesis of thieno[3,2-b]pyridines and pyridine pyrans. The methodology is based on the
“domino”-type reaction. The high regio-selectivity in this reaction is gained by the in-situ
generation of the mono-potassium salt of 2-cyano-1-mercaptoethenethiolate. We also
demonstrate, that the use of ethyl 2-cyanoacetate in this reaction as a CH-acid leads to the
termination of the domino sequence at the Dieckmann condensation step and yields novel ethyl
3-(4-cyano-3-hydroxy-5-(alkylthio)thiophen-2-yl)-3-oxopropanoate.
25 Accepted
Available online
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Keywords:
domino reactions
multicomponent reactions
2013 Elsevier Ltd. All rights reserved.
30 thieno[3,2-b]pyridines
combination of reaction types
2-amino-4H-pyrans
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mixtures of S-mono- and S-,S-disubstituted unsaturated nitriles.12
Moreover, for reaction mixtures of chloro-acetonitrile and
disodium 2,2-dicyanoethylene-1,1-bis(thiolate) at any molar
ratios the reaction always proceeds as two SN2 and two Thorpe-
Ziegler condensations and yields thienothiophenes.12 This creates
significant complications for the facile combinatorial synthesis of
heterocyclic libraries.
1. Introduction
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Substituted thieno[3,2-b]pyridines are pharmacologically
important molecules with several types of biological activity.
Previously, they were demonstrated as γ-aminobutyric acid
ligands,1 immune modulators,1,2 inhibitors of calcium channels1
and as herbicides.1 Thiophenes, containing N-substituted amides
in the three positions, have became an interest of several recent
studies.3 These molecules and their derivatives annulated with
carbo- and heterocycles were shown as cannabinoid receptor
ligands,4 tumor growth inhibitors,5 AMPA receptor modulators,6
dihydroorthotetragenase inhibitors,7 herbicides,8 and mammalian
hyperproliferative disorders agents.9
2. Results and Discussion
Here, we demonstrate a novel combinatorial, multicomponent
and highly regio-selective method for the preparation of
thieno[3,2-b]pyridines 9 with combination of CH acids 1 (Figure
1) and alkylhalides 8 (Figure 2). The proposed methodology is
unique and is based on the initial in-situ generation of the mono
potassium salt of 2-cyano-1-mercaptoethenethiolates 3 directly
from CH acids 1a-f, carbondisulfide 2 and one equivalent of
potassium hydroxide.
Previously, we explored the synthesis of thieno[3,2-
b]pyridines using thiophene derivatives as primary scaffolds.10 In
another study, the thieno[3,2-b]pyridine structure was
constructed from a pyridine derivative.1 We also demonstrated a
one-pot synthesis of thieno[3,2-b]pyridines directly from
cyanodithioethylene salts with concomitant cyclization of both
thiophen and pyridine rings. Using this methodology, we
synthesized
7-hydroxy-5-oxo-2-(R-methylenthio)-4,5-
dihydrothieno[3,2-b]pyridines from dipotassium 2-cyanoethene-
1,1-ditiolathe and 4-chloroacetoacetic ester.10 Similarly,
dipotassium N-cyanodithioimidocarbonate and
a
4-
chloroacetoacetate were used in the domino reaction to prepare 7-
hydroxy[1,3]thiazolo[4,5-b]pyridin-5(4H)-ones.11 However, the
yield of the synthesized compounds was moderate to low. It is
known, that the dipotassium or disodium salts reacts with one
Figure 1. CH-acids 1a-g.
___________

* Corresponding author E-mail address: amsh@ioc.ac.ru.
61 equivalent of α-halogenated carbonyl compounds and give
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Tetrahedron
ACCEPTED MANUSCRIPT
The following SN2 reaction of salts
3
and 4-
The reaction of cyanoacetic ester 1g with carbon sulfide and
chloroacetoacetic ester 4 proceeds with high regio-selectivity at
only one sulfur atom in contrast to the dipotassium salt reaction,
which consumes both sulfur atoms.12,13
α-halogengeminal compounds containing electron-withdrawing
moieties lead to the formation of 4-amino-3-ethoxycarbonyl
thiophenes.14-19 However, the same reaction was also used to
form 3-cyano-4-hydroxy thiophenes20,21 or a mixture of the both
isomers.22 The reaction with 4-bromoacetoacetic ester yields a
structure similar to the intermediate 6.17 However, under a
relatively mild conditions (NaH, THF, room temperature) the
subsequent cyclization is avoided. In contrast, we demonstrate
that cyanoacetic ester (1g) shows different reactivity in the same
reaction sequence, yielding substituted 4-hydroxythiophenes as
the final products.
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Compound 1g reacts with carbon disulfide with the ester
group, excluding the cyano group from the domino sequence all
together (Scheme 2). Such difference in reactivity causes the
intermediate 10 to undergo Dieckmann cyclization, as opposed to
Thorpe-Ziegler condensation in intermediate 5, and yields
potassium salt 11 as a final product. The solution of salt 11 can
be directly reacted with alkyl halides 8i,n,p,u,v without isolation
and purification. The resulting thiophenes 12a–e represent a new
class of previously unknown heterocyclic molecules.
Scheme 2. Synthesis of thiophenes 12a-e.
Figure 2. Alkylhalides 8a-v.
The subsequent “domino”-type Thorpe-Ziegler and Thorpe-
Guareschi reactions begin after the addition of two more
equivalents of potassium hydroxide and conclude with the
formation of potassium salt of thieno[3,2-b]pyridine 7 (Scheme
1). The solution of salt 7 is then divided into portions and reacted
27 with alkylhalides 8a-t. The remarkable regio-selectivity of each
step ensures the high yields (58–88%) of final substituted
thieno[3,2-b]pyridines 9a–af in this five step multicomponent
one-pot synthesis (Table 1).
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The IR spectra of compounds 12a–e contain characteristic
absorption bands of cyano, carbonyl and ester groups. H NMR
spectra of 12a–e contain proton signal of ethyl (1.16–1.17 and
4.08–4.09 ppm) and methylene (3.85–3.87 ppm) groups. The
structures of thiophenes 12a–e were also confirmed by HRMS
spectroscopy.
1
Here for the first time, beside malonodinitrile (1a) and
cyanoacetamide (1b), we used N-substituted cyanoacetamides:
N-(3-methoxypropyl)-
(1c),
N-cyclopropyl-
(1d),
N-
benzylcyanoacetamide (1e) and phenylsulfonyl acetonitrile (1f).
These new CH-acids significantly expand the variety of
synthetically available thieno[3,2-b]pyridines and provides
access to molecules with pharmacologically important functional
groups.
Thieno[3,2-b]pyridines 9 contain several reactive groups and
can be further modified via alkylation and cyclization reactions.
As such, compounds 9q,u,w,z,ab undergo three-component
“domino”-type reaction (Knoevenagel condensation – Michal
addition – hetero Thorpe-Ziegler condensation) when reacted
with aromatic aldehydes 13a-c (Figure 3) and malonodinitrile
(1a) (Scheme 3).
Scheme 1. Synthesis of thieno[3,2-b]pyridines 9a-af.
Figure 3. Aldehydes 13a-c.
This multicomponent reaction yields pharmacologically
important annulated pyrans 16.12,23
Scheme 3. Synthesis of pyrans 16a-f.
The structures of the prepared compounds were confirmed using
NMR and IR analyses. The IR spectra of compounds 9a–af
contain characteristic absorption bands of the amide group and
pyridine ring at 3360 – 3240 cm-1 and the absorption band of the
carbonyl group at 1630 cm-1. The IR spectra of phenylsulfonyl
derivatives 9ac–af contain signals of the SO2R group at 1170 and
1
1130 cm-1. H NMR spectra of compounds 9a–af show NH- and
OH- proton peaks and a characteristic C(6)H peak at 5.77 – 6.08
ppm.

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Table 1. Thieno[3,2-b]pyridines 9a-af.
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Entry
Product
Z
R
Yield, %
59 (4310)
62 (4610)
58 (3810)
65
1
2
3
4
9a
CN
CN
CN
CN
3-F-C6H4-NHCO
(CH3)2CH-NHCO
4-CF3-C6H4-NHCO
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2
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9b
9c
9d
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9e
CN
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9f
CN
CN
3-Cl-4-CH3-C6H3-NHCO
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82
9g
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9h
CN
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9
9i
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
CONH2
4-CH3-C6H4
88 (8610)
10
11
12
13
14
15
9j
Ad1-CO
87 (8610)
9k
9l
4-(CH3)2N-C6H4-NHCO
4-Cl-C6H4-CH2NHCO
(CH3)2CHNHCO
3,4-OCH2O-C6H3-CO
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63
58
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60
9m
9n
9o
16
9p
CONH2
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9q
9r
9s
9t
CH3O(CH2)3NHCO
CH3O(CH2)3NHCO
CH3O(CH2)3NHCO
CH3O(CH2)3NHCO
CH3O(CH2)3NHCO
C6H5
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83
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H
C6H5CO
2-OCH3-4-Cl-5-CH3-C6H2-NHCO
4-C2H5OOC-C6H4-NHCO
2-CH3-C6H4
9u
9v
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9w
9x
4-CH3-C6H4
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85
86
84
2-OCH3-4-Cl-5-CH3-C6H2-NHCO
9y
C6H5CO
H
9z
9aa
C6H5CH2NHCO
4-CH3-C6H4

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Tetrahedron
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9ab
9ac
9ad
9ae
9af
C6H5CH2NHCO
H
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C6H5 SO2
4-CH3-C6H4
C6H5
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2
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5
C6H5SO2
C6H5SO2
C6H5SO2
C6H5CO
2,5-(CH3)2-C6H3-NHCO
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Table 2. Thiophenes 12a-e.
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Entry
Product
R
Yield, %
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5
12a
C6H5CO
C6H5
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50
63
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12b
12c
4-CH3-C6H4
C2H5OOC
CH3CO
12d
12e
Table 3. Pyrans 16a-f.
Entry
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2
Product
16a
16b
Z
R
Ar
C6H5
C6H5
Yield, %
58
66
CH3O(CH2)3NHCO
C6H5
H
3
16c
H
4-CH3O-C6H4
63
4
5
6
16d
16e
16f
C6H5CH2NHCO
CH3O(CH2)3NHCO
H
C6H5
C6H5
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73
76
4-C2H5OOC-C6H4-NHCO
4-CH3-C6H4
4-F-C6H4
The corresponding CH-acid 1a-f (25 mmol) was dissolved in a
solution of potassium hydroxide (1.4 g, 25 mmol) in ethanol (50
ml) at 10 ºC. In several cases after addition of 1 a precipitate was
formed, which did not have an effect on the reaction conditions
or the final product. After stirring for 1 min carbon disulfide (1.5
ml, 25 mmol) was added to the resulting solution, and the
reaction mixture was stirred for 20 mins. Water (10–15 ml) was
added to the mixture to dissolve the resulting precipitate.
Subsequently, ester 4 (3.4 ml, 25 mmol) in ethanol (20 ml) was
added to the reaction mixture dropwise for 1 h, which was
quenched with potassium hydroxide solution (2.8 g, 50 mmol) in
ethanol (100 ml), after stirring for 10 min. The resulting reaction
mixture was refluxed for 2.5 h. After cooling to room
temperature, the solution was quenched with concentrated HBr
(2.8 ml, 25 mmol), stirred for 30 min, and divided into five equal
portions. Each portion was then reacted with the corresponding
alkylhalide 8a-t (5 mmol) under refluxing conditions for 1 min.
After cooling the reaction to room temperature, the resulting
precipitate was filtered off and rinsed on the filter to give pure
thieno[3,2-b]pyridines 9a–af in 58–88 % yield.
The IR spectra of compounds 16a–f contain absorption bands
of the amine and amide groups at 3400–3200 cm-1, the cyano
group at 2200–2180 cm-1 and the carbonyl group at 1670 and
1630 cm-1. 1H NMR spectra of compounds 16a–f contain
characteristic singlet of the C(6) pyran ring proton at 4.40–4.59
ppm.
3. Conclusion
In conclusion, we demonstrated that complex tricyclic
heterocycles can be prepared in 8 consecutive steps via two
multicomponent reactions by cross-coupling two types of
“domino” reaction: (1) SN2 → Thorpe-Ziegler → Thorpe-
Guareschi and (2) Knoevenagel → Michal → hetero Thorpe-
Ziegler. The presented combinatorial methodology is highly
flexible and permits the use of different CH acids 1a-f, alkyl
halides 8a-t and aromatic aldehydes 13. The use of cyanoacetic
ester 1g in this reaction changes the regio-selectivity of the initial
cyclization and yields 4-cyano-3-hydroxythiophenes 12.
4. Experimental Section
4.1. General
The analytical properties of compounds 9a-c,i,j were identical to
the previously reported literature data.10
IR spectra were recorded on “Bruker Alpha” spectrometer in
KBr pellets. NMR 1H and 13C analyses were performed on
“Bruker AM300” (300.13 and 75.47 MHz) spectrometer in
DMSO-d6 solution. High resolution mass spectra were obtained
on “micrOTOF” mass-spectrometer. All reagents and solvents
4.2.1. 2-({3-Cyano-7-hydroxy-5-oxo-4H,5H-
thieno[3,2-b]pyridin-2-yl}sulfanyl)-N-(3-methyl-
1,2-oxazol-5-yl)acetamide (9d).
Yield: 1.18 g (65%); mp > 300 °C (des.).
IR (KBr): 3500, 3272, 3224, 3138, 2230, 1631 cm-1.
were
purchased
from
Sigma-Aldrich.
N-Substituted
1H NMR (300 MHz, DMSO-d6): δ = 2.38 (s, 3H, CH3), 4.16 (s,
2H, SCH2), 6.01 (s, 1H, C(6)H), 6.60 (s, 1H, CH), 11.23 (s, 1H,
NH), 11.82 (br s, 1H, N(4)H). The protons of the OH group are
subject to deutero exchange and were not resolved completely.
cyanoacetamides 1{3-5} were prepared from ethylcyanoacetate
and corresponding amines using previously published method.24
4.2. General Experimental Procedure for 9a–af.

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13C NMR (75 MHz, DMSO-d6): δ = 11.9, 39.6, 93.3, 96.1, 105.7,
112.9, 114.2, 131.2, 151.9, 157.7, 160.2, 165.3, 165.5, 169.8.
Anal. Calcd for C14H10N4O4S2: C, 46.40; H, 2.78; N, 15.46.
Found: C, 46.67; H, 2.95; N, 15.79.
Anal. Calcd for C H N O S : C, 42.85; H, 2.21; N, 15.37.
8 4 3 3
Found: C, 42.54; H, 2.04; N, 15.06.
ACCEPTED MANUSCRIPT 13
4.2.6. 2-[({[4-
1
2
3
4
5
6
7
8
9
(Dimethylamino)phenyl] carbamoyl}methyl)sulfanyl]
-7-hydroxy-5-oxo-4H,5H-thieno[3,2-b]pyridine-3-
carboxamide (9k).
4.2.2. N-(3-Cyano-4,5,6,7-tetrahydro-1-
benzothiophen-2-yl)-2-({3-cyano-7-hydroxy-5-oxo-
4H,5H-thieno[3,2-b]pyridin-2-
Yield: 1.47 g (70%); mp > 300 °C (des.).
IR (KBr): 3422, 3327, 3263, 3185, 1641 cm-1.
yl}sulfanyl)acetamide (9e).
Yield: 1.62 g (73%); mp > 300 °C.
1H NMR (300 MHz, DMSO-d6): δ = 2.84 (s, 6H, 2CH3), 4.01 (s,
2H, SCH2), 6.04 (s, 1H, C(6)H), 6.71 (d, J = 8.8 Hz, 2H, C6H4,),
7.41 (d, J = 8.8 Hz, 2H, C6H4,), 7.65 (br s, 1H, NH2), 9.24 (br s,
1H, NH2), 10.08 (s, 1H, NH), 10.78 (br s, 1H, OH), 11.67 (br s,
1H, N(4)H).
IR (KBr): 3413, 3267, 3222, 3090, 2212, 1639 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.77 (m, 4H, CH2-CH2),
2.50 (m, 2H, CH2 overlaped with DMSO), 2.60 (m, 2H, CH2),
4.24 (br s, 2H, SCH2), 6.03 (s, 1H, C(6)H), 11.23 (br s, 1H, NH),
11.67 (br s, 2H, N(4)H, OH).
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13C NMR (75 MHz, DMSO-d6): δ = 40.4, 90.6, 112.2, 112.7,
120.6, 120.8, 128.6, 138.4, 147.1, 160.2, 163.8, 164.1, 164.6. The
signal of CH2S is overlapped with DMSO, the signal of C(9) is
overlapped with Ar C(1).
13C NMR (75 MHz, DMSO-d6): δ = 21.6, 22.5, 23.3, 23.4, 93.2,
93.5, 106.3, 112.9, 113.9, 127.8, 130.9, 135.9, 145.9, 149.8,
151.4, 160.3, 165.2, 165.3. The signal of CH2S is overlapped
with DMSO.
Anal. Calcd for C18H18N4O4S2: C, 51.66; H, 4.34; N, 13.39.
Found: C, 51.38; H, 4.07; N, 13.12.
Anal. Calcd for C19H14N4O3S3: C, 51.57; H, 3.19; N 12.66.
Found: C, 51.28; H, 3.06; N 12.22.
4.2.7. 2-[({[(4-
Chlorophenyl)methyl] carbamoyl}methyl)sulfanyl] -
7-hydroxy-5-oxo-4H,5H-thieno[3,2-b]pyridine-3-
carboxamide (9l).
4.2.3. N-(3-Chloro-4-methylphenyl)-2-({3-cyano-7-
hydroxy-5-oxo-4H,5H-thieno[3,2-b]pyridin-2-
yl}sulfanyl)acetamide (9f).
Yield: 1.34 g (63%); mp 296-299 °C.
Yield: 1.18 g (58%); mp 270-273 °C (des.).
IR (KBr): 3393, 3269, 3154, 3100, 1657 cm-1.
IR (KBr): 3443, 3327, 3188, 3093, 2224, 1630 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 2.28 (s, 3H, CH3), 4.13 (s,
2H, SCH2), 6.01 (s, 1H, C(6)H), 7.28 (d, J = 8.6 Hz, 2H, C6H3),
7.33 (d, J = 8.6 Hz, 2H, C6H3,), 7.73 (s, 1H, C6H3), 10.36 (s, 1H,
NH), 11.38 (br s, 1H, N(4)H). The protons of the OH group are
subject to deutero exchange and were not resolved completely.
13C NMR (75 MHz, DMSO-d6): δ = 18.9, 40.2, 93.3, 105.5,
113.0, 114.1, 117.9, 119.2, 130.4, 131.2, 133.1, 137.6, 149.9,
152.3, 160.3, 165.2, 165.3.
1H NMR (300 MHz, DMSO-d6): δ = 3.90 (s, 2H, SCH2), 4.30 (d,
J = 5.5 Hz, 2H, CH2), 6.03 (s, 1H, C(6)H), 7.27 (d, J = 7.5 Hz,
2H, C6H4,), 7.33 (d, J = 7.5 Hz, 2H, C6H4,), 7.63 (br s, 1H, NH2),
8.81 (t, J = 5.5 Hz, 1H, NH,), 9.22 (br s, 1H, NH2), 10.78 (s, 1H,
OH), 11.67 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 90.7, 112.2, 120.7, 120.8,
121.3, 127.2, 128.6, 128.7, 137.6, 160.2, 163.8, 164.1, 165.7. The
signals of CH2S and CH2NH is overlapped with DMSO.
Anal. Calcd for C17H14ClN3O4S2: C, 48.17; H, 3.33; N, 9.91.
Found: C, 47.96; H, 3.14; N, 9.64.
Anal. Calcd for C17H12ClN3O3S2: C, 50.31; H, 2.98; N, 10.35.
Found: C, 50.58; H, 3.09; N, 10.62.
4.2.8. 7-Hydroxy-5-oxo-2-({[(propan-2-
yl)carbamoyl] methyl}sulfanyl)-4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9m).
4.2.4. N-(3-Cyano-4,5-dimethylthiophen-2-yl)-2-
({3-cyano-7-hydroxy-5-oxo-4H,5H-thieno[3,2-
b]pyridin-2-yl}sulfanyl)acetamide (9g).
Yield: 1 g (58%); mp > 300 °C (des.).
Yield: 1.7 g (82%); mp 285-287 °C (des.).
IR (KBr): 3359, 3285, 3160, 3092, 1644 cm-1.
IR (KBr): 3443, 3267, 3225, 3092, 2216, 1630 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 2.11 (s, 3H, CH3), 2.24 (s,
3H, CH3), 4.28 (s, 2H, SCH2), 6.02 (s, 1H, C(6)H), 11.27 (br s,
1H, NH), 11.76 (br s, 2H, N(4)H, OH).
1H NMR (300 MHz, DMSO-d6): δ = 1.07 (d, J = 6.6 Hz, 6H,
2CH3), 3.78 (s, 2H, SCH2), 3.83 (m, 1H, CH), 6.01 (s, 1H,
C(6)H), 7.63 (br s, 1H, NH2), 8.15 (d, J = 7.3 Hz, 1H, NH,), 9.24
(br s, 1H, NH2), 10.76 (br s, 1H, OH), 11.64 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 22.1, 38.1, 40.9, 90.8, 112.2,
121.1, 127.1, 150.4, 160.2, 163.7, 164.1, 165.5.
13C NMR (75 MHz, DMSO-d6): δ = 12.4, 12.8, 93.1, 93.5, 106.3,
113.0, 113.9, 127.4, 130.3, 135.9, 145.9, 149.7, 151.1, 160.3,
165.1, 165.3. The signal of CH2S is overlapped with DMSO.
Anal. Calcd for C17H12N4O3S3: C, 49.02; H, 2.90; N, 13.45.
Found: C, 48.73; H, 2.64; N, 13.18.
Anal. Calcd for C13H15N3O4S2: C, 45.73; H, 4.43; N, 12.31.
Found: C, 45.51; H, 4.23 N, 12.05.
4.2.9. 2-{[2-(2H-1,3-Benzodioxol-5-yl)-2-
oxoethyl]sulfanyl}-7-hydroxy-5-oxo-4H,5H-
thieno[3,2-b]pyridine-3-carboxamide (9n).
4.2.5. 2-({3-Cyano-7-hydroxy-5-oxo-4H,5H-
thieno[3,2-b]pyridin-2-yl}sulfanyl)-N-(1,3-thiazol-
2-yl)acetamide (9h).
Yield: 1.19 g (59%); mp 265-268 °C.
Yield: 1.17 g (64%); mp 230-233 °C (des.).
IR (KBr): 3422, 3357, 3170, 3089, 1638 cm-1.
IR (KBr): 3491, 3424, 3337, 3202, 3183, 2226, 1638 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 4.22 (s, 2H, SCH2), 5.98 (s,
1H, C(1)H), 7.25 (d, J = 7.4 Hz, 1H, CH,), 7.49 (d, J = 7.4 Hz,
1H, CH,), 11.96 (br s, 2H, N(4)H, OH). The protons of the NH
group are subject to deutero exchange and were not resolved
completely.
1H NMR (300 MHz, DMSO-d6): δ = 4.79 (s, 2H, SCH2), 6.02 (s,
1H, C(6)H), 6.16 (s, 2H, OCH2O), 7.09 (d, J = 8.1 Hz, 1H,
C6H3), 7.55 (s, 1H, CH), 7.63 (br s, 1H, NH2), 7.74 (d, J = 8.1
Hz, 1H, C6H3), 9.17 (br s, 1H, NH2), 10.57 (br s, 1H, OH), 11.62
(br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 41.6, 90.6, 102.2, 107.7,
108.1, 112.1, 121.2, 125.1, 128.5, 129.8, 137.8, 147.9, 152.0,
160.2, 163.7, 164.1, 191.6.
13C NMR (75 MHz, DMSO-d6): δ = 93.4, 106.2, 112.9, 113.9,
114.8, 137.7, 149.6, 151.2, 157.6, 160.9, 165.4, 165.5. The signal
of CH2S is overlapped with DMSO.

6
Tetrahedron
Anal. Calcd for C H N O S : C, 50.49; H, 2.99; N, 6.93.
IR (KBr): 3356, 3284, 1692, 1624 cm-1.
ACCEPTED MANUSCRIPT
17 12
2
6 2
Found: C, 50.72; H, 2.84; N, 6.72.
1H NMR (300 MHz, DMSO-d6):
δ = 1.81 (m, 2H,
CH2CH2CH2OCH3), 3.25 (s, 3H, OCH3), 3.30-3.43 (m, 4H,
CH2CH2CH2OCH3), 4.89 (s, 2H, SCH2), 6.06 (s, 1H, C(6)H),
7.58 (m, 2H, C6H5), 7.70 (m, 1H, C6H5), 8.08 (d, J = 7.6 Hz, 2H,
C6H5), 9.77 (br s, 1H, CONH), 10.76 (br s, 1H, OH), 11.63 (br s,
1H, N(4)H).
4.2.10. 7-Hydroxy-5-oxo-2-({[(1,3-thiazol-2-
yl)carbamoyl] methyl}sulfanyl)-4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9o).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Yield: 1.15 g (60%); mp 291-293 °C.
13C NMR (75 MHz, DMSO-d6): δ = 29.4, 35.7, 41.9, 57.9, 69.7,
90.9, 112.1, 121.3, 128.4, 128.8, 133.8, 135.3, 147.9, 160.3,
162.5, 163.7, 193.7. The signal of C(9) is overlapped with Aryl.
Anal. Calcd for C20H20N2O5S2: C, 55.54; H, 4.66; N, 6.48. Found:
C, 55.30; H, 4.42; N, 6.20.
IR (KBr): 3438, 3172, 3139, 3089, 1636 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 4.18 (s, 2H, SCH2), 6.04 (s,
1H, C(6)H), 7.25 (d, J = 3.5 Hz, 1H, CH), 7.50 (d, J = 3.5 Hz,
1H, CH), 7.68 (br s, 1H, NH2), 9.21 (br s, 1H, NH2), 10.81 (s,
1H, OH), 11.70 (br s, 1H, N(4)H), 12.51 (br s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): δ = 93.6, 112.3, 113.8, 114.8,
137.7, 149.4, 151.2, 157.4, 160.9, 165.4, 165.5, 167.1 The signal
of CH2S is overlapped with DMSO.
4.2.15. 2-({[(4-Chloro-2-methoxy-5-
methylphenyl)carbamoyl]methyl}sulfanyl) -7-
hydroxy-N-(3-methoxypropyl)-5-oxo-4H,5H-
thieno[3,2-b]pyridine-3-carboxamide (9t).
Anal. Calcd for C13H10N4O4S3: C, 40.83; H, 2.64; N, 14.65.
Found: C, 40.64; H, 2.48; N, 14.42.
Yield: 1.61 g (61%); mp 198-201 °C.
IR (KBr): 3296, 1684, 1628 cm-1.
4.2.11. 7-Hydroxy-2-({[(5-methyl-1,2-oxazol-3-
yl)carbamoyl] methyl}sulfanyl)-5-oxo-4H,5H-
thieno[3,2-b]pyridine-3-carboxamide (9p).
1H NMR (300 MHz, DMSO-d6):
δ = 1.82 (m, 2H,
CH2CH2CH2OCH3), 2.22 (s, 3H, CH3), 3.25 (s, 3H, OCH3), 3.30-
3.42 (m, 4H, CH2CH2CH2OCH3), 3.83 (s, 3H, OCH3), 4.15 (s,
2H, SCH2), 6.08 (s, 1H, C(6)H), 7.10 (s, 1H, CH), 7.94 (s, 1H,
CH), 9.63 (s, 1H, NH) 9.79 (br s, 1H, NH), 10.82 (br s, 1H, OH),
11.71 (br s, 1H, N(4)H).
Yield: 1.13 g (59%); mp > 300 °C.
IR (KBr): 3416, 3377, 3213, 3145, 3098, 1626 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 2.37 (s, 3H, CH3), 4.10 (s,
2H, SCH2), 6.03 (s, 1H, C(6)H), 6.61 (s, 1H, CH), 7.67 (br s, 1H,
NH2), 9.23 (br s, 1H, NH2), 10.79 (s, 1H, OH), 11.34 (br s, 1H,
NH), 11.70 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 18.9, 29.3, 35.7, 56.2, 57.9,
69.7, 91.0, 111.9, 112.2, 121.4, 123.4, 123.6, 125.8, 126.6, 128.0,
148.4, 151.0, 160.3, 162.4, 163.7, 166.0. The signal of CH2S is
overlapped with DMSO.
24 13C NMR (75 MHz, DMSO-d6): δ = 12.1, 38.1, 90.8, 96.2, 112.2,
121.4, 151.0, 153.0, 157.9, 160.3, 163.9, 164.1, 166.1, 169.8.
Anal. Calcd for C14H12N4O5S2: C, 44.20; H, 3.18; N, 14.73.
Found: C, 44.48; H, 3.27; N, 14.95.
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Anal. Calcd for C22H24ClN3O6S2: C, 50.23; H, 4.60; N, 7.99.
Found: C, 50.48; H, 4.83; N, 8.25.
4.2.16. Ethyl
4-[2-({7-hydroxy-3-[(3-
4.2.12. 2-(Benzylsulfanyl)-7-hydroxy-N-(3-
methoxypropyl)-5-oxo-4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9q).
methoxypropyl)carbamoyl] -5-oxo-4H,5H-
thieno[3,2-b]pyridin-2-
yl}sulfanyl)acetamido]benzoate (9u).
Yield: 1.52 g (75%); mp 197-200 °C.
IR (KBr): 3364, 3332, 1624 cm-1.
Yield: 1.54 g (59%); mp 268-271 °C.
IR (KBr): 3312, 3240, 1700, 1676, 1640, 1616 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.30 (t, J = 7.0 Hz, 3H,
CH3CH2), 1.81 (m, 2H, CH2CH2CH2OCH3), 3.25 (s, 3H, OCH3),
3.32-3.43 (m, 4H, CH2CH2CH2OCH3), 4.11 (s, 2H, SCH2), 4.28
(q, J = 7.0 Hz, 2H, CH3CH2), 6.04 (s, 1H, C(6)H), 7.73 (d, J =
8.7 Hz, 2H, C6H4), 7.93 (d, J = 8.7 Hz, 2H, C6H4), 9.75 (br s, 1H,
NH), 10.58 (br s, 1H, NH), 10.68 (br s, 1H, OH), 11.67 (br s, 1H,
N(4)H).
1H NMR (300 MHz, DMSO-d6):
δ = 1.79 (m, 2H,
CH2CH2CH2OCH3), 3.24 (s, 3H, OCH3), 3.28-3.43 (m, 4H,
CH2CH2CH2OCH3), 4.33 (s, 2H, SCH2), 6.03 (s, 1H, C(6)H),
7.25-7.40 (m, 3H, C6H5), 7.47 (m, 2H, C6H5), 9.74 (br s, 1H,
CONH), 10.79 (br s, 1H, OH), 11.67 (s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 29.3, 35.6, 37.9, 57.9, 69.7,
90.8, 112.1, 120.4, 127.4, 127.8, 128.5, 129.1, 136.1, 148.5,
160.3, 162.4, 163.7.
13C NMR (75 MHz, DMSO-d6): δ = 14.1, 29.4, 35.7, 57.9, 60.4,
69.7, 90.8, 112.1, 118.5, 121.3, 124.6, 130.3, 130.8, 143.0, 150.1,
160.3, 162.4, 163.7, 165.2, 166.2. The signal of CH2S is
overlapped with DMSO.
Anal. Calcd for C23H25N3O7S2: C, 53.17; H, 4.85; N, 8.09. Found:
C, 53.41; H, 4.88; N, 8.15.
Anal. Calcd for C19H20N2O4S2: C, 56.42; H, 4.98; N, 6.93. Found:
C, 56.19; H, 4.72; N, 6.64.
4.2.13. 7-Hydroxy-N-(3-methoxypropyl)-2-
(methylsulfanyl)-5-oxo-4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9r).
Yield: 1.18 g (72%); mp 182-185 °C.
IR (KBr): 3336, 3268, 1628 cm-1.
4.2.17. N-Cyclopropyl-7-hydroxy-2-{[(2-
methylphenyl)methyl]sulfanyl}-5-oxo-4H,5H-
thieno[3,2-b]pyridine-3-carboxamide (9v).
1H NMR (300 MHz, DMSO-d6):
δ = 1.80 (m, 2H,
CH2CH2CH2OCH3), 2.56 (s, 3H, SCH3), 3.24 (s, 3H, OCH3),
3.28-3.43 (m, 4H, CH2CH2CH2OCH3), 6.04 (s, 1H, C(6)H), 9.77
(br s, 1H, CONH), 10.74 (br s, 1H, OH), 11.62 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 16.7, 29.4, 35.6, 57.9, 69.7,
90.3, 112.0, 120.3, 128.5, 147.8, 160.3, 162.5, 163.7.
Yield: 1.45 g (75%); mp 133-135 °C.
IR (KBr): 3348, 3244, 1656, 1636 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 0.63 (m, 2H, (CH2)2CH),
0.73 (m, 2H, (CH2)2CH), 2.39 (s, 3H, CH3), 2.82 (m, 1H,
(CH2)2CH), 4.31 (s, 2H, SCH2), 6.03 (s, 1H, C(6)H), 7.15-7.25
(m, 3H, C6H4), 7.40 (d, J = 6.7 Hz, 1H, CH), 9.68 (br s, 1H, NH),
10.86 (br. s., 1H, OH), 11.69 (br s, 1H, N(4)H).
Anal. Calcd for C13H16N2O4S2: C, 47.54; H, 4.91; N, 8.53. Found:
C, 47.29; H, 4.71; N, 8.32.
13C NMR (75 MHz, DMSO-d6): δ = 6.2, 18.7, 22.2, 36.3, 90.9,
112.4, 120.8, 126.2, 127.9, 129.9, 130.4, 133.6, 136.9, 150.3,
160.4, 163.6, 163.8. The signal of C(9) is overlapped with aryl.
4.2.14. 7-Hydroxy-N-(3-methoxypropyl)-5-oxo-2-
[(2-oxo-2-phenylethyl)sulfanyl] -4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9s).
Yield: 1.79 g (83%); mp 175-177 °C.

7
Anal. Calcd for C H N O S : C, 59.05; H, 4.69; N, 7.25. Found:
C, 58.83; H, 4.48; N, 7.03.
Anal. Calcd for C H N O S : C, 48.63; H, 4.08; N, 9,45.
12 2 3 2
Found: C, 48.36; H, 3.85; N, 9,29.
ACCEPTED MANUSCRIPT 12
19 18
2
3
2
4.2.18. N-Cyclopropyl-7-hydroxy-2-{[(4-
methylphenyl)methyl]sulfanyl}-5-oxo-4H,5H-
thieno[3,2-b]pyridine-3-carboxamide (9w).
4.2.22. N-Benzyl-7-hydroxy-2-{[(4-
methylphenyl)methyl]sulfanyl}-5-oxo-4H,5H-
thieno[3,2-b]pyridine-3-carboxamide (9aa).
1
2
3
4
5
6
7
8
9
Yield: 1.62 g (84%); mp 145-147 °C.
Yield: 1.84 g (84%); mp 140-143 °C.
IR (KBr): 3352, 3284, 1616 cm-1.
IR (KBr): 3264, 1628 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 0.63 (m, 2H, (CH2)2CH),
0.73 (m, 2H, (CH2)2CH), 2.28 (s, 3H, CH3), 2.82 (m, 1H,
(CH2)2CH), 4.28 (s, 2H, SCH2), 6.01 (s, 1H, C(6)H), 7.17 (d, J =
7.8 Hz, 2H, C6H4), 7.35 (d, J = 7.8 Hz, 2H, C6H4), 9.70 (br s, 1H,
NH), 10.84 (br s, 1H, OH), 11.66 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 6.1, 20.7, 22.2, 37.6, 90.8,
112.2, 120.6, 129.0, 129.1, 132.9, 136.8, 150.4, 160.4, 163.6,
163.8. The signal of C(9) is overlapped with aryl.
1H NMR (300 MHz, DMSO-d6): δ = 2.28 (s, 3 H, CH3), 4.29 (s,
2H, SCH2), 4.55 (d, J = 6.2 Hz, 2H, C6H5CH2NH,), 6.08 (s, 1H,
C(6)H), 7.15-7.40 (m, 9H, Ar), 10.36 (br s, 1H, NH), 10.85 (br s,
1H, OH), 11.75 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 20.7, 37.6, 41.7, 90.7, 112.1,
120.4, 126.7, 127.1, 128.0, 128.3, 129.0, 129.1, 132.8, 136.7,
139.7, 151.7, 160.4, 162.6, 163.7.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Anal. Calcd for C23H20N2O3S2: C, 63.28; H, 4.62; N, 6.42. Found:
C, 62.97; H, 4.45; N, 6.26.
Anal. Calcd for C19H18N2O3S2: C, 59.05; H, 4.69; N, 7.25. Found:
C, 59.31; H, 4.70; N, 7.27.
4.2.23. N-Benzyl-7-hydroxy-2-(methylsulfanyl)-5-
oxo-4H,5H-thieno[3,2-b]pyridine-3-carboxamide
(9ab).
4.2.19. 2-({[(4-Chloro-2-methoxy-5-
methylphenyl)carbamoyl]methyl}sulfanyl) -N-
cyclopropyl-7-hydroxy-5-oxo-4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9x).
Yield: 1.32 g (76%); mp 272-275 °C.
IR (KBr): 3312, 3284, 1636, 1620 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 2.58 (s, 3 H, SCH3), 4.56 (d,
J = 6.2 Hz, 2H, C6H5CH2NH), 6.06 (s, 1H, C(6)H), 7.20-7.35 (m,
5H, C6H5), 10.36 (br s, 1H, NH), 10.81 (br s, 1H, OH), 11.68 (br
s, 1H, N(4)H).
Yield: 1.44 g (58%); mp 185-188 °C.
IR (KBr): 3340, 1628 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 0.64 (m, 2H, (CH2)2CH),
0.73 (m, 2H, (CH2)2CH), 2.22 (s, 3H, CH3), 2.87 (m, 1H,
(CH2)2CH), 3.83 (s, 3H, OCH3), 4.16 (s, 2H, SCH2), 6.07 (s, 1H,
C(6)H), 7.09 (s, 1 H, C6H2), 7.94 (s, 1H, C6H2), 9.63 (s, 1H, NH),
9.70 (br s, 1H, NH), 10.81 (br s, 1H, OH), 11.77 (br s, 1H,
N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 16.7, 41.6, 90.2, 112.1,
119.9, 126.6, 127.0, 128.0, 128.3, 139.7, 149.9, 160.3, 162.6,
163.7.
Anal. Calcd for C16H14N2O3S2: C, 55.47; H, 4.07; N, 8.09. Found:
C, 55.72; H, 3.84; N, 7.75.
13C NMR (75 MHz, DMSO-d6): δ = 6.1, 18.9, 22.1, 56.2, 90.8,
112.0, 112.3, 121.0, 123.4, 125.8, 126.6, 128.0, 128.6, 148.4,
152.1, 160.3, 163.5, 163.7, 166.0. The signal of CH2S is
overlapped with DMSO.
4.2.24. 3-(Benzenesulfonyl)-7-hydroxy-2-{[(4-
methylphenyl)methyl]sulfanyl}-4H,5H-thieno[3,2-
b]pyridin-5-one (9ac).
Anal. Calcd for C21H20ClN3O5S2: C, 51.06; H, 4.08; N, 8.51.
Found: C, 51.29; H, 4.15; N, 8.83.
Yield: 1.56 g (70%); mp 252-255 °C.
IR (KBr): 3348, 1632, 1172, 1136 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 2.26 (s, 3H, CH3), 4.40 (s,
2H, SCH2), 5.77 (s, 1H, C(6)H), 7.12 (d, J = 7.7 Hz, 2H, C6H4),
7.27 (d, J = 7.7 Hz, 2H, C6H4), 7.62 (m, 2H, C6H5), 7.74 (t, J =
7.2 Hz, 1H, C6H5), 8.13 (d, J = 7.7 Hz, 2H, C6H5), 11.84 (br s, 1
H, N(4)H). The protons of the OH group are subject to deutero
exchange and were not resolved completely.
4.2.20. N-Cyclopropyl-7-hydroxy-5-oxo-2-[(2-oxo-
2-phenylethyl)sulfanyl] -4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9y).
Yield: 1.7 g (85%); mp 212-214 °C.
IR (KBr): 3308, 1688, 1644, 1620 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 0.60-0.80 (m, 4H,
(CH2)2CH), 2.86 (m, 1H, (CH2)2CH), 4.89 (s, 2H, SCH2), 6.02 (s,
1H, C(6)H), 7.55-7.75 (m, 3H, C6H5), 8.09 (d, J = 7.5 Hz, 2H,
C6H5), 9.71 (br s, 1H, NH), 10.86 (br s, 1H, OH), 11.67 (br s, 1H,
N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 20.6, 38.1, 94.0, 122.1,
126.0, 127.1, 128.4, 128.9, 129.1, 129.3, 131.8, 134.2, 137.1,
140.3, 152.6, 160.2, 163.3.
Anal. Calcd for C21H17NO4S3: C, 56.86; H, 3.86; N, 3.16. Found:
C, 57.09; H, 3.72; N, 3.31.
13C NMR (75 MHz, DMSO-d6): δ = 6.2, 22.2, 41.9, 90.8, 112.2,
121.0, 128.5, 128.9, 133.8, 135.0, 150.7, 160.3, 163.7, 163.8,
193.7.
4.2.25. 3-(Benzenesulfonyl)-2-(benzylsulfanyl)-7-
hydroxy-4H,5H-thieno[3,2-b]pyridin-5-one (9ad).
Anal. Calcd for C19H16N2O4S2: C, 56.98; H, 4.03; N, 7.00. Found:
C, 56.72; H, 3.87; N, 6.65.
Yield: 1.25 g (63%); mp 148-150 °C.
IR (KBr): 3344, 1616, 1172, 1136 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 4.45 (s, 2H, SCH2), 5.77 (s,
1H, C(6)H), 7.2-7.45 (m, 5H, C6H5), 7.62 (m, 2H, C6H5), 7.74
(m, 1H, C6H5), 8.14 (d, J = 7.7 Hz, 2H, C6H5), 9.76 (br s, 1H,
OH), 11.89 (br s, 1 H, N(4)H).
4.2.21. N-Cyclopropyl-7-hydroxy-2-
(methylsulfanyl)-5-oxo-4H,5H-thieno[3,2-
b]pyridine-3-carboxamide (9z).
Yield: 1.27 g (86%); mp 257-259 °C.
IR (KBr): 3356, 3260, 1632, 1616 cm-1.
13C NMR (75 MHz, DMSO-d6): δ = 38.3, 94.0, 126.0, 127.1,
127.7, 128.6, 129.0, 129.2, 129.4, 134.2, 135.0, 140.3, 152.4,
160.2, 163.4.
1H NMR (300 MHz, DMSO-d6): δ = 0.58-0.78 (m, 4H,
(CH2)2CH), 2.55 (m, 2H, SCH3), 2.84 (m, 1H, (CH2)2CH), 6.01
(s, 1H, C(6)H), 9.71 (br s, 1H, NH), 10.84 (br s, 1H, OH), 11.67
(br s, 1H, N(4)H).
Anal. Calcd for C20H15NO4S3: C, 55.92; H, 3.52; N, 3.26. Found:
C, 56.23; H, 3.32; N, 3.17.
13C NMR (75 MHz, DMSO-d6): δ = 6.2, 16.7, 22.1, 90.3, 112.1,
120.0, 127.9, 151.2, 160.3, 163.6, 163.7.

8
Tetrahedron
HRMS (ESI): m/z calcd for C H NO S [M + H]+: 362.0521,
4.2.26. 3-(Benzenesulfonyl)-7-hydroxy-2-[(2-oxo-
ACCEPTED MANUSCRIPT
17 16
4 2
2-phenylethyl)sulfanyl] -4H,5H-thieno[3,2-
b]pyridin-5-one (9ae).
found: 362.0515.
4.3.3. Ethyl
3-(4-cyano-3-hydroxy-5-{[(4-
Yield: 1.51 g (66%); mp 225-228 °C.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
IR (KBr): 3352, 1676, 1632, 1172, 1136 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 5.11 (s, 2H, SCH2), 5.78 (s,
1H, C(6)H), 7.5-7.8 (m, 6H, C6H5, C6H5), 8.05 (d, J = 7.5 Hz,
2H, C6H5), 8.19 (d, J = 7.7 Hz, 2H, C6H5), 9.86 (br s, 1H, OH),
11.82 (br s, 1H, N(4)H).
methylphenyl)methyl]sulfanyl}thiophen -2-yl)-3-
oxopropanoate (12c).
Yield: 1.19 g (63%); mp 80-82 °C.
IR (KBr): 3422, 2228, 1717, 1681 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.17 (t, J = 7.1 Hz, 3H,
CH2CH3), 2.28 (s, 3H, CH3), 3.85 (s, 2H, COCH2CO), 4.08 (q, J
= 7.1 Hz, 2H, CH2CH3), 4.46 (s, 2H, SCH2), 7.16 (d, J = 7.7 Hz,
2H, C6H4), 7.32 (d, J = 7.7 Hz, 2H, C6H4), 8.12 (br s, 1H, OH).
13C NMR (75 MHz, DMSO-d6): δ = 13.9, 20.7, 37.9, 46.6, 60.5,
101.9, 112.2, 119.0, 128.9, 129.2, 131.9, 137.3, 158.2, 159.3,
167.3, 183.1.
13C NMR (75 MHz, DMSO-d6): δ = 43.1, 93.8, 110.6, 122.4,
127.1, 128.5, 128.9, 129.4, 129.6, 134.1, 134.3, 134.9, 140.5,
152.7, 160.2, 163.6, 192.7.
Anal. Calcd for C21H15NO5S3: C, 55.13; H, 3.30; N, 3.06. Found:
C, 55.38; H, 3.12; N, 3.18.
HRMS (ESI): m/z calcd for C18H18NO4S2 [M + H]+: 376.0677,
found: 376.0672.
4.2.27. 2-{[3-(Benzenesulfonyl)-7-hydroxy-5-oxo-
4H,5H-thieno[3,2-b]pyridin-2-yl] sulfanyl}-N-(2,5-
dimethylphenyl)acetamide (9af).
4.3.4. Ethyl
3-{4-cyano-5-[(2-ethoxy-2-
Yield: 1.51 g (60%); mp 242-245 °C.
IR (KBr): 3360, 3256, 1648, 1168, 1132 cm-1.
oxoethyl)sulfanyl] -3-hydroxythiophen-2-yl}-3-
oxopropanoate (12d).
1H NMR (300 MHz, DMSO-d6): δ = 2.14 (s, 3H, CH3), 2.23 (s,
3H, CH3), 4.26 (s, 2H, SCH2), 5.83 (s, 1H, C(6)H), 6.90 (d, J =
7.7 Hz, 1H, C6H3), 7.08 (d, J = 7.7 Hz, 1H, C6H3), 7.21 (s, 1H,
C6H3), 7.61 (m, 2H, C6H5), 7.72 (t, J = 7.2 Hz, 1H, C6H5), 8.20
(d, J = 7.7 Hz, 2H, C6H5), 9.71 (s, 1H, NH), 11.84 (br s, 1 H,
N(4)H). The protons of the OH group are subject to deutero
exchange and were not resolved completely.
Yield: 1.29 g (72%); mp 82-84 °C.
IR (KBr): 3438, 2228, 1725, 1691 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.10-1.25 (m, 6H, 2 CH3),
3.87 (s, 2H, COCH2CO), 4.05-4.20 (m, 4H, 2 CH2CH3), 4.24 (s,
2H, SCH2), 7.30 (br s, 1H, OH).
13C NMR (75 MHz, DMSO-d6): δ = 13.9, 14.0, 36.2, 46.7, 60.6,
61.8, 103.1, 112.1, 119.5, 157.0, 159.2, 167.3, 167.4, 183.3.
HRMS (ESI): m/z calcd for C14H16NO6S2 [M + H]+: 358.0419,
found: 358.0414.
24 13C NMR (75 MHz, DMSO-d6): δ = 17.3, 20.5, 38.9, 93.8, 110.6,
121.9, 125.2, 126.2, 127.1, 128.4, 129.4, 129.6, 130.2, 134.3,
25
135.1, 135.5, 140.5, 152.9, 160.2, 163.6, 164.8.
Anal. Calcd for C23H20N2O5S3: C, 55.18; H, 4.03; N, 5.60. Found:
C, 54.86; H, 3.85; N, 5.51.
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
4.3.5. Ethyl
3-{4-cyano-3-hydroxy-5-[(2-
oxopropyl)sulfanyl] thiophen-2-yl}-3-oxopropanoate
(12e).
4.3. General Experimental Procedure for 12a–e. The
procedure of synthesis of thiophenes 12 is same as for 9, starting
from ethylcyanoacetate (1g).
Yield: 0.89 g (54%); mp 97-99 °C.
IR (KBr): 3432, 2229, 1722, 1686 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.17 (t, J = 7.1 Hz, 3H,
CH2CH3), 2.27 (s, 3 H, CH3CO), 3.86 (s, 2H, COCH2CO), 4.09
(q, J = 7.1 Hz, 2H, CH2CH3), 4.47 (s, 2H, SCH2), 6.91 (br s, 1H,
OH).
4.3.1. Ethyl
3-{4-cyano-3-hydroxy-5-[(2-oxo-2-
phenylethyl)sulfanyl]thiophen-2-yl}-3-
oxopropanoate (12a).
13C NMR (75 MHz, DMSO-d6): δ = 14.0, 28.5, 45.1, 46.5, 60.5,
102.1, 112.2, 118.6, 158.2, 159.7, 167.4, 182.9, 200.8.
HRMS (ESI): m/z calcd for C13H14NO5S2 [M + H]+: 328.0313,
found: 328.0308.
Yield: 1.13 g (58%); mp 154-156 °C.
IR (KBr): 3435, 2221, 1742, 1677 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.17 (t, J = 7.1 Hz, 3H,
CH3), 3.86 (s, 2H, COCH2CO), 4.09 (q, J = 7.1 Hz, 2H,
CH2CH3), 5.17 (s, 2H, SCH2), 7.58 (m, 2H, C6H5), 7.72 (t, J = 7.3
Hz, 1H, C6H5), 8.06 (d, J = 7.4 Hz, 2H, C6H5). The protons of the
OH group are subject to deutero exchange and were not resolved
completely.
4.4. General Experimental Procedure for Pyrans 16a-f. The
solution of dioxipyridines 9 (0.9 mmol), malonodinitrile (1a)
(0.06 g, 0.9 mmol), aldehydes 13 (0.9 mmol) and Et3N (0.015 g,
0.15 mmol) in 8 ml of EtOH was refluxed for 30 min, then
cooled to room temperature and the precipitate filtered off to
obtain pyrans 16a-f.
13C NMR (75 MHz, DMSO-d6): δ = 14.0, 42.9, 46.6, 60.5, 102.1,
112.2, 119.0, 128.6, 128.9, 134.1, 134.7, 158.2, 159.3, 167.4,
183.1, 192.4.
HRMS (ESI): m/z calcd for C18H16NO5S2 [M + H]+: 390.0470,
found: 390.0464.
4.4.1. 8-Amino-2-(benzylthio)-7-cyano-N-(3-
methoxypropyl)-5-oxo-6-phenyl-4,6-dihydro-5H-
pyrano[2,3-d] thieno[3,2-b]pyridine-3-carboxamide
(16a).
4.3.2. Ethyl
3-[5-(benzylsulfanyl)-4-cyano-3-
hydroxythiophen-2-yl] -3-oxopropanoate (12b).
Yield: 0.91 g (50%); mp 73-75 oC.
Yield: 0.29 g (58%); mp 158-160 °C.
IR (KBr): 3372, 3290, 3204, 2196, 1668, 1624 cm-1.
IR (KBr): 3430, 2226, 1720, 1686 cm-1.
1H NMR (300 MHz, DMSO-d6):
δ = 1.76 (m, 2H,
1H NMR (300 MHz, DMSO-d6): δ = 1.16 (t, J = 7.1 Hz, 3H,
CH2CH3), 3.85 (s, 2 H, COCH2CO), 4.08 (q, J = 7.1 Hz, 2H,
CH2CH3), 4.50 (s, 2H, SCH2), 7.25-7.5 (m, 5H, C6H5), 8.09 (br s,
1H, OH).
CH2CH2CH2OCH3), 3.20 (s, 3H, OCH3), 3.27-3.45 (m, 4H,
CH2CH2CH2OCH3), 4.36 (s, 2H, SCH2), 4.54 (s, 1H, C(6)H),
7.05-7.5 (m., 12H, 2 C6H5, NH2), 9.35 (br s, 1 H, CONH), 11.61
(br s, 1 H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 13.8, 37.8, 46.6, 60.5, 101.8,
112.2, 118.9, 127.4, 127.8, 128.5, 138.4, 158.3, 159.4, 167.3,
183.1.
13C NMR (75 MHz, DMSO-d6): δ = 29.5, 36.0, 36.6, 57.9, 58.3,
69.8, 101.3, 109.6, 119.6, 120.2, 127.0, 127.4, 127.6, 127.8,

9
128.3, 128.5, 129.0, 135.9, 144.4, 150.2, 155.2, 158.2, 160.4,
2H, C H ), 9.49 (br s, 1H, CONH), 10.70 (br s, 1H, CONH),
6 4
11.63 (br s, 1 H, N(4)H).
ACCEPTED MANUSCRIPT
162.3. The signal of CH2S is overlapped with DMSO.
Anal. Calcd for C29H26N4O4S2: C, 62.35; H, 4.69; N, 10.03.
Found: C, 62.04; H, 4.83; N, 10.34.
13C NMR (75 MHz, DMSO-d6): δ = 14.2, 29.2, 36.0, 36.5, 57.9,
58.3, 60.4, 69.7, 102.4, 111.8, 118.6, 119.6, 124.6, 126.7, 127.4,
128.3, 130.3, 143.0, 144.4, 150.3, 153.8, 158.5, 160.3, 161.8,
165.2, 166.2. The signal of CH2S is overlapped with DMSO.
Anal. Calcd for C33H31N5O7S2: C, 58.83; H, 4.64; N, 10,39.
Found: C, 58.54; H, 4.42; N, 10,18.
1
2
3
4
5
4.4.2. 8-Amino-7-cyano-N-cyclopropyl-2-
(methylthio)-5-oxo-6-phenyl-4,6-dihydro-5H-
pyrano[2,3-d] thieno[3,2-b]pyridine-3-carboxamide
(16b).
6
7
8
9
4.4.6. 8-Amino-7-cyano-N-cyclopropyl-6-(4-
fluorophenyl)-2-[(4-methylbenzyl)thio] -5-oxo-4,6-
dihydro-5H-pyrano[2,3-d]thieno[3,2-b]pyridine-3-
carboxamide (16f).
Yield: 0.27 g (66%); mp 302-304 °C.
IR (KBr): 3376, 3256, 3188, 2188, 1660, 1620 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 0.55-0.71 (m, 4H,
(CH2)2CH), 2.62 (s, 3H, SCH3), 2.84 (m, 1H, (CH2)2CH), 4.57 (s,
1H, C(6)H), 7.15-7.35 (m, 7 H, C6H5, NH2), 9.41 (br s, 1H,
CONH), 11.64 (s, 1H, N(4)H).
10
11
12
13
14
15
16
17
18
19
20
21
Yield: 0.38 g (76%); mp 276-278 °C.
IR (KBr): 3380, 3305, 3184, 2196, 1664, 1628 cm-1.
13C NMR (75 MHz, DMSO-d6): δ = 5.9, 16.9, 22.2, 36.5, 58.2,
101.1, 109.8, 119.6, 123.4, 126.7, 127.4, 127.9, 128.3, 138.3,
144.5, 150.3, 158.5, 160.2, 163.1.
Anal. Calcd for C22H18N4O3S2: C, 58.65; H, 4.03; N, 12.44.
Found: C, 58.91; H, 3.86; N, 12.23.
1H NMR (300 MHz, DMSO-d6): δ = 0.53-0.75 (m, 4H,
(CH2)2CH), 2.29 (s, 3H, CH3), 2.83 (m, 1H, (CH2)2CH), 4.31 (s,
2H, SCH2), 4.59 (s, 1H, C(6)H), 7.05-7.4 (m, 10H, 2 C6H4, NH2),
9.37 (br s, 1H, CONH), 11.68 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 5.9, 20.7, 22.3, 35.9, 37.7,
58.1, 100.7, 110.0, 114.9, 115.1, 119.5, 126.6, 128.9, 129.1,
129.4, 129.5, 132.6, 136.9, 140.7, 150.1, 154.2, 158.4, 159.4,
160.3, 162.6, 163.0. The signal of C(2) is overlapped with Aryl.
Anal. Calcd for C29H23FN4O3S2: C, 62.35; H, 4.15; N, 10.03.
Found: C, 62.14; H, 3.94; N, 9.78.
4.4.3. 8-Amino-7-cyano-N-cyclopropyl-6-(4-
methoxyphenyl)-2-(methylthio)-5-oxo-4,6-dihydro-
5H-pyrano[2,3-d] thieno[3,2-b]pyridine-3-
carboxamide (16c).
22 Yield: 0.27 g (63%); mp 275-277 °C.
IR (KBr): 3376, 3324, 3272, 3184, 2200, 1668, 1628 cm-1.
5. References
23
1H NMR (300 MHz, DMSO-d6): δ = 0.55-0.75 (m, 4H,
24
1. Litvinov, V. P.; Dozenko, V. V.; Krivokolysko, S. G. Advances in
Heterocycle Chemistry, Vol. 93; Katritzky, A. R., Ed.; Elsevier
Ltd Academic Press: Amsterdam. 2007, 117 – 178.
2. Litvinov, V. P. Russ. Chem. Bull. 1998, 47, 2053 – 2073.
3. Wang, K.; Kim, D.; Do¨mling, A. J. Comb. Chem. 2010, 12, 111 –
118.
4. Carroll, W. A.; Dart, M. J.; Perez-Medrano, A.; Nelson, D. W.
U.S. Patent 2009018114, 2009. http://www.espacenet.com.
5. Ashwell, S.; Gero, T.; Ioannidis, S.; Janetka, J.; Lyne, P; Oza, V.;
Springer, S.; Su, M.; Yu, D. W.O. Patent 200516909, 2005.
http://www.espacenet.com.
6. Jamieson, C.; Campbell, R. A.; Cumming, I. A.; Gillen, K. J.;
Gillespie, J.; Kiczun, M.; Lamont, Y.; Lyons, A. J.; MacLean, J.
K. F.; Moir, E. M.; Morrow, J. A.; Papakosta, M.; Rankovic, Z.;
Smith, L.; Basten, S.; Kazemier, B. Bioorg. Med. Chem. Lett.
2010, 20, 5753 – 5756.
7. Booker, M. L.; Celatka, C. A.; Clardy, J. C.; Patel, V. P.;
Wiegand, R. C.; Wirth, D. F. W.O. Patent 2009137081, 2009.
http://www.espacenet.com.
(CH2)2CH), 2.62 (s, 3H, SCH3), 2.84 (m, 1H, (CH2)2CH), 3.70 (s,
3H, OCH3), 4.52 (s, 1H, C(6)H), 6.84 (d, J = 6.2 Hz, 2H, C6H4),
7.08 (d, J = 6.2 Hz, 2H, C6H4), 7.20 (s, 2H, NH2), 9.40 (br s, 1H,
CONH), 11.62 (br s, 1 H, N(4)H).
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
13C NMR (75 MHz, DMSO-d6): δ = 5.9, 16.9, 22.2, 35.7, 55.0,
58.5, 100.8, 110.2, 113.7, 119.7, 119.9, 128.5, 136.6, 150.1,
158.1, 158.4, 160.2, 163.2, 163.7. The signal of C(2) is
overlapped with Aryl.
Anal. Calcd for C23H20N4O4S2: C, 57.48; H, 4.19; N, 11.66.
Found: C, 57.19; H, 4.02; N, 11.89.
4.4.4. 8-Amino-N-benzyl-7-cyano-2-(methylthio)-5-
oxo-6-phenyl-4,6-dihydro-5H-pyrano[2,3-
d]thieno[3,2-b]pyridine-3-carboxamide (16d).
Yield: 0.36 g (80%); mp 279-281 °C.
IR (KBr): 3544, 3480, 3312, 2180, 1656, 1628 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 2.63 (s, 3H, SCH3), 4.45-
4.60 (m, 3H, C(6)H, CH2), 7.12-7.35 (m, 12H, 2 C6H5, NH2),
10.07 (br s, 1H, CONH), 11.61 (br s, 1H, N(4)H).
13C NMR (75 MHz, DMSO-d6): δ = 17.0, 36.5, 41.7, 58.3, 100.0,
110.0, 119.6, 126.6, 126.7, 127.0, 127.4, 128.3, 128.4, 130.4,
139.5, 144.5, 150.4, 152.3, 158.5, 160.3, 162.2. The signal of
C(13) is overlapped with Aryl.
8. Gesing, E. R.F.; Geller, T.; Feucht, D.; Kehne, H.; Auler, T.; Hills,
M. W.O. Patent 2006012983, 2006. http://www.espacenet.com.
9. Collins, M.; Cripps, S.; Deal, J.; Kania, R. S.; Lou, J.; He, M.;
Palmer, C. L.; Romines, W. H.; Zhou, R. W.O. Patent
2004009965, 2004. http://www.espacenet.com.
10. Shestopalov, A. M.; Rodinovskaya, L. A.; Shestopalov, A. A. J.
Comb. Chem. 2010, 12, 9 – 12.
11. Shestopalov, Anatoliy M.; Rodinovskaya, Liudmila A.;
Shestopalov, Alexander A. Tetrahedron, 2010 ,66, 8945 – 8948.
12. Litvinov, Y. M.; Shestopalov, A. M. In: Advances in Heterocyclic
Chemistry, Vol. 103; Katritzky, A. R., Ed.; Elsevier Ltd Academic
Press: Amsterdam, 2011, 175.
13. El-shafei, A. K.; Abdel-ghany, H. A.; Sultan A. A.; Elsaghier, A.
M. M. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 73, 15 – 26.
14. Padmavathi, V.; Venkatesh, B. C.; Muralikrishna, A.; Padmaja, A.
Chem. Pharm. Bull. 2012, 60, 449 – 458.
15. Soliman, A. M. Phosphorus, Sulfur Silicon Relat. Elem. 1994, 97,
1 – 8.
16. Fishwick, B. R.; Rowles, D. K.; Stirling, C. J. M. J. Chem. Soc.,
Perkin Trans. 1: Org. Bio-Org. Chem. 1986, 1171 – 1180.
17. Chiba, T.; Sato, H.; Kato, T. Chem. Pharm. Bull. 1983, 31, 2480 –
2483.
Anal. Calcd for C26H20N4O3S2: C, 62.38; H, 4.03; N, 11.19.
Found: C, 62.07; H, 3.84; N, 11.36.
50 4.4.5. Ethyl
4-({[(8-amino-7-cyano-3-{[(3-
methoxypropyl)amino] carbonyl}-5-oxo-6-phenyl-
4,6-dihydro-5H-pyrano[2,3-d]thieno[3,2-b]pyridin-
2-yl)thio]acetyl}amino)benzoate (16e).
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Yield: 0.44 g (73%); mp 289-291 °C.
IR (KBr): 3456, 3308, 3276, 3200, 2200, 1700, 1672, 1628 cm-1.
1H NMR (300 MHz, DMSO-d6): δ = 1.30 (t, J = 6.2 Hz, 3H,
CH2CH3), 1.79 (m, 2H, CH2CH2CH2OCH3), 3.21 (s, 3H, OCH3),
3.25-3.45 (m, 4H, CH2CH2CH2OCH3), 4.14 (s, 2H, SCH2), 4.28
(q, J = 6.2 Hz, 2H, CH2CH3), 4.56 (s, 1H, C(6)H), 7.15-7.35 (m,
5H, C6H5), 7.73 (d, J = 8.4 Hz, 2H, C6H4), 7.94 (d, J = 8.4 Hz,
18. Henriksen, L.; Autrup, H. Acta Chem. Scand. 1972, 26, 3342 –
3346.
19. Gompper, R. Justus Liebigs Ann. Chem. 1962, 659, 90 – 101.
20. Sommen, G.; Comel, A.; Kirsch, G. Synthesis 2003, 5, 735 – 741.

10
Tetrahedron
ACCEPTED MANUSCRIPT
21. Luteijn, J. M.; Dolman, H.; Wals, H. C. Tetrahedron 1988, 44,
5921 – 5928
22. Briel, D. Pharmazie 1990, 45, 895 – 899.
23. Shestopalov, A.M.; Shestopalov, A. A.; Rodinovskaya, L.A.
Synthesis 2008, 1, 1 – 25.
24. Demin, P., Rounova, O., Grunberger, T., Cimpean, L., Sharfe, N.,
Roifman, C.M. Bioorg. Med. Chem. 2004, 12, 3019 – 3026.
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