New method for the synthesis of substituted thieno[3,2-b]pyridines and 5H-pyrano[2,3-d]thieno[3,2-b]pyridines derived from them

Article abstract of DOI:10.1007/s11172-013-0182-2

A new highly selective method was developed for the synthesis of substituted thieno[3,2-b]-pyridines based on the domino reaction of monopotassium salt (rather than dipotassium one) of carbamoylcyanodithioacetic acid with ethyl 4-chloroacetoacetate. Substituted 5H-pyrano[2,3-d]-thieno[3,2-b] pyridines were synthesized based on these thieno[3,2-b]pyridines.

Full text of DOI:10.1007/s11172-013-0182-2

Russian Chemical Bulletin, International Edition, Vol. 62, No. 5, pp. 1304—1306, May, 2013
1304
New method for the synthesis of substituted thieno[3,2ꢀb]pyridines
and 5Hꢀpyrano[2,3ꢀd]thieno[3,2ꢀb]pyridines derived from them
N. A. Larionova, A. A. Zubarev, L. A. Rodinovskaya, and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: zan@ioc.ac.ru
A new highly selective method was developed for the synthesis of substituted thieno[3,2ꢀb]ꢀ
pyridines based on the domino reaction of monopotassium salt (rather than dipotassium one) of
carbamoylcyanodithioacetic acid with ethyl 4ꢀchloroacetoacetate. Substituted 5Hꢀpyrano[2,3ꢀd]ꢀ
thieno[3,2ꢀb]pyridines were synthesized based on these thieno[3,2ꢀb]pyridines.
Key words: thieno[3,2ꢀb]pyridines, Nꢀsubstituted cyanoacetamides, potassium cyanoꢀ
ethanedithioate, domino reactions, ethyl 4ꢀchloroacetoacetate, 2ꢀaminoꢀ3ꢀcyanopyrans, multiꢀ
component condensation.
Substituted thieno[3,2ꢀb]pyridines possess pronounced
the domino reaction and led to a simultaneous closure of
thiophene and pyridine rings.11
biological activity. Among them were found ligands of
ꢀaminobutyric acid receptors,1 immunomodulators,1,2
calcium channel inhibitors,1,3 and herbicides.1 Lately, an
interest grows to thiophenes containing an Nꢀsubstituted
amide group at position 3.4 Among these compounds, inꢀ
cluding those with annulated carboꢀ or heterocycles, are
found ligands of cannabinoid receptors,5 compounds inꢀ
hibiting development of malignant tumors,6 AMPAꢀreꢀ
ceptor modulators,7 antiplasmodium agents,8 herbicides,9
and agents used against breast cancer.10
The present work is devoted to the development of
a new highly selective method for the synthesis of such
compounds based on the use of the monopotassium salt of
substituted dithioacetic acids. NꢀSubstituted cyanoacetꢀ
amides were used as the starting compounds, that made it
possible to obtain thieno[3,2ꢀb]pyridines containing poꢀ
tentially pharmacophoric groups.
Results and Discussion
Earlier,11 we have developed an approach to the synꢀ
thesis of thieno[3,2ꢀb]pyridines based on malononitrile
and cyanoacetamide. A key step of this method consists in
the generation in solution of the dipotassium salt of 2,2ꢀdiꢀ
cyanoethenedithiol or its 2ꢀcarbamoyl analog. Its subseꢀ
quent reaction with ethyl 4ꢀchloroacetoacetate followed
The synthesis was carried out by the domino reactions.
Since the alkylation at one or both sulfur atoms of 2,2ꢀdiꢀ
cyanoethenedithiol dipotassium salt is known to be nonselꢀ
ective1,12 and results in the decreased yields of the target
products, we developed an alternative approach (Scheme 1).
Scheme 1
Regents
1a, 5a
1b, 5b
1c, 5b
Z
R
Ph
H
Products
6a
Regents and conditions: i. KOH, EtOH, 10 C;
ii. 1) ClCH2COCH2CO2Et (3), 20 C; 2) 2 KOH, EtOH, D;
iii. PhCH2Cl (5a) or MeI (5b).
MeO(CH2)3NHCO
cycloꢀC3H5NHCO
PhCH2NHCO
6b
6c
H
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1304—1308, May, 2013.
1066ꢀ5285/13/6205ꢀ1304 © 2013 Springer Science+Business Media, Inc.

3ꢀ(NꢀSubstituted carbamoyl)thieno[3,2ꢀb]pyridines Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
1305
This approach is distinguished by the generation in
solution of the monopotassium salt of carbamoylcyanꢀ
odithioacetic acid (2) from cyanoacetic acid amides 1a—c
and carbon disulfide. Further alkylation of salt 2 with ethyl
4ꢀchloroacetoacetate (3) proceeded highly regioselectiveꢀ
ly at one sulfur atom, rather than at both. To complete the
domino reaction procedure, an excess of KOH in ethanol
was added to the reaction mixture to run the consecutive
Thorpe—Ziegler and Thorpe—Guareshi reactions (see
Scheme 1). The thus obtained solution of thieno[3,2ꢀb]ꢀ
pyridine potassium salt 4 was treated with alkyl halides
5a,b. Such a sequence of reactions increases the regioꢀ
selectivity of the process and the yields (by 7—10%) of the
final compounds 6a—c as compared to the unsubstituted
amides described earlier.11
The IR spectra of compounds 9a—c exhibit absorpꢀ
tion bands of the NH2 and NH groups in the region
3400—3200 cm–1, the nitrile group at 2200—2180 cm–1
,
and the carbonyl groups at 1670 and 1630 cm–1. The presꢀ
ence of the signal for the proton at atom C(6) as a singlet
1
in the region  4.5—4.6 is characteristic of the H NMR
spectra of compounds 9.
In conclusion, we developed a new highly selective
method for the synthesis of substituted thieno[3,2ꢀb]ꢀ
pyridines. This method is based on the generation of the
monopotassium salt of Nꢀsubstituted carbamoylcyanꢀ
odithioacetic acids and its reaction with ethyl 4ꢀchloroꢀ
acetoacetate following the domino reaction. The thienoꢀ
[3,2ꢀb]pyridines obtained were used to synthesize substiꢀ
tuted 5Hꢀpyrano[2,3ꢀd]thieno[3,2ꢀb]pyridines.
The following Nꢀsubstituted cyanoacetamides were
used as the starting compounds: Nꢀ(3ꢀmethoxypropyl)ꢀ
(1a), Nꢀcyclopropylꢀ (1b), and Nꢀbenzylcyanoacetꢀ
amide (1c).
The structure of thienopyridines 6a—c was confirmed
by 1H NMR and IR spectroscopy. The IR spectra of comꢀ
pounds 6 exhibit characteristic absorption bands of the
NH bonds of the amide and pyridone groups in the region
3360—3260 cm–1 and the signals of the carbonyl groups in
Experimental
Melting points were determined on a Kofler heating stand.
IR spectra were recorded on a Bruker Alpha spectrophotometer
in KBr pellets, 1H and 13C NMR spectra were recorded on
a Bruker AM 300 spectrometer (300.13 and 75.47 MHz, respecꢀ
tively) in DMSOꢀd6. Nꢀsubstituted cyanoacetamides 1 were obꢀ
tained from ethyl cyanoacetate and the corresponding amines
according to the known method.14
Synthesis of substituted 5,7ꢀdioxythieno[3,2ꢀb]pyridines 6a—c
(general procedure). A corresponding nitrile 1 (25 mmol) was
added to a solution of KOH (1.4 g, 25 mmol) in EtOH (50 mL)
at 10 C, and the mixture was stirred until it dissolved. Carbon
disulfide (1.5 mL, 25 mmol) was added to the solution obtained,
which was stirred for 20 min. Then, H2O (10—15 mL) was added
to the reaction mixture until a precipitate formed was dissolved,
followed by the addition of ester 3 (3.4 mL, 25 mmol) and stirꢀ
ring for 10 min. After this, a solution of KOH (2.8 g, 50 mmol) in
EtOH (100 mL) was added, and the mixture was refluxed for
2.5 h. A dark red solution was cooled and, after addition of
concentrated HBr (2.8 mL, 25 mmol), stirred for 30 min. A corꢀ
responding alkyl halide 5 (25 mmol) was added to the solution
obtained, which was heated to boiling point and cooled. A preꢀ
cipitate formed was filtered off to obtain thieno[3,2ꢀb]pyridines
6a—c in 75—86% yields.
the region 1630 cm–1
.
1
The H NMR spectra have the characteristic signals
for the protons of the NH and OH groups, as well as the
signal for the C(6)H proton at  6.01—6.06.
Compounds 6a—c have several reactive centers and
can be used for further synthesis as convenient building
blocks. Thus, they give a threeꢀcomponent reaction with
malononitrile (7) and benzaldehyde (8), which leads to
the formation of annulated pyrans 9a—c (Scheme 2),
whose analogs possess high antitumor activity.13
Scheme 2
2ꢀ(Benzylthio)ꢀNꢀ(3ꢀmethoxypropyl)ꢀ5ꢀoxoꢀ7ꢀoxyꢀ4,5ꢀdiꢀ
hydrothieno[3,2ꢀb]pyridineꢀ3ꢀcarboxamide (6a). The yield was
75%, m.p. 197—200 C. IR, /cm–1: 3364, 3332 (NH), 1624
(CO). 1H NMR, : 1.79 (m, 2 H, CH2CH2CH2OCH3); 3.24
(s, 3 H, OCH3); 3.28—3.43 (m, 4 H, CH2CH2CH2OCH3); 4.33
(s, 2 H, SCH2); 6.03 (s, 1 H, C(6)H); 7.25—7.40 (m, 3 H, C6H5,
H(3, 4, 5)); 7.47 (m, 2 H, C6H5, H(2, 6)); 9.74 (br.s, 1 H,
CONH); 10.79 (br.s, 1 H, OH); 11.67 (s, 1 H, N(4)H). 13C NMR,
: 29.38, 35.72, 38.02, 57.90, 69.78, 90.97, 112.17, 127.48, 128.52,
128.58, 129.10, 136.09, 160.35, 162.44, 163.74. The signals in
the 13C NMR spectrum partially overlap. Found (%): C, 56.19;
H, 4.72; N, 6.64. C19H20N2O4S2. Calculated (%): C, 56.42;
H, 4.98; N, 6.93.
NꢀCyclopropylꢀ2ꢀmethylthioꢀ5ꢀoxoꢀ7ꢀoxyꢀ4,5ꢀdihydrothiꢀ
eno[3,2ꢀb]pyridineꢀ3ꢀcarboxamide (6b). The yield was 86%, m.p.
257—259 C. IR, /cm–1: 3356, 3260 (NH), 1632, 1616 (CO).
1H NMR, : 0.58—0.78 (m, 4 H, (CH2)2CH); 2.55 (m, 3 H,
SCH3); 2.84 (m, 1 H, (CH2)2CH); 6.01 (s, 1 H, C(6)H); 9.71
Regents
6a
6b
Z
R
Ph
H
Products
9a
CH3O(CH2)3NHCO
cycloꢀC3H5NHCO
C6H5CH2NHCO
9b
9c
6c
H

1306
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 5, May, 2013
Larionova et al.
(br.s, 1 H, NH); 10.84 (br.s, 1 H, OH); 11.67 (br.s, 1 H, N(4)H).
Found (%): C, 48.36; H, 3.85; N, 9,29. C12H12N2O3S2. Calcuꢀ
lated (%): C, 48.63; H, 4.08; N, 9,45.
(m, 3 H, C(6)H, CH2); 7.12—7.35 (m, 12 H, 2 C6H5, NH2);
10.07 (br.s, 1 H, CONH); 11.61 (br.s, 1 H, N(4)H). Found (%):
C, 62.07; H, 3.84; N, 11.36. C26H20N4O3S2. Calculated (%):
C, 62.38; H, 4.03; N, 11.19.
NꢀBenzylꢀ2ꢀmethylthioꢀ5ꢀoxoꢀ7ꢀoxyꢀ4,5ꢀdihydrothienoꢀ
[3,2ꢀb]pyridineꢀ3ꢀcarboxamide (6c). The yield was 76%, m.p.
272—275 C. IR, /cm–1: 3312, 3284 (NH), 1636, 1620 (CO).
1H NMR, : 2.58 (s, 3 H, SCH3); 4.56 (d, 2 H, C6H5CH2NH,
J = 6.2 Hz); 6.06 (s, 1 H, C(6)H); 7.20—7.35 (m, 5 H, C6H5);
10.36 (br.s, 1 H, NH); 10.81 (br.s, 1 H, OH); 11.68 (br.s, 1 H,
N(4)H). Found (%): C, 55.72; H, 3.84; N, 7.75. C16H14N2O3S2.
Calculated (%): C, 55.47; H, 4.07; N, 8.09.
Synthesis of substituted 8ꢀaminoꢀ7ꢀcyanoꢀ5ꢀoxoꢀ6ꢀphenylꢀ
4,6ꢀdihydroꢀ5Hꢀpyrano[2,3ꢀd]thieno[3,2ꢀb]pyridines 9a—c (genꢀ
eral procedure). A mixture of the corresponding thienopyridine 6
(5 mmol), malononitrile (0.33 g, 5 mmol), benzaldehyde (0.53 g,
5 mmol), and Et3N (1 mL, 7 mmol) in EtOH (30 mL) was
refluxed for 30 min and cooled. A precipitate formed was filtered
off to obtain pyrans 9a—c in 58—78% yields.
8ꢀAminoꢀ2ꢀbenzylthioꢀ7ꢀcyanoꢀNꢀ(3ꢀmethoxypropyl)ꢀ5ꢀoxoꢀ
6ꢀphenylꢀ4,6ꢀdihydroꢀ5Hꢀpyrano[2,3ꢀd]thieno[3,2ꢀb]pyridineꢀ
3ꢀcarboxamide (9a). The yield was 58%, m.p. 158—160 C. IR,
/cm–1: 3372, 3290, 3204 (NH2, NH), 2196 (CN), 1668, 1624 (CO,
C=C,  NH2). 1H NMR, : 1.76 (m, 2 H, CH2CH2CH2OCH3);
3.20 (s, 3 H, OCH3); 3.27—3.45 (m, 4 H, CH2CH2CH2OCH3);
4.36 (s, 2 H, SCH2); 4.54 (s, 1 H, C(6)H); 7.05—7.5 (m, 12 H,
2 C6H5, NH2); 9.35 (br.s, 1 H, CONH); 11.61 (br.s, 1 H, N(4)H).
Found (%): C, 62.04; H, 4.83; N, 10.34. C29H26N4O4S2. Calcuꢀ
lated (%): C, 62.35; H, 4.69; N, 10.03.
References
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8ꢀAminoꢀ7ꢀcyanoꢀNꢀcyclopropylꢀ2ꢀmethylthioꢀ5ꢀoxoꢀ6ꢀpheꢀ
nylꢀ4,6ꢀdihydroꢀ5Hꢀpyrano[2,3ꢀd]thieno[3,2ꢀb]pyridineꢀ3ꢀcarbꢀ
oxamide (9b). The yield was 66%, m.p. 302—304 C. IR, /cm–1
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3376, 3256, 3188 (NH2, NH), 2188 (CN), 1660, 1620 (CO,
C=C,  NH2). 1H NMR, : 0.55—0.71 (m, 4 H, (CH2)2CH);
2.62 (s, 3 H, SCH3); 2.84 (m, 1 H, (CH2)2CH); 4.57 (s, 1 H,
C(6)H); 7.15—7.35 (m, 7 H, C6H5, NH2); 9.41 (br.s, 1 H,
CONH); 11.64 (s, 1 H, N(4)H). Found (%): C, 58.91; H, 3.86;
N, 12.23. C22H18N4O3S2. Calculated (%): C, 58.65; H, 4.03;
N, 12.44.
8ꢀAminoꢀNꢀbenzylꢀ7ꢀcyanoꢀ2ꢀmethylthioꢀ5ꢀoxoꢀ6ꢀphenylꢀ
4,6ꢀdihydroꢀ5Hꢀpyrano[2,3ꢀd]thieno[3,2ꢀb]pyridineꢀ3ꢀcarboxꢀ
amide (9c). The yield was 78%, m.p. 279—281 C. IR, /cm–1
:
3544, 3480, 3312 (NH2, NH), 2180 (CN), 1656, 1628 (CO,
C=C,  NH2). 1H NMR, : 2.63 (s, 3 H, SCH3); 4.45—4.60
Received February 4, 2013;
in revised form February 28, 2013