A facile one-pot synthesis of substituted thieno[2,3- b ]pyridines from enaminones

Article abstract of DOI:10.1055/s-0031-1289633

A facile and efficient one-pot synthesis of substituted thieno[2,3-b]pyridines has been developed. Treatment of enamin-ones, such as 2-acetyl-3-(dimethylamino)propenamides and -propenoates, with 2-cyanothioacetamide in the presence of potassium carbonate in N,N-dimethylformamide at 80 C followed by addition of methylene-active bromides at room temperature provided, via intramolecular cyclization, 2,3,5,6-tetrasubstituted thieno[2,3-b]pyridines in yields of 78-90%. This protocol, which combines construction and modification of the thieno[2,3-b]pyridine ring, increases the structural diversity of the final products from readily available materials. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289633

PAPER
201
A Facile One-Pot Synthesis of Substituted Thieno[2,3-b]pyridines from
Enaminones
S
ynthesis of Subs
a
titute
d
T
hi
o
eno[2,3-
b
]py
c
ridines hang Gao,a,b Dewen Dong,b Jie Zhang,a Changjiang Ding,*a Chunming Dong,b Yongjiu Liang,b Rui Zhang*b
a
Department of Chemistry, Jilin University, Changchun 130012, P. R. of China
Fax +86(431)85262676; E-mail: ariel@ciac.jl.cn; E-mail: dcjiang@163.com
b
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. of China
Received 7 September 2011; revised 14 November 2011
During the course of our studies on the chemistry of
enaminones, we have developed efficient syntheses of
substituted pyridin-2(1H)-ones,15,16 pyrimidin-4(3H)-
ones,17 dihydrofurans,18 and pyrrolin-4-ones19 from a va-
Abstract: A facile and efficient one-pot synthesis of substituted
thieno[2,3-b]pyridines has been developed. Treatment of enamin-
ones, such as 2-acetyl-3-(dimethylamino)propenamides and -prope-
noates, with 2-cyanothioacetamide in the presence of potassium
carbonate in N,N-dimethylformamide at 80 °C followed by addition riety of enaminones. Recently, we achieved the synthesis
of methylene-active bromides at room temperature provided, via in-
tramolecular cyclization, 2,3,5,6-tetrasubstituted thieno[2,3-b]py-
of functionalized pyridin-2(1H)-ones bearing formyl and
halo substituents at the 3- and 4-positions, respectively,
ridines in yields of 78–90%. This protocol, which combines
via the Vilsmeier–Haack reaction of enaminones 1
construction and modification of the thieno[2,3-b]pyridine ring, in-
(Scheme 1).15 In connection with this previous work and
creases the structural diversity of the final products from readily
following on from our research on the synthesis of highly
valuable heterocycles through enaminones, we became
interested in the synthetic potential of the readily available
enaminones 1, and designed the reaction of 1 with 2-cya-
nothioacetamide (2) and methylene-active bromides 4. As
a result of these studies, we have provided a facile and
convenient one-pot synthesis of thieno[2,3-b]pyridines.
Herein, we wish to report our experimental results.
available materials.
Key words: enaminones, cyclization, heterocycles, pyridine-
2(1H)-thiones, thieno[2,3-b]pyridines
Pyridines and their benzo/hetero-fused analogues have
emerged as an important class of aza-heterocycles due to
their presence in numerous natural products and synthetic
organic compounds that have diverse biophysio- and
pharmacological activity.1,2 These scaffolds are also of
widespread interest in supramolecular and coordination
chemistry, as well as for materials science.3 As represen-
tatives of such heterocycles, thieno[2,3-b]pyridines have
received considerable attention since they show a wide
variety of bioactivity, for example antiviral,4 antidiabet-
ic,5 antimicrobial,6 antitumor,7 antiparasitic,8 and neuro-
tropic activities.9 Actually, the key unit of thieno[2,3-
b]pyridines is found as the central fragment in many clin-
ical pharmaceuticals.10 The pharmacological importance
of thieno[2,3-b]pyridines has directed considerable re-
search activity towards the construction of the skeleton of
such heterocycles. Many synthetic approaches to
thieno[2,3-b]pyridines have been developed involving
multistep procedures from either a thiophene or a pyridine
ring and further ring closure. The condensation reaction of
2-chloropyridine-3-carbonitriles,11 2-(alkylthio)pyridine-
3-carbonitriles,9,12 or 2-aminothiophene-3-carbonitriles13
with alkyl mercaptoacetates, alkyl chloroacetates, or ke-
tones, respectively, is one of the most general synthetic
procedure for this heterocyclic-fused system. Additional-
ly, the synthesis of thieno[2,3-b]pyridines from acyclic
substrates such as 2-cyanothioacetamides via a multistep
procedure has also been reported.14
O
O
O
Ar
OHC
X
Vilsmeier reagent
N
NHAr
NMe2
1
Scheme 1 Vilsmeier reaction of enaminones 1
The substrates, enaminones 1, were prepared according to
our previously reported procedure from commercially
available b-oxo amides and N,N-dimethylformamide di-
methyl acetal.15 With substrates 1 in hand, we selected 1a
as a model compound to examine its reaction with 2-cya-
nothioacetamide (2) under basic conditions. Thus, the re-
action of 1a and 2 was first attempted in the presence of
potassium carbonate in N,N-dimethylformamide at room
temperature for 8.0 hours, however, no reaction was ob-
served as monitored by TLC. When the mixture was heat
to 60 °C, the reaction proceeded and furnished a yellow
solid after workup and subsequent purification by column
chromatography. The product was characterized as 5-cy-
ano-2-methyl-N-phenyl-6-thioxo-1,6-dihydropyridine-3-
carboxamide (3a, 68% yield) on the basis of its spectral
and analytical data (Scheme 2).
The optimization of the reaction conditions, including
base, reaction temperature, solvent, and the ratio of 2-cy-
anothioacetamide (2) to 1a was then investigated. It was
found that the reaction could proceed in the presence of
sodium alkoxide, sodium hydroxide, or potassium car-
SYNTHESIS 2012, 44, 201–206
Advanced online publication: 05.12.2011
DOI: 10.1055/s-0031-1289633; Art ID: H87411SS
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

202
B. Gao et al.
PAPER
O
O
O
Br
NC
O
O
H2N
S
NC
S
4a
NC
S
base
NHPh
NHPh
NHPh
NHPh
K2CO3, DMF
NC
+
NC
NH2
r.t.
N
H
3a
S
NMe2
N
N
H
5a
H
1a
2
3a
Scheme 2 Reaction of enaminone 1a with 2-cyanothioacetamide
(2)
Scheme 3 Reaction of pyridine-2(1H)-thione 3a with bromoaceto-
nitrile (4a)
bonate. A series of experiments revealed that 1.1 equiva-
lents of 2-cyanothioacetamide (2) was effective for the
synthesis of 3a, and the yield of 3a reached 90% when the
reaction of 1a and 2 (1.1 equiv) was performed in the pres-
ence of potassium carbonate (2.0 equiv) in N,N-dimethyl-
formamide at 80 °C for 6.0 hours (Table 1, entry 1).
trile (4a, 1.1 equiv) was added with stirring. The reaction
furnished 5a in 90% overall yield (Table 2, entry 1). In the
same fashion, a series of reactions of enaminones 1, 2-cy-
anothioacetamide (2) and methylene-active bromides 4
were carried out. As shown in Table 2, all the reactions
proceeded smoothly and afforded the corresponding
thieno[2,3-b]pyridines 5b–m in good yields (entries 2–
13). To expand the scope of the reaction, we then exam-
ined the reaction of 3-[(dimethylamino)methylene]pen-
tane-2,4-dione (1i) under identical conditions, and the
desired product 5n was obtained (entry 14). It should be
noted that the richness of the functionality, e.g. amino, es-
ter, and amide groups, on the thieno[2,3-b]pyridines 5
may render them extremely versatile as synthons in fur-
ther synthetic transformations.20 Therefore, we provide an
alternative one-pot synthesis of substituted thieno[2,3-
b]pyridine of types 5.
Under the optimal reaction conditions, a series of reac-
tions of enaminones 1b–h and 2 were conducted, and the
results are summarized in Table 1. The corresponding
substituted pyridine-2(1H)-thiones 3b–h were obtained in
good yields (entries 2–8). Next, we envisaged further syn-
thetic transformation of the available pyridine-2(1H)-
thiones 3. Thus, the reaction of 3a and bromoacetonitrile
(4a) was attempted in the presence of potassium carbonate
(2.0 equiv) in N,N-dimethylformamide at room tempera-
ture. In this case, substituted thieno[2,3-b]pyridine 5a was
synthesized in 93% yield (Scheme 3).
In summary, we have developed a facile and efficient one-
pot synthesis of substituted thieno[2,3-b]pyridines by
treatment of enaminones with potassium carbonate in
N,N-dimethylformamide followed by stepwise addition of
2-cyanothioacetamide and methylene-active bromides.
This protocol, which combines construction and modifi-
cation of the thieno[2,3-b]pyridine ring, increases the
structural diversity of the final products from readily
available materials. The use of easily available starting
materials, mild reaction conditions, simple execution,
good yields, and wide synthetic potential of the products,
make this new strategy attractive for academic research
and practical applications.
Table 1 Synthesis of Substituted Pyridine-2(1H)-thiones
O
O
O
S
NC
S
K2CO3, DMF
80 °C
R1
R1
NC
+
NH2
N
H
NMe2
1
2
3
Entry Substrate R1
Product Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
PhNH
3a
3b
3c
3d
3e
3f
90
87
85
82
89
81
84
86
4-ClC6H4NH
4-MeC6H4NH
4-MeOC6H4NH
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
2,4-Me2C6H3NH
2-MeOC6H4NH
1
purified by column chromatography over silica gel. H and 13C
NMR spectra were recorded at 400 MHz (or 300 MHz) and 100
MHz, respectively, with TMS as internal standard at 25 °C on a
Varian Inova-400 (or Bruker-300) spectrometer. IR spectra (KBr)
were recorded on a Magna-560 FTIR spectrophotometer in the
range of 400–4000 cm–1. Petroleum ether (PE) used was the fraction
boiling in the range 30–60 °C.
1g
1h
4-Cl-2,5-(MeO)2C6H2NH 3g
5-Cl-2-MeOC6H3NH 3h
a Isolated yield.
3-Amino-2-cyano-6-methyl-N-phenylthieno[2,3-b]pyridine-5-
carboxamide (5a); Typical Procedure
To a solution of 1a (1.0 mmol) and K2CO3 (3.5 equiv) in DMF (15
mL) was added cyanothioacetamide (2, 1.1 mmol) in one portion.
The mixture was heated and stirred at 80 °C for 6.0 h. When con-
The results encouraged us to explore the one-pot synthesis
of thieno[2,3-b]pyridines 5 from enaminones 1. In a rep-
resentative experiment, 1a and 2-cyanothioacetamide (2,
1.1 equiv) were treated with potassium carbonate (3.5
equiv) in N,N-dimethylformamide under 80 °C. After 1a sumption of 1a was complete (TLC), the mixture was cooled to r.t.,
then bromoacetonitrile (4a, 1.1 mmol) was added. The mixture was
stirred for a further 1.5 h, and then poured into sat. aq NaCl (30 mL)
with stirring, and extracted with CH2Cl2 (3 × 20 mL). The combined
organic extracts were washed with H2O (3 × 15 mL), dried (anhyd
had been consumed (TLC monitoring), the reaction mix-
ture was cooled to room temperature, and bromoacetoni-
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© Thieme Stuttgart · New York

PAPER
Synthesis of Substituted Thieno[2,3-b]pyridines
203
Table 2 One-Pot Synthesis of Substituted Thieno[2,3-b]pyridines
S
i)
NC
O
O
O
NH2
K2CO3, DMF, 80 °C
H2N
R2
R1
R1
NMe2
R2
Br
ii)
, r.t.
S
N
5
1
R2 = CN, COOEt
Entry
1
Substrate
1a
R1
PhNH
4-ClC6H4NH
R2
Product
5a
Yielda (%)
CN
90
85
82
78
88
81
82
85
89
83
81
80
79
51
2
1b
1c
CN
5b
5c
3
4-MeC6H4NH
CN
4
1d
1e
4-MeOC6H4NH
2,4-Me2C6H3NH
2-MeOC6H4NH
CN
5d
5e
5
CN
6
1f
CN
5f
7
1g
4-Cl-2,5-(MeO)2C6H2NH
5-Cl-2-MeOC6H3NH
PhNH
CN
5g
8
1h
1i
CN
5h
5i
9
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
10
11
12
13
14
1a
4-ClC6H4NH
5j
1b
1c
4-MeC6H4NH
5k
5l
2-MeOC6H4NH
4-Cl-2,5-(MeO)2C6H2NH
Me
1f
5m
5n
1i
a Isolated yield.
MgSO4), filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (silica gel, PE–Et2O, 10:1) to give
5a (0.277 g, 90%) as a white solid.
Anal. Calcd for C14H10ClN3OS: C, 55.35; H, 3.32; N, 13.83. Found:
C, 55.14; H, 3.27; N, 13.91.
5-Cyano-2-methyl-6-thioxo-N-(p-tolyl)-1,6-dihydropyridine-3-
carboxamide (3c)
Yield: 241 mg (85%); yellow solid; mp 266–267 °C.
5-Cyano-2-methyl-N-phenyl-6-thioxo-1,6-dihydropyridine-3-
carboxamide (3a)
Yield: 242 mg (90%); yellow solid; mp 264–265 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.27 (s, 3 H), 2.57 (s, 3 H),
7.15 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.0 Hz, 2 H), 8.30 (s, 1 H),
10.23 (s, 1 H), 14.28 (s, 1 H).
IR (KBr): 3313, 2239, 1682, 1595, 1541, 1321, 1192, 750, 692
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.58 (s, 3 H), 7.12 (t, J = 7.5
Hz, 1 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 2 H), 8.32 (s,
1 H), 10.37 (s, 1 H), 14.29 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.1, 113.0, 116.7, 119.9,
120.3, 124.0, 128.7, 138.7, 143.6, 155.2, 162.5, 178.3.
13C NMR (100 MHz, DMSO-d6): d = 18.1, 20.5, 113.0, 116.7,
119.9, 120.3, 129.1, 133.0, 136.2, 143.5, 155.2, 162.3, 178.3.
Anal. Calcd for C15H13N3OS: C, 63.58; H, 4.62; N, 14.83. Found:
C, 63.72; H, 4.65; N, 14.77.
5-Cyano-N-(4-methoxyphenyl)-2-methyl-6-thioxo-1,6-dihydro-
pyridine-3-carboxamide (3d)
Yield: 245 mg (82%); yellow solid; mp 269–270 °C.
Anal. Calcd for C14H11N3OS: C, 62.43; H, 4.12; N, 15.60. Found:
C, 62.15; H, 4.16; N, 15.57.
N-(4-Chlorophenyl)-5-cyano-2-methyl-6-thioxo-1,6-dihydropy-
ridine-3-carboxamide (3b)
Yield: 263 mg (87%); yellow solid; mp 308–309 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.57 (s, 3 H), 3.74 (s, 3 H),
6.93 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 8.30 (s, 1 H),
10.19 (s, 1 H), 14.27 (s, 1 H).
IR (KBr): 3360, 2980, 2230, 1672, 1599, 1527, 1493, 1312, 1178,
825 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 18.1, 55.2, 113.0, 113.9,
116.7, 120.3, 121.4, 131.8, 143.5, 155.2, 155.8, 162.0, 178.2.
1H NMR (300 MHz, DMSO-d6): d = 2.58 (s, 3 H), 7.42 (d, J = 8.5
Hz, 2 H), 7.70 (d, J = 9.0 Hz, 2 H), 8.33 (s, 1 H), 10.43 (s, 1 H),
14.30 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.1, 113.0, 116.6, 119.8,
121.4, 127.6, 128.6, 137.6, 143.5, 155.5, 162.5, 178.4.
Anal. Calcd for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found:
C, 59.97; H, 4.31; N, 14.15.
5-Cyano-N-(2,4-dimethylphenyl)-2-methyl-6-thioxo-1,6-dihy-
dropyridine-3-carboxamide (3e)
© Thieme Stuttgart · New York
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204
B. Gao et al.
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Yield: 265 mg (89%); yellow solid; mp 271–272 °C.
Anal. Calcd for C16H12N4OS: C, 62.32; H, 3.92; N, 18.17. Found:
C, 62.21; H, 3.96; N, 18.08.
IR (KBr): 3302, 3018, 2976, 2231, 1690, 1603, 1506, 1298, 1194,
887, 812 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.20 (s, 3 H), 2.27 (s, 3 H),
2.59 (s, 3 H), 7.01 (d, J = 8.0 Hz, 1 H), 7.06 (s, 1 H), 7.25 (d, J = 8.0
Hz, 1 H), 8.32 (s, 1 H), 9.86 (s, 1 H), 14.28 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 17.9, 18.1, 20.5, 113.1, 116.7,
120.3, 125.8, 126.5, 130.9, 132.8, 133.1, 135.1, 143.6, 155.0, 162.7,
178.3.
3-Amino-N-(4-chlorophenyl)-2-cyano-6-methylthieno[2,3-b]py-
ridine-5-carboxamide (5b)
Yield: 291 mg (85%); white solid; mp 291–292 °C.
IR (KBr): 3227, 3229, 2208, 1647, 1560, 1524, 1493, 1400, 1310,
1094, 827, 812 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.65 (s, 3 H), 7.35 (s, 2 H),
7.43 (d, J = 9.0 Hz, 2 H), 7.74 (d, J = 9.0 Hz, 2 H), 8.66 (s, 1 H),
10.74 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 22.9, 71.3, 115.6, 121.1,
121.7, 127.6, 128.8, 130.5, 137.8, 150.3, 157.5, 159.6, 166.2.
Anal. Calcd for C16H15N3OS: C, 64.62; H, 5.08; N, 14.13. Found:
C, 64.69; H, 5.03; N, 14.05.
5-Cyano-N-(2-methoxyphenyl)-2-methyl-6-thioxo-1,6-dihydro-
pyridine-3-carboxamide (3f)
Yield: 242 mg (81%); yellow solid; mp 258–259 °C.
Anal. Calcd for C16H11ClN4OS: C, 56.06; H, 3.23; N, 16.34. Found:
C, 56.31; H, 3.21; N, 16.28.
IR (KBr): 3362, 3283, 2230, 1672, 1645, 1601, 1537, 1263, 1192,
735 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.56 (s, 3 H), 3.82 (s, 3 H),
6.95 (t, J = 7.5 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.5
Hz, 1 H), 7.79 (d, J = 7.5 Hz, 1 H), 8.22 (s, 1 H), 9.66 (s, 1 H), 14.24
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.0, 55.7, 111.5, 116.7,
120.2, 120.7, 123.7, 125.8, 126.4, 140.6, 143.7, 151.0, 154.7, 162.7,
178.2.
3-Amino-2-cyano-6-methyl-N-(p-tolyl)thieno[2,3-b]pyridine-5-
carboxamide (5c)
Yield: 263 mg (82%); white solid; mp 321–322 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.26 (s, 3 H), 2.64 (s, 3 H),
7.16 (d, J = 8.0 Hz, 2 H), 7.34 (s, 2 H), 7.59 (d, J = 8.0 Hz, 2 H),
8.64 (s, 1 H), 10.50 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 20.5, 22.9, 71.2, 115.6, 119.6,
121.7, 129.2, 130.4, 133.0, 136.4, 150.4, 157.5, 159.4, 165.9.
Anal. Calcd for C17H14N4OS: C, 63.33; H, 4.38; N, 17.38. Found:
C, 63.42; H, 4.44; N, 17.42.
Anal. Calcd for C15H13N3O2S: C, 60.18; H, 4.38; N, 14.04. Found:
C, 60.49; H, 4.41; N, 14.12.
3-Amino-2-cyano-N-(4-methoxyphenyl)-6-methylthieno[2,3-
b]pyridine-5-carboxamide (5d)
Yield: 264 mg (78%); white solid; mp 295–296 °C.
N-(4-Chloro-2,5-dimethoxyphenyl)-5-cyano-2-methyl-6-thioxo-
1,6-dihydropyridine-3-carboxamide (3g)
Yield: 305 mg (84%); yellow solid; mp 261–262 °C.
IR (KBr): 3333, 3153, 2193, 1645, 1547, 1510, 1250, 876, 827
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.65 (s, 3 H), 3.73 (s, 3 H),
6.94 (d, J = 9.0 Hz, 2 H), 7.34 (s, 2 H), 7.63 (d, J = 9.0 Hz, 2 H),
8.64 (s, 1 H), 10.46 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 22.9, 55.2, 71.2, 114.0, 115.6,
121.1, 121.7, 129.3, 130.4, 132.0, 150.4, 155.7, 157.5, 159.3, 165.6.
1H NMR (300 MHz, DMSO-d6): d = 2.56 (s, 3 H), 3.79 (s, 3 H),
3.80 (s, 3 H), 7.19 (s, 1 H), 7.76 (s, 1 H), 8.23 (s, 1 H), 9.76 (s, 1 H),
14.26 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.1, 56.5, 56.6, 108.5, 113.0,
113.5, 116.7, 120.3, 126.1, 143.8, 145.0, 148.0, 154.9, 162.9, 178.4.
Anal. Calcd for C16H14ClN3O3S: C, 52.82; H, 3.88; N, 11.55.
Found: C, 52.57; H, 3.86; N, 11.67.
Anal. Calcd for C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56. Found:
C, 60.57; H, 4.26; N, 16.49.
N-(5-Chloro-2-methoxyphenyl)-5-cyano-2-methyl-6-thioxo-1,6-
dihydropyridine-3-carboxamide (3h)
Yield: 287 mg (86%); yellow solid; mp 245–246 °C.
3-Amino-2-cyano-N-(2,4-dimethylphenyl)-6-methylthieno[2,3-
b]pyridine-5-carboxamide (5e)
Yield: 295 mg (88%); white solid; mp 313–314 °C.
IR (KBr): 3348, 3232, 2197, 1643, 1526, 1429, 1302, 876 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.55 (s, 3 H), 3.84 (s, 3 H),
7.10 (d, J = 9.0 Hz, 1 H), 7.21 (dd, J1 = 9.0 Hz, J2 = 2.0 Hz, 1 H),
7.97 (s, 1 H), 8.22 (s, 1 H), 9.80 (s, 1 H), 14.26 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 18.1, 56.1, 112.8, 116.7,
1H NMR (300 MHz, DMSO-d6): d = 2.25 (s, 3 H), 2.27 (s, 3 H),
2.68 (s, 3 H), 7.03 (d, J = 7.5 Hz, 1 H), 7.08 (s, 1 H), 7.29 (d, J = 8.0
Hz, 1 H), 7.38 (s, 2 H), 8.64 (s, 1 H), 9.96 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 17.9, 20.5, 22.9, 71.1, 115.7,
121.7, 125.6, 126.6, 129.4, 130.4, 131.0, 132.7, 133.2, 135.2, 150.4,
157.4, 159.3, 166.3.
120.2, 122.5, 123.7, 124.8, 127.8, 143.7, 149.5, 154.8, 163.0, 178.4.
Anal. Calcd for C15H12ClN3O2S: C, 53.97; H, 3.62; N, 12.59.
Found: C, 54.04; H, 3.57; N, 12.52.
3-Amino-2-cyano-6-methyl-N-phenylthieno[2,3-b]pyridine-5-
carboxamide (5a)
Yield: 277 mg (90%); white solid; mp 283–284 °C.
Anal. Calcd for C18H16N4OS: C, 64.26; H, 4.79; N, 16.65. Found:
C, 63.97; H, 4.81; N, 16.70.
IR (KBr): 3350, 3248, 2201, 1663, 1556, 1445, 1325, 754, 690
cm–1.
1H NMR (300 MHz, DMSO-d6): d = 2.66 (s, 3 H), 7.12 (t, J = 7.0
Hz, 1 H), 7.35–7.39 (m, 4 H), 7.71 (d, J = 8.0 Hz, 2 H), 8.66 (s, 1
H), 10.60 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 22.9, 71.3, 115.6, 119.6,
121.7, 124.0, 128.9, 129.1, 130.5, 138.9, 150.4, 157.5, 159.5, 166.1.
3-Amino-2-cyano-N-(2-methoxyphenyl)-6-methylthieno[2,3-
b]pyridine-5-carboxamide (5f)
Yield: 273 mg (81%); white solid; mp 237–238 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.66 (s, 3 H), 3.80 (s, 3 H),
6.97 (t, J = 7.5 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.5
Hz, 1 H), 7.34 (s, 2 H), 7.88 (d, J = 7.0 Hz, 1 H), 8.60 (s, 1 H), 9.80
(s, 1 H).
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Synthesis of Substituted Thieno[2,3-b]pyridines
205
13C NMR (100 MHz, DMSO-d6): d = 22.9, 55.7, 71.0, 111.6, 115.7,
120.3, 121.6, 123.4, 125.8, 126.6, 129.4, 130.3, 150.4, 151.0, 157.4,
159.3, 166.3.
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.0 Hz, 3 H), 2.24
(s, 3 H), 2.63 (s, 3 H), 4.24 (q, J = 7.0 Hz, 2 H), 7.14 (d, J = 8.0 Hz,
2 H), 7.32 (s, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 8.70 (s, 1 H), 10.51 (s,
1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.4, 20.5, 22.9, 60.0, 93.4,
119.6, 123.0, 128.7, 129.2, 130.6, 132.9, 136.5, 147.8, 157.2, 159.6,
164.4, 166.1.
Anal. Calcd for C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56. Found:
C, 60.59; H, 4.14; N, 16.52.
3-Amino-N-(4-chloro-2,5-dimethoxyphenyl)-2-cyano-6-meth-
ylthieno[2,3-b]pyridine-5-carboxamide (5g)
Yield: 329 mg (82%); white solid; mp 143–144 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.66 (s, 3 H), 3.78 (s, 3 H),
3.80 (s, 3 H), 7.19 (s, 1 H), 7.34 (s, 2 H), 7.86 (s, 1 H), 8.63 (s, 1 H),
9.92 (s, 1 H).
Anal. Calcd for C19H19N3O3S: C, 61.77; H, 5.18; N, 11.37. Found:
C, 61.66; H, 5.21; N, 11.43.
Ethyl 3-Amino-5-[(2-methoxyphenyl)carbamoyl]-6-methyl-
thieno[2,3-b]pyridine-2-carboxylate (5l)
Yield: 309 mg (80%); white solid; mp 126–128 °C.
13C NMR (100 MHz, DMSO-d6): d = 23.1, 56.5, 56.7, 71.1, 108.0,
113.6, 115.7, 116.6, 121.7, 126.5, 129.0, 130.6, 144.9, 148.1, 150.5,
157.5, 159.4, 166.5.
1H NMR (300 MHz, DMSO-d6): d = 1.27 (t, J = 7.0 Hz, 3 H), 2.66
(s, 3 H), 3.79 (s, 3 H), 4.24 (q, J = 7.0 Hz, 2 H), 6.96 (t, J = 7.5 Hz,
1 H), 7.06 (d, J = 7.5 Hz, 1 H), 7.13–7.18 (m, 1 H), 7.33 (s, 2 H),
7.89 (d, J = 7.5 Hz, 1 H), 8.65 (s, 1 H), 9.77 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.4, 23.0, 55.7, 60.0, 93.3,
111.5, 120.3, 122.9, 123.4, 125.7, 126.7, 128.9, 130.5, 147.9, 151.0,
157.2, 159.5, 164.4, 166.6.
Anal. Calcd for C18H15ClN4O3S: C, 53.67; H, 3.75; N, 13.91.
Found: C, 53.82; H, 3.73; N, 13.84.
3-Amino-N-(5-chloro-2-methoxyphenyl)-2-cyano-6-methyl-
thieno[2,3-b]pyridine-5-carboxamide (5h)
Yield: 317 mg (85%); white solid; mp 245–246 °C.
Anal. Calcd for C19H19N3O4S: C, 59.21; H, 4.97; N, 10.90. Found:
C, 58.97; H, 4.91; N, 10.96.
1H NMR (300 MHz, DMSO-d6): d = 2.65 (s, 3 H), 3.82 (s, 3 H),
7.11 (d, J = 9.0 Hz, 1 H), 7.22 (dd, J1 = 9.0 Hz, J2 = 2.5 Hz, 1 H),
7.34 (s, 2 H), 8.07 (s, 1 H), 8.59 (s, 1 H), 9.98 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 23.0, 56.1, 71.1, 112.9, 115.7,
121.6, 122.0, 123.8, 124.8, 128.0, 129.0, 130.5, 149.4, 150.4, 157.4,
159.5, 166.6.
Ethyl 3-Amino-5-[(4-chloro-2,5-dimethoxyphenyl)carbamoyl]-
6-methylthieno[2,3-b]pyridine-2-carboxylate (5m)
Yield: 353 mg (79%); white solid; mp 147–149 °C.
1H NMR (300 MHz, CDCl3): d = 1.40 (t, J = 7.0 Hz, 3 H), 2.84 (s,
3 H), 3.84 (s, 3 H), 3.92 (s, 3 H), 4.37 (q, J = 7.0 Hz, 2 H), 6.04 (s,
2 H), 6.91 (s, 1 H), 8.10 (s, 1 H), 8.21 (s, 1 H), 8.31 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.4, 23.8, 56.3, 56.7, 60.8, 98.8,
104.8, 112.2, 116.5, 122.8, 126.4, 127.6, 128.3, 142.0, 146.0, 149.0,
157.5, 161.5, 165.3, 166.1.
Anal. Calcd for C17H13ClN4O2S: C, 54.77; H, 3.51; N, 15.03.
Found: C, 54.67; H, 3.49; N, 15.01.
Ethyl 3-Amino-6-methyl-5-(phenylcarbamoyl)thieno[2,3-b]py-
ridine-2-carboxylate (5i)
Yield: 317 mg (89%); white solid; mp 264–266 °C.
Anal. Calcd for C20H20ClN3O5S: C, 53.39; H, 4.48; N, 9. 34. Found:
C, 53.18; H, 4.45; N, 9.40.
IR (KBr): 3456, 3267, 1680, 1650, 1620, 1529, 1259, 1128, 1063,
748, 690 cm–1.
Ethyl 3-Amino-5-acetyl-6-methylthieno[2,3-b]pyridine-2-car-
boxylate (5n)
Yield: 117 mg (51%). Compound 5n is a known compound; its
analytical data are in good agreement with those reported in the
literature.21
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.0 Hz, 3 H), 2.65
(s, 3 H), 4.25 (q, J = 7.0 Hz, 2 H), 7.09 (t, J = 7.0 Hz, 1 H), 7.34 (s,
2 H), 7.36 (s, 1 H), 7.73 (d, J = 7.5 Hz, 1 H), 8.75 (s, 1 H), 10.62 (s,
1 H).
13C NMR (100 MHz, DMSO-d6): d = 14.5, 23.0, 60.1, 93.4, 119.7,
123.0, 123.9, 128.6, 128.8, 130.8, 139.0, 147.9, 157.3, 159.7, 164.4,
166.4.
Acknowledgement
Anal. Calcd for C18H17N3O3S: C, 60.83; H, 4.82; N, 11.82. Found:
C, 61.09; H, 4.76; N, 11.89.
Financial support of this research by the National Natural Science
Foundation of China (21172211 and 20872136) is greatly acknow-
ledged.
Ethyl 3-Amino-5-[(4-chlorophenyl)carbamoyl]-6-methyl-
thieno[2,3-b]pyridine-2-carboxylate (5j)
Yield: 323 mg (83%); white solid; mp 295–297 °C.
References
IR (KBr): 3256, 1682, 1647, 1612, 1493, 1292, 1258, 1094, 825,
814 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.0 Hz, 3 H), 2.63
(s, 3 H), 4.24 (q, J = 7.0 Hz, 2 H), 7.34 (s, 2 H), 7.39 (d, J = 9.0 Hz,
2 H), 7.78 (d, J = 9.0 Hz, 2 H), 8.79 (s, 1 H), 10.86 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): d = 15.0, 23.5, 60.6, 93.9, 121.7,
123.5, 128.1, 128.8, 129.3, 131.3, 138.5, 148.3, 157.8, 160.3, 164.9,
167.0.
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© Thieme Stuttgart · New York
Synthesis 2012, 44, 201–206

206
B. Gao et al.
PAPER
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Synthesis 2012, 44, 201–206
© Thieme Stuttgart · New York