A simple and expedient method for the synthesis of ethyl 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylate

Article abstract of DOI:10.1002/jhet.237

(Chemical Equation Presented) 2-Chloro-4,6-diarylnicotinonitrile 1 was reacted with ethyl 2-mercaptoacetate 2 to furnish ethyl 2-(3-cyano-4,6- diarylpyridin-2-ylthio)acetate 3 as intermediates. These intermediates were cyclized by Thorpe-Zeigler cyclizati

Full text of DOI:10.1002/jhet.237

November 2009
A Simple and Expedient Method for the Synthesis of Ethyl
3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylate
1349
Hetal C. Shah,a Vaishali H. Shah,a and Nirmal D. Desaib*
aOrganic Synthesis Laboratory, M. G. Science Institute, Navrangpura, Ahmedabad 380009, India
bLoyola Center for R&D, St. Xavier’s College, Navrangpura, Ahmedabad 380009, India
*E-mail: nirmal.desai@yahoo.com
Received February 5, 2009
DOI 10.1002/jhet.237
Published online 11 November 2009 in Wiley InterScience (www.interscience.wiley.com).
Dedicated to the memory of Dr. Chaitanya G. Dave.
2-Chloro-4,6-diarylnicotinonitrile 1 was reacted with ethyl 2-mercaptoacetate 2 to furnish ethyl 2-(3-
cyano-4,6-diarylpyridin-2-ylthio)acetate 3 as intermediates. These intermediates were cyclized by
Thorpe–Zeigler cyclization using solid–liquid phase-transfer catalysis conditions to give ethyl 3-amino-
4,6-diarylthieno[2,3-b]pyridine-2-carboxylate 4. One-pot heterocyclization without isolating the inter-
mediates was also achieved using solid–liquid phase transfer conditions.
J. Heterocyclic Chem., 46, 1349 (2009).
INTRODUCTION
The Thorpe–Zeigler cyclizations [11] are one of the
most promising lines in the chemistry of amino hetero-
cycles. They are base catalyzed and sodium or potas-
sium alkoxide [12a–f], sodium hydride [12g,h], potas-
sium hydroxide [12i], and lithium hydroxide [12j] were
used frequently. Radical alternatives [13a], solvent free
[13b] strategies as well as iridium hydride complexes
[13c] also have been applied to Thorpe–Ziegler cycliza-
tions. However, a little to our surprise, no attempt has
been made to use comprehensive strategies for Thorpe–
Zeigler cyclization involving phase-transfer conditions.
In light of these considerations, we decided to set an
improved protocol by introducing phase-transfer cataly-
sis conditions for the Thorpe–Ziegler cyclization.
Many thienopyridines have been evaluated pharmaco-
logically and in particular thieno[2,3-b]pyridines are of
special importance due to the reported biological activ-
ities, including antibacterial [1], anti-inflammatory [2],
antiparasitic [3], and antidiabetic [4] agents. Moreover,
thieno[2,3-b]pyridine-5-carbonitrile were synthesizes as
kinase inhibitors [5–7], were as thieno[2,3-b]pyridin-4-
one derivatives were prepared as orally active, nonpep-
tide luteinizing hormone-releasing hormone (LHRH) re-
ceptor antagonists [8].
Despite the recent emergence of the thieno[2,3-b]pyri-
dines moiety as a useful pharmacophore, methodology
for preparation of this interesting heterocyclic ring sys-
tem remains severely limited. Traditionally, the alkyla-
tion of substituted 3-cyano-2(1H)-pyridinethiones [9a–c]
or 2-chloro-4,6-diarylnicotinonitrile [10] and Thorpe–
Ziegler cyclization of the latter in alkali medium to give
3-aminothieno[2,3-b]pyridines have been extensively
studied. Hard base like sodium or potassium alkoxide,
which are relatively difficult to handle are used in such
multistep synthesis.
RESULTS AND DISCUSSION
2-Chloro-4,6-diarylnicotinonitrile 1 was reacted with
ethyl 2-mercaptoacetate 2 in powdered KOH at 40–45ꢀC
using triethylbenzylammonium chloride (TEBA) as
phase transfer catalyst and toluene as solvent to furnish
ethyl 2-(3-cyano-4,6-diarylpyridin-2-ylthio)acetate 3 as
C
V
2009 HeteroCorporation

1350
H. C. Shah, V. H. Shah, and N. D. Desai
Vol 46
Table 1
Synthesis of 2-(3-cyano-4,6-diarylpyridin-2-ylthio)acetate 3a–k.
Entry
R1
R2
Yielda (%)
Mp (ꢀC) Found/Lit. [10]
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-OCH3C6H4
4-FC6H4
3-Cl-4-FC6H3
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-FC6H4
90
93
89
91
80
90
89
88
94
91
93
183–184/181–182
178–179/177–178
188–189
202–203
238–239/238–239
183–184/182–184
191–192
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-FC6H4
195–196
C6H5
4-CH3OC6H4
C6H5
202–203/202–203
200–201/198–199
169–170
3j
3k
a Isolated yields.
intermediates (Table 1). The reaction was optimized
using different reaction conditions and catalysts, for liq-
uid–liquid phase-transfer conditions CH2Cl2/KOH (aq.
40% w/v), the most lipophilic quats, the Aliquat, and
the tetrabutylammonium cation (TBA) were ineffective
phase transfer catalyst were as more hydrophilic cation,
TEBA gave poor yields. However in solid–liquid phase-
transfer conditions Toluene/powdered KOH TEBA was
the preferred choice. These intermediates were cyclized
by Thorpe–Zeigler cyclization using 18-crown-6 and po-
tassium hydroxide complex dissolved in acetonitrile, the
heterocyclization allowed efficient access to various
ethyl 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxy-
late 4 in excellent yields. One-pot heterocyclization
without isolating the intermediates 3 was also achieved
using solid–liquid phase-transfer catalysis (SL-PTC)
conditions (Table 2; Scheme 1).
to expand the scope of this potentially useful phase-
transfer method and optimize its efficiency. To optimize
the synthesis of 4, different catalysts and reaction condi-
tions were examined. For liquid–liquid phase-transfer
conditions CH2Cl2/KOH (aq. 40% w/v), lack of reactiv-
ity was observed in the presence of catalysts such as tet-
rabutylammonium iodide (TBAI) and tricaprylmethy-
R
V
lammonium chloride (Aliquat 336) even after pro-
longed heating (24 h, 40ꢀC). Thus, the most lipophilic
quats, the Aliquat, and the TBA are ineffective as
phase-transfer catalysts. Changing the counter ion in the
TBA quat [iodide (TBAI) or chloride (TBACl)] was
also unsuccessful thus discarding the possibility that the
lack of reactivity in the presence of the catalyst could
be due to the effect of the iodide counter ion (‘‘catalyst
poisoning’’ by association with the quat in the organic
phase [14a–d]) the results also showed that swapping
anions such as BF4ꢁ, ClO4ꢁ, and HSOꢁ4 have no catalytic
activity. On the other hand, smaller and more
Given the frequent appearance of thieno[2,3-b]pyri-
dine fragments in pharmaceutical compounds, we sought
Table 2
Synthesis ethyl 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylate 4a–k.
Yield (%)
Entry
R1
R2
Method I
Method IIa
Mp (ꢀC) Found/Lit. [10]
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
C6H5
C6H5
C6H5
4-OCH3C6H4
4-FC6H4
90
93
89
91
80
90
89
88
94
91
93
80
78
75
79
69
78
75
70
84
82
80
172–173/171–172
184–185/183–184
175–176
C6H5
C6H5
3-Cl-4-FC6H3
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-FC6H4
183–184
175–176/174–175
181–182/181–182
176–177
181–182
188–189
175–176/173–174
161–162
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
4-FC6H4
C6H5
4-CH3OC6H4
C6H5
4j
4k
a Overall yields for method II from compound 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Simple and Expedient Method for the Synthesis of Ethyl 3-amino-4,
6-diarylthieno[2,3-b]pyridine-2-carboxylate
1351
Scheme 1. Synthesis of ethyl 3-amino-4,6-diarylthieno[2,3-b]pyridine-
2-carboxylate 4.
EXPERIMENTAL
Melting points were determined by electro thermal method
in open capillary tube and are uncorrected. The IR spectra
were recorded in cmꢁ1 for KBr pellets on a Buck-500 spectro-
photometer. The 1H NMR spectra were recorded on a Varian
300 MHz spectrophotometer in DMSO-d6 using TMS as inter-
nal standard and the chemical shifts are expressed in d ppm.
MS spectra were recorded on a JEOL/ SX-102 mass spectro-
photometer under electron-impact (EI) ionization. Elemental
analyses were performed on a Carlo Erba 1108 microanalyzer
or Elementar’s Vario EL III microanalyzer. The completion of
the reaction was checked by TLC using silica gel G and spots
were exposed to iodine vapor. 2-Chloro-4,6-diarylnicotinoni-
trile 1 were synthesized by refluxing 2-oxo-4,6-diaryl-1,2-dihy-
dropyridine-3-carbonitrile [16] in phosphoryl trichloride.
General procedure for the synthesis of ethyl 2-(3-cyano-
4,6-diarylpyridin-2-ylthio)acetate (3a-k). To a well stirred
mixture of powdered potassium hydroxide (0.7 g, 12.5 mmol),
triethylbenzylammoniumchloride (0.113 g, 0.5 mmol) and 2-
chloro-4,6-diarylnicotinonitrile 1 (5 mmol) in toluene (25 mL),
was added drop wise ethyl 2-mercaptoacetate 2 (6 mmol). The
reaction mixture was heated up to 40–45ꢀC. After the comple-
tion of reaction 1–1.5 h (TLC), water (25 mL) was added to
the reaction mixture and stirring was continued for 5 min. Or-
ganic layer was separated and aqueous layer was washed with
toluene (15 mL). The combined organic layer was dried over
anhydrous magnesium sulfate, the solvent was removed in
vacuo, and the solid 3a–k thus obtained was crystallized from
EtOH-DMF mixture.
hydrophilic cations such as tributylmethylammonium
and TEBA were unsuccessful to facilitate the reaction.
These results indicate that the structure of the quaternary
ammonium cation (quat) does not seem to be crucial for
the success of the reaction. Catalyst loading, changing
the solvent, or change in temperature resulted the same.
The heterocyclization in SL-PTC conditions using 18-
crown-6, KOH along with acetonitrile as solvent fur-
nished products 4 in excellent yields. One-pot synthesis
of thieno[2,3-b]pyridine-2-carboxylate 4 without isola-
tion of intermediates 3 from 2-chloro-4,6-diarylnicotino-
nitrile 1 using same conditions was successful. Solvents
like toluene, benzene, chlorobenzene, diethyl ether,
methanol, and hexane were used, however, acetonitrile
was the best choice for such heterocyclization.
Ethyl 2-(3-cyano-4,6-diphenylpyridin-2-ylthio)acetate (3a). IR
;
1H NMR
(KBr): m ¼ 3020, 2940, 2228, 1748, 1584 cmꢁ1
(300 MHz, DMSO-d6): d ¼ 1.47 (t, J ¼ 7.2 Hz, 3H,
ACH2CH3), 4.35 (s, 2H, ACH2A), 4.56 (q, J ¼ 7.0 Hz, 2H,
ACH2CH3), 7.60–8.30 (m, 11H, ArAH); MS: m/z ¼ 374
(Mþ). Anal. Calcd for C22H18N2O2S (374.46): C, 70.57; H,
4.85; N, 7.48; Found: C, 70.63; H, 4.90; N, 7.61%.
The structure of compound ethyl 3-amino-4-tolyl-6-
phenylthieno[2,3-b]pyridine-2-carboxylate 4e was con-
firmed using X-ray crystallography [15] (Fig. 1).
Ethyl 2-(3-cyano-4-(4-methoxyphenyl)-6-phenylpyridin-2-
ylthio)acetate (3b). IR (KBr): m ¼ 3030, 2994, 2232, 1756,
A plausible mechanism for the Thorpe–Zeigler cycli-
zation is proposed in Figure 2. The initial complex for-
mation between crown ether and potassium hydroxide
extracts proton from ethyl 2-(3-cyano-4,6-diarylpyridin-
2-ylthio)acetate 3, resulting into the intermediate, fol-
lowed by intramolecular nucleophilic addition of
ACHA onto an imine that could yield an enamine and
also aromatic system for the formation of ethyl 3-
amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylate 4.
1
1590 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼ 1.35 (t, J ¼
CONCLUSIONS
In conclusion, we have described a simple, cleaner, and
convenient synthesis of ethyl 3-amino-4,6-diary-
lthieno[2,3-b]pyridine-2-carboxylate 3, which are impor-
tant building blocks for the construction of various fused
heterocycles. SL-PTC conditions using 18-crown-6 is the
method of choice with excellent yields even for one-pot
heterocyclization. The ease with which phase-transfer cat-
alyst reacts, presents new opportunities for expanding
Thorpe–Zeigler cyclization for the synthesis of numerous
heterocycles.
Figure 1. Ethyl 2-amino-6-phenyl-4-p-tolylthieno[2,3-b]pyridine-3-
carboxylate [15] (4e). [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1352
H. C. Shah, V. H. Shah, and N. D. Desai
Vol 46
Figure 2. A plausible mechanism for the Thorpe–Zeigler cyclization in solid–liquid phase-transfer catalysis conditions.
7.2 Hz, 3H, ACH2CH3), 3.98 (s, 3H, OCH3), 4.25 (s, 2H,
ACH2) 4.52 (q, J ¼ 7.0 Hz, 2H, ACH2CH3), 7.12–8.15 (m,
ArAH); MS: m/z
¼
422 (Mþ). Anal. Calcd for
C23H19ClN2O2S (422.93): C, 65.32; H, 4.53; N, 6.62; Found:
10H, ArAH); MS: m/z
¼
404 (Mþ). Anal. Calcd for
C23H20N2O3S (404.48): C, 68.30; H, 4.98; N, 6.93; Found: C,
C, 65.43; H, 4.56; N, 6.76%.
Ethyl 2-(3-cyano-4-(4-fluorophenyl)-6-p-tolylpyridin-2-ylth-
io)acetate (3h). IR (KBr): m ¼ 3010, 2992, 2232, 1744, 1596
68.35; H, 5.12; N, 7.06%.
Ethyl 2-(3-cyano-4-(4-fluorophenyl)-6-phenylpyridin-2-ylth-
io)acetate (3c). IR (KBr): m ¼ 3004, 2980, 2216, 1758, 1600
cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.39 (t, J ¼ 7.2
Hz, 3H, ACH2CH3), 2.47 (s, 3H, CH3), 4.37 (s, 2H, ACH2),
4.67 (q, J ¼ 7.0 Hz, 2H, ACH2CH3), 7.23–8.55 (m, 9H,
ArAH); MS: m/z ¼ 406 (Mþ). Anal. Calcd for C23H19FN2O2S
(406.47): C, 67.96; H, 4.71 N, 6.89; Found: C, 67.83; H, 4.86;
N, 6.96%.
1
cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼ 1.32 (t, 3H, J ¼
7.2 Hz, ACH2CH3), 4.35 (s, 2H, ACH2), 4.60 (q, J ¼ 7.0 Hz,
2H, ACH2CH3), 7.50–8.31 (m, 10H, ArAH); MS: m/z ¼ 392
(Mþ). Anal. Calcd for C22H17FN2O2S (392.45): C, 67.33; H,
4.37; N, 7.14; Found: C, 67.44; H, 4.26; N, 7.26%.
Ethyl 2-(3-cyano-6-(4-methoxyphenyl)-4-phenylpyridin-2-
ylthio)acetate (3i). IR (KBr): m ¼ 3000, 2988, 2212, 1756, 1584
cmꢁ1; 1H NMR (300 MHz, DMSO-d6): d ¼ 1.43 (t, J ¼ 7.2 Hz,
3H, ACH2CH3), 4.05 (s, 3H, OCH3), 4.30 (s, 2H, ACH2), 4.66
(q, J ¼ 7.0 Hz, 2H, ACH2CH3), 7.20–8.37 (m, 10H, ArAH);
MS: m/z ¼ 404 (Mþ). Anal. Calcd for C23H20N2O3S (404.48):
C, 68.30; H, 4.98; N, 6.93; Found: C, 68.33; H, 5.06; N, 7.12%.
Ethyl 2-(3-cyano-4,6-bis(4-methoxyphenyl)pyridin-2-ylth-
io)acetate (3j). IR (KBr): m ¼ 3010, 2960, 2236, 1756, 1600
Ethyl 2-(4-(3-chloro-4-fluorophenyl)-3-cyano-6-phenylpyri-
din-2-ylthio)acetate (3d). IR (KBr): m ¼ 3020, 2940, 2224,
1
17408, 1580 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼ 1.38
(t, J ¼ 7.2 Hz, 3H, ACH2CH3), 4.32 (s, 2H, ACH2), 4.59 (q,
J ¼ 7.0 Hz, 2H, ACH2CH3), 7.45–8.60 (m, 9H, ArAH); MS:
m/z ¼ 426 (Mþ). Anal. Calcd for C22H16ClFN2O2S (426.89):
C, 61.90; H, 3.78; N, 6.56; Found: C, 61.83; H, 3.66; N,
6.60%.
Ethyl 2-(3-cyano-6-phenyl-4-p-tolylpyridin-2-ylthio)acetate
1H
cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.33 (t, J ¼ 7.2
(3e). IR (KBr): m ¼ 3020, 2980, 2208, 1736, 1600 cmꢁ1
;
Hz, 3H, ACH2CH3), 3.64 (s, 2H, ACH2), 4.12 (s, 6H, OCH3),
4.50 (q, J ¼ 7.0 Hz, 2H, ACH2CH3), 6.99–8.19 (m, 9H,
ArAH); MS: m/z ¼ 434 (Mþ). Anal. Calcd for C24H22N2O4S
(434.51): C, 66.34; H, 5.10; N, 6.45; Found: C, 66.37; H,
5.16; N, 6.55%.
NMR (300 MHz, DMSO-d6): d ¼ 1.43 (t, J ¼ 7.2 Hz, 3H,
ACH2CH3), 2.40 (s, 3H, CH3), 4.44 (s, 2H, ACH2), 4.70 (q, J
¼ 7.0 Hz, 2H, ACH2CH3), 7.12–8.55 (m, 10H, ArAH); MS:
m/z ¼ 388 (Mþ). Anal. Calcd for C23H20N2O2S (388.48): C,
71.11; H, 5.19; N, 7.21; Found: C, 71.14; H, 5.02; N, 7.14%.
Ethyl 2-(3-cyano-4,6-dip-tolylpyridin-2-ylthio)acetate (3f). IR
Ethyl 2-(3-cyano-6-(4-fluorophenyl)-4-phenylpyridin-2-ylth-
io)acetate (3k). IR (KBr): m ¼ 3000, 2980, 2224, 1752, 1604
(KBr): m ¼ 3010, 2940, 2236, 1748, 1612 cmꢁ1
;
1H NMR
cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.38 (t, J ¼ 7.2
(300 MHz, DMSO-d6):
d
¼
1.35 (t,
J
¼7.2 Hz, 3H,
Hz, 3H, ACH2CH3), 4.35 (s, 2H, ACH2), 4.62 (q, J ¼ 7.0 Hz,
2H, ACH2CH3), 7.55–8.48 (m, 10H, ArAH); MS: m/z ¼ 392
(Mþ). Anal. Calcd for C22H17FN2O2S (392.45): C, 67.33; H,
4.37; N, 7.14; Found: C, 67.46; H, 4.26; N, 7.20%.
ACH2CH3), 2.53 (s, 6H, CH3), 4.33 (s, 2H, ACH2), 4.62 (q, J
¼ 7.0 Hz, 2H, ACH2CH3), 7.58–8.56 (m, 9H, ArAH); MS: m/
z ¼ 402 (Mþ). Anal. Calcd for C24H22N2O2S (402.51): C,
71.62; H, 5.51; N, 6.96; Found: C, 71.70; H, 5.46; N, 6.86%.
Ethyl 2-(4-(4-chlorophenyl)-3-cyano-6-p-tolylpyridin-2-ylth-
io)acetate (3g). IR (KBr): m ¼ 3020, 2970, 2228, 1742, 1584
General procedure for the synthesis of ethyl 3-amino-4,6-
diarylthieno[2,3-b]pyridine-2-carboxylate 4a–k. Method
I. To the well stirred solution of MeCN (20 mL), powdered
KOH (0.700 g, 12.5 mmol), and 18-crown-6 (0.132 g, 0.5
mmol) was added ethyl 2-(3-cyano-4,6-diarylpyridin-2-ylth-
io)acetate 3 (5 mmol). The reaction mixture was further stirred
cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.34 (t, J ¼ 7.2
Hz, 3H, ACH2CH3), 2.49 (s, 3H, CH3), 4.38 (s, 2H, ACH2),
4.66 (q, J ¼7.0 Hz, 2H, ACH2CH3), 7.30–8.25 (m, 9H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009
A Simple and Expedient Method for the Synthesis of Ethyl 3-amino-4,
6-diarylthieno[2,3-b]pyridine-2-carboxylate
1353
at 35–40ꢀC for 1.5–2 h (TLC). The solvent was distilled under
reduced pressure and the reaction mixture was poured onto
crushed ice (20 g) and neutralized with acetic acid (50% v/v).
The products thus obtained were filtered, washed with water,
dried, and crystallized from glacial acetic acid.
Method II. Ethyl 2-mercaptoacetate 2 (6 mmol) was added
drop wise to a stirred mixture of powdered potassium hydrox-
ide (15 mmol, 0.84 g) and 18-crown-6 (1 mmol, 0.264 g) in
acetonitrile (20 mL). 2-Chloro-4,6-diarylnicotinonitrile 1 (5
mmol) was added portion wise to the reaction mixture with
stirring. The reaction was further stirred at 35–40ꢀC for 2.5–
3.0 h (TLC). The solvent was distilled under reduced pressure
and the reaction mixture was poured onto crushed ice (20 g)
and neutralized with acetic acid (50% v/v). The products thus
obtained were filtered, washed with water, dried, and crystal-
lized from glacial acetic acid.
(402.51): C, 71.62; H, 5.51; N, 6.96; Found: C, 71.68; H,
5.45; N, 6.89%.
Ethyl 3-amino-4-(4-chlorophenyl)-6-p-tolylthieno[2,3-b]pyr-
idine-2-carboxylate (4g). IR (KBr): m ¼ 3510, 3380, 3000,
1
2940, 1676, 1616 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼
1.35 (t, J ¼7.2 Hz, 3H, ACH2CH3), 2.40 (s, 3H, CH3), 4.36
(q, J ¼ 6.9 Hz, 2H, ACH2CH3), 5.60 (s, 2H, ANH2), 7.18–
8.21 (m, 9H, ArAH); MS: m/z ¼ 422 (Mþ). Anal. Calcd for
C23H19ClN2O2S (422.93): C, 65.32; H, 4.53; N, 6.62; Found:
C, 65.23; H, 4.44; N, 6.55%.
Ethyl 3-amino-4-(4-fluorophenyl)-6-p-tolylthieno[2,3-b]pyri-
dine-2-carboxylate (4h). IR (KBr): m ¼ 3500, 3390, 3010,
1
2940, 1682, 1600 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼
1.33 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 2.39 (s, 3H, CH3), 4.35
(q, J ¼ 6.9 Hz, 2H, ACH2CH3), 5.62 (s, 2H, ANH2), 7.13–
8.19 (m, 9H, ArAH); MS: m/z ¼ 406 (Mþ). Anal. Calcd for
C23H19FN2O2S (406.47): C, 67.96; H, 4.71; N, 6.89; Found:
C, 67.99; H, 4.80; N, 6.86%.
Ethyl 3-amino-4,6-diphenylthieno[2,3-b]pyridine-2-carboxy-
late (4a). IR (KBr): m ¼ 3510, 3380, 3020, 2900, 1686, 1600
Ethyl 3-amino-6-(4-methoxyphenyl)-4-phenylthieno[2,3-b]-
pyridine-2-carboxylate (4i). IR (KBr): m ¼ 3520, 3400, 3000,
cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.42 (t, J ¼ 7.2
Hz, 3H, ACH2CH3), 4.42 (q, J ¼ 6.9 Hz, 2H, ACH2CH3),
5.70 (s, 2H, ANH2), 7.23–8.16 (m, 11H, ArAH); MS: m/z ¼
374 (Mþ). Anal. Calcd for C22H18N2O2S (374.46): C, 70.57;
H, 4.85; N, 7.48; Found: C, 70.51; H, 4.89; N, 7.42%.
1
2980, 1676, 1608 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼
1.39 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 3.98 (s, 3H, OCH3), 4.36
(q, J ¼ 6.9 Hz, 2H, ACH2CH3), 5.96 (s, 2H, ANH2), 7.27–
8.24 (m, 10H, ArAH); MS: m/z ¼ 404 (Mþ). Anal. Calcd for
C23H20N2O3S (404.48): C, 68.30; H, 4.98; N, 6.93; Found: C,
68.38; H, 4.88; N, 6.87%.
Ethyl
b]pyridine-2-carboxylate (4b). IR (KBr): m ¼ 3480, 3380,
3030, 2990, 1664, 1604 cmꢁ1 1H NMR (300 MHz, DMSO-
3-amino-4-(4-methoxyphenyl)-6-phenylthieno[2,3-
;
Ethyl 3-amino-4,6-bis(4-methoxyphenyl)thieno[2,3-b]pyri-
dine-2-carboxylate (4j). IR (KBr): m ¼ 3510, 3300, 3020,
d6): d ¼ 1.41 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 3.95 (s, 3H,
AOCH3), 4.49 (q, J ¼ 6.9 Hz, 2H, ACH2CH3), 5.85 (s, 2H,
ANH2), 7.18–8.10 (m, 10H, ArAH); MS: m/z ¼ 404 (Mþ).
Anal. Calcd for C23H20N2O3S (404.48): C, 68.30; H, 4.98; N,
6.93; Found: C, 68.35; H, 4.88; N, 6.88%.
1
2970, 1672, 1596 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼
1.42 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 4.02 (s, 6H, OCH3), 4.39
(q, J ¼ 6.9 Hz, 2H, ACH2CH3), 5.99 (s, 2H, ANH2), 7.26–
8.20 (m, 9H, ArAH); MS: m/z ¼ 434 (Mþ). Anal. Calcd for
C24H22N2O4S (434.51): C, 66.34; H, 5.10; N, 6.45; Found: C,
66.30; H, 5.12; N, 6.39.
Ethyl 3-amino-4-(4-fluorophenyl)-6-phenylthieno[2,3-b]pyr-
idine-2-carboxylate (4c). IR (KBr): m ¼ 3480, 3380, 3030,
1
2990, 1664, 1604 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼
Ethyl 3-amino-6-(4-fluorophenyl)-4-phenylthieno[2,3-b]pyr-
idine-2-carboxylate (4k). IR (KBr): m ¼ 3500, 3390, 3010,
1.43 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 4.40 (q, J ¼ 6.9 Hz, 2H,
ACH2CH3), 5.65 (s, 2H, ANH2), 7.45–8.15 (m, 10H, ArAH);
MS: m/z ¼ 392 (Mþ). Anal. Calcd for C22H17FN2O2S
(392.45): C, 67.33; H, 4.37; N, 7.14; Found: C, 67.41; H,
4.45; N, 7.10%.
1
2980, 1668, 1600 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼
1.45 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 4.46 (q, J ¼ 6.9 Hz, 2H,
ACH2CH3), 5.55 (s, 2H, ANH2), 7.21–8.24 (m, 10H, ArAH);
MS: m/z ¼ 392 (Mþ). Anal. Calcd for C22H17FN2O2S
(392.45): C, 67.33; H, 4.37; N, 7.14; Found: C, 67.22; H,
4.25; N, 7.26.
Ethyl 3-amino-4-(3-chloro-4-fluorophenyl)-6-phenylthieno-
[2,3-b]pyridine-2-carboxylate (4d). IR (KBr): m ¼ 3455, 3300,
3010, 2980, 2204, 1624, 1596 cmꢁ1 1H NMR (300 MHz,
;
DMSO-d6): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, ACH2CH3), 4.24 (q,
J ¼ 6.9 Hz, 2H, ACH2CH3), d ¼ 5.34 (s, 2H, NH2), 7.67–
8.14 (m, 9H, ArAH); MS: m/z ¼ 426 (Mþ). Anal. Calcd for
C22H16ClFN2O2S (426.89): C, 61.90; H, 3.78; N, 6.56; Found:
C, 61.81; H, 3.88; N, 6.60%.
Acknowledgment. The authors thank the Regional Sophisti-
cated Instrumentation Center, Central Drug Research Institute,
1
Lucknow and Chandigarh, India for H NMR and mass spectral
analysis, and Dishman Pharmaceuticals and Chemicals Ltd. for
their support.
Ethyl
2-amino-6-phenyl-4-p-tolylthieno[2,3-b]pyridine-2-
carboxylate (4e). IR (KBr): m ¼ 3520, 3400, 3000, 2980,
1
1674, 1608 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼ 1.30
REFERENCES AND NOTES
(t, J ¼ 7.2 Hz, 3H, ACH2CH3), 2.45 (s, 3H, CH3), 4.42 (q, J
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