Efficient Approach to the Synthesis of Ethyl 3-Amino-4,6-diarylfuro[2,3-b] pyridine-2-carboxylate

Article abstract of DOI:10.1080/00397910902730986

Novel ethyl 3-amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate were synthesized by Thorpe-Ziegler cyclization using solid-liquid phase-transfer catalysis conditions.

Full text of DOI:10.1080/00397910902730986

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Efficient Approach to the
Synthesis of Ethyl 3-Amino-4,6-
diarylfuro[2,3-b]pyridine-2-
carboxylate
Hetal C. Shah a , Vaishali H. Shah a & Nirmal D. Desai
b
a Organic Synthesis Laboratory, M. G. Science
Institute, Navrangpura, Ahmedabad, India
b Loyola Center for Research and Development, St.
Xavier's College, Navrangpura, Ahmedabad, India
Version of record first published: 03 Aug 2009.
To cite this article: Hetal C. Shah , Vaishali H. Shah & Nirmal D. Desai (2009):
Efficient Approach to the Synthesis of Ethyl 3-Amino-4,6-diarylfuro[2,3-b]pyridine-2-
carboxylate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:17, 3126-3140
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Synthetic Communications1, 39: 3126–3140, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902730986
Efficient Approach to the Synthesis
of Ethyl 3-Amino-4,6-diarylfuro
[2,3-b]pyridine-2-carboxylate
Hetal C. Shah,1 Vaishali H. Shah,1 and Nirmal D. Desai2
1Organic Synthesis Laboratory, M. G. Science Institute, Navrangpura,
Ahmedabad, India
2Loyola Center for Research and Development, St. Xavier’s College,
Navrangpura, Ahmedabad, India
Abstract: Novel ethyl 3-amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate were
synthesized by Thorpe–Ziegler cyclization using solid–liquid phase-transfer
catalysis conditions.
Keywords: Furo[2,3-b]pyridine, heterocyclization, solid–liquid PTC, Thorpe–
Zeigler reaction
INTRODUCTION
The furopyridine nucleus represents a useful pharmacophore in a variety
of therapeutic areas.[1] This structural unit recently has been incorporated
into HIV protease inhibitor candidates such as L-754,394.[2] Despite its
importance, however, synthetic methodologies for its construction
remain limited,[3] and the provision of sufficient amounts of these sub-
stances may represent a bottleneck for further studies and development
in medicinal chemistry.[4]
In conjunction with a recent drug development program, we became
interested in the furopyridine ring system, a key structural subunit
Received November 11, 2008.
Dedicated to the memory of Dr. Chaitanya G. Dave.
Address correspondence to Nirmal D. Desai, Loyola Center for Research and
Development, St. Xavier’s College, Navrangpura, Ahmedabad 380009, India.
E-mail: nirmal.desai@yahoo.com
3126

Furo[2,3-b]pyridine
3127
prevalent in numerous natural products and structural analogs associated
with interesting biological activities.[5]
The Thorpe–Zeigler[6] reactions are some of the most promising lines
in the chemistry of amino heterocycles. They are base catalyzed, and
sodium or potassium alkoxide,[7a–f] sodium hydride,[7g,h] potassium
hydroxide,[7i] and lithium hydroxide[7j] were employed frequently.
Radical alternatives,[8a] solvent-free[8b] strategies as well as iridium
hydride complexes,[8c] also have been applied to the Thorpe–Ziegler reac-
tion. Yet, a little to our surprise, no attempt has been made to employ
comprehensive strategies for the Thorpe–Zeigler reaction involving
phase-transfer conditions.
RESULTS AND DISCUSSION
Traditionally, furo[2,3-b]pyridines were prepared in a multistep synthesis
using a hard base such as sodium or potassium alkoxide,[7f] sodium
hydride, etc., which are relatively difficult to handle, and moreover the
yields were low.[7g] Despite the recent emergence of the furo[2,3-b]pyri-
dine moiety as a useful pharmacophore, methodology for preparation
of this interesting heterocyclic ring system remains severely limited. In
lieu of these findings, we decided to set an improved protocol by introdu-
cing phase-transfer catalysis conditions for the Thorpe–Ziegler reaction.
2-Oxo-4,6-diaryl-1,2-dihydropyridine-3-carbonitrile 1 was reacted with
ethyl bromoacetate in powdered potassium hydroxide (KOH) at
60–70ꢀC using triethylbenzylammonium chloride (TEBA) as phase-
transfer catalyst (PTC) and toluene as solvent to furnish ethyl 2-(3-cyano-
4,6-diarylpyridin-2-yloxy)acetate 2 (Scheme 1, Table 1). It was envisioned
that target compound 1 involves an ambident anion and can be expected
to yield a mixture of N- and O-alkylated products. However, O-alkylated
product was the main dominant product because of chain length of alky-
lating reagent and by the steric hindrance offered by the substituted aryl
ring present at position 6 of the pyridine ring. The reaction was optimized
Scheme 1. Synthesis of ethyl 2-(3-cyano-4,6-diarylpyridin-2-yloxy)acetate 2.

3128
H. C. Shah, V. H. Shah, and N. D. Desai
Table 1. Synthesis of ethyl 2-(3-cyano-4,6-diarylpyridin-2-
yloxy)acetate 2a–m
Entry
R1
R2
Yielda (%) Mp (ꢀC)
2a
2b
2c
2d
2e
2f
C6H5
C6H5
C6H5
C6H5
C6H5
80
78
76
72
75
81
78
84
79
72
80
88
79
136–137
184–185
173–175
158–160
140–141
167–168
145–146
150–151
147–149
189–190
129–130
130–131
135–137
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
C6H5
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4 C6H5
4-ClC6H4
2g
2h
2i
4-CH3OC6H4 4-CH3OC6H4
4-ClC6H4
4-ClC6H4
2-Furyl
2-Furyl
2-Thienyl
C6H5
4-CH3C6H4
C6H5
4-CH3C6H4
C6H5
2j
2k
2l
2m
aIsolated yields.
using various PTCs, and TEBA was the preferred choice. As this occurs
between phases, interphase, stirring was important and was optimized at
150 rpm.
Intermediates 2 were cyclized by the Thorpe–Zeigler cyclization using
18-crown-6 and KOH complex dissolved in acetonitrile; the hetero-
cyclization allowed efficient access to various furo[2,3-b]pyridine nucleus
in excellent yields (Scheme 2, Table 2). The structure of compound
ethyl 3-amino-6-phenyl-4-tolylfuro[2,3-b]pyridine-2-carboxylate[9] was
confirmed using x-ray crystallography (Fig. 1).
Given the frequent appearance of furo[2,3-b]pyridine fragments in
pharmaceutical compounds, we sought to expand the scope of this poten-
tially useful phase-transfer method and optimize its efficiency. To opti-
mize the synthesis of 3a–m, different catalysts and reaction conditions
were examined. For liquid–liquid phase-transfer conditions, CH2Cl2=
KOH (aq. 40% w=v), lack of reactivity was observed in the presence
Scheme 2. Synthesis of ethyl 3-amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate 3.

Furo[2,3-b]pyridine
3129
Table 2. Ethyl 3-amino-4,6-diarylfuro[2,3-b]pyridine-2-car-
boxylate 3a–m
Entry
R1
R2
Yielda (%) Mp (ꢀC)
3a
3b
3c
3d
3e
3f
C6H5
C6H5
C6H5
C6H5
C6H5
82
65
75
78
60
70
77
81
72
65
80
70
72
185–187
148–149
155–156
161–162
165–166
185–186
169–170
152–154
167–168
192–193
205–207
180–182
177–178
4-CH3C6H4
4-CH3OC6H4
4-ClC6H4
C6H5
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4 C6H5
4-ClC6H4
3g
3h
3i
4-CH3OC6H4 4-CH3OC6H4
4-ClC6H4
4-ClC6H4
2-Furyl
2-Furyl
2-Thienyl
C6H5
4-CH3C6H4
C6H5
4-CH3C6H4
C6H5
3j
3k
3l
3m
aIsolated yields.
of catalysts such as tetrabutylammonium iodide (TBAI) and tricapryl-
methylammonium chloride (Aliquat1 336) even after prolonged heating
(24 h, 40ꢀC). Thus, the most lipophilic quats, the Aliquat, and the
tetrabutylammonium cation (TBA) are ineffective as PTCs. Changing
Figure 1. X-ray structure of ethyl 3-amino-6-phenyl-4-tolylfuro[2,3-b]pyridine-2-
carboxylate.[9]

3130
H. C. Shah, V. H. Shah, and N. D. Desai
the counter ion in the TBA quat [iodide (TBAI) or chloride (TBACl)] was
also unsuccessful, thus discarding the possibility that the lack of reactiv-
ity in the presence of the catalyst could be due to the effect of the iodide
counterion (‘‘catalyst poisoning’’ by association with the quat in the
organic phase[10]). On the other hand, smaller and more hydrophilic
cations such as tributylmethylammonium and TEBA did not 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 changing the
temperature resulted in the same. The heterocyclization in solid–liquid
phase-transfer catalysis conditions using 18-crown-6 KOH along with
acetonitrile as solvent furnished products 3a–m in excellent yields.
Solvents such as toluene, benzene, chlorobenzene, diethyl ether, methanol,
and hexane were employed; however, acetonitrile was the best choice
for such heterocyclization. Synthesis of furo[2,3-b]pyridine-2-carboxylate
3
without isolation of intermediates
2
1 using solid–liquid phase-transfer
from 2-oxo-4,6-diaryl-1,
2-dihydropyridine-3-carbonitrile
conditions was unsuccessful.
A plausible mechanism for the Thorpe–Zeigler reaction is proposed
in Fig. 2. The initial complex formation between crown ether and
KOH extracts the proton from ethyl 2-(3-cyano-4,6-diarylpyridin-2-yloxy)
acetate 2, resulting in the intermediate, which was followed by intra-
molecular nucleophilic addition of -CH- onto an imines that could yield
Figure 2. A plausible mechanism for the Thorpe–Zeigler cyclization in solid–
liquid phase-transfer catalysis conditions.

Furo[2,3-b]pyridine
3131
an enamine and also an aromatic system for the formation of ethyl
3-amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate 3.
CONCLUSIONS
In conclusion, we have described a simple, clean, and convenient
synthesis of ethyl 3-amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate 3,
which is an important building block for the construction of various
fused heterocycles. A comparison of the conventional method and
solid–liquid PTC suggests that the solid–liquid PTC conditions using
18-crown-6 is the method of choice with excellent yields. The ease with
which the PTC reacts presents new opportunities for expanding the
Thorpe–Zeigler reaction for the synthesis of numerous heterocycles.
EXPERIMENTAL
Melting points were determined by the electrothermal method in an open
capillary tube and are uncorrected. The infrared (IR) spectra were
recorded in cmꢁ1 for KBr pellets on a Buck-500 spectrophotometer. The
1H NMR spectra were recorded on a Varian 300-MHz spectrophotometer
in CDCl3 using tetramethylsilane (TMS) as internal standard, and the che-
mical shifts are expressed in d ppm. Mass spectra (MS) were recorded on a
Jeol SX-102 mass spectrophotometer under electron-impact (EI) ioniza-
tion. Elemental analyses were performed on a Carlo Erba 1108 microana-
lyzer or Elementar’s Vario EL III microanalyzer. The purity of the
compounds was routinely checked by thin-layer chromatography (TLC)
using silica gel G, and spots were exposed to iodine vapor.
Synthesis of Ethyl 2-(3-cyano-4,6-p-tolylpyridin-2-yloxy)acetate
2a–m: General Procedure
Ethyl bromoacetate (6mmol) was added dropwise to a well-stirred mixture
of powdered KOH (0.7 g, 12.5 mmol), triethylbenzylammoniumchloride
(0.113 g, 0.5 mmol), and 2-oxo-4,6-diaryl-1,2-dihydropyridine-3-carbonitrile
1 (5mmol) in toluene (25mL). The reaction mixture was heated up to
60–70ꢀC. After the completion of the reaction ca. 1 h (TLC), water
(25 mL) was added to the reaction mixture and stirring was continued
for 5 min. The organic layer was separated, and the 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
solids (2a–w) thus obtained were crystallized from methanol.

3132
H. C. Shah, V. H. Shah, and N. D. Desai
Data
Ethyl 2-(3-Cyano-4,6-diphenylpyridin-2-yloxy)acetate (2a)
1
IR (KBr): n ¼ 3020, 2940, 2228, 1748, 1584 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.38 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.32 (q, J ¼ 7.0 Hz, 2H,
-CH2CH3), 4.72 (s, 2H, -CH2), 7.51–8.65 (m, 11H, Ar-H); MS: m=z ¼ 358
(Mþ). Anal. calcd. for C22H18N2O3 (358.39): C, 73.73; H, 5.06; N, 7.82.
Found: C, 73.83; H, 5.26; N, 7.76%.
Ethyl 2-(3-Cyano-4-phenyl-6-p-tolylpyridin-2-yloxy)acetate (2b)
1
IR (KBr): n ¼ 3004, 2980, 2222, 1752, 1596 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.39 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.51 (s, 3H, CH3), 4.36
(q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.72 (s, 2H, -CH2), 7.55–8.60 (m, 10H,
Ar-H); MS: m=z ¼ 372 (Mþ). Anal. calcd. for C23H20N2O3 (372.42): C,
74.18; H, 5.41; N, 7.52. Found: C, 74.23; H, 5.26; N, 7.76%.
Ethyl 2-(3-Cyano-6-(4-methoxyphenyl)-4-phenylpyridin-2-yloxy)acetate (2c)
1
IR (KBr): n ¼ 3030, 2994, 2232, 1756, 1590 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 3.89 (s, 3H, OCH3),
4.36 (q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.79 (s, 2H, -CH2), 7.56–8.35
(m, 10H, Ar-H); MS: m=z ¼ 388 (Mþ). Anal. calcd. for C23H20
N2O4 (388.42): C, 71.12; H, 5.19; N, 7.21. Found: C, 71.18; H, 5.31;
N, 7.32%.
Ethyl 2-(6-(4-Chlorophenyl)-3-cyano-4-phenylpyridin-2-yloxy)acetate (2d)
1
IR (KBr): n ¼ 3004, 2980, 2216, 1758, 1600 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.32 (t, 3H, J ¼ 7.2 Hz, -CH2CH3), 4.34 (q, J ¼ 7.0 Hz, 2H,
-CH2CH3), 4.87 (s, 2H, -CH2), 7.50–8.31 (m, 10H, Ar-H); MS: m=z ¼ 392
(Mþ). Anal. calcd. for C22H17ClN2O3 (392.83): C, 67.26; H, 4.36; N, 7.13.
Found: C, 67.12; H, 4.29; N, 7.21.
Ethyl 2-(3-Cyano-6-phenyl-4-p-tolylpyridin-2-yloxy)acetate (2e)
1
IR (KBr): n ¼ 3010, 2940, 2236, 1748, 1612 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.53 (s, 3H, CH3), 4.39
(q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.75 (s, 2H, -CH2), 7.58–8.56 (m, 10H,

Furo[2,3-b]pyridine
3133
Ar-H); MS: m=z ¼ 372 (Mþ). Anal. calcd. for C23H20N2O3 (372.42): C,
74.18; H, 5.41; N, 7.52. Found: C, 74.12; H, 5.39; N, 7.41.
Ethyl 2-(6-(4-Chlorophenyl)-3-cyano-4-p-tolylpyridin-
2-yloxy)acetate (2f)
1
IR (KBr): n ¼ 3010, 2992, 2232, 1744, 1596 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.39 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.52 (s, 3H, CH3), 4.37
(q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.77 (s, 2H, -CH2), 7.58–8.51 (m, 9H,
Ar-H); MS: m=z ¼ 406 (Mþ). Anal. calcd. for C23H19ClN2O3 (406.86):
C, 67.90; H, 4.71; N, 6.89. Found: C, 67.87; H, 4.65; N, 6.81.
Ethyl 2-(3-Cyano-4-(4-methoxyphenyl)-6-phenylpyridin-
2-yloxy)acetate (2g)
IR (KBr): n ¼ 3000, 2988, 2212, 1756, 1584 cmꢁ1;1H NMR (300 MHz,
CDCl3): d ¼ 1.40 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 3.98 (s, 3H, OCH3),
4.40 (q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.86 (s, 2H, -CH2), 7.50–8.41 (m,
10H, Ar-H); MS: m=z ¼ 388 (Mþ). Anal. calcd. for C23H20N2O4
(388.42): C, 71.12; H, 5.19; N, 7.21. Found: C, 71.14; H, 5.34; N, 7.31.
Ethyl 2-(3-Cyano-4,6-bis(4-methoxyphenyl)pyridin-2-yloxy)acetate (2h)
1
IR (KBr): n ¼ 3010, 2960, 2236, 1756, 1600 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.42 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 3.92 (s, 6H, OCH3),
4.38 (q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.84 (s, 2H, -CH2), 7.58–8.49 (m,
9H, Ar-H); MS: m=z ¼ 418 (Mþ). Anal. calcd. for C24H22N2O5
(418.44): C, 68.89; H, 5.30; N, 6.69. Found: C, 68.99; H, 5.34; N, 6.51.
Ethyl 2-(4-(4-Chlorophenyl)-3-cyano-6-phenylpyridin-2-yloxy)acetate (2i)
1
IR (KBr): n ¼ 3000, 2980, 2224, 1752, 1604 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.38 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.35 (q, J ¼ 7.0 Hz, 2H,
-CH2CH3), 4.79 (s, 2H, -CH2), 7.55–8.48 (m, 10H, Ar-H); MS: m=z ¼ 392
(Mþ). Anal. calcd. for C22H17ClN2O3 (392.83): C, 67.26; H, 4.36; N, 7.13.
Found: C, 67.44; H, 4.30; N, 7.31.
Ethyl 2-(4-(4-Chlorophenyl)-3-cyano-6-p-tolylpyridin-2-yloxy)acetate (2j)
1
IR (KBr): n ¼ 3020, 2970, 2228, 1742, 1584 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.49 (s, 3H, CH3), 4.38

3134
H. C. Shah, V. H. Shah, and N. D. Desai
(q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.80 (s, 2H, -CH2), 7.50–8.42 (m, 9H,
Ar-H); MS: m=z ¼ 406 (Mþ). Anal. calcd. for C23H19ClN2O3 (406.86):
C, 67.90; H, 4.71; N, 6.89. Found: C, 67.74; H, 4.60; N, 6.74.
Ethyl 2-(3-Cyano-4-(furan-2-yl)-6-phenylpyridin-2-yloxy)acetate (2k)
1
IR (KBr): n ¼ 3010, 2990, 2216, 1744, 1608 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.43 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.30 (q, J ¼ 7.0 Hz, 2H,
-CH2CH3), 4.76 (s, 2H, -CH2), 6.79–7.48 (m, 9H, Ar-H); MS: m=z ¼ 348
(Mþ). Anal. calcd. for C20H16N2O4 (348.35): C, 68.96; H, 4.63; N, 8.04.
Found: C, 68.74; H, 4.60; N, 8.19.
Ethyl 2-(3-Cyano-4-(furan-2-yl)-6-p-tolylpyridin-2-yloxy)acetate (2l)
1
IR (KBr): n ¼ 3000, 2980, 2220, 1740, 1596 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.41 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.59 (s, 2H, CH3), 4.35
(q, J ¼ 7.0 Hz, 2H, -CH2CH3), 4.78 (s, 2H, -CH2), 6.75–7.46 (m, 9H,
Ar-H); MS: m=z ¼ 362 (Mþ). Anal. calcd. for C21H18N2O4 (362.38): C,
69.60; H, 5.01; N, 7.73. Found: C, 69.74; H, 4.89; N, 7.56.
Ethyl 2-(3-Cyano-6-phenyl-4-(thiophen-2-yl)pyridin-2-yloxy)acetate (2m)
1
IR (KBr): n ¼ 3020, 2960, 2228, 1756, 1600 cmꢁ1; H NMR (300 MHz,
CDCl3): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.37 (q, J ¼ 7.0 Hz, 2H,
-CH2CH3), 4.70 (s, 2H, -CH2), 6.65–7.43 (m, 9H, Ar-H); MS: m=z ¼ 364
(Mþ). Anal. calcd. for C20H16N2O3S (364.42): C, 65.92; H, 4.43; N, 7.69.
Found: C, 65.74; H, 4.59; N, 7.56.
Synthesis of Ethyl 3-Amino-4,6-diarylfuro[2,3-b]pyridine-2-carboxylate
3a–m: General Procedure
Ethyl 2-(3-cyano-4,6-diarylpyridin-2-yloxy)acetate (5 mmol) was added
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). The reaction mixture
was further stirred at 40–50ꢀC 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 absolute ethyl alcohol.

Furo[2,3-b]pyridine
3135
Data
Ethyl 3-Amino-4,6-diphenylfuro[2,3-b]pyridine-2-carboxylate (3a)
IR (KBr): n ¼ 3510, 3380, 3020, 2900, 1686, 1600 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.42 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.42 (q,
J ¼ 6.9 Hz, 2H, -CH2CH3), 5.25 (s, 2H, -NH2), 7.23–8.16 (m, 11H,
Ar-H); MS: m=z ¼ 358 (Mþ). Anal. calcd. for C22H18N2O3 (358.39): C,
73.73; H, 5.06; N, 7.82. Found: C, 73.64; H, 5.19; N, 7.76.
Ethyl 3-Amino-4-phenyl-6-p-tolylfuro[2,3-b]pyridine-2-carboxylate (3b)
IR (KBr): n ¼ 3490, 3390, 3030, 2950, 1674, 1612cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.44 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.48 (s, 3H,
CH3), 4.35 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.09 (s, 2H, -NH2), 7.18–8.10
(m, 10H, Ar-H); MS: m=z ¼ 372 (Mþ). Anal. calcd. for C23H20N2O3
(372.42): C, 74.18; H, 5.41; N, 7.52. Found: C, 74.21; H, 5.55; N, 7.76.
Ethyl 3-Amino-6-(4-methoxyphenyl)-4-phenylfuro[2,3-b]
pyridine-2-carboxylate (3c)
IR (KBr): n ¼ 3480, 3380, 3030, 2990, 1664, 1604cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.41 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.48 (s, 3H,
CH3), 4.41 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.09 (s, 2H, -NH2), 7.18–8.10
(m, 10H, Ar-H); MS: m=z ¼ 388 (Mþ). Anal. calcd. for C23H20N2O4
(388.42): C, 71.12; H, 5.19; N, 7.21. Found: C, 71.22; H, 5.25; N, 7.36.
Ethyl 3-Amino-6-(4-chlorophenyl)-4-phenylfuro[2,3-b]
pyridine-2-carboxylate (3d)
IR (KBr): n ¼ 3480, 3380, 3030, 2990, 1664, 1604 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.43 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.40 (q,
J ¼ 6.9 Hz, 2H, -CH2CH3), 5.18 (s, 2H, -NH2), 7.45–8.15 (m, 10H,
Ar-H); MS: m=z ¼ 392 (Mþ). Anal. calcd. for C22H17ClN2O3 (392.83):
C, 67.26; H, 4.36; N, 7.13. Found: C, 67.22; H, 4.25; N, 7.36.
Ethyl 3-Amino-6-phenyl-4-p-tolylfuro[2,3-b]pyridine-2-carboxylate (3e)
IR (KBr): n ¼ 3480, 3380, 3030, 2990, 1664, 1604 cmꢁ1; 1H NMR (300MHz,
CDCl3): d ¼ 1.39 (t, J¼ 7.2 Hz, 3H, -CH2CH3), 2.42 (s, 3H, CH3), 4.43 (q,

3136
H. C. Shah, V. H. Shah, and N. D. Desai
J¼ 6.9 Hz, 2H, -CH2CH3), 5.21 (s, 2H, -NH2), 7.38–8.11 (m, 10H, Ar-H);
MS: m=z ¼ 372 (Mþ). Anal. calcd. for C23H20N2O3 (372.42): C, 74.18; H,
5.41; N, 7.52. Found: C, 74.22; H, 5.25; N, 7.36.
Ethyl 3-Amino-6-(4-chlorophenyl)-4-p-tolylfuro[2,3-b]
pyridine-2-carboxylate (3f)
IR (KBr): n ¼ 3500, 3390, 3010, 2940, 1682, 1600 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.33 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.39 (s, 3H,
CH3), 4.35 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.25 (s, 2H, -NH2), 7.13–8.19
(m, 9H, Ar-H); MS: m=z ¼ 406 (Mþ). Anal. calcd. for C23H19
ClN2O3 (406.86): C, 67.90; H, 4.71; N, 6.89. Found: C, 67.98; H, 4.89;
N, 6.76.
Ethyl 3-Amino-4-(4-methoxyphenyl)-6-phenylfuro[2,3-b]
pyridine-2-carboxylate (3g)
IR (KBr): n ¼ 3520, 3400, 3000, 2980, 1676, 1608 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.39 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 3.98 (s, 3H,
OCH3), 4.36 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.20 (s, 2H, -NH2),
7.27–8.24 (m, 10H, Ar-H); MS: m=z ¼ 388 (Mþ). Anal. calcd. for
C23H20N2O4 (388.42): C, 71.12; H, 5.19; N, 7.21. Found: C, 71.12; H,
4.99; N, 7.16.
Ethyl 3-Amino-4,6-bis(4-methoxyphenyl)furo[2,3-b]
pyridine-2-carboxylate (3h)
IR (KBr): n ¼ 3510, 3300, 3020, 2970, 1672, 1596 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.42 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 3.88 (s, 6H,
OCH3), 4.39 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.19 (s, 2H, -NH2),
7.26–8.20 (m, 9H, Ar-H); MS: m=z ¼ 418 (Mþ). Anal. calcd. for
C24H22N2O5 (418.44): C, 68.89; H, 5.30; N, 6.69. Found: C, 68.99; H,
5.12; N, 6.89.
Ethyl 3-Amino-4-(4-chlorophenyl)-6-phenylfuro[2,3-b]
pyridine-2-carboxylate (3i)
IR (KBr): n ¼ 3500, 3390, 3010, 2980, 1668, 1600 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.45 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.46 (q,
J ¼ 6.9 Hz, 2H, -CH2CH3), 5.25 (s, 2H, -NH2), 7.21–8.24 (m, 10H,

Furo[2,3-b]pyridine
3137
Ar-H); MS: m=z ¼ 392 (Mþ). Anal. calcd. for C22H17ClN2O3 (392.83): C,
67.26; H, 4.36; N, 7.13. Found: C, 67.22; H, 4.25; N, 7.36.
Ethyl 3-Amino-4-(4-chlorophenyl)-6-p-tolylfuro[2,3-b]
pyridine-2-carboxylate (3j)
IR (KBr): n ¼ 3510, 3380, 3000, 2940, 1676, 1616 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.40 (s, 3H,
CH3), 4.36 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.22 (s, 2H, -NH2), 7.18–8.21
(m, 9H, Ar-H); MS: m=z ¼ 406 (Mþ). Anal. calcd. for C23H19
ClN2O3 (406.86): C, 67.90; H, 4.71; N, 6.89. Found: C, 67.78; H, 4.68;
N, 6.95.
Ethyl 3-Amino-4-(furan-2-yl)-6-phenylfuro[2,3-b]
pyridine-2-carboxylate (3k)
IR (KBr): n ¼ 3490, 3390, 3000, 2950, 1672, 1612 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.43 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.37 (q,
J ¼ 6.9 Hz, 2H, -CH2CH3), 4.98 (s, 2H, -NH2), 7.08–8.25 (m, 9H,
Ar-H); MS: m=z ¼ 348 (Mþ). Anal. calcd. for C20H16N2O4 (348.35): C,
68.96; H, 4.63; N, 8.04. Found: C, 68.74; H, 4.80; N, 8.12.
Ethyl 3-Amino-4-(furan-2-yl)-6-p-tolylfuro[2,3-b]
pyridine-2-carboxylate (3l)
IR (KBr): n ¼ 3490, 3370, 3020, 2980, 1668, 1616 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.38 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 2.44 (s, 3H,
CH3), 4.45 (q, J ¼ 6.9 Hz, 2H, -CH2CH3), 5.15 (s, 2H, -NH2), 7.05–8.14
(m, 8H, Ar-H); MS: m=z ¼ 362 (Mþ). Anal. calcd. for C21H18N2O4
(362.38): C, 69.60; H, 5.01; N, 7.73. Found: C, 69.42; H, 5.25; N, 7.66.
Ethyl 3-Amino-6-phenyl-4-(thiophen-2-yl)
furo[2,3-b]pyridine-2-carboxylate (3m)
IR (KBr): n ¼ 3490, 3370, 3020, 2980, 1668, 1616 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): d ¼ 1.34 (t, J ¼ 7.2 Hz, 3H, -CH2CH3), 4.41 (q,
J ¼ 6.9 Hz, 2H, -CH2CH3), 5.07 (s, 2H, -NH2), 7.10–8.21 (m, 9H,
Ar-H); MS: m=z ¼ 362 (Mþ). Anal. calcd. for C20H16N2O3S (362.42):
C, 65.92; H, 4.43; N, 7.69. Found: C, 65.99; H, 4.25; N, 7.66.

3138
H. C. Shah, V. H. Shah, and N. D. Desai
ACKNOWLEDGMENTS
We thank the Regional Sophisticated Instrumentation Center, Central
Drug Research Institute, Lucknow and Chandigarh, India, for 1H
NMR and mass spectral analysis and Dishman Pharmaceuticals and
Chemicals Ltd. for their support.
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