Synthesis of some new 3-substituted benzofuran derivatives by cyclization of various phenoxy acetic acid ethyl esters

Article abstract of DOI:10.1080/00397910903457308

Six new 2-[3-(1-benzofuran-3-yl)-1H-pyrazol-1-yl] pyridines were synthesized by cyclization of various phenoxy acetic acid ethyl esters using NaOEt in ethanol at room temperature. Copyright

Full text of DOI:10.1080/00397910903457308

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Synthesis of Some New 3-Substituted
Benzofuran Derivatives by Cyclization of
Various Phenoxy Acetic Acid Ethyl Esters
M. J. Pawar a & B. K. Karale a
a Department of Chemistry, Radhabai Kale Mahavidyalaya,
Maharashtra, India
Version of record first published: 09 Nov 2010
To cite this article: M. J. Pawar & B. K. Karale (2010): Synthesis of Some New 3-Substituted
Benzofuran Derivatives by Cyclization of Various Phenoxy Acetic Acid Ethyl Esters, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:24, 3603-3608
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Synthetic Communications1, 40: 3603–3608, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457308
SYNTHESIS OF SOME NEW 3-SUBSTITUTED
BENZOFURAN DERIVATIVES BY CYCLIZATION OF
VARIOUS PHENOXY ACETIC ACID ETHYL ESTERS
M. J. Pawar and B. K. Karale
Department of Chemistry, Radhabai Kale Mahavidyalaya, Maharashtra,
India
Six new 2-[3-(1-benzofuran-3-yl)-1H-pyrazol-1-yl] pyridines were synthesized by
cyclization of various phenoxy acetic acid ethyl esters using NaOEt in ethanol at room
temperature.
Keywords: Benzo[b]furan; phenoxy acetic acid; pyrazole; pyridine
INTRODUCTION
Benzo[b]furans are of great synthetic interest because of their wide distribution
in nature and useful biological activities. The various physiological activities associa-
ted with benzofuran derivatives led in recent years to the synthesis of a large number
of such compounds.[1–7] The benzo[b]furan ring is often incorporated in pharmaceu-
tical agents as a core structural motif and as a result continues to attract extensive
synthetic efforts. These compounds have also found use in the synthesis of polycyclic
hetrocycles.[8–10]
This article describes the synthesis of 2-{3-[1-benzofuran-3-yl]-1H-pyrazol-
1-yl} pyridine. The benzofuran ring-forming reaction has been discussed previously
in the chemical literature and clearly involves a number of discrete transformations.
A wide variety of benzo[b]furans were synthesized efficiently via a CuI-catalyzed
ring closure of 2-halo aromatic aldehydes and ketones.[11] Samizu and Ogasawara[12]
have reported the synthesis of methyl 3-benzofuranylacetate employing the Heck
reaction between 2-iodophenol and 2,5-dihydro-2,5-dimethoxyfuran as a key step.
Mooradian[13] has reported the rearrangement of substituted O-Aryl oximes to sub-
stituted benzofurans. Johnson[14] and coworkers reported the synthesis and screening
of a series of 5-(3-pyridylmethyl) benzofuran-2-carboxylic acids as selective throm-
boxane A2 (TxA2) synthase inhibitors. Rao and coworkers reported the synthesis
and antifeedant activity of 3-(1-phenyl-1H-pyrazol-4-yl)benzofuran-2-carboxylic
acids,[15] where they have reported the presence of carboxylic acid at 2-positon of
Received July 20, 2009.
Address correspondence to B. K. Karale, Department of Chemistry, Radhabai Kale
Mahavidyalaya, Ahmednagar, Maharashtra 414001, India. E-mail: bkkarale@yahoo.com
3603

3604
M. J. PAWAR AND B. K. KARALE
benzofuran using the same protocol as of ours. Herein, we report the absence of
1
carboxylic acid at 2-positon of benzofuran, which we have proved by H NMR
with D2O exchange, Mass data as well as the failure in esterification of benzofuran
derivatives 2a–f.
RESULTS AND DISCUSSION
In the present work the required ethyl {2-[(1-(pyridin-2-yl)-1H-pyrazol-
4-yl)carbonyl]phenoxy} acetates 1a–f were prepared from reported literature
methods.[15] These phenoxy acetic acid esters 1a–f on treatment with NaOEt in
ethanol at room temperature undergo cyclisation to corresponding benzofuran
derivatives (Scheme 1). In earlier study, Rao and colleagues[15] have reported syn-
thesis of 3-(1-phenyl-1H-pyrazol-4-yl)benzofuran-2-carboxylic acids having carboxyl
functionality at 2-position but in our case we do not find carboxyl functionality,
1
which was confirmed by H NMR with D2O exchange, mass data. The proposed
mechanism for the reaction probably proceeds via nucleophilic attack of the carba-
nion to the carbonyl carbon resulting into five membered ring formation followed by
the bicyclic b-lactone formation,[16] the b-lactone formed further undergoes decar-
boxylation[17] to get desired benzofuran derivative (Scheme 2). The structures of
1
these compounds were confirmed by spectral techniques (MS, IR, and H NMR).
The IR absorption spectra of compounds 2a–f showed disappearance of absorption
ꢀ1
band in the range of 1740–1760 cmꢀ1 for C O of ester group and 1630–1660 cm
=
1
for C O of ketone group of starting material 1a–f and H NMR spectra show a
=
singlet in the range of 8.80–9.00 d for C2-H proton of benzofuran 2a–f, which is
not exchangeable with D2O.
EXPERIMENTAL
Commercial solvents and reagents were used without further purification. The
monitoring of reaction and checking of purity of the product were done using
pre-coated silica gel plates and visualization using iodine=UV lamp. Melting points
were taken in open capillaries and are uncorrected. IR spectra were recorded on
1
Perkin-Elmer 1420 spectrophotometer. H NMR spectra were recorded on Varian
Scheme 1.

NEW BENZOFURAN DERIVATIVES
3605
Scheme 2. Proposed mechanism.
300 MHz spectrometer in CDCl3 or DMSO as a solvent and TMS as an internal
standard. Peak values are shown in d (ppm). Mass spectra were recorded on a
Thermo Finnigan LCQ DECA XP MAX (ION TRAP) LCMSMS mass spec-
trometer using direct infusion technique. Elemental analysis was performed on a
Perkin-Elmer analyzer. Compounds 1a–f were prepared using previously reported
procedures.
General Procedure for Cyclization
The esters 1a–f (0.01 mol) was added in NaOEt solution (prepared from
0.02 mol of Na and 20 mL of EtOH) and the solution stirred at room temperature
Table 1. Characterization data of various compounds prepared
Calcd (%) (Found)
Compound
R1
H
R2
H
R3
H
R4
H
Mp (ꢁC)
125
Yield (%)
C
H
N
2a
2b
64
68
73.55
(73.48
56.49
(56.24
74.17
(74.15
65.92
(65.88
74.72
(74.50
74.17
(74.00
63.15
(63.04
50.77
(50.67
64.09
(64.00
58.15
(58.04
64.95
(64.80
64.09
(64.00
4.24
4.10
2.96
2.78
4.76
4.68
3.90
3.85
5.23
5.04
4.76
4.70
4.05
3.96
3.01
2.94
4.48
4.38
3.80
3.72
4.88
4.76
4.48
4.30
16.08
15.95)
12.35
12.10)
15.26
15.20)
13.57
13.46)
14.52
14.25)
15.26
15.10)
13.00
12.90)
10.45
10.28)
12.46
12.34)
11.30
11.18)
11.96
11.80)
12.46
12.32)
H
H
Br
H
124
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
CH3
CH3
H
H
Cl
H
H
H
H
H
H
H
H
H
H
71
181
137
233
107
114
97
64
66
65
66
24
28
22
26
20
18
C2H5
CH3
H
H
3a
3b
3c
3d
3e
3f
H
H
Br
CH3
CH3
H
H
Cl
121
110
142
C2H5
CH3
H

3606
M. J. PAWAR AND B. K. KARALE
Table 2. Spectral data of compounds 2a–f
Benzofuran
derivative
Spectral data
2a
2b
2c
IR (KBr, cmꢀ1): 3138, 2890, 1588, 1478, 1466, 1088, 778. 1H NMR (CDCl3): d 7.20–7.30
(m, 1H), 7.30–7.44 (m, 2H), 7.55 (d, 1H, J ¼ 7.2 Hz), 7.80–7.90 (m, 3H), 8.00–8.08
(m, 2H), 8.46 (d, 1H, J ¼ 3.3 Hz), 8.91 (s, 1H). MS (Mþ þ 1): 262.34.
IR (KBr, cmꢀ1): 3132, 2921, 1594, 1478, 1456, 1098, 773. 1H NMR (CDCl3): d 7.20–7.30
(m, 1H), 7.40–7.52 (m, 2H), 7.82–8.04 (m, 5H), 8.47 (s, 1H), 8.87 (s, 1H). MS (Mþ þ 1):
340.66, (Mþ þ 3):342.63.
IR (KBr, cmꢀ1): 3118, 2902, 1598, 1480, 1454, 1086, 786. 1H NMR(CDCl3): d 2.51
(s, 3H), 7.17 (d, 1H, J ¼ 7.2 Hz), 7.20–7.34 (m, 1H), 7.36 (s, 1H), 7.72 (d, 1H,
J ¼ 8.1 Hz), 7.80 (s, 1H), 7.86 d (t, 1H, J ¼ 8.4 Hz), 7.98–8.08 (m, 2H), 8.46
(d, 1H, J ¼ 3.6 Hz), 8.89 (s, 1H). MS (Mþ þ 1): 276.61.
2d
2e
2f
IR (KBr, cmꢀ1): 3160, 2944, 1600, 1490, 1468, 1110, 790. 1H NMR (CDCl3): d 2.50
(s, 3H), 7.18–7.34 (m, 1H), 7.41 (s, 1H), 7.76–7.84 (m, 2H), 7.86 (t, 1H, J ¼ 7.2 Hz),
7.96–8.10 (m, 2H), 8.47 (d, 1H, J ¼ 3.6 Hz), 8.87 (s, 1H). MS (Mþ þ 1): 310.55,
(Mþ þ 3):312.77.
IR (KBr, cmꢀ1): 3142, 2942, 1590, 1488, 1466, 1090, 794. 1H NMR (CDCl3): d 1.32
(t, 3H, J ¼ 7.8 Hz), 2.81 (q, 2H, J ¼ 7.5 Hz), 7.18–7.36 (m, 2H), 7.46 (d, 1H,
J ¼ 8.4 Hz), 7.62 (s, 1H), 7.78–7.94 (m, 3H), 8.00–8.08 (m, 2H), 8.47 (d, 1H,
J ¼ 3.3 Hz), 8.89 (s, 1H). MS (Mþ þ 1): 290.44.
IR (KBr, cmꢀ1): 3154, 2932, 1584, 1474, 1460, 1102, 760. 1H NMR (CDCl3): d 2.51
(s, 3H), 7.16–7.32 (m, 2H), 7.43 (d, 1H, J ¼ 8.4 Hz), 7.62 (s, 1H), 7.78–7.94
(m, 2H), 7.98–8.08 (m, 2H), 8.48 (s, 1H), 8.89 (s, 1H). MS (Mþ þ 1): 276.94.
Table 3. Spectral data of compounds 3a–g
Acid
derivative
Spectral data
3a
IR (KBr, cmꢀ1): 3168, 3065, 1744, 1723, 1629, 1596, 1547, 1460, 1217, 1167, 785. 1H
NMR (CDCl3): d 4.83 (s, 2H), 7.11 (d, 1H, J ¼ 8.1 Hz), 7.18–7.32 (m, 2H), 7.68 (d, 1H,
J ¼ 7.5 Hz), 7.58 (t, 1H, J ¼ 7.5 Hz), 7.85 (t, 1H, J ¼ 7.2 Hz), 8.02 (d, 1H, J ¼ 7.8 Hz),
8.23 (s, 1H), 8.44 (d, 1H, J ¼ 3.6 Hz), 9.02 d (s, 1H).
3b
3c
IR (KBr, cmꢀ1): 3224, 3125, 1756, 1728, 1609, 1574, 1522, 1432, 1209, 1142, 754. 1H
NMR (CDCl3): d 4.18 (brs, 1H, due to OH), 4.78 (s, 2H), 6.96–7.02 (m, 1H), 7.40–7.50
(m, 1H), 7.60–8.10 (m, 3H), 8.21 (s, 1H), 8.44–8.52 (m, 1H), 8.88 (s, 1H), 9.03 (s, 1H).
IR (KBr, cmꢀ1): 3162, 3076, 1752, 1732, 1634, 1588, 1547, 1460, 1167, 782. 1H NMR
(CDCl3): d 2.44 (s, 3H), 4.83 (s, 2H), 6.93 (s, 1H), 7.01 (d, 1H, J ¼ 8.1 Hz), 7.20–7.34
(m, 1H), 7.59 (d, 1H, J ¼ 7.8 Hz), 7.89 (t, 1H, J ¼ 6.9 Hz), 8.04 (d, 1H, J ¼ 8.1 Hz), 8.43
(d, 1H, J ¼ 3.6 Hz), 9.02 (s, 1H).
3d
3e
3f
IR (KBr, cmꢀ1): 3164, 3072, 1748, 1718, 1622, 1586, 1534, 1220, 1160, 764. 1H NMR
(CDCl3): d 2.43 (s, 3H), 4.12 (brs, 1H, due to OH), 4.77 (s, 2H), 6.96 (s, 1H), 7.20–7.34
(m, 1H), 7.60 (d, 1H), 7.87 (t, 1H, J ¼ 7.2 Hz), 8.02 (d, 1H, J ¼ 8.4 Hz), 8.20 (s, 1H),
8.43 (s, 1H), 9.02 (s, 1H). MS (M-1): 370.14.
IR (KBr, cmꢀ1): 3122, 3021, 1746, 1713, 1642, 1596, 1544, 1444, 1217, 765. 1H NMR
(CDCl3): d 4.83 (s, 2H), 7.11 (d, 1H, J ¼ 8.1 Hz), 7.18–7.32 (m, 2H), 7.68 (d, 1H,
J ¼ 7.5 Hz), 7.58 (t, 1H, J ¼ 7.5 Hz), 7.85 (t, 1H, J ¼ 7.2 Hz), 8.02 (d, 1H, J ¼ 7.8 Hz),
8.23 (s, 1H), 8.44 (d, 1H, J ¼ 3.6 Hz), 9.02 (s, 1H).
IR (KBr, cmꢀ1): 3088, 2978, 1734, 1712, 1589, 1544, 1430, 1207, 1147, 778. 1H NMR
(CDCl3): d 2.36 (m, 3H), 6.98 (d, 1H, J ¼ 8.4 Hz), 7.20–7.40 (m, 2H), 7.71 (s, 1H), 7.90
(t, 1H, J ¼ 6.6 Hz), 8.06 (d, 1H, J ¼ 8.4 Hz), 8.21 (s, 1H), 8.48 (s, 1H), 9.12 (s, 1H).

NEW BENZOFURAN DERIVATIVES
3607
for 18 h, diluted with water (20 mL) and neutralized with acetic acid. The aqueous
layer was extracted with ethyl acetate and washed with water, brine and dried over
anhydrous sodium sulphate and purified through column chromatography to yield
desired benzofuran derivative 2a–f as off-white solid and a part of starting material
get hydrolysied to phenoxy acetic acid 3a–f as side product, was also isolated.
Compounds synthesized by the above procedure are listed in Table 1 and their
characterization is given in Tables 2 and 3.
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3608
M. J. PAWAR AND B. K. KARALE
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