One-pot synthesis of benzamidonaphtho[2,1-b]furans and benzamidobenzo[b] furans as novel polycyclic heteroaromatic compounds

Article abstract of DOI:10.1002/jccs.201300126

An operationally simple, green and efficient procedure for one-pot synthesis of novel polycyclic heteroaromatic compounds such as benzamidonaphtho[2,1-b]furans and benzamidobenzo[b]furans has been developed from the reaction of arylglyoxals, benzamide, and phenols. The reactions were mediated with low amounts of yttrium nitrate hexahydrate as a suitable Lewis acid catalyst without using solvent.

Full text of DOI:10.1002/jccs.201300126

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
One-pot Synthesis of Benzamidonaphtho[2,1-b]furans and Benzamidobenzo[b]furans
as Novel Polycyclic Heteroaromatic Compounds
a a,b
Hamid Reza Vahabinia, Bahador Karami * and Saeed Khodabakhshi
a
a
Department of Chemistry, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran
Department of Chemistry, Yasouj University, Yasouj, Zip Code: 75918-74831 P.O.Box 353, Iran
b
(Received: Mar. 7, 2013; Accepted: Jun. 27, 2013; Published Online: Aug. 29, 2013; DOI: 10.1002/jccs.201300126)
An operationally simple, green and efficient procedure for one-pot synthesis of novel polycyclic heteroar-
omatic compounds such as benzamidonaphtho[2,1-b]furans and benzamidobenzo[b]furans has been de-
veloped from the reaction of arylglyoxals, benzamide, and phenols. The reactions were mediated with low
amounts of yttrium nitrate hexahydrate as a suitable Lewis acid catalyst without using solvent.
Keywords: Heteroaromatic; Benzamidobenzo[b]furans; Benzamidonaphtho[2,1-b]furans;
Arylglyoxals; Yttrium nitrate hexahydrate.
INTRODUCTION
Among polycyclic heteroaromatic compounds, ben-
lowed by reaction with phenolic substrate 5 to produce fi-
nal benzofurans 6 in a regiospecific manner. However, af-
ter characterization by FT-IR and NMR spectroscopy, we
found that only regioisomer 6 have been formed and no
trace for oxazole 7 was observed during the control of the
reaction progress by thin layer chromatography (TLC).
The formation of benzofuran 6 showed that at the first reac-
tion, the imine 3 cannot be formed. However, it is clear that
the ketones are less active than aldehyde group under
nucleophilic attack.
zofurans have been known for organic chemists. They are
usually important constituents of plant extracts used in tra-
1
ditional medicine. They have also shown biological prop-
2
erties, such as anti-bacterial, anti-fungal, anti-inflamma-
3
4
5
6
tory anti-depressant and anti-convulsant, activities. Re-
garding to this background, a synthetic route leading to
benzo[b]furans would be of general interest. So far, several
strategies for the synthesis of benzofurans have been re-
ported in literature. Almost all of the reported methods can
be classified into two categories including (A) the intra-
molecular cyclization of benzene derivatives and (B) the
In order to find the optimal reaction conditions for the
synthesis of compounds 6, the reaction of phenylglyoxal
(1a), benzamide (2) and b-naphthol 5a was selected as a
model (Scheme II). It was found that in the absence of cata-
lyst, the reaction did not complete, even at long reaction
times in high temperatures. Through screening, it was
found that this reaction is completed with yttrium nitrate
hexahydrate (10 mol%) under solvent-free conditions at 70
ºC for the first step and 110 ºC for the second step.
7
creation of an annulated carbocyclic ring. However, the
traditional methods for the synthesis of benzofuran deriva-
tives are the preparation via O-alkylation of salicylalde-
hyde with chloroacetic acid followed by dehydration of the
8
resulting ether (category A) and via Perkin rearrangement
in which a coumarin is reacted with a hydroxide (category
9-11
B) Recently, the new strategies have been also reported
Avoidance of organic solvents during chemical reac-
tions requires a fundamental understanding of green chem-
istry factors. These concepts provide direction for im-
provements in organic synthesis and finishing of environ-
mental and economic concerns. The advantages of sol-
vent-free procedures include cost savings, reduced energy
consumption, decreased reaction times, and a considerable
reduction in reactor size and, therefore, capital investment.
These attributes have inspired a substantial research effort
directed toward the development of solvent-free reac-
for the preparation of amino and amido-substituted benzo-
1
2-14
[
b]furans.
RESULTS AND DISCUSSION
In continuation of our studies on the synthesis of
5-18
1
heterocyclic compounds
1
and catalyzed organic reac-
9-21
tions,
we treated arylglyoxals 1 (which in turn are ob-
tained by selenium dioxide oxidation of the corresponding
phenyl ketones) and benzamide (2) in the presence of yt-
trium nitrate hexahydrate as an efficient catalyst under sol-
vent-free conditions for in situ generation of imine 4 fol-
2
2-24
tions.
After optimization, the scope was explored for differ-
*
Corresponding author. E-mail: karami@mail.yu.ac.ir
J. Chin. Chem. Soc. 2013, 60, 1323-1327
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1323

Article
Vahabinia et al.
Scheme I Regiospecific reactions for preparation of
Table 1. Synthesis of benzofuran derivatives using yttrium
nitrate hexahydrate under optimized reaction conditions
novel benzofurans
[
a]
Entry
Product
Yielda (%)
Mp (ºC)
O
6
6
6
a
b
c
80
230-232
HN
O
Ph
MeO
O
75
85
80
239-241
286-288
270-272
HN
Ph
O
Br
O
HN
Ph
O
Cl
O
6
6
d
e
HN
Ph
O
OMe
O
85
75
198-200
220-222
HN
Ph
O
O
6
f
HN
Ph
O
Scheme II A model for the optimization of the reac-
O
OH
OH
tion conditions
6
6
g
85
75
248-250
225-227
HN
Ph
Cl
O
O
h
HN
Ph
OHO
[
a] Refers to isolated yields.
amidobenzofuran (6g) and 7-hydroxy-2-phenyl-3-benz-
amidobenzofuran (6h) were also obtained (Table 1, Entry
ent arylglyoxals (Table 1, Entry 6a-6f). Some hydroxylated
benzofurans also play an important role in the natural de-
5
fense mechanisms of their plants. For example, euparin
2
6
h and 6g).
As a representative sample, the H NMR (DMSO-d
00 MHz) spectrum of 6d exhibited a sharp singlet identi-
1
2
6
27
28
,
coumestrol, dehydrotremetone, and cicerfuran. Due to
this effect, a synthetic route leading to hydroxylated ben-
zofurans would be of general interest. Another test of the
efficiency of the developed procedure was our attempt to
use pyrogallol and resorcinol as phenolic substrate in this
research. Therefore, in this case, two novel hydroxylated
benzo[b]furans such as 6,7-dihydroxy-2-phenyl-3-benz-
6
4
fied as amide (d = 10.78) protons. The distinct signals (d =
8.23-7.51) corresponded to the aromatic protons (Figure
1
3
1). The proton decoupled C NMR spectrum of 6d also
showed 21 distinct resonances in agreement with the pro-
posed structure. The appearance of the signal for carbonyl
1324
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© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2013, 60, 1323-1327

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Polycyclic Heteroaromatic Compounds
We belive that one of the driving forces of this regio-
specificity may be less reactivity of benzamido group than
that of benzoyl group.
In summary, the reaction between benzamide, various
arylglyoxals, and phenols in the presence of yttrium nitrate
hexahydrate provides a simple one-pot entry for the syn-
thesis of novel polycyclic heteroaromatic compounds of
potential synthetic and pharmaceutical interest. This method
has advantages such as high yields of products and a simple
workup procedure.
1
Fig. 1. Regular (A) and extended (B) H NMR spec-
trums for compound 6d.
EXPERIMENTAL
General. Arylgloxals were prepared by the appropriate re-
2
of amide group at 166.63 ppm can prove that the com-
pounds 6d have been formed as only isomer. Another evi-
dence for the formation of regioisomer 6d is the appearance
of one peak in the infrared for secondary amide at 3205
9,30
ported procedure.
All other chemicals used in this study were
commercially available and purchased from Merck and Aldrich.
The reactions were monitored by TLC (silica gel 60 F254, hex-
ane/EtOAc). IR spectra were recorded on a FT-IR JASCO-680
and the NMR spectra were obtained on a Bruker-Instrument
DPX-400 MHz Avance III model. The varioEl CHNS Isfahan In-
dustrial University was used for elemental analysis.
-
1
cm .
On the basis of the general mechanistic pathway for
the formation of compounds 6, Scheme III shows a reason-
able mechanism. The reaction is thought to take place in
three steps. It is reasonable to assume that the initial event
involves the generation of intermediate 1 via condensation
of the amide and arylglyoxal. In the next step, intramolecu-
lar cyclization of intermediate 2 gives intermediate 3 fol-
lowed by dehydration to form corresponding product 6.
General procedure for the synthesis of benzofurans 6. A
mixture of arylglyoxal (1 mmol), benzamide (1 mmol), and yt-
trium nitrate hexahydrate (0.1 mmol) was stirred and heated at 70
°
C in a preheated oil bath for 30 min. Then the phenolic substrate
was added and the mixture was stirred at 110 °C for an appropriate
time (4-6 h). After completion of the reaction as indicated by TLC
(
EtOAc/hexane, 1:2), the reaction mixture was dissolved in hot
EtOH and recrystallized to obtain pure products 6.
Scheme III Suggested mechanism for the formation
of benzofurans 6 using yttrium nitrate
hexahydrate
1-Benzamido-2-phenylnaphtho[2,1-b]furan (6a). Mp
2
1
1
30-232 ºC; IR (KBr) v: 3160, 3110, 2089, 1640, 1485, 1260,
-
1 1
040, 800, 700 cm ; H NMR (DMSO-d
6
, 400 MHz): 10.78 (s,
H), 8.26 (d, 1H, J = 7.6 Hz), 8.21 (d, 2H, J = 7.2 Hz), 8.09 (d, 1H,
J = 8.0 Hz), 7.90-8.04 (m, 4H), 7.74-7.65 (m, 3H), 7.53, 7.57 (2d,
1
H, J = 8.0, 7.6 Hz), 7.43 (t, 1H, J = 7.6 Hz); C NMR
3
4
(
DMSO-d , 100 MHz): 167.21, 150.86, 149.10, 134.07, 132.72,
6
1
1
30.92, 129.83, 129.54, 129.47, 129.38, 129.25, 128.27, 127.66,
27.18, 126.87, 125.84, 125.41, 122.67, 121.40, 117.26, 113.05;
Anal. Calcd. for C25
2.90; H, 4.65; N, 3.77. 1-Benzamido-2-(4-methoxyphenyl)-
naphtho[2,1-b]furan (6b). Mp 239-241 ºC; IR (KBr) v: 3165,
2
H17NO : C, 82.63; H, 4.72; N, 3.85. Found: C,
8
-
1 1
3
110, 2950, 1640, 1510, 1475, 1260, 1040, 800, 700 cm ; H
NMR (DMSO-d , 400 MHz): 10.70 (s, 1H), 8.22 (d , 1H, J = 8.0
Hz), 8.24 (d , 2H, J = 6.8 Hz), 8.07 (d , 1H, J = 8.0 Hz), 7.89 (t ,
6
4
3
1
1
H, J = 8.4 Hz), 7.64-7.74 (m, 3H), 7.50-7.56 (m, 2H), 3.81 (s,
1
3
6
H), 7.11 (d, 1H); C NMR (DMSO-d , 100 MHz): 167.20,
60.10, 150.46, 149.46, 134.11, 132.66, 130.89, 129.40, 129.35,
28.25, 127.58, 127.45, 126.99, 126.20, 125.28, 122.65, 122.36,
J. Chin. Chem. Soc. 2013, 60, 1323-1327
© 2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1325

Article
Vahabinia et al.
1
21.54, 115.61, 115.05, 112.95, 55.77; Anal. Calcd. for
: C, 79.37; H, 4.87; N, 3.56. Found: C, 79.51; H, 4.80;
7.44-7.61 (m, 8H), 6.48 (d, 1H, J = 8.4 Hz), 6.28 (d, 1H, J = 8.4
1
3
C
26
H
19NO
3
6
Hz); C NMR (DMSO-d , 100 MHz): 166.82, 166.74, 146.84,
N, 3.45. 1-Benzamido-2-(4-bromophenyl)naphtho[2,1-b]fu-
ran (6c). Mp 286-288 ºC; IR (KBr) v: 3200, 1650, 1490, 1395,
144.76, 135.66, 134.31, 133.73, 133.62, 131.82, 129.15, 128.69,
128.61, 128.54, 128.19, 127.93, 119.57, 114.25, 107.35; IR (KBr)
v: 3520-3100, 1620, 1521, 1470, 1285, 710, 690, 668; Anal.
-
1 1
1
270, 1090, 800, 690 cm ; H NMR (DMSO-d
s, 1H), 8.22 (d, 1H, J = 8.4 Hz), 8.17 (d, 2H, J = 7.6 Hz), 8.09 (d,
H, J = 8.0 Hz), 7.96 (d, 1H, J = 8.8 Hz), 7.91-7.87 (m, 3H), 7.76
dd, 2H, J = 6.8, 2.0 Hz), 7.72 (d, 1H, J = 7.1 Hz), 7.66 (t, 2H, J =
6
, 400 MHz): 10.78
(
4
Calcd. for C21H15NO : C, 73.03; H, 4.38; N, 4.06. Found: C,
1
73.15; H, 4.32; N, 3.95. 7-Hydroxy-2-phenyl-3-benzamido-
benzofuran (6h). Mp 225-227 ºC; IR (KBr) v: 3410-3200,
(
1
.6 Hz), 7.57-7.53 (m, 2H); C NMR (DMSO-d
3
1
3050-3000, 1668-1615, 1540-1498, 1100-1098, 740-689; H
7
1
1
1
6
, 100 MHz):
67.10, 151.00, 148.13, 133.90, 132.79, 132.59, 130.93, 129.51,
29.39, 128.94, 128.28, 127.68, 127.58, 127.29, 127.25, 125.53,
22.65, 122.48, 121.24, 117.67, 113.03; Anal. Calcd. for
NMR (DMSO-d
Hz), 8.00-8.02 (m, 2H), 7.90-7.95 (m, 2H), 7.48-7.72 (m, 6H);
NMR (DMSO-d , 100 MHz): 166.56, 166.48, 138.78, 133.61,
132.81, 132.37, 131.32, 130.46, 130.03, 129.38, 128.89, 128.03,
126.03, 122.12, 120.01; Anal. Calcd. for C21 : C, 69.33;
6
, 400 MHz): 10.74 (s, 1H), 9.31 (d, 1H, J = 8
1
3
C
6
C
25
H
16BrNO
2
: C, 67.89; H, 3.65; N, 3.17. Found: C, 68.01; H,
.48; N, 3.02. 1-Benzamido-2-(4-chlorophenyl)naphtho[2,1-
b]furan (6d). Mp 270-272 ºC; IR (KBr) v: 3205, 1640, 1485,
3
H14ClNO
3
H, 3.88; N, 3.85. Found: C, 69.55; H, 3.71; N, 3.70.
-
1 1
1
6
395, 1280, 1090, 800, 710, 690 cm ; H NMR (DMSO-d , 400
MHz): 10.78 (s, 1H), 8.22 (d, 1H, J = 7.6 Hz), 8.17 (d, 2H, J = 8.0
Hz), 8.09 (d, 1H, J = 7.8 Hz), 7.97-7.89 (m, 4H), 7.74-7.61 (m,
ACKNOWLEDGEMENTS
Partial financial support from the Islamic Azad Uni-
versity of Gachsaran is gratefully acknowledged.
1
3
5
1
1
1
6
H), 7.58-7.51 (m, 2H). C NMR (DMSO-d , 100 MHz): 166.63,
50.47, 147.50, 133.43, 133.25, 132.26, 130.41, 129.19, 129.00,
28.87, 128.11, 127.78, 127.08, 126.94, 126.77, 126.70, 125.00,
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2
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1
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3
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7
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1
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8
9
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6
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3
(
(
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1
1
29 2
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1
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