An efficient synthesis of benzofuran derivatives under conventional/non-conventional method

Article abstract of DOI:10.1016/j.cclet.2010.06.038

1-Methyl-3-ethyl imidazolium bromide [meim]Br/basic alumina (Al₂O₃) has been found to promote the cyclocondensation of chloroacetone/chloroethyl acetate with salicylaldehydes under conventional as well as microwave irradiation to yield benzofuran derivatives.

Full text of DOI:10.1016/j.cclet.2010.06.038

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1439–1442
www.elsevier.com/locate/cclet
An efficient synthesis of benzofuran derivatives under
conventional/non-conventional method
Suryakant B. Sapkal, Kiran F. Shelke, Bapurao B. Shingate, Murlidhar S. Shingare *
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (M.S.) 431004, India
Received 20 April 2010
Abstract
1-Methyl-3-ethyl imidazolium bromide [meim]Br/basic alumina (Al2O3) has been found to promote the cyclocondensation of
chloroacetone/chloroethyl acetate with salicylaldehydes under conventional as well as microwave irradiation to yield benzofuran
derivatives.
# 2010 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: [meim]Br/Al2O3; Benzofuran; Cyclocondensation; Conventional; Non-conventional methods
Benzofurans are very important compounds due to their broad spectrum of biological and pharmacological effects.
Benzofurans are considered as non-steroidal anti-inflammatory drugs [1], COX-2 inhibitor; in addition, diverse
pharmacological properties have been associated with benzofuran derivatives [2]. Moreover, phosphodiesterase
inhibitory activity, analgesic, antimicrobial, bacteriostatic, bacteriocidal, fungicidal, anticancer, anti-HIV and more
has been exhibited [3].
Realizing the importance of benzofuran derivatives in the synthesis of various drug sources reported in few classical
methods such as, cyclocondensation of salicylaldehyde with a-halo ketones/esters [4], catalyzed by KOH/EtOH [5],
(PPh)2PdCl2/Et3N [6], sodium acetate and acetic acid [7], EtO2CNHNH2/SOCl2/K2CO3 [8], HBF4ÁOEt2 [9], by flash
vacuum pyrolysis at 850 8C [10] and other reagents [11]. More recently, K2CO3 catalyzed synthesis of benzofurans in
dry acetone within 13 h has been reported [3e].
Nowadays, the use of heterogeneous catalysts [12] has received considerable interest because of some features
such as, solid supported reagents are easily removed from reaction by filtration, excess reagents can be used to
drive reaction, recycling and recovered reagents are economical [13]. Different kinds of solid materials have
commonly been used for surface organic chemistry [14] including aluminas, silica gels, clays, and zeolites. In
recent years, ionic liquid with heterogeneous supports as catalysis is a concept which combines the advantages of
ionic liquids with those of heterogeneous supporting materials and has been explored their potential catalytic
applications [15].
* Corresponding author.
E-mail address: msshingare_org@rediffmail.com (M.S. Shingare).
1001-8417/$ – see front matter # 2010 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.06.038

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S.B. Sapkal et al. / Chinese Chemical Letters 21 (2010) 1439–1442
Scheme 1. [meim]Br catalyzed synthesis of benzofuran derivatives.
1. Experimental
Microwave method: A mixture of salicylaldehyde (2 mmol), chloroacetone/chloroethyl acetate (2 mmol), ionic
liquid (2 mmol) and basic alumina (1 g) was refined in a Borosil beaker with the help of glass rod. This homogenized
reaction mixture was then irradiated in a microwave oven (360 W) by interval of 10 s (Scheme 1). The progress of
reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled at room
temperature and poured on crushed ice. Thus solid obtained was filtered, dried, and purified by crystallization in
ethanol where alumina get separated as residue; melting points were noted and used for further spectroscopic analysis.
Conventional method: A mixture of salicylaldehyde (2 mmol), chloroacetone/chloroethyl acetate (2 mmol), ionic
liquid (3 mmol) and basic alumina (0.5 g) was taken in a round bottom flask. This reaction mixture was heated at
80 8C. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction was worked-up
as like microwave method.
3a: IR (KBr, ymax/cmÀ1) 1675 (>C O), 1558 (>C C<), 1148 (C–O–C); 1H NMR (CDCl3): d 7.7–6.8 (m, 5H, Ar-
H), 2.6 (s, 3H, CO-CH3); m/z 161 (M+); (3h) IR (KBr, ymax/cmÀ1) 1695 (>C O), 1530 (>C C<), 1169 (C–O–C); 1H
NMR (CDCl3): d 8.0–7,7 (m, 7H, Ar-H), 2.7 (s, 3H, CO-CH3); m/z 211 (M+). 3i: IR (KBr, ymax/cmÀ1) 1671 (>C O),
1515 (>C C<), 1163 (C–O–C); 1H NMR (CDCl3): d 7.6–7.8 (m, 5H, Ar-H), 4.1 (q, 2H, J = 7.1 CH2-CH3), 2.3 (s, 3H,
Ar-CH3); m/z 205 (M+)
2. Results and discussion
In continuation of our work in the development of facile and efficient methodologies using ionic liquids and various
organic transformations [16], in this work we wish to propose an effective strategy for the synthesis of 2-acetyl/carbo
ethoxy benzofuran derivatives. For this synthesis we have condensed the substituted salicylaldehydes 1 with
chloroacetone/chloroethyl acetate 2 to form respective benzofurans 3(a-l).
In order to evaluate the efficiency of the process, scope, and limitations of the different catalysts/solvents, these
were examined with salicylaldehyde 1a and chloroacetone 2a as model reactants as given in Table 1. All the reactions
exhibit 100% selectivity, but % yield and reaction time varied with catalyst materials. Initially, we have screened the
catalytic performance of chloramine T; because previously it has been used for various organic transformations [17]. It
is a N-chloro compound contains electrophilic chlorine and nitrogen anion. The efficiency of chloramine T was
examined in different traditional solvents for model reaction by conventional as well as under microwave irradiation. It
has been found that no appreciable product formation was takes place (Table 1, entries 1–3), however chloramine T
with 1-methyl-3-ethyl imidazolium bromide has formed comparatively more yield (Table 1, entry 4). Also the same
reaction was carried out as solvent-free in the presence of chloramine T, under microwave irradiation at 360 W
(Table 1, entry 5). The % yield was less and reaction time was more because in chloramine T the sulfur adjacent to
nitrogen may be stabilize a nitrogen anion so that the nitrogen anion is inadequate to act as a base. Therefore,
chloramine T is not suitable catalyst for preferred reaction. In the later step of the experiment, we have carried out
benzofuran synthesis using Bronsted as well as Lewis acids in the presence of solvents and without solvent by
conventional and in microwave oven respectively (Table 1, entries 6–14). Besides, using neutral alumina it was found
that product formation was very low and reaction time was very high under microwave irradiation (Table 1, entry 15).
It indicates that the reactants have less affinity towards the acid and neutral catalysts.
Our next attempt was to perform the reaction using basic alumina under solvent-free microwave irradiation, which
gives appreciable yield (Table 1, entry 16). Encouraged by this result, we turned our attention towards the combination
of ionic liquid and basic alumina as a heterogeneous reagent to perform the cyclocondensation of said reactants under
microwave irradiation at 360 W by the interval of 10 s amazingly the product formation was 92% within 10 min

S.B. Sapkal et al. / Chinese Chemical Letters 21 (2010) 1439–1442
1441
Table 1
Screening of catalysts for the synthesis of 2-acetyl benzofuran.
Entry
Catalyst/solvent
Reaction condition
Time
4 h
Yield (%)
1
2
Chloramine T/EtOH
Chloramine T/DMF
Chloramine T/CCl4
Chloramine T/IL
Chloramine T
NaHSO4/IL
NaHSO4/IL
SnCl2/IL
Reflux
Reflux
Reflux
80 8C
MW
35
40
4 h
4 h
3
50
4
3 h
65
5
20 min
4 h
45
6
80 8C
MW
20
7
30 min
30 min
4 h
30
8
MW
25
9
SnCl2/IL
80 8C
MW
>20
29
10
11
12
13a
14a
15b
16c
17c
18c
19
AlCl3
30 min
4 h
SiO2/IL
80 8C
MW
30
SiO2/IL
30 min
4 h
35
Al2O3/IL
80 8C
MW
30
Al2O3/IL
30 min
40 min
30 min
10 min
30 min
45 min
45
Al2O3
MW
>20
75
Al2O3
MW
Al2O3/IL
MW
92
Al2O3/IL
80 8C
80 8C
90
IL
>30
IL = Ionic liquid [meim]Br.
a
Acidic alumina.
b
Neutral alumina.
c
Basic alumina.
(Table 1, entry 17). On the other hand, in case of conventional method the ionic liquid was used in excess amount with
basic alumina, the reaction mixture was then heated at 80 8C, interestingly 90% product yield was obtained within
30 min (Table 1, entry 18).
In this optimized conditions both ionic liquid and basic alumina play dual role. In particular, ionic liquid promotes
the rate of reaction and helps to kept homogeneities in the reactants but itself alone unable to gave appreciable yields
for same reaction (Table 1, entry 19). From last few years, ionic liquids have been used in catalytic organic reactions
[18] mainly because of the peculiar properties such as, high solubility, low vapor pressure, and high chemical and
thermal stability. Likewise, basic alumina act as a catalyst as well as provide more active support to the reactants on
Table 2
Synthesis of benzofuran derivatives catalyzed by [meim]Br/Al2O3.
Producta
Aldehyde
X
Microwave
Time (min)
Conventional
Time (min)
Mp(8C)
Yield (%)b
Yield (%)b
3a
3b
3c
3d
3e
3f
R = H
CH3
10
8
92
92
90
90
93
89
89
93
92
92
88
90
30
30
30
30
30
40
45
30
35
35
40
40
90
92
92
93
93
85
83
95
89
90
90
92
73–75
102–104
120–122
148–150
127–129
110–112
138–140
165–167
92–94
R = 3-CH3
CH3
R = 4-Cl
CH3
12
10
8
R = 4-Br
CH3
R = 4-OCH3
R = 4-NO2
CH3
CH3
15
12
15
12
15
15
20
3g
3h
3i
R = 3-NO2
CH3
2-OH-1-Naphthaldehyde
R = 3-CH3
CH3
OC2H5
OC2H5
OC2H5
OC2H5
3j
R = 4-Cl
107–109
133–135
84–86
3k
3l
R = 4-OCH3
2-OH-1-Naphthaldehyde
a
The products were prepared using (2 mmol) salicylaldehydes and (2 mmol) chloroacetone/chloroethyl acetate and characterized from their
spectroscopic (IR, 1H NMR and MS) data.
b
Isolated yields.

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S.B. Sapkal et al. / Chinese Chemical Letters 21 (2010) 1439–1442
which surface reaction is more favorable. Basic alumina resists attack of strong alkali and acid at elevated temperature
and hence it able to provide more efficient surface area to the reactants this could be one of the advantages of alumina.
With optimized reaction condition in hand, we have explored the scope and generality of the methodology. Herein,
the series of benzofuran derivatives have been prepared by applying the methods mentioned above. We found that the
substituted salicylaldehydes containing different functional groups i.e. electron withdrawing as well as electron
donating groups reacted smoothly, similarly 2-hydroxy-1-naphthaldehyde worked well and did not show the
differences in the yield of products and reaction time as shown in Table 2.
3. Conclusion
In conclusion, we have described an efficient one-pot cyclocondensation between different salicylaldehydes/2-
hydroxy-1-naphthaldehyde and chloroacetone/chloroethyl acetate in the presence of ionic liquid and basic alumina i.e.
[meim]Br/Al2O3 as a catalyst by conventional heating as well as under microwave irradiation. The synthetic utility of
the methodologies demonstrated in this work, whilst contributing the part of green and clean chemistry to sustain the
human health and environment unaffected. The present ecofriendly strategy offered advantages like shorter reaction
time, simple work-up procedure, use of non-chromatographic isolation technique, and higher product yields.
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