An easy access to benzofurans via DBU induced condensation reaction of active 2-hydroxy acetophenones with phenacyl chlorides: A novel class of antioxidant agents

Article abstract of DOI:10.1002/jhet.1971

A convenient and efficient one-pot synthesis of benzofurans 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3m, 3n, 3o, 3p, 3q, 3r, 3s, 3t has been described from 2-hydroxy acetophenones and phenacyl chlorides in the presence of DBU. The procedure was applicable for a variety of phenacyl chlorides and provides a variety of benzofurans with higher yields. DBU acts as a base and as well as nucleophiles. All the derivatives were subjected to in vitro antioxidant screenings against representative 2,2'-diphenyl-1-picryl-hydrazyl and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radicals and results worth for further investigations.

Full text of DOI:10.1002/jhet.1971

Month 2014 An Easy Access to Benzofurans via DBU Induced Condensation Reaction
of Active 2-Hydroxy Acetophenones with Phenacyl Chlorides: A Novel
Class of Antioxidant Agents
a
b
a
a
*
*
J. Rangaswamy, H. Vijay Kumar, S. T. Harini, and Nagaraja Naik
aDepartment of Studies in Chemistry, University of Mysore, Mysore 570006, India
bDepartment of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
*
E-mail:drnaikchem@gmail.com; vijaycftri@gmail.com
Received September 30, 2012
DOI 10.1002/jhet.1971
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A convenient and efficient one-pot synthesis of benzofurans 3(a–t) has been described from 2-hydroxy
acetophenones and phenacyl chlorides in the presence of DBU. The procedure was applicable for a variety
of phenacyl chlorides and provides a variety of benzofurans with higher yields. DBU acts as a base and as
well as nucleophiles. All the derivatives were subjected to in vitro antioxidant screenings against represen-
tative 2,20-diphenyl-1-picryl-hydrazyl and 2,20-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) radicals and
results worth for further investigations.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
lack of reference available. In the interest of earlier findings,
we inspired to develop a simple and efficient synthesis of
substituted benzofurans from efficient easy access method.
DBU has been employed as an organic base for various
organic reaction such as deprotonation agent [12], excellent
catalytic activity in Baylis–Hillman reaction, acts as nucleo-
phile [13] and carbonylation of di-n-propylamine [14]. Our
trial employing DBU as a base, which is cheap and commer-
cially available, leads to a successful furnished o-alkylated
acetophenone derivative. To the best of our knowledge, there
is no report on the synthesis of benzofurans from 2-hydroxy
acetophenone moieties by using organic base DBU. In
continuation of our research work on the synthesis and anti-
oxidant activity of novel classes heterocyclic derivatives
[15–17] and encouraged by the successful results obtained
from these work, the present investigation we wish to propose
a general method for the synthesis of novel benzofurans
(Scheme 1 and Table 1). This synthetic strategy affords some
advantages such as operational simplicity, lower cost, reac-
tion carried out at RT, and simple workup procedure.
The benzofuran nucleus is a well-known pharmaco-
phore. Multiply substituted benzofurans represent an inter-
esting class of heterocycles, which are intensively studied
in connection with a variety of applications [1]. A wide
variety of pharmacological properties has been shown to
be associated with benzofuran [2]. The benzofuran ring
system itself is a common structural element that appears
in a large number of medicinally important compounds
[3]. Benzofuran and its heterocyclic systems are known
to exhibit a wide range of biological properties such as
antihyperglycemic, analgesic, antiinflammatory, antioxi-
dants, antimicrobial, and antitumor activities [4–7]. Realiz-
ing the biological importance of benzofurans, there is
continuous interest in the development of convenient and
efficient synthesis of benzofurans. Most commonly, the
Rap–Stoermer reaction [8] has been employed for the syn-
thesis of benzofuran, which involves the cyclization of
phenacyl bromide with o-hydroxy benzaldehyde in the
presence of a base. However, the reported methods have
some disadvantages such as use of corrosive strong bases
[9]. In addition to this, some of the methods require expen-
sive palladium catalyst, high boiling solvents (DMF) [10],
and longer reaction time (24–72 h) [11].
RESULTS AND DISCUSSION
Benzofurans were obtained in modified Rap–Stoermer
reaction condition using an inorganic base that is, K2CO3
[18]. However, using of K2CO3 (6 mmol) failed to deliver
In the literature survey, approaching to synthesis of
benzofurans from 2-hydroxy acetophenone moieties indicates
© 2014 HeteroCorporation

J. Rangaswamy, H. V. Kumar, S. T. Harini, and N. Naik
Vol 000
Scheme 1. DBU induced synthesis of benzofurans 3(a–t).
the total conversion of acetophenones to benzofurans even
under reflux condition and longer reaction time (4 h) with
lesser yields (62–70%). In this study, scrutiny with
catalytic amount of DBU (4 mmol) as an organic base
was found that the conversion was achieved under mild
condition (RT) with lesser reaction time (except com-
pounds 3d, 3j, and 3l) with good yields (Table 1). In addi-
tion, the reactivity of various mono substituted 2-hydroxy
Table 1
An overview of synthesized benzofurans with yield 3(a–t).
Entry
2-Hydroxy acetophenones
Phenacyl chlorides
Time (h)
Product
Yield (%)
Melting point (ꢀC)
3a
3b
3c
3d
R═H
3.0
2.5
2.0
4.0
R═H
91.00
90.20
88.32
72.00
202–204
231–233
224–226a
170–172
R═OCH3
R═CH3
R═OH
R═OCH3
R═CH3
R═OH
3e
3f
3g
3h
R═H
2.0
1.5
2.0
3.0
R═H
83.00
77.20
80.35
88.54
218–220
195–197
191–193
222–224
R═OCH3
R═CH3
R═OH
R═OCH3
R═CH3
R═OH
3i
R═H
3.5
4.0
3.0
4.0
R═H
85.10
92.15
89.16
91.10
234–236
188–200
212–214
221–223
3j
3k
3l
R═OCH3
R═CH3
R═OH
R═OCH3
R═CH3
R═OH
3m
3n
3o
R═H
1.5
2.0
3.0
3.0
R═H
80.00
75.00
76.20
81.00
85–87
R═OCH3
R═CH3
R═OH
R═OCH3
R═CH3
R═OH
234–236
191–193
205–207
3p
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Easy Access to Benzofurans via DBU Induced Condensation Reaction of Active 2-Hydroxy
Acetophenones with Phenacyl Chlorides: A Novel Class of Antioxidant Agents
Table 1
(Continued)
Entry
2-Hydroxy acetophenones
Phenacyl chlorides
Time (h)
Product
Yield (%)
Melting point (ꢀC)
3q
3r
3s
3t
R═H
2.0
1.5
2.5
3.0
R═H
75.00
63.55
59.85
73.20
256–258
231–233
249–251
271–273
R═OCH3
R═CH3
R═OH
R═OCH3
R═CH3
R═OH
aIndicates the boiling point.
Scheme 2. General synthetic mechanism of the title compounds 3(a–t).
acetophenones was found to be efficient under the present
conditions. Herein, we described a DBU assisted one-pot
synthesis of benzofurans (Scheme 1). Initially, we have
carried out the reaction of 2-hydroxy acetophenone (2 mmol),
phenacyl chloride (2 mmol), and DBU (2 mmol) in dichloro-
methane (DCM) containing molecular sieves under N2 atm
(1.5–4 h), afforded expected product (3-methylbenzofuran-2-
yl)(phenyl)methanone (3a), which was isolated in 65% yield.
To improve the yield, we performed the reaction with
increased DBU (3, 4 mmol). It was noted that, DBU (4 mmol)
was optimal and isolated in 91% yield. But, increased
(5–6 mmol) and decreased (1 mmol) in the DBU concentration
did not favor improved yield.
Optimization of reaction conditions was carried out at
different solvents such as acetone, THF, DCM, acetoni-
trile, MeOH, and EtOH, respectively. However, DCM
was the better solvent in regard to best yield and reaction
time. To extend the scope of one-pot procedure, next, we
discovered various substituted 2-hydroxy acetophenones
and phenacyl chlorides in the optimized condition. It was
observed that, 2-hydroxy acetophenones emphasizes with
either electron-withdrawing or electron-donating substitu-
ents reacted effectively with phenacyl chlorides and led
to good yields of benzofurans 3(a–t). It was noticed that,
present synthetic strategy was very efficient and applicable
for a variety of phenacyl chlorides results in corresponding
benzofurans (Scheme 1). This method may be applicable
for the preparation of large number of benzofurans under
mild condition because of the easy availability of phenacyl
chlorides and 2-hydroxy acetophenones (Table 1). The
mechanism involves, o-alkylation of substituted 2-hydroxy
acetophenones (d) with phenacyl chlorides (a) in presence of
DBU (b) as organic base furnished o-alkylated derivative (e),
which subsequently generates enolate anion (f) undergo intra-
molecular cyclocondensation reaction afforded benzofurans
(h) in excellent yields (Scheme 2).
such as 2,20-diphenyl-1-picryl-hydrazyl (DPPH) [19] and
2,20-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS)
[20] free radical scavenging activity (RSA).
Free radical scavenging is one of the best known mech-
anism by which antioxidants inhibit the oxidation and
offers a rapid technique for screening the RSA of specific
compounds. Majority of the tested compounds in these
series showed low to moderate interaction with DPPH
and ABTS radical (Table 2). Ascorbic acid was used as
standard antioxidant. In the both assays, among the tested
compounds, 3a, 3e, 3i, 3m, and 3q, which does not have
any substituents on the phenacyl ring and as well as benzo-
furan ring, does not boost up the activity. Compounds 3b,
3f, and 3n, which contains electron-donating methoxy
group on the phenacyl ring showed moderate inhibitory
effect. The reaction of 4-hydroxy substituted phenacyl
chloride with substituted 2-hydroxy acetophenones led to
the compounds 3d, 3h, 3l, and 3t exhibited good antioxi-
dant activity but less than the standard. The maximum
The synthesized compounds were also evaluated
for their antioxidant activity by using two in vitro assays,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Rangaswamy, H. V. Kumar, S. T. Harini, and N. Naik
Vol 000
Table 2
EXPERIMENTAL
The 50% inhibition of DPPH and ABTS radical by compounds 3(a–t).
Each value represents mean ꢂ SD (n = 3).
All reagents and solvents were purchased from Merck
(Darmstadt, Germany) chemical AR grade and were used as
provided. DPPH, ABTS, and ascorbic acid were purchased from
Sigma-Aldrich chemical Co. (St. Louis, MO, USA). TLC analysis
was performed on alumina sheets precoated with silica gel 60 F-254
and SiO2, 200–400 mesh (Merck) was used for column chroma-
DPPH activity IC50
ABTS activity IC50
Compound no
(mM/mL)a
(mM/mL)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
> 500
485 ꢂ 0.09
126 ꢂ 0.15
174 ꢂ 0.36
56 ꢂ 0.19
> 500
116 ꢂ 0.54
159 ꢂ 0.23
58 ꢂ 0.20
> 500
146 ꢂ 0.51
342 ꢂ 0.23
86 ꢂ 0.12
> 500
1
tography. H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra
110 ꢂ 0.12
163 ꢂ 0.13
68 ꢂ 0.25
495 ꢂ 0.13
103 ꢂ 0.32
142 ꢂ 0.14
49 ꢂ 0.35
472 ꢂ 0.56
152 ꢂ 0.56
315 ꢂ 0.12
71 ꢂ 0.68
> 500
were obtained AC Bruker spectrometer (Madison, Wisconsin,
USA) in the appropriate (DMSO-d6) solvent. Melting points
were obtained on a Reichert Thermopan mp apparatus (Mumbai,
India), equipped with a microscope and are uncorrected. Mass
spectra were obtained by Water-Q-TOF ultima spectrometer
(Kratos, Manchester, UK). Micro analytical data were obtained
by elemental-Vario EL-III ( Frankfurt, Germany).
General procedure for synthesis of benzofurans 3(a–t). A
mixture of 2-hydroxy acetophenones (1) (2 mmol), phenacyl
chlorides (2) (2 mmol), and 1,8-diaza bicyclo [5.4.0] undec-
7-ene (4mmol) in 10 mL of DCM containing molecular sieves
was stirred under N2 atm for the stipulated period (Table 1).
Progress of the reaction was monitored by TLC using hexane:
ethyl acetate (8:2) mixture as mobile phase. After the completion
of the reaction, the reaction mixture was washed with 10% HCl
solution followed by water. The organics were dried over
anhydrous sodium sulfate. The solids were obtained by
desolventized in a rotary evaporator at RT affords respective
benzofurans 3(a–t). All the structures of products were
characterized by IR, 1H and 13C-NMR, ESI-MS, and elemental
analysis. The spectral and analytical data for compounds (3a–d)
[21(a-d)], (3j) and (3l) [22(a)], (3 m) [18] and (3n-o) [22(b-c)] are
3m
3n
3o
3p
3q
89 ꢂ 0.59
130 ꢂ 0.14
39 ꢂ 0.52
> 500
96 ꢂ 0.35
126 ꢂ 0.66
45 ꢂ 0.41
> 500
3r
3s
3t
254 ꢂ 0.23
395 ꢂ 0.52
101 ꢂ 0.14
17 ꢂ 0.32
289 ꢂ 0.16
412 ꢂ 0.55
152 ꢂ 0.21
26 ꢂ 0.71
Ascorbic acid
DPPH, 2,20-diphenyl-1-picryl-hydrazyl; ABTS, 2,20-azino-bis(3-ethyl-
benzthiazoline-6-sulfonic acid) .
aThe values are expressed as mM concentration. Lower IC50 values indicate
higher radical scavenging activity.
in agreement with that reported in the literature.
(3,6-Dimethylbenzofuran-2-yl)(phenyl)methanone (3e).
Off white solid. IR (KBr)nmax(cmꢁ1): 1683 (C═O), 1560
(C═C); 1H-NMR (DMSO-d6 400 MHz) d ppm: 7.89 (d, 2H, J=8.9Hz,
C6H5CO), 7.77 (d, 1H, J = 8.3 Hz, CH3C6H3), 7.70–762 (m, 1H,
C6H5CO), 7.64–7.53 (m, 2H, C6H5CO), 7.15 (m, 1H,
CH3C6H3), 6.90 (d, 1H, J = 8.0 Hz, C6H5CO), 2.55 (s, 3H,
CH3C4O), 2.34 (s, 3H, C6H3CH3); 13C-NMR (DMSO-d6
100 MHz) d ppm: 167.1, 158.8, 150.4, 138.0, 132.9, 132.4,
129.7, 128.8, 129.5, 123.6, 118.1, 111.6, 21.3, 9.8; MS (ESI)
m/z: 250.10 (M+). Anal. Calcd. for C17H14O2: C, 81.58; H,
RSA was observed in compound 3p, containing methoxy
and hydroxy substituents on the benzofuran and as well as
phenacyl ring. Whereas, compounds 3c, 3g, and 3o posses-
sing methyl group on phenacyl ring at para position exposed
the considerable activity. The remaining benzofurans 3j, 3k,
3r, and 3s contains electron-withdrawing (nitro) and halogens
(bromo) groups on benzofuran ring might be the reason,
which does not favor the noteworthy activity compared with
standard. Interestingly, from both the antioxidant assays, we
noted that presence of hydroxy and electron-donating group
substituents at different C-terminals of phenacyl ring and as
well as benzofuran ring may be favorable for significant
increase in the activity.
In summary, we have developed a simple and efficient
one-pot synthetic procedure for preparation of benzofur-
ans. The advantage of this methodology lies in higher
yields, operational simplicity, use of simple and inexpen-
sive catalyst, and less pollution to environment. More-
over, this procedure will provide a good to excellent
method for synthesis of substituted benzofurans. Among
the tested benzofurans, compounds 3p exhibited better
in vitro antioxidant activity, suggesting that the benzofur-
ans moiety may be a beneficial scaffold for therapeutic
purpose. The preliminary antioxidant activity results are
very interesting, the further investigation with increased
antioxidant potency is currently underway.
5.64; O, 12.78; found: C, 81.60; H, 5.60; O, 12.81%.
(3,6-Dimethylbenzofuran-2-yl)(4-methoxyphenyl)methanone
(3f).
Off white solid. IR (KBr)nmax(cmꢁ1): 1678 (C═O),
1562 (C═C); 1H-NMR (DMSO-d6 400 MHz) d ppm: 7.75
(d, 2H, J=8.5Hz, OCH3C6H4CO), 7.68 (d, 1H, J=8.0Hz,
CH3C6H3), 7.52–7.29 (m, 1H, CH3C6H3), 7.18 (d, 2H, J=8.1Hz,
OCH3C6H4CO), 6.92 (d, 1H, J=8.5Hz, CH3C6H3), 3.82
(s, 3H, OCH3), 2.52 (s, 3H, CH3C4O), 2.35 (s, 3H, C6H3CH3);
13C-NMR (DMSO-d6 100 MHz) d ppm: 167.1, 164.3, 158.9, 150.4,
133.0, 130.8, 129.6, 123.6, 114.5, 118.1, 111.6, 55.8, 21.6, 9.6; MS
(ESI) m/z: 280.12 (M+). Anal. Calcd. for C18H16O3: C, 77.12; H,
5.75; O, 17.12; found: C, 77.08; H, 5.72; O, 17.16%.
(3,6-Dimethylbenzofuran-2-yl)(p-tolyl)methanone (3g). Light
gray solid. IR (KBr)nmax(cmꢁ1): 1680 (C═O), 1563 (C═C);
1H-NMR (DMSO-d6 400 MHz) d ppm: 7.77 (d, 2H, J = 8.3 Hz,
CH3C6H4CO), 7.64–7.57 (m, 1H, CH3C6H3), 7.45 (d, 2H,
J = 9.0 Hz, CH3C6H4CO), 7.34–7.29 (m, 1H, CH3C6H3),
6.93 (d, 1H, J = 8.3 Hz, CH3C6H3), 2.52 (s, 3H, CH3C4O), 2.35
(s, 6H, C6H3CH3 and C6H4CH3); 13C-NMR (DMSO-d6
100 MHz) d ppm: 167.3, 158.6, 150.4, 142.4, 135.3, 132.9,
129.7, 129.0, 123.6, 118.0, 111.5, 21.6, 21.3, 9.3; MS (ESI)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
An Easy Access to Benzofurans via DBU Induced Condensation Reaction of Active 2-Hydroxy
Acetophenones with Phenacyl Chlorides: A Novel Class of Antioxidant Agents
m/z: 250.10 (M+). Anal. Calcd. for C18H16O2: C, 81.58; H,
5.64; O, 12.78; found: C, 81.60; H, 5.60; O, 12.81%.
(3,6-Dimethylbenzofuran-2-yl)(4-hydroxyphenyl)methanone
(d, 2H, J = 8.4 Hz, OCH3C6H4CO), 3.82 (s, 3H, OCH3), 2.55
(s, 3H, CH3C4O); 13C-NMR (DMSO-d6 100 MHz) d ppm: 167.5,
164.5, 162.7, 150.3, 131.5, 130.5, 129.7, 123.1, 117.8, 115.1,
114.4, 55.8, 9.8; MS (ESI) m/z: 344.00 (M+). Anal. Calcd. for
C17H13BrO3: C, 59.15; H, 3.80; Br, 23.15; O, 13.90; found: C,
(3h). Off white solid. IR (KBr)nmax(cmꢁ1): 1675 (C═O), 1559
(C═C); 1H-NMR (DMSO-d6 400 MHz) d ppm: 7.78 (d, 1H,
J = 8.3 Hz, CH3C6H3), 7.70 (d, 2H, J = 8.3 Hz, OHC6H4CO),
7.21 (m, 1H, CH3C6H3), 6.97 (d, 1H, J = 8.0 Hz, CH3C6H3),
6.89 (d, 2H, J = 9.0 Hz, OHC6H4CO), 5.30 (s, 1H, OH), 2.53 (s,
3H, CH3C4O), 2.34 (s, 3H, C6H3CH3); 13C-NMR (DMSO-d6
100 MHz) d ppm: 167.5, 162.4, 158.7, 150.4, 132.8, 131.1,
130.7, 129.7, 129.4, 123.6, 118.0, 116.0, 111.4, 21.5, 9.4; MS
(ESI) m/z: 266.09 (M+). Anal. Calcd. for C17H14O3: C, 76.68;
59.21; H, 3.85; Br, 23.12; O, 13.85%.
(6-Bromo-3-methylbenzofuran-2-yl)(p-tolyl)methanone (3s).
Brown solid. IR (KBr)nmax(cmꢁ1): 1679 (C═O), 1558 (C═C);
1H-NMR (DMSO-d6 400 MHz) d ppm: 8.24–8.19 (m, 1H,
BrC6H3), 7.75 (d, 2H, J = 8.5 Hz, CH3C6H4CO), 7.55 (d, 1H,
J=8.0Hz, BrC6H3), 7.42 (d, 2H, J=8.8Hz, CH3C6H4CO), 7.25
(d, 1H, J=7.5Hz, BrC6H3), 2.55 (s, 3H, CH3C4O), 2.34 (s, 3H,
C6H4CH3); 13C-NMR (DMSO-d6 100 MHz) d ppm: 167.3, 162.5,
150.5, 142.3, 135.3, 131.4, 129.5, 129.0, 127.9, 123.1, 117.8,
115.1, 21.2, 9.6; MS (ESI) m/z: 328.01 (M+). Anal. Calcd. for
C17H13BrO2: C, 62.03; H, 3.98; Br, 24.27; O, 9.72; found: C,
H, 5.30; O, 18.02; found: C, 76.71; H, 5.28; O, 18.04%.
(3-Methyl-5-nitrobenzofuran-2-yl)(phenyl)methanone (3i). Light
yellow solid. IR (KBr)nmax(cmꢁ1): 1673 (C═O), 1558 (C═C),
1543 (N-O); 1H-NMR (DMSO-d6 400 MHz) d ppm: 8.42
(m, 1H, NO2C6H3), 8.10 (d, 1H, J = 7.9 Hz, NO2C6H3), 7.92
(d, 1H, J = 8.0 Hz, NO2C6H3), 7.85 (d, 2H, J = 7. 9 Hz,
C6H5CO), 7.73–7.68 (m, 1H, C6H5CO), 7.69–7.64 (m, 2H,
C6H5CO), 2.52 (s, 3H, CH3C4O); 13C-NMR (DMSO-d6
100 MHz) d ppm: 167.3, 162.2, 150.4, 145.8, 138.2, 133.4,
132.6, 129.7, 128.5, 120.2, 116.8, 112.4, 9.5; MS (ESI) m/z:
281.07 (M+). Anal. Calcd. for C16H11NO4: C, 68.32; H,
3.94; N, 4.98; O, 22.75; found: C, 68.35; H, 3.90; N, 5.01;
62.00; H, 4.12; Br, 24.15; O, 9.79%.
(6-Bromo-3-methylbenzofuran-2-yl)(4-hydroxyphenyl)methanone
(3t). Light brown solid. IR (KBr)nmax(cmꢁ1): 1678 (C═O), 1563
1
(C═C); H-NMR (DMSO-d6 400 MHz) d ppm: 8.26–8.20 (m, 1H,
BrC6H3), 7.81 (d, 1H, J=8.0Hz, BrC6H3), 7.72 (d, 2H, J=8.7Hz,
OHC6H4CO), 7.35 (d, 1H, J=9.0Hz, BrC6H3), 6.88 (d, 2H,
J= 8.8 Hz, OHC6H4CO), 5.32 (s, 1H, OH), 2.57 (s, 3H, CH3C4O);
13C-NMR (DMSO-d6 100 MHz) d ppm: 167.2, 162.6, 162.4, 150.2,
131.5, 131.0, 130.9, 127.8, 123.1, 117.8, 116.0, 115.1, 9.6; MS (ESI)
m/z: 329.99 (M+). Anal. Calcd. for C16H11BrO3: C, 58.03; H, 3.35;
Br, 24.13; O, 14.49; found: C, 58.13; H, 3.28; Br, 24.18; O, 14.35%.
Antioxidant evaluation
Assay for DPPH scavenging potential. The evaluation of
antioxidant activity of newly synthesized benzofurans 3(a–t)
was performed by DPPH RSA assay. Internal standard
Ascorbic acid and the synthesized compounds of different
concentrations were prepared in distilled EtOH, 1 mL of each
compound solutions having different concentrations (10, 25,
50, 100, 200, and 500 mM) were taken in different test tubes,
4 mL of 0.1 mM EtOH solution of DPPH was added and
shaken vigorously. The tubes were then incubated in the dark
room at RT for 20 min. A DPPH blank was prepared without
compound, and EtOH was used for the baseline correction.
Changes (decrease) in the absorbance at 517 nm were
measured using a UV-visible spectrophotometer, and the
remaining DPPH was calculated. The percent decrease in the
absorbance was recorded for each concentration, and percent
quenching of DPPH was calculated on the basis of the
observed decreased in absorbance of the radical. The RSA was
expressed as the inhibition percentage and was calculated
using the formula:
O, 22.73%.
(3-Methyl-5-nitrobenzofuran-2-yl)(p-tolyl)methanone (3k). Off
white solid. IR (KBr)nmax(cmꢁ1): 1681 (C═O), 1555 (C═C), 1545
1
(N-O); H-NMR (DMSO-d6 400 MHz) d ppm: 8.51–8.41 (m, 1H,
NO2C6H3), 8.12 (d, 1H, J=8.1Hz, NO2C6H3), 7.92 (d, 1H,
J=7.0Hz, NO2C6H3), 7.77 (d, 2H, J=8.0Hz, CH3C6H4CO), 7.40
(d, 2H, J=8.9Hz, CH3C6H4CO), 2.54 (s, 3H, CH3C4O), 2.32
(s, 3H, C6H4CH3); 13C-NMR (DMSO-d6 100 MHz) d ppm: 167.3,
1614, 150.4, 145.3, 142.3, 138.7, 133.3, 129.6, 129.1, 120.8,
116.8, 112.2, 21.2, 9.6; MS (ESI) m/z: 295.07 (M+). Anal. Calcd.
for C17H13NO4: C, 69.15; H, 4.44; N, 4.74; O, 21.67; found: C,
69.19; H, 4.46; N, 4.70; O, 21.63%.
(4-Hydroxyphenyl)(6-methoxy-3-methylbenzofuran-2-yl)methanone
(3p).
Brown solid. IR (KBr)nmax(cmꢁ1): 1681 (C═O), 1555
(C═C); 1H-NMR (DMSO-d6 400 MHz) d ppm: 7.72 (d, 2H,
J = 8.5 Hz, OHC6H4CO), 7.64 (d, 1H, J = 8.5 Hz, OCH3C6H3),
7.22 (m, 1H, OCH3C6H3), 6.98 (d, 1H, J = 8.0 Hz, OCH3C6H3),
6.88 (d, 2H, J = 9.0 Hz, OHC6H4CO), 5.32 (s, 1H, OH), 3.83
(s, 3H, OCH3), 2.55 (s, 3H, CH3C4O); 13C-NMR (DMSO-d6
100 MHz) d ppm: 167.4, 162.4, 161.3, 157.6, 150.4, 131.1, 130.7,
129.7, 124.8, 118.8, 116.0, 111.3, 96.3, 55.8, 9.7; MS (ESI) m/z:
282.09 (M+). Anal. Calcd. for C17H14O4: C, 72.33; H, 5.00; O,
22.67; found: C, 72.35; H, 5.10; O, 22.60%.
(6-Bromo-3-methylbenzofuran-2-yl)(phenyl)methanone (3q).
Dark brown solid. IR (KBr)nmax(cmꢁ1): 1670 (C═O), 1561
(C═C); 1H-NMR (DMSO-d6 400 MHz) d ppm: 8.26 (m, 1H,
BrC6H3), 7.89 (d, 2H, J = 8.7 Hz, C6H5CO), 7.79 (d, 1H,
J = 8.5 Hz, BrC6H3), 7.75–7.69 (m, 1H, C6H5CO), 7.62–7.53 (m,
2H, C6H5CO), 7.30 (d, 1H, J = 8.0 Hz, BrC6H3), 2.53 (s, 3H,
CH3C4O); 13C-NMR (DMSO-d6 100 MHz) d ppm: 167.0, 162.5,
150.3, 138.7, 132.5, 131.5, 129.8, 128.9, 127.8, 123.0, 117.5,
115.0, 9.6; MS (ESI) m/z: 313.95 (M+). Anal. Calcd. for
C16H11BrO2: C, 60.98; H, 3.52; Br, 25.35; O, 10.15; found: C,
Radical scavenging activity ð%Þ ¼ ½ðAo ꢁ A1Þ=Ao X 100ꢃ
where Ao is the absorbance of the control (blank, without com-
pound), and A1 is the absorbance of the compound.
Assay for ABTS+ scavenging potential. The ability of the
test sample to scavenge ABTS+ radical cation was determined
according to the literature method. The ABTS+ radical cation was
pregenerated by mixing 7 mM ABTS+ stock solution with
2.45 mM potassium persulfate (final concentration) and incubating
for 12–16 h in the dark at RT until the reaction was complete, and
the absorbance was stable. The absorbance of the ABTS+ solution
was equilibrated to 0.70 (ꢂ 0.02) by diluting with water at RT,
then 1 mL was mixed with different concentration of the test
sample (10–500 mM), and the absorbance was measured at 734 nm
61.03; H, 3.58; Br, 25.31; O, 10.25%.
(6-Bromo-3-methylbenzofuran-2-yl)(4-methoxyphenyl)methanone
(3r).
Brown solid. IR (KBr)nmax(cmꢁ1): 1673 (C═O), 1565
(C═C); 1H-NMR (DMSO-d6 400 MHz) d ppm: 8.31 (m, 1H,
BrC6H3), 7.78 (d, 2H, J = 8.0 Hz, OCH3C6H4CO), 7.75 (d, 1H,
J = 7.6 Hz, BrC6H3), 7.35 (d, 1H, J = 8.1 Hz, BrC6H3), 7.33
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Rangaswamy, H. V. Kumar, S. T. Harini, and N. Naik
Vol 000
after 6 min. The scavenging capability of ABTS+ radical was
calculated using the following equation:
[8] (a) Rap, E. Gazz Chim Ital 1895, 285, 2511. (b) Steormer,
R. Liebigs Ann Chem 1900, 331, 312.
[9] Saberi, M. R.; Vinh, T. K.; Yee, S. W.; Griffiths, B. J. N. et al.
J Med Chem 2006, 49, 1016.
[10] Cruz, M. D. C.; Tamariz, J. Tetrahedron 2005, 61, 10061.
[11] Cruz, M. D. C.; Tamariz, J. Tetrahedron Lett 2004, 45, 2377.
[12] Safti, D.; Zini, B.; Visnjevac, A. Tetrahedron 2012, 68, 933.
[13] Yeom, C. E.; Kim, M. J.; Kim, B. M. Tetrahedron 2007, 63,
904.
ABTSþ scavenging effect ð%Þ ¼ ½ðAc ꢁ AsÞ=Acꢃ x 100
where Ac is the initial concentration of the ABTS+, and As is the
absorbance of the remaining concentration of ABTS+ in the
presence of compounds.
[14] Mizuno, T.; Takahashib, J.; Ogawab, A. Tetrahedron 2003,
59, 1327.
[15] Kumar, H. V.; Kumar, C. K.; Naik, N. Med Chem Res 2011,
20, 101.
[16] Kumar, H. V.; Naik, N. Eur J Med Chem 2010, 45, 2.
[17] Rangaswamy, J.; Kumar, H. V.; Harini, S. T.; Naik, N. Bioorg
Med Chem Lett 2012, 22, 4773.
Acknowledgments. The authors are also thankful to NMR Research
Center, Indian Institute of Science, Bangalore for providing
spectral data.
[18] Karaburun, N. G.; Benkli, K.; Tunali, Y.; Ucucu, U.;
Demirayak, S.; Eur J Med Chem 2006, 41, 651.
REFERENCES AND NOTES
[19] Blois, M. S. Nature 1958, 181, 1199.
[20] Re, R.; Pellergini, N.; Proteggenete, A.; Pannala, A. et al. Free
Rad Biol Med 1999, 26, 1231.
[1] Yang, X. F.; Kong, L. Y. Chin Chem Lett 2007, 18, 380.
[2] Ragab, F. A.; Taufeek, H. Eur J Med Chem 1987, 22, 265.
[3] Yoo, S. E.; Lee, S. H.; Kim, S. K.; Lee, S. H. Bioorg Med
Chem 1997, 5, 445.
[4] Habermann, J.; Ley, S. V.; Smits, R. J Chem Soc Perkin Trans
1999, 1, 2421.
[5] Mustafa, A.; Furopyrans, F. Chapter III: Furochromones; John
Wiley and Sons: New York, 1967; pp 102–159.
[6] Gammill, R. B.; Hyde, B. R. J Org Chem 1983, 48, 3863.
[7] Kim, S.; Salim, A. A.; Swanson, S. M.; Kinghorn, A. D. Med
Chem 2006, 6, 319.
[21] (a) Shang, Y.; Wang, C.; He, X.; Ju, K.; Zhang, M.; Yu, S.;
Wu, J. Tetrahedron 2010, 66, 9629; (b) Sharifi, A.; Abaee, M. S.;
Tavakkoli, A.; Mirzaei, M. J Iran Chem Soc 2008, 5, S113; (c) Shafiee,
A.; Behnam, E. J Heterocycl Chem 1978, 15, 589; (d) Tiwari, S. S.;
Kumar, S. Indian J Heterocycl Chem 1970, 33, 165.
[22] (a) Gubin, J.; Lucchetti, J.; Inion, H.; Chatelain, P.; Rosseels,
G.; Kilenyi, S. Eur Pat Appl 1992, EP 471609 A1 19920219; (b)
Mackenzie, J. B. D.; Robertson, A.; Bushra, A.; Towers, R. J Chem Soc
1949, 2057; (c) Butler, R. J. E.; Sturton, G. Eur Pat Appl 1993, EP
551662 A1 19930721.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet