Microwave-assisted parallel synthesis of benzofuran-2-carboxamide derivatives bearing anti-inflammatory, analgesic and antipyretic agents

Article abstract of DOI:10.1016/j.tetlet.2014.02.116

A series of benzofuran-2-carboxamides of biological and medicinal significance were synthesized by a microwave-assisted one-pot parallel approach via O-alkylation/Knoevenagel condensation. All the compounds were characterized and assayed for their in vivo anti-inflammatory, analgesic and antipyretic activities. The activity data of all compounds were listed and discussed in detail, among which some derivatives exhibited potent activities of particular interest.

Full text of DOI:10.1016/j.tetlet.2014.02.116

Accepted Manuscript
Microwave-assisted parallel synthesis of benzofuran-2-carboxamide deriva-
tives bearing anti-inflammatory, analgesic and antipyretic agents
Yong-Sheng Xie, Deepak Kumar, B.V.D. Vijaykumar, Tarani P. Shrivastava,
Bao-Xiang Zhao, Jun-Ying Miao, Kiwan Jang, Dong-Soo Shin
PII:
S0040-4039(14)00368-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.116
TETL 44303
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 December 2013
22 February 2014
27 February 2014
Please cite this article as: Xie, Y-S., Kumar, D., Vijaykumar, B.V.D., Shrivastava, T.P., Zhao, B-X., Miao, J-Y.,
Jang, K., Shin, D-S., Microwave-assisted parallel synthesis of benzofuran-2-carboxamide derivatives bearing anti-
inflammatory, analgesic and antipyretic agents, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.02.116
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Tetrahedron Letters
journal hom epage: www.elsevier.com
Microwave-assisted parallel synthesis of benzofuran-2-carboxamide derivatives
bearing anti-inflammatory, analgesic and antipyretic agents
Yong-Sheng Xiea,b,#, Deepak Kumara,#, B. V. D. Vijaykumara, Tarani P. Shrivastavac, Bao-Xiang Zhaod, Jun-Ying Miaod,
Kiwan Janga, Dong-Soo Shina,*
aDepartments of Chemistry and Physics, Changwon National University, Changwon, 641-773, S. Korea
bCollege of Chemical and Environmental Engineering, Chongqing Three Gorges University, Chongqing, 404100, P.R. China
cDepartment of Pharmacology, School of Pharmacy and Research centre, People's University, Bhopal, 462 037, India
dInstitute of Organic Chemistry and DevelopmentalBiology, Shandong University, Jinan, 250100, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of benzofuran-2-carboxamides of biological and medicinal significance were
synthesized by a microwave-assisted one-pot parallel approach via O-alkylation/Knoevenagel
condensation. All the compounds were characterized and assayed for their in vivo anti-
inflammatory, analgesic and antipyretic activities. The activity data of all compounds were
listed and discussed in detail, among which some derivatives exhibited potent activities of
particular interest.
Available online
Keywords:
Benzofuran-2-carboxamides
Microwave-assisted synthesis
Knoevenagel condensation
Anti-inflammatory activity
Analgesic activity
2013 Elsevier Ltd. All rights reserved.
Antipyretic activity
The amide bond exists widely in both natural and synthetic
compounds. It is a core structure in pharmaceutical chemistry,
being present in 25% of all synthetic drugs1. Partially,
benzofuran-2-carboxamide derivatives are now known to possess
extensive biological and medicinal activities such as anti-
Thus, using computer managed automatic microwave technology,
synthesis of compound libraries for lead compounds including
their screening and optimization can be achieved within very
short span of time that required by classical thermal methods. In
continuation to our previous efforts towards microwave assisted
transformations,20,21 we herein present a novel one-pot parallel
approach via O-alkylation/Knoevenagel–condensation sequence
under microwave conditions to obtain the library of benzofuran-
2-carboxamide derivatives and their anti-inflammatory, analgesic
and antipyretic activities in detail.
cancer,2-4
anti-depression,5,6
antimicrobial,7
anti-
hyperlipidemic,8,9 nAChR agonist,10,11 PtS inhibitor,12 virus cell
entry inhibitor,13 Cathepsin K inhibitor14 and MMP-13 inhibitor15
activities. Even though, many synthetic approaches are reported
to make these moieties, still there is a demand for new methods.
Thus, the use of combinatorial approaches to the high-throughput
synthesis of this drug-like scaffold would be a powerful advance
in helping to speed up drug discovery.
O
O
R2
R4
N
Cs2CO3, DMF
R1
R1
R3
Cl
R3
R2
OH
1 = H, halide, CH3
+
N
M.W., 80 oC, 30 min,
then 140 oC, 30 min
R4
O
O
1-20
I
II
(25-80%)
On the other hand, microwave-assisted synthesis has become
increasingly popular within the drug discovery due to their
advantages of speed and convenience.16-19 Comparing with the
classic thermal transmission, microwave heating can effectively
increase the rate of heating and chemical reaction. Furthermore,
dedicated commercial microwave reactors have been developed
for microwave-assisted parallel and combinatorial chemistry. A
series of compounds can be prepared, sequentially in an
automated single-mode instrument or in a parallel multimode
instrument with multiple reactions.
R
R2 = H, alkyl, phenyl
R3 = H, aryl, pyridyl
O
R1
R
4 = H, Bn
R4
N
R2
R3
O
O
III
Scheme 1. Microwave assisted benzofuran-2-carboxamides in one hour
Generally, the carboxamide bond formation is typically
mediated between carboxylic acid and amine by one of a myriad
of coupling reagents, such as EDCI, DCC and CDI. However, the
lack of diversity of commercial benzofuran-2-carboxylic acid
________
*Corresponding author: E-mail: dsshin@changwon.ac.kr
Phone: +82-55-213-3437, Fax: +82-55-213-3439
# Equally contributed
brings
a challenge to construct benzofuran-2-carboxamide
library, because synthesis of these acid compounds must undergo
a three-step two-pot or three-pot procedure that is time-
consuming with low efficiency.22,23 Our sequential studies on

2
Tetrahedron Letters
Smiles rearrangement24 for the synthesis of N-substituted
Table 1. Benzofuran-2-carboxamides from orthoacetylphenols and 2-
anilines turned out to be a Knoevenagel condensation with 2-
acylphenols within an hour. This encouraged us to avoid
difficulties mentioned above and to achieve efficient synthesis of
benzofuran-2-carboxamide library. Thus, we’ve designed a novel
chloroacetamides.
Conditionsa
Product
Yield (%)b
75
Entry 2-Acyl/formylphenol Chloroacetamide
O
O
O
2.5 equiv of
Cs2CO3 in
DMF
microwave-assisted
one-pot
O-alkyalation/Knoevenagel-
Cl
1
NH2
O
NH2
OH
O
condensation reaction sequence. Preliminarily, 2-chloroacetyl
amides were prepared by simple acetylation of amines with 2-
chloroacetyl chloride. Thereafter, the reaction between these
amides and 2-acyl/formyl phenols afforded corresponding
benzofuran-2-carboxamide under microwave irradiation in two-
step one-pot manner involving O-alkylation of phenols followed
by Knoevenagel type condensation as shown in Scheme 1.
IIa
1
Ia
O
O
O
Cl
O
Cl
2.5 equiv of
Cs2CO3 in
DMF
Cl
Cl
Cl
2
3
4
49
45
NH2
NH2
NH2
O
NH2
OH
O
IIa
IIa
2
Ib
Ic
Br
O
Br
2.5 equiv of
Cs2CO3 in
DMF
O
NH2
OH
O
3
O
2.5 equiv of
Cs2CO3 in
DMF
As a model reaction, we first examined the reaction of 1-(5-
59
50
O
NH2
OH
O
IIa
IIa
4
Id
bromo-2-hydroxyphenyl)ethanone
(1
equiv.)
with
2-
Ph
O
O
O
chloroacetamide (1.2 equiv.) in DMF in the presence of different
bases (2.5 equiv.). The reaction mixture was irradiated by
O
2.5 equiv of
Cs2CO3 in
DMF
Ph
Cl
Cl
Cl
5
NH2
NH2
NH2
O
NH2
OH
O
o
o
5
Ie
If
microwave at 80 C for 30 min followed at 145 C for 30 min.
After removing the solvent under reduced pressure, the residue
was directly adsorbed on silica gel and purified by flash column
chromatography (CombiFlash automatic, Teledyne, Inc.). Among
all the bases used, Cs2CO3 (45% yield) found to be better than
K2CO3 (35% yield) or Na2CO3 (30% yield). By changing the
solvent from DMF to CH3CN or addition of KI as catalyst along
with all the above bases lead to drastic decrease in yields. Now,
with the optimal reaction conditions in hand, the scope of
microwave-assisted one-pot synthesis between 2-acyl phenols
and 2-chloroacetyl amines was explored through a parallel
approach and the yields of products (1-20) have been presented
in Table 1.25 The structures of all synthesized benzofuran-2-
carboxamide derivatives were confirmed by NMR and HRMS
Ph
Cl
Cl
O
2.5 equiv of
Cs2CO3 in
DMF
Ph
6
7
74
70
76
O
NH2
OH
O
IIa
IIa
6
Ph
2.5 equiv of
Cs2CO3 in
DMF
Ph
O
OH
O
Ig
O
NH2
7
O
O
2.5 equiv of
Cs2CO3 in
DMF
Cl
8
NH2
O
NH2
OH
O
IIa
8
Ih
Ii
O
O
O
2.5 equiv of
Cs2CO3 in
DMF
H
Cl
Cl
9
50
43
57
NH2
NH2
O
NH2
OH
O
IIa
IIa
9
O
2.5 equiv of
Cs2CO3 in
DMF
H
10
11
analysis where the known compounds (1, 3-5 and 826a, 926a,b, 626c
,
O
10
NH2
OH
O
Ij
1026d,e and 1226f) are matched with the reported data. In addition,
this method is faster and exploits the use of microwave over
conventional heating processes which take more than 7 h for
Knoevenagel condensation.26e
Cl
O
O
2.5 equiv of
Cs2CO3 in
DMF
Cl
N
O
HN
11
Cl
H
OH
O
Ia
Ia
IIb
O
O
2.5 equiv of
Cs2CO3 in
DMF
Cl
12
13
55
25
N
O
12
HN
H
The two protons of NH2 of N-unsubstituted benzofuran-2-
carboxamide derivatives (1-10) showed separate signals in the 1H
NMR. For example, 1H NMR of compound 9 showed two
protons of NH2 exhibited different peaks. Only one chemical
shift for amino proton was observed in 1H NMR of N-
monosubstituted benzofuran-2-carboxamides (11-19). The
products with low yields can be accounted by functional groups
present either in amides or phenols, which affect the
transformation. Even though, there is no big difference in the
yields from all phenols, the ones with an electron withdrawing
aryl group (2, 3 & 6) or an aldehyde at acyl subunit (9 and 10)
gave comparatively low yields. A substitution on the nitrogen of
chloroacetamides also made considerable decrease in the yields
to obtain adducts. Aryl amides with electron withdrawing group
on aryl group (11 and 16) gave moderate yields. The aryl amides
with electron donating group (13, 17, 18 and 19) ended up with
comparatively low yields may be due to mesomeric effects,
which decreases the stability of carbanion in Knoevenagel
condensation. A dibenzyl substituted chloroacetamide gave the
corresponding product in good yields. The advantages over other
synthetic methods involve short reaction periods, parallel
synthesis, and moderate to good yields. After characterization, all
the benzofuran-2-carboxamide derivatives were evaluated for
their anti-inflammatory, analgesic and anti-pyretic activities at 50
mg/kg p.o.
OH
O
IIc
OMe
O
2.5 equiv of
Cs2CO3 in
DMF
O
Cl
N
H
O
HN
13
OMe
OH
O
Ia
IIc
O
O
2.5 equiv of
Cs2CO3 in
DMF
Cl
N
14
15
47
53
H
O
HN
O
14
OH
O
IId
Ia
Ia
O
2.5 equiv of
Cs2CO3 in
DMF
Cl
N
H
O
HN
Ph
15
OH
O
IIe
Cl
O
2.5 equiv of
Cs2CO3 in
DMF
O
Ph
Cl
16
17
18
43
30
30
N
H
OH
O
O
HN
Cl
IIc
Ig
Ia
Ig
16
O
O
2.5 equiv of
Cs2CO3 in
DMF
Cl
N
H
N
N
O
HN
Ph
OH
O
IIf
17
N
O
2.5 equiv of
Cs2CO3 in
DMF
O
Ph
Cl
N
H
O
HN
OH
O
IIf
18
N
N
Ph
O
O
2.5 equiv of
Cs2CO3 in
DMF
Ph
Cl
Cl
19
20
40
65
N
H
N
O
HN
OH
O
IIf
19
Ie
Ia
O
O
2.5 equiv of
Cs2CO3 in
DMF
Bn
N
Bn
O
20
N Bn
OH
IIg
Bn
a30 min (t) at 80 oC and further 30 min (t) at 145 oC. Reaction time (t)
is the hold time after ramp time 10 min.
bYields refer to isolated pure compounds after column
chromatography.

Table 2. Anti-inflammatory activity of benzofuran-2-carboxamide derivatives (1-20) by carrageenan induced rat paw edema method in rats, analgesic
activity by tail flick method and antipyretic activity by brewer’s yeast induced method.
Analgesic activity
% Increase
in reaction time
Antipyretic activity
% Reduction
in rectal temperature
Anti-inflammatory activity
Increase in paw volume ml ± SEM ( % inhibition of inflammation)
Entry
1h
2h
3h
4h
60 min
5 h
—
—
—
74
5
Control
0.34 0.002
0.25 0.010
—
0.74 0.002
0.27 0.011
—
0.91 0.002
0.25 0.016
—
1.03 0.002
—
—
Diclofenac
0.27 0.001 (74)
—
Pentazocine
217
—
Paracetamol
—
—
—
—
1
2
0.35 0.009
0.37 0.007
0.30 0.005**
0.36 0.005
0.34 0.012
0.29 0.005
0.34 0.007
0.30 0.004
0.29 0.005**
0.38 0.003
0.29 0.007**
0.33 0.011
0.33 0.009**
0.29 0.009**
0.34 0.012
0.33 0.009**
0.30 0.005
0.33 0.005**
0.32 0.013**
0.33 0.009**
0.77 0.017
0.72 0.005
0.47 0.003**
0.73 0.008
0.87 0.007
0.44 0.012
0.76 0.018
0.46 0.007
0.36 0.007**
0.85 0.015
0.35 0.005**
0.42 0.015
0.38 0.007**
0.37 0.002**
0.65 0.013
0.38 0.005**
0.42 0.005
0.39 0.007**
0.34 0.007**
0.39 0.007**
0.84 0.005
0.88 0.009
0.76 0.007**
0.85 0.007
0.86 0.009
0.77 0.005
0.86 0.011
0.77 0.005
0.37 0.005**
0.89 0.003
0.37 0.002**
0.44 0.005
0.39 0.004**
0.38 0.003**
0.66 0.011
0.38 0.005**
0.71 0.002
0.38 0.003**
0.35 0.005**
0.39 0.007**
1.00 0.013 (3)
1.00 0.007 (3)
0.83 0.009** (19)
0.96 0.011 (7)
1.00 0.010 (3)
0.82 0.013 (20)
0.99 0.011 (4)
0.83 0.012 (19)
0.36 0.009** (64)
1.00 0.008 (3)
0.37 0.002** (64)
0.51 0.005 (50)
0.39 0.005** (60)
0.35 0.003** (66)
0.79 0.004 (23)
0.38 0.005** (63)
0.80 0.002 (22)
0.38 0.013** (63)
0.37 0.002** (64)
0.38 0.009** (63)
2
1
6
3
172
134
136
153
135
152
160
134
160
161
167
138
153
160
169
160
160
160
45
46
6
4
5
6
46
6
7
8
45
64
7
9
10
11
12
13
14
15
16
17
18
19
20
46
48
49
68
47
45
63
62
60
46
SEM- standard error mean; n=6, *p <0.05, **p <0.01, ***p <0.001; -, not determined.
Anti-inflammatory
activity
was
evaluated
against
indicates that the compounds 9, 14, 17 and 18 exhibit potent
antipyretic activity causing more than 58% reduction in rectal
temperature. The compounds 3, 4, 6, 8, 11, 12, 13, 15, 16, 19 and
20 showed moderate activity (45-49%) as compared with other
tested series.
carrageenan-induced paw edema method in Wistar rats.27 The
results are shown in Table 2. The standard drug diclofenac
sodium was administered at dose of 20 mg/kg p.o. which gives
74% inhibition of inflammation at 4 h. Among the N-
unsubstituted benzofuran-2-carboxamide derivatives, compound
9 showed good anti-inflammatory activity (65% inhibition)
compared to other scaffolds. The methyl group at 5-position of
benzofuran ring might be responsible for the anti-inflammatory
activity.
In conclusion, a new series of benzofuran-2-carboxamide
derivatives has been prepared by one pot microwave-assisted
parallel synthesis that involves an O-alkylation followed by
Knoevenagel condensation reaction sequence. All the compounds
were fully characterized by spectral data. Most of the twenty
synthesized compounds exhibited significant activities, among
which, compound 9, 11, 14, 18 and 19 showed best anti-
inflammatory, analgesic and anti-pyretic activities. This indicates
that benzofuran-2-carboxamide derivatives can be considered as
potential anti-inflammatory, analgesic and anti-pyretic agents.
Further studies in relation to cytotoxicity and ADME are also
warranted for the better understanding.
In the N-substituted series, compounds 11, 12, 13, 14, 16, 18,
19 and 20 exhibited significant activity (50-66% inhibition) as
compared to other compounds. The remaining benzofuran-2-
carboxamide derivatives showed weak anti-inflammatory activity.
Radiant heat tail-flick method in rats was used to screen the
analgesic activity.28 The effects of synthesized compounds and
reference drug pentazocine (10 mg/kg i.p.) have been shown in
Table
2 and expressed as percentage analgesia. Except
Acknowledgements
compounds 1 and 2, all the other synthesized compounds showed
significant analgesia activity with 134-172% increase in reaction
after 1 h treatment.
This work was supported by the grants from Ministry of
Environment (KME, 412-111-008), National Research
Foundation (NRF-2009-0094063) and Ministry of Knowledge
Economy (MKE, R0000495), South Korea.
Furthermore, the antipyretic activity was evaluated against
brewer’s yeast induced method.29 Paracetamol was used as
standard drug at a dose of 150 mg/kg p.o. The percentage
reduction in temperature after 5 h are summarized in Table 2,
Supplementary data

4
Tetrahedron Letters
3879–3882. (e) Bathe, A. US20100036139(A1), Feb. 11, 2010. (f)
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Microwave-assisted parallel synthesis of
benzofuran-2-carboxamide derivatives
bearing anti-inflammatory, analgesic and
antipyretic agents
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Yong-Sheng Xie, Deepak Kumar, B. V. D. Vijaykumar, Tarani P. Shrivastava, Bao-Xiang Zhao, Jun-Ying
Miao, Kiwan Jang, Dong-Soo Shin*