Efficient and Convenient Method for Synthesis of Benzofuran-3-acetic Acids and Naphthafuran-acetic Acids

Article abstract of DOI:10.1080/00397911.2015.1068943

Herein, we report an efficient and convenient method for synthesis of benzofuran-3-acetic acids and naphthafuran-acetic acids 5a-p by the reaction of substituted-4-bromomethylcoumarins with aqueous sodium hydroxide at refluxing temperature. The obtained products are characterized by infrared, ¹H NMR, ¹³C NMR, and mass spectral data. Structures 5a and 5e are confirmed by their single x-ray diffraction studies. The advantages of this method are good yields, easy workup, and no chromatographic purifications.

Full text of DOI:10.1080/00397911.2015.1068943

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Efficient and Convenient Method for
Synthesis of Benzofuran-3-acetic Acids
and Naphthafuran-acetic Acids
a
b
a
Mahantesha Basanagouda , Narayanachar , Iranna B. Majati ,
a
a
a
Shiddappa S. Mulimani , Satish B. Sunnal , Rohit V. Nadiger , Ashok
a
a
c
d
S. Ghanti , Siddeshwar F. Gudageri , Ravi Naik & Akshata Nayak
a
P.G. Department of Chemistry, P.C. Jabin Science College, Hubli,
Karnataka, India
Click for updates
b
Department of Chemistry, L.V.D. College, Raichur, Karnataka, India
c
College of Pharmacy, Dongguk University–Seoul, Seoul, Republic of
Korea
d
College of Pharmacy, Graduate School of Pharmaceutical Sciences,
Ewha Woman's University, Seoul, Republic of Korea
Accepted author version posted online: 20 Jul 2015.Published
online: 20 Jul 2015.
To cite this article: Mahantesha Basanagouda, Narayanachar, Iranna B. Majati, Shiddappa S. Mulimani,
Satish B. Sunnal, Rohit V. Nadiger, Ashok S. Ghanti, Siddeshwar F. Gudageri, Ravi Naik & Akshata Nayak
(2015): Efficient and Convenient Method for Synthesis of Benzofuran-3-acetic Acids and Naphthafuran-
acetic Acids, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1068943
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1
Synthetic Communications , 0: 1–8, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1068943
EFFICIENT AND CONVENIENT METHOD FOR
SYNTHESIS OF BENZOFURAN-3-ACETIC ACIDS AND
NAPHTHAFURAN-ACETIC ACIDS
1
2
1
1
Mahantesha Basanagouda, Narayanachar, Iranna B. Majati,
1
1
Shiddappa S. Mulimani, Satish B. Sunnal, Rohit V. Nadiger,
Ashok S. Ghanti, Siddeshwar F. Gudageri, Ravi Naik, and
1
1
3
4
Akshata Nayak
1
P.G. Department of Chemistry, P.C. Jabin Science College,
Hubli, Karnataka, India
2
Department of Chemistry, L.V.D. College, Raichur, Karnataka, India
3
College of Pharmacy, Dongguk University–Seoul, Seoul, Republic of Korea
4
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha
Woman's University, Seoul, Republic of Korea
GRAPHICAL ABSTRACT
Abstract Herein, we report an efficient and convenient method for synthesis of benzofuran-
3
-acetic acids and naphthafuran-acetic acids 5a–p by the reaction of substituted-4-
bromomethylcoumarins with aqueous sodium hydroxide at refluxing temperature. The
1
13
obtained products are characterized by infrared, H NMR, C NMR, and mass spectral
data. Structures 5a and 5e are confirmed by their single x-ray diffraction studies. The
advantages of this method are good yields, easy workup, and no chromatographic
purifications.
Keywords Benzofuran; coumarin; heterocycles; Perkin; transformation
Received January 28, 2015.
This manuscript is dedicated to Prof. Manohar V. Kulkarni’s (K.U. Dharwad) 60th birthday.
Address correspondence to Mahantesha Basanagouda, P. G. Department of Chemistry, P. C.
Jabin Science College, Hubli 580031, Karnataka, India. E-mail: mahanteshachem@gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1

2
M. BASANAGOUDA ET AL.
INTRODUCTION
Benzofuran derivatives are an important class of oxygen heterocycles with a
wide range of biological activities including anti-inflammatory, antitumor, cytotoxic,
antimicrobial, antitubercular, antioxidant, antiplasmodial, enzyme inhibitory,
hepatitis C virus (HCV) inhibitory, and human immunodeficiency virus (HIV)
[1–4]
inhibitory activities, which have been reviewed.
Benzofurans have been the subject of more extensive studies for the develop-
[
5,6]
ment of efficient routes for the synthesis.
The naphthofuran skeleton is present
in many natural products with biological importance and its synthetic derivatives
[
7]
display diverse biological activities. Compared to benzofurans, synthetic methods
[
8,9]
for the preparation of naphthofurans have been less reported.
The arylalkanoic acids are a group of structurally similar compounds, many of
which have interesting anti-inflammatory, analgesic, and antipyretic properties and
so have been in wide clinical use for a number of years (Fig. 1).
The derivatives of 2,3-dihydro-benzofuranyl-3-acetic acids have been reported
to be potent, selective, and orally bioavailable G protein-coupled receptor 40
(
GPR40) and free fatty acid receptor 1 agonists (FFA1) and glucose-dependent
[
10–12]
insulinotropic agents (Fig. 2).
It is well known that certain coumarin derivatives are transformed to other het-
[
13]
[14]
erocycles such as pyrazoles
and pyrimidines
by their reaction with hydrazine
hydrate and acetamidine or benzimidine, involving the cleavage of the lactone,
respectively. The reaction of 4-formyl coumarins with phenyl hydrazine resulted in
[
15]
pyridazines.
The ring transformation of 3-halo-4-methoxycoumarins to pyrazo-
[16]
lines has been reported.
The reaction of 1,2-diamines with 4-hydroxycoumarins
Figure 1. Biologically important arylalkanoic acids.

BENZOFURAN-3-ACETIC AND NAPHTHAFURAN-ACETIC ACIDS
3
Figure 2. Structures of 2,3-dihydro-benzofuranyl-3-acetic acids as potent G protein-coupled receptor 40
[
10–13]
agonist.
resulted in diazepine by intramolecular nucleophilic attack of the amino group onto
[17]
the enolic carbon.
3-Halocoumarins were readily converted into benzofuran-2-
carboxylic acids via Perkin reaction by ring contraction of coumarins to benzofuran
[
18]
under microwave irradiation.
To the best of our knowledge, premier research work on Perkin rearrangement
of 4-chloromethylcoumarins to benzofuran-3-acetic acids using aqueous alkali
[
19]
[20]
medium was reported.
Later, some researchers exploited this method
and
[
21]
reported the anti-inflammatory activity of benzofuran-3-acetic acids. The deriva-
tives of naphthofuran-acetic acids were used as amino acid fluorescence labeling.
As continuation of research work on heterocyclic transformation of 4-bromo-
[
22,23]
[
24–26]
methylcoumarins to other heterocycles
and the use of better leaving property of
bromine than chlorine, herein we report a base-catalyzed Perkin rearrangement of
substituted-4-bromomethylcoumarins to benzofuran-3-acetic acids and naphtho-
furan-acetic acids.
RESULTS AND DISCUSSION
The synthesis of the benzofuran- and naphthofuran acetic acids is illustrated in
Scheme 1. The required substituted-4-bromomethylcoumarins 4 were prepared by
the Pechmann cyclization of substituted phenols 3 with 4-bromoethylacetoacetate
[27]
2
using sulfuric acid as the condensing agent. Subsequent reaction of these substi-
tuted-4-bromomethylcoumarins 4 and 1 M sodium hydroxide was carried out at
reflux, for 1–2 h, resulted in the formation of benzofuran- and naphthofuran-acetic
acids 5a–p. The structures of the compounds were substantiated by infrared (IR),
1
13
H NMR, C NMR, mass spectrometry (MS), and CHN analysis. The purity of
these compounds was ascertained by thin-layer chromatography (TLC) and spectral
analysis (Supplementary Data).

4
M. BASANAGOUDA ET AL.
Scheme 1. Synthesis of benzofuran- and naphthofuran acetic acids 5(a–p).
In the IR spectrum of the prototype, compound 5a exhibited absorption band
ꢀ
1
ꢀ1
1
of carbonyl group at 1722 cm and hydroxyl group at 3439 cm . The H NMR
displayed two singlets at d 2.39 and 3.65 for methyl and methylene protons,
respectively. Peaks in between d 7.11 and 7.83 affirmed the presence of four aromatic
protons. The presence of carboxylic acid proton is confirmed by downfield peak at d
1
3
1
2.46. The C NMR indicated presence of methyl carbon with peak at d 20.88,
methylene carbon gave a peak at d 28.95, and the carbonyl carbon resonated at d
71.92. Peaks for eighteen carbons in the aromatic region from d 110.74 to 152.92
1
underlined the presence of the required aromatic skeleton. Further formation of
product was confirmed by mass spectra (LC-MS), which showed a molecular ion
peak at m=z 191 (MþH).

BENZOFURAN-3-ACETIC AND NAPHTHAFURAN-ACETIC ACIDS
5
Table 1. Structure and ORTEP diagram of compounds 5a and 5e
Structure
ORTEP diagram
To know the crystal packing, hydrogen bonding in the molecules, and orien-
tation of acetic acid moiety with benzofuran, two compounds 5a and 5e were grown
for single-crystal x-ray study by slow evaporation technique using an ethanol and
ethyl acetate mixture. The compound 5a exists as a dimeric form. The structures
and ORTEP diagrams of compounds 5a (CCDC No. 1401315) and 5e (CCDC
No. 1401314) are given in Table 1.
EXPERIMENTAL
The melting points were determined by open capillary method and are uncor-
rected. The IR spectra (KBr disc) were recorded on a Nicolet-5700 FT-IR spectro-
1
13
photometer. H NMR and C NMR spectra were recorded on Bruker 400-MHz
spectrometer using dimethylsulfoxide (DMSO-d ) as solvent and tetramethylsilane
6
(TMS) as an internal standard. The chemical shifts are expressed in d ppm. The mass
spectra were recorded using an Agilent-Single Quartz LC-MS instrument. The
elemental analysis was carried out using a Heraus CHN rapid analyzer at the
University Scientific Instrumentation Centre (USIC), Karnatak University,
Dharwad. The purity of the compounds was checked by TLC. All the chemicals

6
M. BASANAGOUDA ET AL.
purchased were of analytical grade, and were used without further purification unless
otherwise stated, from Sigma-Aldrich Chemicals (India) and S.D. Fine Chemicals
(India).
Synthesis of (5-Methyl-benzofuran-3-yl)-acetic Acid (5a)
The substituted-4-bromomethylcoumarin 4 (10 mM) was refluxed in 1 M
NaOH (100 mL) for 1-2 h (monitored by TLC). The reaction mixture was cooled
and neutralized with 1 M HCl, and then the obtained product was filtered and dried.
The obtained products were sufficiently pure and hence were not recrystallized.
[
15]
ꢀ1
Mp 97–98 °C (literature mp 98–100 °C),
yield 95%; IR (KBr, n in cm ):
1
3
439 (br, OH), 1722 (C=O); H NMR (400 MHz, DMSO-d ): d 2.39 (s, 3H,
6
C5-CH ), 3.65 (s, 2H, C3-CH ), 7.11 (d, J ¼ 8.4 Hz, 1H, C6-H), 7.37 (d, J ¼ 0.4 Hz,
3
2
1
H, C4-H), 7.42 (d, J ¼ 8.4 Hz, 1H, C7-H), 7.83 (s, 1H, C2-H), 12.46 (s, 1H, COOH);
1
3
C NMR (400 MHz, DMSO-d ): 20.88, 28.95, 110.74, 113.68, 119.71, 125.42,
6
1
27.81, 131.39, 143.44, 152.92, 171.92. LCMS m=z: 191 [M þ 1]. Anal. calcd. for
C H O : C, 69.46; H, 5.30. Found: C, 69.38; H, 5.28.
1
1
10
3
CONCLUSION
In summary, we have demonstrated a synthetic method for the transformation
of substituted-4-bromomethylcoumarins to benzofuran-3-acetic acids and
naphthofuran acetic acids. In particular, most reactions proceeded to completion
in 1–2 h with very simple workup and direct isolation of the products in good yields
without purification by either recrystallization or chromatographic assistance. The
single-crystal x-ray structures of compounds 5a and 5e may be used to study and
compare the biological activities associated with acetic acid moieties.
ACKNOWLEDGMENTS
The authors thank the SAIF Indian Institute of Technology Madras, Chennai,
1
for the data collection; Sigma-Aldrich Chemicals Pvt. Ltd., Bangalore, India, for H
1
3
NMR and C NMR spectra; and USIC K.U. Dharwad for IR spectral data.
FUNDING
Mahantesha B. thanks the University Grants Commission–SWRO, Bangalore,
for providing Minor Research Project (Ref. No. 1415-MRP=14-15=KAKA067=
UGC-SWRO, Diary No. 1709).
SUPPLEMENTAL MATERIAL
1
13
Full experimental details, H and
C NMR spectra, crystallographic
information, and other spectral data for this article can be accessed on the
publisher’s website.

BENZOFURAN-3-ACETIC AND NAPHTHAFURAN-ACETIC ACIDS
7
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