Efficient room-temperature synthesis and antimicrobial study of novel 2-aroylbenzofuran-3-ols from substituted methyl salicylates and phenacyl bromides

Article abstract of DOI:10.1080/00397911.2013.804932

The article describes a convenient and efficient synthetic route for the construction of 2-aroylbenzofuran-3-ols from readily available diverse methyl salicylates and phenacyl bromides using K₂CO₃ as catalyst in dimethylformamide as solvent at room temperature. The reaction involves two steps, which occur in quick succession within 1 h to deliver the product with reasonably high yields. All the synthesized 2-aroylbenzofuran-3-ols (4a-u) were subjected for their antimicrobial studies, and some of these have shown prominent activity. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.804932

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Efficient Room-Temperature Synthesis
and Antimicrobial Study of Novel 2-
Aroylbenzofuran-3-ols from Substituted
Methyl Salicylates and Phenacyl
Bromides
Rashmi S. Kulkarni a , Suresha Kumara T. Hanumanthappa a ,
Nagendrappa Gopalpur a , Sowmya H. B. Vijaya Kumar a & Sunil S.
More b
a PG Department of Chemistry , Jain University , Bangalore ,
Karnataka , India
b PG Department of Biochemistry , Jain University , Bangalore ,
Karnataka , India
Published online: 20 Nov 2013.
To cite this article: Rashmi S. Kulkarni , Suresha Kumara T. Hanumanthappa , Nagendrappa Gopalpur ,
Sowmya H. B. Vijaya Kumar & Sunil S. More (2014) Efficient Room-Temperature Synthesis and
Antimicrobial Study of Novel 2-Aroylbenzofuran-3-ols from Substituted Methyl Salicylates and
Phenacyl Bromides, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:3, 331-339, DOI: 10.1080/00397911.2013.804932
To link to this article: http://dx.doi.org/10.1080/00397911.2013.804932
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Synthetic Communications1, 44: 331–339, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.804932
EFFICIENT ROOM-TEMPERATURE SYNTHESIS AND
ANTIMICROBIAL STUDY OF NOVEL
2-AROYLBENZOFURAN-3-OLS FROM SUBSTITUTED
METHYL SALICYLATES AND PHENACYL BROMIDES
Rashmi S. Kulkarni,1 Suresha Kumara T. Hanumanthappa,1
Nagendrappa Gopalpur,1 Sowmya H. B. Vijaya Kumar,1 and
Sunil S. More2
1PG Department of Chemistry, Jain University, Bangalore, Karnataka, India
2PG Department of Biochemistry, Jain University, Bangalore, Karnataka,
India
GRAPHICAL ABSTRACT
Abstract The article describes a convenient and efficient synthetic route for the construction
of 2-aroylbenzofuran-3-ols from readily available diverse methyl salicylates and phenacyl
bromides using K2CO3 as catalyst in dimethylformamide as solvent at room temperature.
The reaction involves two steps, which occur in quick succession within 1 h to deliver the
product with reasonably high yields. All the synthesized 2-aroylbenzofuran-3-ols (4a–u)
were subjected for their antimicrobial studies, and some of these have shown prominent
activity.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 2-Aroylbenzofuran-3-ols; Antimicrobial activity; K2CO3=DMF; methyl
salicylate; phenacyl bromide; room temperature
INTRODUCTION
Benzo[b]furan derivatives have gained considerable importance in the past few
decades. They form part of a wide range of natural products and pharmacological
Received March 7, 2013.
Address correspondence to Suresha Kumara T. Hanumanthappa, PG Department of Chemistry,
127=2 Bull Temple Road, Jain University, Bangalore 560019, Karnataka, India. E-mail: suresha.
kumara@gmail.com; sureshhanumanthappa@yahoo.com
331

332
R. S. KULKARNI ET AL.
substances and find applications in molecular electronic devices and functional poly-
mers.[1] Liphagal, a natural product containing benzofuran moiety, was recently
investigated as a selective phosphoinositide-3-kinase a inhibitor.[2] Bufuralol is
an effective drug for the treatment of hypertension,[3] a potent non-selective b-
adrenergic receptor antagonist,[4] and an inhibitor of testosterone 6b-hydroxylase,[5]
and is widely used in the studies of cytochrome P450.[6] Benzofurans exhibit antitu-
mor and antiviral activities.[7] They possess potent, reversible, and nonselective
aromatase inhibitory effect[8] and selective toxicity against tumorigenic cell lines.[9]
2-Aroylbenzofuran-3-ols are reported to display promising antitumor activity.[10]
2-Aroylbenzofuran-3-ols occupy a significant position among benzofurans
because of their use as intermediates in the synthesis of several pharmaceutical com-
pounds[11] and antitumor and anti-inflammatory activities.[12] Because of their wide
application, several routes for their synthesis have been developed and the effort is
continuing. Some of the important methods include Dieckmann condensation[10d]
of methyl 2-(2-oxo-2-aroylethoxy)benzoates,[13] cyclocondensation of 2-aroylacetyl-
phenol by bromination,[13,14] oxidative cyclization of 2-aroylacetylphenol,[15]
rearrangement of 3-haloflavones,[14] biotransformation of 2-hydroxychalcones in cell
suspension cultures,[16] and more recently microwave-assisted[10a] and basic ionic
liquid–catalyzed[10b] Baker–Venkataraman-type reaction = Dieckmann cyclization
of intermediates formed in the reaction of substituted methyl salicylates with
2-bromo-1-aroyl-ethanones by a one-pot procedure.[10] Most of the base-catalyzed
techniques described by earlier workers involve high-temperature conditions and
are of limited use because of poor yields or lack of general applicability, particularly
when the reactants contain electron-withdrawing substituents. Also, some of them
involve reaction conditions that are not simple. Consequently, there is considerable
scope to develop improved and more efficient methods for the synthesis of
2-aroylbenzofuran-3-ols.
A simpler synthesis, particularly one carried out at room temperature, is highly
desirable as this cuts the cost of energy input, is environmental friendly,[17] and
eliminates the chance of decomposition of reactants or products, leading to purer
Scheme 1. Condensation of methyl salicylates (1) with phenacyl bromides (2) using K2CO3=DMF at room
temperature.

2-AROYLBENZOFURAN-3-OLS
333
Table 1. Trial experiments for the reaction of 1 with 2 at room temperature using K2CO3
Entry
Solvent
Compound
Time (h)
Yield (%)
1
2
3
4
Acetone
MeCN
THF
4a–u
4b,4i
4b,4g
4a–u
>15–20
>10–15
>10
5–35
15–30
10–15
>80
DMF
<1–1
products in greater yields. The present method follows these principles. We report
here a novel, highly efficient, one-pot, room-temperature reaction for the synthesis
of 2-aroylbenzofuran-3-ols 4a–u containing a variety of substituents, both electron
donating as well as electron withdrawing (Scheme 1, Table 1). All the products were
subjected to antibacterial and antifungal studies (Table 2).
There are several methods known in the literature for the synthesis of
2-aroylbenzfuran-3-ols. Baker–Venkataraman-type = Dieckmann cyclization of
methyl 2-(2-oxo-2-aroylethoxy)benzoates is apparently the most straightforward
procedure for the preparation of these target compounds. However, as the prep-
aration of starting compounds is difficult, Zhou et al.[10a] circumvented this problem
Table 2. Antibacterial and antifungal activity of 2-aroylbenzofuran-3-ols (4a–u)
Antimicrobial activity
Bacteria
Fungus
Gram positive Gram negative
No. Compound (Bacillus flexus) (Pseudomonas spp.) (Scopulariopsis spp.) (Aspergillustereus)
Standard
4a
4b
4c
—
þþþ
þ
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
þþþþ
þþ
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
1
2
3
þ
4
4d
4e
—
—
—
5
þþ
þþþ
—
6
4f
—
7
4g
4h
4i
þþþþ
—
—
8
þþ
—
9
10
11
12
13
14
15
16
17
18
19
20
21
4j
þþ
—
—
þ
4k
4l
—
—
—
—
4m
4n
4o
4p
4q
4r
þ
þþþ
—
—
þþ
—
þþþ
—
þþþ
—
þþ
—
4s
4t
4u
þþþ
—
þþþ
—
Notes. þþþþ ¼ 15 mm, þþþ ¼ 11 mm, þþ ¼ 8 mm, and þ ¼ 4 mm.

334
R. S. KULKARNI ET AL.
by direct microwave irradiation of mixtures of substituted methyl salicylates
and phenacyl bromides. It is obvious that in these reactions methyl 2-(2-oxo-2-
aroylethoxy)benzoates are formed as intermediates.
Starting from three methyl salicylates and four phenacyl bromides, Zhou et al.
obtained 12 2-aroylbenzofuran-3-ols[10a] under microwave irradiation at 100 ꢀC for
15 min. To optimize the reaction conditions, they carried out the cyclization of the
unsubstituted methyl salicylate and phenacyl bromide. After trying the experiment
with four bases, namely, sodium acetate, sodium carbonate, potassium carbonate,
and potassium hydroxide, in acetone as solvent, which gave only traces of the
product, they found that potassium phosphate in acetone gave excellent yields.
However, the reaction had to be carried out under rather drastic condition which
consisted of simultaneous heating and microwave irradiation. It thus consumes
much energy. They also found that the electron-withdrawing group NO2 on methyl
salicylate leads to poor yields, and if NO2 is present on the phenyl ring of phenacyl
bromide, the reaction does not proceed at all.
RESULTS AND DISCUSSION
Our aim was to bring about the cyclization at room temperature. To achieve
this goal we conducted trial experiments with potassium carbonate as base in acet-
one, tetrahydrofuran (THF), acetonitrile, and dimethylformamide (DMF). The
results are summarized in Table 1. These results clearly indicate that the reactions
run in DMF were faster than our expectations and the yields obtained were excellent.
For these trial runs we used all the substrates in acetone solvent and three to four
different reactants in CH3CN and THF. In every one of these experiments the time
taken was much less, and yields obtained were greater than 80% in DMF, but in
other solvents the yields were very poor, despite running the reactions for much
longer (Table 1). Once we ascertained the efficacy of DMF as solvent in driving
the reaction to completion at room temperature in a short time, we used that method
to prepare 21 different 2-aroylbenzofuran-3-ols. The reactions proceeded smoothly
and most of the reactants disappeared in about 30 to 45 mins. However, the stirring
was continued for a total period of 1 h, following which the products were isolated.
The results are recorded in Table 3. The minor impurities present in the products
were removed by column chromatography using ethyl acetate and petroleum ether
mixtures as eluents (1:9, 2:8, and 3:7 ratio). The 2-aroylbenzofuran-3-ols (4) have
been characterized by their spectral data. These data and the preparative procedure
are given in the experimental section.
It is an interesting question to ask why DMF works so well in this reaction.
The reaction takes place in two distinct steps (Scheme 1). The first step involves
the apparent formation of the intermediate methyl 2-(2-oxo-2-aroylethoxy)benzoates
(3) from methyl salicylates (1) and phenacyl bromides (2) through substitution. This
is very likely to be a base-catalyzed process, and therefore the availability of base is
crucial for its success. In addition, the substitution may be of borderline mechanism
between SN1 and SN2. Because of high polarity and dielectric constant of DMF
compared to other solvents used, K2CO3 concentration in it could be significantly
more than in other solvents and enough to sufficiently accelerate this reaction.
Further, DMF would favor SN1 reaction. We presume that both these features

2-AROYLBENZOFURAN-3-OLS
335
Table 3. K2CO3=DMF-catalyzed synthesis of 2-aroylbenzofuran-3-ols in <1 h at room temperature
Entry
R1
R2
R3
R4
Yield (%)
4a
4b
4c
4d
4e
4f
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
Cl
F
80
82
86
90
81
89
91
82
83
84
86
82
83
90
81
80
80
80
81
83
85
Br
Br
H
H
Br
H
F
H
Cl
Cl
H
H
4g
4h
4i
Br
Cl
H
Cl
Br
CN
Cl
F
H
Br
H
4j
NO2
H
H
4k
4l
NO2
H
NO2
H
F
4m
4n
4o
4p
4q
4r
4s
4t
NO2
H
Cl
Br
H
H
H
F
NO2
NO2
H
H
NO2
NO2
H
H
CH3
CH3
H
H
H
F
CH3
CH3
4u
H
H
Notes. Each reaction took less than 1 h. Extra stirring time (15 min) was allowed to ensure that no traces
of starting compounds were left.
accelerate the reaction. The second step in which 3 cyclizes to 4 must be a fast step as
the former seemed to form but disappeared swiftly during the course of the reaction,
which has been followed by thin-layer chromatography (TLC).
A glance at Table 3 shows that K2CO3 in DMF works as an excellent catalyst
for the synthesis of 2-aroylbenzfuran-3-ols 4a–u with a variety of substituents, both
electron donating and withdrawing. It is noteworthy that while Zhou et al. obtained
poor yields with methyl 3-nitrosalicylate and found that no reaction occurs when
4-nitrophenacyl bromide was used, with our much simpler protocol the reaction of
these two nitro-substituted compounds completed smoothly within 1 h and, in gen-
eral, our yields are far better. This shows that electronic effects exert little influence
on the yield or the reaction time in the present method. Prompted by the success of
the reaction in the highly polar DMF solvent, we carried out the reaction in
dimethylsulfoxide (DMSO) and found that it occurs equally smoothly. The results
in DMSO are almost identical to those obtained in DMF. The present synthetic pro-
cedure conforms to many of the green chemistry principles. The product yield is
quantitative; no wasteful by-product is formed. Much of the reaction solvent
DMF can be recovered. The workup procedure involves solvents that can be easily
recovered. Because the reaction is conducted at room temperature, no extra energy is
supplied, except for stirring. The reaction seems to have general applicability as it
has worked with a variety of substituted methyl salicylates and phenacyl bromides
containing both electron-withdrawing and electron-donating substituents. All these
compounds (4a–u) are new. Considering all these factors, the present method is

336
R. S. KULKARNI ET AL.
perhaps the simplest and the best available to date for synthesis of these novel
aroylbenzofuran-3-ols 4a–u.
ANTIMICROBIAL ACTIVITY
Antibacterial Assay
The agar well diffusion method was followed for the screening of antibacterial
activities of the synthesized chemical compounds.[18] All the bacterial strains were
incubated at 37 ꢀC for about 48 h by inoculation in nutrient broth (Difco). The mol-
ten nutrient agar was inoculated with 100 ml of the inoculum and poured into the
Petri plate. After medium solidified, a well was made in the plates with the help of
a cup-borer (0.85 cm). The synthesized test compound was introduced into the well
and Petri plates were incubated at 37 ꢀC ꢁ 0.1 ꢀC for 48 h. The synthesized com-
pounds were dissolved in DMSO to get stock solutions. Commercial bactericide
ciprofloxacin was used as standard (100 mg per 100 ml of sterilized distilled water)
with the test samples. The diameter of inhibition zones (in mm) was determined,
and data were statistically evaluated by Tukey’s pair-wise comparison test.
Antifungal Assay
The agar well diffusion method was followed for the screening of antifungal
activities of the synthesized chemical compounds.[18] All the fungal strains were incu-
bated at 37 ꢀC for about 72 h by inoculation into potato dextrose broth (Himedia).
The molten PDA media was inoculated with 100 ml of the inoculum and poured into
the Petri plate. After medium solidified, a well was made in the plates with the help of
a cup-borer (0.85 cm). The synthesized test compound was introduced into the well
and Petri plates were incubated at 37 ꢀC ꢁ 0.1 ꢀC for 72 h. The synthesized com-
pounds were dissolved in DMSO to get stock solutions. Commercial antifungal
Nystatin was used as standard (100 mg per 100 ml of sterilized distilled water) with
the test samples. The diameter of inhibition zones (in mm) was determined, and data
were statistically evaluated by Tukey’s pair-wise comparison test. All compounds
showed comparable antimicrobial activity (Table 2).
Some compounds showed both antibacterial and antifungal activity against
Bacillus flexus (Gram-positive bacteria) and Scopulariopsis spp. respectively. The
compound 4a showed maximum antifungal activity against Scopulariopsis spp.
whereas compound 4g showed maximum antibacterial activity against Bacillus
flexus. The compound 4n showed minimal antibacterial activity and 4k showed
minimal antifungal activity. The compounds 4a, 4b, 4n, 4p, and 4r have both anti-
bacterial and antifungal activity. The compounds 4c, 4g, and 4j have only antibac-
terial activity and no antifungal activity. The compounds 4e, 4f, 4h, and 4k have
antifungal activity and no antibacterial activity. The compounds 4d, 4i, 4l, 4m, 4o,
4q, 4s, and 4u have no antibacterial (Gram-positive) or antifungal activity (Scopular-
iopsis spp.).
The compounds did not show any antibacterial and antifungal activity
with respect to Pseudomonas spp. (Gram-negative bacteria) and Aspergillus tereus
respectively.

2-AROYLBENZOFURAN-3-OLS
337
EXPERIMENTAL
Melting points were recorded in open capillaries and are uncorrected. Chemi-
cals were obtained from SD-fine and Sigma-Aldrich companies and were used with-
out further purification. The CH analysis were recorded in Elementar Vario Micro
cube and electrospray ionization–mass spectra (ESI-MS) were measured using
5-mM ammonium acetate–acetonitrile (95:5 mixture) and 5 mM acetonitrile–
ammonium acetate (5:95 mixture) as mobile phases A and B respectively by using
1
an OpenLynx ESI-LCMS spectrometer. H and 13C NMR spectra were recorded
in CDCl3 or d6-DMSO using Bruker AV-400 spectrometers and tetramethylsilane
(TMS) as an internal reference. The purity of the synthesized compounds was
demonstrated by TLC, and further purification was made with silica-gel column
chromatography. The agar well diffusion method was followed for the screening
of antibacterial and antifungal activity.[18]
Typical Procedure for the Synthesis of 2-(4-Chlorobenzoyl)-
5-bromobenzofuran-3-ol (4g) as an Example
Activated (heated at 100 ꢀC in a hot-air oven for about 24 h) K2CO3 (896.1 mg,
6.4 mmol) was added into a 100-ml, round-bottomed flask containing a stirred mix-
ture of 5-bromomethyl salicylate (500.0 mg, 2.1 mmol) and 4-chlrophenacyl bromide
(601.7, 498.0 mg, 2.1 mmol) in 10 ml of dried DMF at room temperature under nitro-
gen. The stirring was continued, and the progress of the reaction was monitored by
TLC. Most of the reactants had disappeared in about 30 min. However, the reaction
mixture was stirred for a total period of 1 h. Then, about 50 g of crushed ice were
added into the mixture and acidified with 1 N HCl. The precipitated solid was
collected by filtration and chromatographed on a silica-gel column by using 1:9,
2:8, and 3:7 mixtures of ethyl acetate and petroleum ether to get 700.0 mg of 4g
(2.0 mmol, 91%).
Spectral Data
1
White solid; mp 162–165 ꢀC; H NMR (400 MHz, CDCl3): d ¼ 7.39–7.41 (d,
J ¼ 8.8 Hz, 1H, H14), 7.53–7.55 (d, J ¼ 8.8 Hz, 2H, H3, H5), 7.64–7.67 (dd, J ¼ 10.8,
2 Hz, 1H, H13), 7.96–7.97 (d, J ¼ 2 Hz, 1H, H11), 8.31–8.33 (d, J ¼ 6.8 Hz, 2H, H2,
H6); 13C NMR (100 MHz, CDCl3): d ¼ 114.8 (C14), 116.9 (C12), 121.9 (C11), 124.5
(C13), 129.5 (C3, C5), 131.5 (C2, C6), 133.8 (C9), 134.3 (C1), 136.6 (C10), 140.5
(C4), 153.6 (C8), 156.6 (C15), 182.5 (C7); negative LC-ESI-MS, m=z: 350.97
[M-H]ꢂ. Anal. calcd. for C15H8BrClO3: C, 51.24; H, 2.29. Found: C, 51.33; H, 2.15.
By adopting the same procedure, the other 2-aroylbenzofuran-3-ols 4a–f and
4h–u were prepared. All the products (4a–u) were characterized by melting-point
analysis, 1H NMR and 13C NMR spectroscopic analyses, ESI-LCMS, and elemental
analysis.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra, and LCMS spectra can be
found via the Supplementary Content section of this article’s Web page.

338
R. S. KULKARNI ET AL.
ACKNOWLEDGMENT
The authors are thankful to the authorities of Jain University for financial
support and encouragement.
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