Photochemical synthesis and antimicrobial screening of some substituted dihydrobenzofurans

Article abstract of DOI:10.1007/s11164-012-0555-4

Dihydrobenzofurans containing carbomethoxy-ethenyl at 2-position and phenyl and hydroxyl at 3-position were synthesized by photochemical methods and screened for antibacterial activity. These dihydrobenzofurans were moderately active against bacteria, bot

Full text of DOI:10.1007/s11164-012-0555-4

Res Chem Intermed
DOI 10.1007/s11164-012-0555-4
Photochemical synthesis and antimicrobial screening
of some substituted dihydrobenzofurans
•
K. Ravi K. Selvam M. Swaminathan
•
Received: 15 February 2012 / Accepted: 3 April 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Dihydrobenzofurans containing carbomethoxy-ethenyl at 2-position and
phenyl and hydroxyl at 3-position were synthesized by photochemical methods and
screened for antibacterial activity. These dihydrobenzofurans were moderately active
against bacteria, both Gram-positive (Staphylococcus aureus) and Gram-negative
(Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa), while compound
3-(6-chloro-3-hydroxy-3-phenyl-2,3-dihydrobenzofuran-2-yl)acrylic acid methyl ester
showed promising activity against both the Gram-positive and Gram-negative bacteria.
Keywords Photochemical synthesis Á Substituted dihydrobenzofurans Á
Antimicrobial screening
Introduction
The photochemical studies and synthesis of phenoxy ethers of 2-hydroxybenzophe-
nones, the photosubstrates for construction of benzofuran moieties have received
significant attention due to their useful properties, and it has been shown that these
molecules are good precursors for the effective synthesis of substituted benzofurans
systems [1–8]. 2-Allyloxy-5-chloro-benzophenone has been shown to possess a
parasiticide effect against Tetranychus bimaculatus [9]. A detailed literature survey
on the synthesis and application of various ethers of substituted 2-hydroxybenzo-
phenone systems reveals that these molecules find extensive applications in
pharmaceutical [7] and pesticide industries and also as triplet sensitizers [10–15].
Certain benzophenone derivatives are useful as anticancer agents [16]. A recent
report shows that some compounds prepared using ethers of substituted 2-hydroxy-
benzophenone are useful as inhibitors of both wild-type and mutant variants of HIV
K. Ravi Á K. Selvam Á M. Swaminathan (&)
Department of Chemistry, Annamalai University, Annamalainagar, 608 002 Tamilnadu, India
e-mail: chemres50@gmail.com
123

K. Ravi et al.
reverse transcriptase [17, 18]. In this communication, we report a novel synthesis of
some substituted dihydrobenzofurans containing carbomethoxyethenyl moiety,
which are used as building blocks in the synthesis of drugs and drug intermediates,
by irradiation of hitherto unreported four methyl crotonate esters of substituted
2-hydroxybenzophenones.
Experimental
1
All solvents and reagents used were of laboratory grade. H NMR and 13C NMR
spectra were recorded on a Bruker 500 MHz instrument with TMS as internal
standard and CDCl3 as solvent. IR spectra were recorded on a Perkin Elemer FT-IR
instrument. Mass analysis was performed using JEOL GC mate under EI? mode.
HPLC analysis was done using Shimadzu analytical HPLC on C18 column.
Synthesis of 4-(2-benzoylphenoxy)-2-butenoic acid methyl esters
Eighty millilitres of anhydrous dimethylsulfoxide was placed in a dry 500-mL RB
flask. Potassium carbonate (36 g, 0.26 mol) was added and the contents were stirred
at room temperature. To this mixture, 5-chloro-2-hydroxybenzophenones (20 g,
0.086 mol) was added and stirred at room temperature. 4-Bromomethylcrotonate
(36 g, 0.17 mol, 85% pure) was added slowly over a period of 15–20 min. The
contents were stirred for 4–6 h under ambient conditions. Inorganic solids were
separated by filtration and the filtrate was quenched with ice water (320 mL) and
then extracted with dichloromethane. The organic extract was washed thrice with
water and then dried over anhydrous sodium sulfate and concentrated under vacuum
to get an oily residue. This was leached with hexane (\10 °C) until a solid mass
separated. The solid mass was separated by filtration and washed with ice cold
hexane and dried under vacuum. These compounds were further purified by silica
gel chromatography column using a mixture of hexane and ethyl acetate (96:4).
Synthesis of 2,3-dihydrobenzofurans
Amounts of 1 9 10-3 mol of the respective esters in benzene were photolyzed in a
Heber immersion type photoreactor model HIPR-LP 6/8/116 (150 mL capacity) at
365 nm for 4–6 h. Reaction was followed by TLC using hexane and ethyl acetate as
mobile phase and by HPLC. After complete consumption of starting esters, solution
was concentrated using vacuum evaporator and purified by silica gel chromatog-
1
raphy. Structures of the products were established by H and 13C NMR spectra.
Compound 1a
1
Pale cream solid, m.p (°C) 86–87; H NMR (CDCl3): d (ppm) 6.86–7.80 (m, 8H,
aromatic), 6.76–6.84 (td, 1H, –OCH2–CHa=CH–, Jab = 15.6 Hz), 5.49–5.56 (td,
1H, –CH=CHb–COOMe, Jab = 15.6 Hz), 4.48–4.60 (q, 2H, –OCH2–CH=CH–),
3.69 (s, 3H, COOCH3); 13C NMR (CDCl3): d (ppm) 194.68 (Ar–C–O–Ar), 166.23
123

Photochemical synthesis and antimicrobial screening
(–COOCH3), 154.28 (C1), 140.96 (–OCH2–CH=CH–), 126.74–137.47 (8 signals,
aromatic carbons), 121.44 (–CH=CH–COOMe), 113.97 (C6), 67.17 (–OCH2–
CH=CH–), 51.61 (–COOCH3); IR (KBr): m (cm-1) 1,718 (–C=O–OCH3), 1,652
(Ar–C=O–Ar).
Compound 1b
1
Pale cream solid, m.p (°C) 67–68; H NMR (CDCl3): d (ppm) 6.84–7.82 (m, 8H,
aromatic), 6.78–6.84 (td, 1H, –CH2–CHa=CH–, Jab = 15.6 Hz), 5.49–5.54 (td, 1H,
–CH=CHb–COOMe, Jab = 16.05 Hz), 4.56–4.58 (q, 2H, –OCH2–CH=CH–), 3.69
(s, 3H, COOCH3), 2.34 (s, 3H, CH3–Ar); 13C NMR (CDCl3): d (ppm) 196.57
(Ar–C=O–Ar), 166.42 (–COOCH3), 153.73 (C1), 141.73 (OCH2–CH=CH–),
128.30–138.22 (8 signals, aromatic carbons), 121.02 (–CH=CH–COOMe), 112.60
(C6), 66.95 (–OCH2–CH=CH–), 51.54 (–COOCH3), 20.38 (CH3–Ar); IR (KBr):
m (cm-1) 1,710 (–C=O–OCH3), 1,638 (Ar–C=O–Ar).
Compound 1c
Pale cream solid, m.p (°C) 108–109; 1H NMR (CDCl3): d (ppm) 6.94–7.80 (m, 8H,
aromatic), 6.79–6.83 (td, 1H, –OCH2–CHa=CH–, Jab = 16.0 Hz), 5.50–5.53 (td,
1H, –CH=CHb–COOMe, Jab = 16.0 Hz), 4.46–4.61 (q, 2H, –OCH2–CH=CH–),
3.70 (s, 3H, COOCH3); 13C NMR (CDCl3): d (ppm) 195.16 (Ar–C=O–Ar), 166.21
(–COOCH3), 156.43 (C1), 140.60 (OCH2–CH=CH–), 127.59–137.90 (aromatic
carbons), 121.72 (–CH=CH–COOMe), 121.44 (C2 and C4), 113.17 (C6), 66.99
(–OCH2–CH=CH–), 51.62 (–COOCH3); IR (KBr): m (cm-1) 1,716 (–C=O–OCH3),
1,655 (Ar–C=O–Ar).
Compound 1d
1
Pale yellow solid, m.p (°C) 68–69; H NMR (CDCl3): d (ppm) 6.86–7.81 (m, 8H,
aromatic), 6.78–6.81 (td, 1H, –OCH2–CHa=CH–, Jab = 15.5 Hz), 5.50–5.53 (td,
1H, –CH=CHb–COOMe, Jab = 16.0 Hz), 4.52–4.53 (d, 2H, –OCH2–CH=CH–),
3.78 (s, 3H, COOCH3), 3.67 (s, 3H, CH3O–Ar); 13C NMR (CDCl3): d (ppm)
196.03 (Ar–C=O–Ar), 166.40 (–COOCH3), 154.15 (C1), 149.87 (C4), 143.19
(OCH2–CH=CH–), 128.34–137.93 (5 signals, aromatic carbons), 120.97 (–CH=
CH–COOMe), 114.40–117.70 (C3, C5 and C6), 67.71 (–OCH2–CH=CH–), 55.82
(CH3O–Ar), 51.52 (–COOCH3); IR (KBr): m (cm-1) 1,719 (–C=O–OCH3), 1,660
(Ar–C=O–Ar).
Compound 2a
1
Off white powder, m.p (°C) 118–122; H NMR (CDCl3): d (ppm) 7.02–7.06 (1H,
–OCH–CHa=CH–, Jab = 16.0 Hz), 6.94–7.43 (m, 8H, aromatic), 6.20–6.23 (dd,
1H, –CH=CHb–COOMe, Jab = 16.0 Hz), 5.12–5.13 (dd, 1H, –OCH–), 3.76 (s, 3H,
COOCH3); 13C NMR (CDCl3): d (ppm) 166.07 (–COOCH3), 156.43 (C8), 140.69
(C10), 139.12 (OCH–CH=CH–), 123.72–133.92 (aromatic carbons), 112.10 (C7),
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K. Ravi et al.
92.91 (C3), 83.38 (C2), 51.82 (–COOCH3); IR (DCM): m (cm-1) 3,415 (–OH), 1,697
(–C=O–OCH3); MS (EI): m/z 330.9.
Compound 2b
1
Off white powder, m.p (°C) 106–110; H NMR (CDCl3): d (ppm) 7.02–7.05 (1H,
–OCH–CHa=CH–, Jab=17.0 Hz), 6.80–7.44 (m, 8H, aromatic), 6.11–6.15 (dd, 1H,
–CH=CHb–COOMe, Jab = 19.5 Hz), 4.99 (bs, 1H, –OCH–), 3.66 (s, 3H,
COOCH3), 2.18 (s, 3H, CH3); 13C NMR (CDCl3): d (ppm) 166.12 (–COOCH3),
157.39 (C8), 141.45 (C10), 139.94 (OCH–CH=CH–), 123.05–132.34 (aromatic
carbons), 110.24 (C7), 92.51 (C3), 83.41 (C2), 51.82 (–COOCH3), 20.62 (CH3); IR
(DCM): m (cm-1) 3,467 (–OH), 1,707 (–C=O–OCH3); MS (EI): m/z 310.0.
Compound 2c
1
Off white powder, m.p (°C) 138–142; H NMR (CDCl3): d (ppm) 7.01–7.04 (1H,
–OCH–CHa=CH–, Jab = 16.0 Hz), 6.96–7.49 (m, 8H, aromatic), 6.20–6.23 (dd,
1H, –CH=CHb–COOMe, Jab = 16.0 Hz), 5.12–5.13 (dd, 1H, –OCH–), 3.77 (s, 3H,
COOCH3); 13C NMR (CDCl3): d (ppm) 166.07 (–COOCH3), 160.35 (C8), 140.93
(C10), 139.12 (OCH–CH=CH–), 122.41–136.48 (8 signals, aromatic), 111.68 (C7),
93.13 (C3), 82.97 (C2), 51.83 (–COOCH3); IR (DCM): m (cm-1) 3,415 (–OH), 1,697
(–C=O–OCH3); MS (EI): m/z 330.1.
Antibacterial activity
All the synthesized compounds 1a–1d and 2a–2c were evaluated for their antibacterial
activity against the pathogenic strains viz., Staphylococcus aureus, Escherichia coli,
Klebsiella pneumoniae, and Pseudomonas aeruginosa by the disc diffusion method.
Filter discs of 7 mm diameter were prepared and sterilized. Using ethanol dipped and
flamed forceps, these discs were aseptically placed over nutrient agar plates seeded
with the respective test microorganisms. One hundred microliters of the various
compound solutions (100%) were aseptically transferred to these discs. The plates
were incubated in an upright position at 37 °C for 24 h. The diameter of inhibition
zones were measured in mm and the results were recorded. Inhibition zones with
diameter less than 8 mm were considered as having no antibacterial activity. Diameter
between 8 and 12 mm were considered moderately active, and those with[12 mm
were considered highly active. All the media used in the present investigation were
obtained from Hi-Media Laboratories, Mumbai, India.
Results and discussion
Four methyl crotonate esters, viz., 4-(2-benzoylphenoxy)-2-butenoic acid methyl
esters, were synthesized by treating the corresponding substituted 2-hydroxyben-
zophenone with 4-bromomethyl-crotonate in presence of K2CO3 in DMSO at room
temperature (Scheme 1). The progress of the reaction was monitored by TLC using
123

Photochemical synthesis and antimicrobial screening
O
COOCH3
OH
R
R
COOCH3
O
O
DMSO/K2CO3
RT, 4–6 h
+
Br
a−d
1a−1d
Scheme 1 Synthesis of 4-(2-benzoylphenoxy)-2-butenoic acid methyl esters
Table 1 Yield of substituted
4-(2-benzoyl-phenoxy)-2-
butenoic acid methyl esters
Substituted
2-hydroxybenzophenone
Ester
Yield (%)
5-Cl (a)
1a
1b
1c
1d
77
55
70
73
5-Me (b)
4-Cl (c)
5-OMe (d)
16
7
4
6
O
COOCH3
O
COOCH3
8
9
6
5
5
1
1
2
17
R
R
4
O
3
2
OH
11
h
ν
7
3
10
8
15
14
Benzene
365 nm
13
12
9
12
10
13
11
1a−1d
2a−2c
Scheme 2 Synthesis of 2,3-dihydrobenzofurans
hexane:ethylacetate (85:15) as mobile phase. The TLC analysis reveals that there
are no starting materials, i.e., 2-hydroxybenzophenones, after 4–6 h. The results are
compiled in Table 1.
Irradiation of these esters in benzene (10-3 mol) at room temperature under
nitrogen atmosphere at 365 nm for 6 h resulted in complete conversion of the
starting material. On usual workup, almost a quantitative yield was obtained as a
thick viscous oil, and purification by silica gel column chromatography using
hexane and ethyl acetate gave the respective substituted 2,3-dihydrobenzofuran
(Scheme 2). Their yields are presented in Table 2.
The substituted dihydrobenzofurans and their starting photo substrate were
characterized by spectral data. The IR spectrum, recorded as KBr pellets, revealed
that the absorption bands observed at 1,640–1,660 cm-1 (benzophenone carbonyl)
in the esters are not found with the isolated 2,3-dihydrobenzofurans, and the band
1
observed at 3,413–3,467 cm-1 (–OH) is not found in the starting esters. The H
NMR spectrum recorded in CDCl3 solvent for the esters showing a signal at
4.53–4.60 ppm (–OCH2–) is absent and a new signal at 5.1–5.2 ppm (–OCH–) is
observed for the cyclized product. Up-field shifts for olefinic protons are observed at
Ha
Ha
COOMe
COOMe
6.2–6.3 ppm Hb
Ha
and at 7.0–7.1 ppm Ha
Ha
against 5.5–5.6 ppm Hb
COOMe . Signals in the region of 6.8–7.5 ppm are
Hb
Hb
OH2C
OH2C
COOMe
and at 6.67–6.80 ppm Ha
Hb
Hb
OH2C
OH2C
123

K. Ravi et al.
Yield (%)
Table 2 Yield of substituted
2,3-dihydro-benzofurans
Photosubstrate
Benzofuran
1a
1b
1c
1d
2a
60
55
80
–
2b
2c
No reaction
due to aromatic protons. The signal observed at 7.8 ppm (aromatic ortho protons to
–C=O group) is absent with the photolyzed product. The 13C NMR spectrum of
these photolyzed product also revealed the absence of benzophenone carbonyl at
195–196 ppm as observed with the starting esters, thereby indicating cyclization
through 1,5-biradical formation and d hydrogen abstraction. No major changes
for signals of ester carbonyl at 166 ppm and for olefinic carbons at 140.96 ppm
Ha
Ha
COOMe
COOMe , and 121 ppm C–Hb
are observed. The 1H NMR spectrum for
C
C
C C
C–Ha
Hb
Hb
OH2
C
OH2C
these compounds shows the signals for the olefin protons with a coupling constant
of 15–16 Hz corresponding to trans geometry. However, compound 1d failed to
undergo cyclization under these conditions and the starting material recovered
almost quantitatively.
All the synthesized compounds 1a–1d and 2a–2c were evaluated for their
antibacterial activity against the pathogenic strains, viz., Staphylococcus aureus,
Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa by the disc
diffusion method. Streptomycin was used as a standard drug whose minimum inhibitory
concentration values are furnished in Table 3. Substituted benzofuran compounds 3-(5-
chloro-3-hydroxy-3-phenyl-2,3-dihydrobenzofuran-2-yl)acrylic acid methyl ester (2a),
3-(5-methyl-3-hydroxy-3-phenyl-2,3-dihydrobenzofuran-2-yl)acrylicacidmethylester
(2b), and 3-(6-chloro-3-hydroxy-3-phenyl-2,3-dihydrobenzofuran-2-yl)acrylic acid
methyl ester (2c) are more active (15 mm) against the pathogenic strains than the
substituted acetophenone derivatives 4-(2-benzoyl-4-chlorophenoxy)but-2-enoic acid
methyl ester (1a), 4-(2-benzoyl-4-methylphenoxy)but-2-enoic acid methyl ester (1b),
Table 3 Activity of substituted esters and benzofurans
Compound
Mean inhibition zone in mm
S. aureus
E. coli
K. pneumoniae
P. aeruginosa
1a
–
8
10
8
8
8
8
8
1b
1c
12
12
12
14
15
50
14
12
13
10
15
12.5
10
8
12
8
1d
2a
8
8
2b
8
8
2c
Streptomycin (MIC) in lg mL-1
14
50
12
25
\8 mm inactive, 8–12 mm moderate; [12 mm active. Experimental error 0.1 mm
123

Photochemical synthesis and antimicrobial screening
4-(2-benzoyl-5-chlorophenoxy)-but-2-enoicacidmethylester(1c), and 4-(2-benzoyl-4-
methoxyphenoxy)but-2-enoic acid methyl ester (1d).
It is inferred from Table 3 that compounds having electron withdrawing
substituents (1a, 1c, 2a, 2c) showed better activity (12–15 mm) against the strains
used than the compounds with electron releasing substituents (1b, 1d, 2b).
Especially, 1c was more potent against E. coli (14 mm), S. aureus, and
P. aeruginosa (12 mm). When 4-chloro substitution at the aryl ring was changed
into the C-5 position of the aryl ring, then the compound 1a exhibited moderate
activity against E. coli and it completely eliminated the antibacterial activity against
S. aureus. The same trend was observed for benzofuran derivatives (2a–2c), i.e., the
compound 2c exhibited superior activity against S. aureus, E. coli, and K. pneu-
moniae ([12 mm) and moderate activity was observed against P. aeruginosa
compared with the compound 2a. This observation reveals that the position of the
substituent also affects the microbial activity of the target compounds.
Conclusion
Photochemical synthesis of pharmacologically important and biologically active
dihydrobenzofurans containing carbomethoxyethenyl moity from hitherto unre-
ported 4-(2-benzoylphenoxy)-2-butenoic acid methyl esters is reported by a simple
procedure. 3-(6-chloro-3-hydroxy-3-phenyl-2,3-dihydrobenzofuran-2-yl)acrylic acid
methyl ester showed promising activity against both the Gram-positive and Gram-
negative bacteria. Further work on the synthesis of cyclopropyl derivatives of
crotonate esters is under progress in our laboratory.
Acknowledgment One of the authors, K. Selvam, is thankful to CSIR, New Delhi for the award of
Senior Research Fellowship.
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