Indian Journal of Chemistry

Vol. 44B, August 2005, pp. 1674-1678

Synthesis and anti-inflammatory activity of 4-(5'-acetyl-6'-hydroxy -3'-methylbenzofuran-2'-yl) coumarin and 6-acetyl-3, 7-dimethyl-2-(coumarin-4'-yl)
furo [3,2-g] chromen-5-one
Manjunath Ghate* & Manohar V Kulkarni
Department of Chemistry, Karnatak University, Dharwad 580 003, India

Department of Pharmaceutical Chemistry, Krupanidhi College of Pharmacy, Koramangala, Bangalore 560 034, India
Received 19 November 2003; accepted (revised) 1 March 2005
E-mail: ghate72@yahoo.com

Various 4-bromomethylcoumarins 1 have been reacted with diacetyl resorcinol 2 to afford corresponding ethers 3,
which undergo intermolecular aldol condensation followed by dehydration to form 4-(5'-acetyl-6'-hydroxy-3'methylbenzofuran-2'-yl) coumarin 4. Further compound 4 on reaction with sodium acetate and acetic anhydride afford 6acetyl-3, 7-dimethyl-2-(coumarin 4'-yl) furo [3,2-g] chromen-5-one 5. Their structures have been confirmed by IR, NMR
and mass spectral data. Of these compounds, 4e, 4f and 5e show good anti-inflammatory and analgesic activity.
Keywords: Bromomethylcoumarins, diacetyl resorcinol, aldol condensation, chromone, anti-inflammatory activity

IPC: Int.Cl.7 C 07 D 311/00 // A 61 P 29/00

Coumarins are well-known natural products displaying a broad range of biological activities1. Most
of the synthetic coumarin derivatives have been found
to possess diverse biological activities namely anticoagulant2, spasmolytic3, anthelmintic4, diuretic5 and
anti-inflammatory6 activities. 4-Pyridyl and 4-piperidylcoumarins have been found to exhibit CNS
depresssant and analgesic activities in animal models7-9.
The halogenated furanylcoumarins show antimicrobial action10, whereas isoxazolinyl and oxadiazolyl coumarins11 inhibit enzymes like glucouronidase and 1,2-lipoxygenase. Further, 2-biheterocyclic
benzofurans with furan12, chromone13 ring systems
exhibit antibacterial, psychotropic and anti-inflammatory properties.
Recently, we have found that ether linkage with
biocompatible fragments like vanillin which were
cyclised to form benzofuranyl coumarins leads to
compounds with pronounced anti-inflammatory
activity14. In view of these observations and in continuation of our work on biheterocyclic coumarins15-17
the present paper reports the synthesis of 4-(furochromonyl)coumarin and 4-(benzofuranyl)coumarin
and their pharmacological activities. The nucleophilic
reactivity of diacetyl resorcinol has been exploited for
the synthesis of these compounds.

The basic synthetic route is outlined in Scheme I.

The required 4-bromomethylcoumarins 1 have been
synthesized by the Pechmann cyclization of various
phenols with 4-bromoethylacetoacetate. Reaction of
4-bromomethyl coumarins 1 with 2,4-diacetylresorcinol
2 in the presence of anhydrous potassium carbonate in
dry actone gives ethers 3. The ether 3 on refluxing in dry
dioxane in the presence of K2CO3 undergoes an intramolecular aldol condensation followed by dehydration
to afford 4-(5'-acetyl-6'-hydroxy-3'-methyl-benzofuran2'-yl)coumarin 4. After the reaction was completed the
product was concentrated and precipitated by pouring
into ice. The formation of benzo[b]furanylcoumarin 4
involves the generation of carbanion at the active
methylene group (4-CH2) which undergoes an
intramolecular aldol condensation via 2, 3-dihydrobenzofuran-3-ol followed by dehydration resulting in the
formation of a conjugated biheterocyclic system.
Towards the end of the subjection the compound 4
having ortho-hydroxyacetophenone moiety underwent
Kostanecki method of cyclisation in the presence of
sodium acetate and acetic anhydride to afford
6-acetyl-3,7-dimethyl-2-(coumarin-4'-yl) furo [3,2-g]chromen 5-one 5 (Table I). It is interesting to note
that the acylated product was obtained instead of
3-methylchromone. It is worthy to note that the reaction

GHATE et al.: SYNTHESIS OF 4-(FUROCHROMONYL)- AND 4-(BENZOFURANYL)-COUMARIN

H3C
HO
R
O

CH3
O

Br

OH

H3C

CH3
O

2a-f

K2 CO3
acetone, stirr

OH

O
O

O
3a-f

R
K2 CO3
Dioxane, reflux

OH

1675

CH3
H3C

(CH3CO)2 O
CH3COONa
150-160oC

CH3

O
O

CH3
H3C

5a-d

4a-f

Scheme I

did not proceed by the addition of equimolar quantity

of the acetic anhydride instead the reaction underwent
smoothly by the addition of excess amount of acetic
anhydride. IR, NMR and mass spectral data
confirmed the formation of acylated product.
Results and Discussion
The intermediates 3 (R= 6-CH3) exhibited two
bands in the IR spectrum around 1670 and 1716 cm1
that were assignable to aromatic carbonyl and lactone
carbonyl stretching, respectively. The OH stretching
vibration was observed around 3084cm-1, is due to the
intramolecular hydrogen bonding. The 1H NMR
spectrum indicated the presence of CH3 and two
COCH3 protons as a singlet at 2.44 and 2.54,
respectively. The methylene protons were observed as
singlet at 5.32, whereas the C3-H of coumarin was
found at 6.52 and the aromatic multiplet was
observed in the region at 7.27-7.50. The OH proton
was observed in the downfield region at 12.94 as
singlet, which is exchangeable with D2O (Table I).
Compound 4 (R=6-CH3) in its IR spectum exhibited lactone carbonyl stretching band at 1728 cm-1
whereas the carbonyl of acetophenone moiety was
observed at 1672cm-1 which is due to the hydrogen
bonding with orthohydroxy group. A band observed
at 3085 cm-1 was due to OH stretching vibration. The
1
H NMR spectrum indicated the presence of CH3 of
coumarin, CH3 of benzofuran and CO-CH3 of
benzofuran as a singlet at 2.49, 2.57 and 2.66,
respectively. The absence of methylene proton in the

region of 5-6 indicate that CH2 was involved in the

cyclization. The C3-H of coumarin was observed as
singlet at 6.63 and the aromatic multiplet observed
at 7-8.2. The OH proton was observed in downfield
region at 12.95 which disappeared on D2O
exchange.
Compound 5 (R=6-CH3) exhibited broad band in
the IR spectrum around 1710 and 1718 cm-1 which
was assigned to lactone carbonyl of coumarin and
chromone. The absence of OH band at the region of
3000-3400 cm-1 was indicated by the formation of
cyclised product. The 1H NMR spectrum of 5 (R=6CH3) indicated four singlets at 2.42, 2.45, 2.49 and
2.67 due to CH3 of coumarin, CH3 of benzofuran, CH3
of chromone and CO-CH3 of chromone respectively.
The C3-H of coumarins observed at 6.50, whereas
the aromatic multiplet was observed around 7.128.12. However, the absence of OH peak in the region
11-12 indicated the formation possible cyclised
product chromone 5.
Pharmacological Screening
Seven of the new compounds prepared were
screened for their pharmacological activity.
Anti-inflammatory activity
The compounds 4a, 4b, 4e, 4f, 5a, 5b, 5d were
screened for anti-inflammatory activity by the
carageenan induced edema model in rats18 using
phenylbutazone as standard. The rats were divided
into two groups of six animals. One group was kept as

INDIAN J. CHEM., SEC B, AUGUST 2005

1676

Table I Characterization data of compounds 3a-f, 4a-f and 5a-d

Calcd (Found) %
C
H

Compd

Mol.
formula

m.p.
o
C

Yield
(%)

3a

6-CH3

C21H18O6

210

78

68.75
(68.85

4.98
4.95)

2.44 (s, 3H, CH3), 2.60 (s, 6H, CO-CH3), 4.50 (s, 2H,
CH2O), 6.52 (s, 1H, C3-H of coumarin), 7.27-7.50 (m, 5H,
Ar-H), 12.94 (s, 1H, OH).

3b

7-CH3

C21H18O6

212

74

68.72
(68.85

4.84
4.95)

2.48 (s, 3H, CH3), 2.67 (s, 6H, CO-CH3), 4.49 (s, 2H,
CH2O), 6.47 (s, 1H, C3-H of coumarin), 7.10-7.63 (m, 5H,
Ar-H), 12.48 (s, 1H, OH).

3c

5,6-Benzo

C24H18O6

218

72

71.54
(71.64

4.68
4.51)

2.44 and 2.58 (s, 6H, CO-CH3), 5.32 (s, 2H, CH2O), 6.64
(s, 1H, C3-H of coumarin), 7.27-8.00 (m, 8H, Ar-H), 12.69
(s, 1H, OH).

3d

7,8-Benzo

C24H18O6

215

72

71.52
(71.64

4.76
4.51)

2.49 and 2.65 (s, 6H, CO-CH3), 5.64 (s, 2H, CH2O), 6.34
(s, 1H, C3-H of coumarin), 6.54-8.87 (m, 8H, Ar-H), 12.99
(s, 1H, OH).

3e

6-OCH3

C21H18O7

210

68

65.98
(65.96

4.82
4.74)

3.90 (s, 3H, OCH3), 2.60 (s, 6H, CO-CH3), 5.25 (s, 2H,
CH2O) 6.53 (s, 1H, C3-H of coumarin), 6.57-7.70 (m, 5H,
Ar-H), 12.76 (s, 1H, OH).

3f

6-Cl

C20H15O6Cl

235

66

62.11
(62.44

3.91
3.76)

2.62 (s, 6H, CO-CH3), 5.26 (s, 2H, CH2O) 6.38 (s, 1H, C3H of coumarin), 6.80-7.80 (m, 5H, Ar-H), 12.84 (s, 1H,
OH).

4a

6-CH3

C21H16O5

168

74

72.24
(72.41

4.55
4.63)

2.49 (s, 3H, CH3), 2.57 (s, 3H, CH3 of benzofuran), 2.66
(s, 3H, CO-CH3), 6.52 (s, 1H, C3-H of coumarin), 6.538.38 (m, 5H, Ar-H), 12.96 (s, 1H, OH).

4b

7-CH3

C21H16O5

178

74

72.49
(72.41

4.53
4.63)

2.45 (s, 3H, CH3), 2.59 (s, 3H, CH3 of benzofuran, 2.65 (s,
3H, CO-CH3), 6.42 (s, 1H, C3-H of coumarin), 6.53-8.37
(m, 5H, Ar-H), 12.93 (s, 1H, OH).

4c

5,6-Benzo

C24H16O5

185

70

74.91
(74.99

4.28
4.20)

2.53 (s, 3H, CH3 of benzofuran, 2.69 (s, 3H, CO-CH3),

6.55 (s, 1H, C3-H of coumarin), 7.17-8.27 (m, 8H, Ar-H),
13.44 (s, 1H, OH).

4d

7,8-Benzo

C24H16O5

183

70

74.78

4.16
4.20)

2.55 (s, 3H, CH3 of benzofuran, 2.62 (s, 3H, CO-CH3),

6.40 (s, 1H, C3-H of coumarin), 7.32-8.20 (m, 8H, Ar-H),
13.22 (s, 1H, OH).

(74.99

H NMR (, ppm)

4e

6-OCH3

C21H16O6

194

70

69.23
(69.14

4.43
4.55)

3.88 (s, 3H, OCH3), 2.58 (s, 3H, CH3 of benzofuran), 2.60
(s, 3H, CO-CH3), 6.53 (s, 1H, C3-H of coumarin), 6.627.37 (m, 5H, Ar-H), 12.76 (s, 1H, OH)).

4f

6-Cl

C20H15O5Cl

210

68

65.23
(65.14

3.56
3.55)

2.58 (s, 3H, CH3 of benzofuran), 2.60 (s, 3H, CO-CH3),

6.43 (s, 1H, C3-H of coumarin), 6.61-8.60 (m, 5H, Ar-H),
12.98 (s, 1H, OH).

5a

6-CH3

C25H18O6

202

72

72.48
(72.46

4.50
4.38)

2.42 (s, 3H, CH3), 2.45 (s, 3H, CH3 of benzofuran), 2.49
(s, 3H, CH3 of chromone) 2.67 (s, 3H, CO-CH3), 6.50 (s,
1H, C3-H of coumarin), 7.2-8.12 (m, 6H, Ar-H).

5b

7-CH3

C25H18O6

205

74

72.42
(72.46

4.35
4.38)

2.45 (s, 3H, CH3), 2.47 (s, 3H, CH3 of benzofuran), 2.49
(s, 3H, CH3 of chromone) 2.68 (s, 3H, CO-CH3), 6.52 (s,
1H, C3-H of coumarin), 7.12-8.25 (m, 6H, Ar-H).

5c

5,6-Benzo

C28H18O6

212

74

74.60
(74.66

4.11
4.03)

2.48 (s, 3H, CH3 of benzofuran),2.52 (s, 3H, CH3 of

chromone) 2.69 (s, 3H, CO-CH3), 6.51 (s, 1H, C3-H of
coumarin), 7.2-8.47 (m, 9H, Ar-H).

5d

7,8-Benzo

C28H18O6

222

72

74.54
(74.66

4.22
4.03)

2.48 (s, 3H, CH3 of benzofuran),2.53 (s, 3H, CH3 of

chromone), 2.70 (s, 3H, CO-CH3), 6.53 (s, 1H, C3-H of
coumarin), 7.28-8.45 (m, 9H, Ar-H).

OH signal was disappeared on D2O exchange

GHATE et al.: SYNTHESIS OF 4-(FUROCHROMONYL)- AND 4-(BENZOFURANYL)-COUMARIN

control and other as standard had received 0.5%

sodium carboxymethyl cellulose and phenylbutazone
at a dose of 100mg/kg body weight orally. Out of the
five compounds tested, three compounds showed
significant (p < 0.05) activity. Among these
compounds the compound 5a (R=6-CH3) was found
to be highly active with 62.5% edema inhibition and
compounds 4e and 4f with methoxy and chloro
groups were also found to be quite active. However,
the other compounds were found to be less active.
The edema volume and percentage inhibitions after
3hr are given in Table II.
Analgesic activity
The method was based on acetic acid induced
writhing in mice19. Group of three mice (in each
group) were administered with test compounds,
control and standard. The standard drug used was
aspirin at a dose of 100mg/kg body weight orally.
Among these compounds only three compounds 4e,
4f and 5a showed significant activity compared to
standard phenylbutazone. However, other compounds
were found to be less active compared to the standard.
Compound 4e having the methoxy substitution in the
6th position of coumarin ring was found to be more
active (62.5%) among all these compounds. The
percentage writhing inhibitions in 15 min are given in
Table II Anti-inflammatory activity of the compounds 4a,
4b, 4e, 4f, 5a, 5b and 5d
Group

Compd

Edema volume
(mL) SD after
3hr

1677

Table III.
Experimental Section
The melting points were determined in open
capillaries and are uncorrected. The IR spectra were
recorded on a Thermo Nicolet spectrometer; and
1
H NMR on a Bruker Varian 300 MHz in
CDCl3+DMSO-d6.
Preparation of 4-[(2',4'-diaacetyl-5'-hydroxy)phenoxymethyl]coumarins 3. A mixture of equimolar quantity of diacetyl resorcinol (0.004 mole,
0.53 g) and substituted 4-bromomethylcoumarins
(0.004 mole, 1 g) was stirred for 10 hr in the presence
of potassium carbonate (0.5 g) in dry acetone. The
reaction was carried out in dry condition fitted with a
guard tube. The reaction mixture was concentrated
and poured onto crushed ice. The solid separated was
filtered and washed with 10% HCl and twice with 100
mL of water. A white coloured solid thus obtained,
was dried and recrystallised from dioxane-alcohol
mixture to get 3 (Table I).
Preparation
of
4-(5'-acetyl-6'-hydroxy-3'methyl-benzofuran-2'-yl)coumarin 4. Equimolar
quantity of compound 3 and anhydrous potassium
carbonate was refluxed in dry dioxane for 24 hr. The
excess dioxane was removed under reduced pressure
and the reaction mixture was poured into crushed ice.
The solid separated was filtered and washed with dil.
Table III Analgesic activity of compounds 4a, 4b, 4e, 4f,
5a, 5b and 5d

Edema
inhibition in
(%)

Group

Compd

No. of
writhing in15
minutes

Writhing
inhibition in
(%)

4a

0.400.04

4.7

4a

629

8.8

4b

0.320.04

23.8

4b

618

10.2

4e

0.180.05

57.1*

4e

418

36.9*

4f

0.180.04

58.1*

4f

465

32.3*

5a

0.150.04

62.5*

5a

459

30.7*

5b

0.290.04

25.6

5b

507

26.4

5d

0.260.05

33.3

5d

4810

28.4

Control

0.420.03

Control

688

Phenylbutazone

0.130.04

69.0*

Phenylbutazone

2817

58.8*

SD: Edema volume measured 3 hr after carageenan injection

SD: No. of writhes in 15 minutes beginning 5minutes after

and expressed as mean standard deviation.

* Statistically significant (p<0.05 Mann Whitney).

acetic acid injection, and expressed as std deviation

* Statistically significant (p<0.05 student "t" test).

1678

INDIAN J. CHEM., SEC B, AUGUST 2005

HCl (10%) and finally with water and dried.

Recrystallisation was done in dioxane to get 4
(Table I).
Preparation of 6-acetyl-3, 7-dimethyl-2-(coumarin-4'-yl) furo [3, 2-g] chromen-5-one 5. A
mixture of benzo furanyl coumarins 2 (0.5 g), sodium
acetate (1 g) and acetic anhydride (1 mL) was
refluxed at 150-60oC for 3 hr. The reaction mixture
was poured onto crushed ice, stirred and left
overnight. The separated product was filtered and
washed with water and dried in vacuo. It was
recrystallised from dioxane to get 5 (Table I).
Conclusion
The new series of coumarinyl furochromones 5
were prepared from benzofuranylcoumarins 4. Some
of these compounds were tested for their analgesic
and anti-inflammatory activities in animal models. It
is evident from the animal experiments that
compounds 4e, 4f and 5a showed very significant
anti-inflammatory and analgesic activities. However,
other compounds were moderately less active.
Acknowledgement
Authors are thankful to the Chairman, Department
of Chemistry, Karnatak University, Dharwad and to
Prof. Amit Kumar Das, Principal, Krupanidhi College
of Pharmacy, Bangalore.
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