First synthesis of furo[3,4-c]coumarins

Article abstract of DOI:10.1002/jhet.5570430643

Various 1,3-dimethyl and 1-methyl-3-phenylfuro[3,4-c]coumarins (5a-h and 6a-h) have been synthesized by demethylation cyclization of the respective 3-aryl-4-ethoxycarbonyl furans (3a-h and 4a-h). These ethoxycarbonyl furans were prepared by reacting appro

Full text of DOI:10.1002/jhet.5570430643

Nov-Dec 2006
First Synthesis of Furo[3,4-c]coumarins
1699
Dinker I. Brahmbhatt*, Jitendra M. Gajera, Chirag N. Patel, Vishwesh P. Pandya
and Urvish R. Pandya
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar-388 120, Gujarat, India.
Tel.: +91-2692-226855/56, Fax: +91-2692-236475
E-mail: dib.chem@spu.ernet.in
Received January 23, 2006
O
O
OMe
CHO
R
R
R'
3
steps
O
Me
Various 1,3-dimethyl and 1-methyl-3-phenylfuro[3,4-c]coumarins (5a-h and 6a-h) have been
synthesized by demethylation cyclization of the respective 3-aryl-4-ethoxycarbonyl furans (3a-h and 4a-h).
These ethoxycarbonyl furans were prepared by reacting appropriate 1-aryl-2-nitro-prop-1-ene (1a-h) with
ethyl acetoacetate or ethyl benzoylacetate under Nef reaction condition.
J. Heterocyclic Chem., 43, 1699 (2006).
Introduction.
interest. Very recently, synthesis, natural occurrence
and biological activity of furocoumains have been
reviewed [11].
Coumarins (2H-1-benzopyran-2-ones) are best known
as aromatic lactones isolated from variety of plant
sources [1]. Owing to their diverse bioactivities viz.
anticoagulant [2], antibacterial, and antifungal [3] etc.
many natural, semi synthetic and synthetic coumarins
have become important class of molecules in drug
research. In this direction, several biological activities
have been claimed for compounds comprising both
coumarins and coumarins fused to a heterocyclic ring.
As the name suggests, these compounds are based on a
skeleton formed by fusion of a furan ring to coumarin
unit. Among furocoumarins if one restricts the fusion of
furan ring with the lactone ring of coumarin, three
structural isomers; furo[2,3-c] (I), furo[3,2-c] (II) and
furo[3,4-c] (III) are possible (Figure 1). In literature a
large number of reports are documented for the synthesis
of furo[2,3-c] and furo[3,2-c] coumarins [12-20], however
the synthesis of furo[3,4-c]coumarin to our knowledge
has not been reported except for a single report on a
saturated skeletal analog of furo[3,4-c]coumarin [21].
Hence in continuation of our interest in heterocyclic fused
coumarins [20,22-24] it was thought worthwhile to
envisage a synthetic route to such novel molecules.
Therefore in the present work we report the first synthesis
of various 1,3-dimethyl and 1-methyl-3-phenyl-furo[3,4-
c]coumarins (5a-h and 6a-h).
Among
the
heterocyclic
fused
coumarins,
furocoumarins are one of the important derivatives.
Numbers of furocoumarins are naturally occurring and
show a wide range of biological properties, the most
prominent of which is the photobiological effects it that
can exert upon irradiation with long-wavelength UV
light. Thus many furocoumarins are potent
photosensitizers to human skin with valuable
application in medicine especially for the treatment of
skin diseases [4-6]. Many furocoumarins are recorded to
have phototoxic effects to insects, fungi, viruses and
bacteria [7-10]. Owing to the natural occurrence and
varied biological activities, the synthesis of
furocoumarins has remained a subject of an active
Results and Discussion.
Our strategy for the synthesis of 5a-h and 6a-h was
based on the straight-forward disconnection illustrated
in Scheme 1.
O
O
O
O
2
O
O
c
3
5
c
3
c
2
4
4
3
O
2
O
O
5
4
5
(I)
(II)
(
III)
Furo[2,3-c]coumarin
Furo[3,2-c]coumarin
Furo[3,4-c]coumarin
Figure - 1

1
700
D. I. Brahmbhatt, J. M. Gajera, C. N. Patel, V. P. Pandya and U. R. Pandya
Vol 43
Scheme - 1
O
O
OMe
CO Et
OMe
CO Et
2
2
+
R
R
O
R
O
O
NO2
Scheme - 2
R1
R
1
R2
OMe
R
2
OMe
O
Piperidine
CO Et
2
+
R
3
OEt
MeOH
R3
R
R4
R4
O
Me NO
O
R
2
Me
3a-h (R = CH3)
a-h (R = Ph)
1
a-h
2
4
R = CH , Ph
3
R
1
R1
R
R
2
OMe
CO
R2
R3
O
O
2
Et
HBr/AcOH
3
R
R
R4
R4
O
O
Me
Me
3
a-h (R = CH
3
)
5a-h (R = CH
3
)
4a-h (R = Ph)
6a-h (R = Ph)
a
: R
1
: R
1
: R
1
: R
1
: R
1
: R
1
: R
1
: R
1
= R
= R
= R
= R
= R
= R
= R
= R
2
3
2
2
2
3
2
2
= R
= R
= R
= R
= R
3
4
4
4
4
= R
= H, R
= H, R
= H, R
= H, R
4
= H
= OCH
3
b
c
d
e
f
2
3
= CH
= Cl
= Br
= H
3
3
3
= Br, R
= R = H, R
= H, R + R
2 4
= R
g
h
4
3
= NO
4
= Benzo
2
3
Table I
Characterization of Compounds 5a-h and 6a-h
Found (Cal.)
mp
Yield
%)
NMR
(ꢀ, ppm)
Compd.*
Mol. Formula
(
% C
72.9
% H
% N
5
5
5
5
5
a
b
c
d
e
C
C
C
13
14
14
H
H
H
10
12
12
O
O
O
3
4
3
175
168
155
183
191
246
208
225
176
50
50
60
55
50
50
65
50
55
4.7
4.6)
5.0
--
--
--
--
--
--
--
--
--
2
.61 & 2.65 (6H, 2 x s, 2 x CH3), 7.0-7.6 (4H, m, Ar-H)
(
72.8
68.9
2.65 & 2.75 (6H, 2 x s, 2 x CH3), 4.05 (3H, s, OCH3), 6.8-7.5
(3H, m, Ar-H)
(
68.8
4.9)
5.3
73.7
2
2
2
2
2
2
2
.58 & 2.64 (9H, 2 x s, 2 x CH3), 6.8-7.7 (3H, m, Ar-H)
.59 & 2.64 (6H, 2 x s, 2 x CH3), 6.9-7.6 (3H, m, Ar-H)
.6 & 2.64 (6H, 2 x s, 2 x CH3), 6.9-7.8 (3H, m, Ar-H)
.7 & 2.75 (6H, 2 x s, 2 x CH3), 7.67 (2H, m, Ar-H)
.6 & 2.7 (6H, 2 x s, 2 x CH3), 7.1-8.6 (3H, m, Ar-H)
.6 & 2.65 (6H, 2 x s, 2 x CH3), 7.1-8.6 (6H, m, Ar-H)
.7 (3H, s, CH3), 7.1-8.6 (9H, m, Ar-H)
(
73.6
5.2)
3.7
C
13
H
9
ClO
BrO
Br
NO
3
3
62.8
(
62.7
3.6)
3.1
13 9
C H
53.3
(
53.2
3.0)
2.2
--
--
5
f
C
13
H
8
2
O
3
42.0
(
41.9
2.1)
3.5
--
5.5
5.4)
--
5g
5h
6a
C
13
H
9
5
60.3
(
60.2
3.4
C
17
H
12
12
O
O
3
77.3
4.6
(
77.2
4.5)
4.1
--
C
18
H
3
78.1
--
(
78.2
4.3)
--

Nov-Dec 2006
First Synthesis of Furo[3,4-c]coumarins
1701
Table I (Continued)
Found (Cal.)
mp
Yield
%)
NMR
(ꢀ, ppm)
Compd.*
Mol. Formula
(
% C
74.3
% H
% N
6b
6c
6d
6e
C
19
19
H
H
14
14
O
O
4
3
180
204
195
208
195
198
210
53
63
57
60
62
52
59
4.3
--
2
2
2
2
2
2
2
.7 (3H, s, CH3), 3.9 (3H, s, OCH3), 6.9-8.0 (8H, m, Ar-H)
.4 & 2.7 (6H, 2 x s, 2 x CH3), 7.0-8.6 (8H, m, Ar-H)
.7 (3H, s, CH3), 7.2-8.4 (8H, m, Ar-H)
(
74.5
4.6)
4.7
--
--
C
78.5
(
78.6
4.8)
3.4
--
--
C
18
H
H
11ClO
11BrO
3
3
69.6
(
69.5
3.5)
3.0
--
C
18
60.5
--
.7 (3H, s, CH3), 7.1-8.3 (8H, m, Ar-H)
(
60.8
3.1)
2.4
--
6
f
C
18
H
10Br
2
O
3
49.6
--
.7 (3H, s, CH3), 7.2-8.3 (7H, m, Ar-H)
(
49.8
2.3)
3.2
--
6
6
g
h
C
18
H
11NO
5
67.1
4.2
4.3)
--
.7 (3H, s, CH3), 7.1-8.4 (8H, m, Ar-H)
(
67.3
3.4
4.5
C
22
H
14
O
3
80.7
.7 (3H, s, CH3), 7.1-8.5 (11H, m, Ar-H)
(
80.9
4.3)
--
-
1
*
All compounds exhibit IR frequency bands at ~1735 (ꢀ-lactone carbonyl of coumarin), ~1121 cm (furan –C–O–C– stretching).
Thus title compounds (5a-h and 6a-h) have been
synthesized by demethylation-cyclization reaction of the
intermediates, 3-substituted-4-ethoxycarbonyl furans (3a-
h and 4a-h). These furans (3a-h and 4a-h) were obtained
by the base catalyzed Nef reaction [25,26] of correspon-
ding 1-aryl-2-nitro-prop-1-ene (1a-h) with either ethyl-
acetoacetate or ethyl benzoyl acetate in refluxing
methanol containing catalytic amount of piperidine
Synthesis of Ethoxycarbonyl Furan derivatives (3a-h and 4a-h).
General Procedure.
To a well-stirred solution of the appropriate 1-aryl-2-nitro-prop-1-ene
(1, 0.02 mole) in 40 mL of methanol, 3-4 drops of piperidine were added
at room temperature. To this ethyl acetoacetate or ethyl benzoyl acetate
(0.02 moles) was added dropwise with stirring. The reaction mixture
was then refluxed for 4 hrs. Excess of methanol was then removed and
the residue was poured into water. It was then extracted with chloroform
(3 x 30 mL). The chloroform extract was washed with dil. HCl and
(
Scheme – 2). The starting materials (1a-h) were prepared
water successively. It was then dried over anhydrous sodium sulphate.
Removal of chloroform gave a viscous residue which was subjected to
column chromatography using silica gel as an absorbent and hexane-
toluene (1:1) as an eluent to afford the furans as thick oils.
using literature procedure [27].
For the demethylation and in situ lactonization step
several reagents where tried, of which, pyridine hydro-
chloride and HBr in acetic acid were found promising.
However, owing to the highly hygroscopic nature of
pyridine hydrochloride and elevated reaction temperatures
required, HBr in acetic acid was finally chosen as the
reagent of choice to afford the title compounds in moderate
to good yields (Table – 1). Structures of all the compounds
synthesized (3/4a-h and 5/6a-h) have been supported by
elemental and spectral data.
All compounds exhibit IR frequency bands at 1720 (C=O
stretching of carbethoxy group), 1121 (furan –C–O–C–
-1
stretching), 3020 cm (aromatic C-H stretching).
Compound 3a: Yield: 40%, Found
C
C
C
68.9%; H 6.5%
67.2%; H 6.5%
70.7%; H 6.8%
C H O required C 70.1%; H 6.6%.
1
6
18
4
Compound 3b: Yield: 35%, Found
C H O required C 67.1%; H 6.6%.
17 20
5
Compound 3c: Yield: 35%, Found
C H O required C 70.8%; H 6.9%.
1
7
20
4
Compound 3d: Yield: 40%, Found C 62.1%; H 5.4%
C H ClO required C 62.2%; H 5.5%.
1
6
17
4
Compound 3e: Yield: 42%, Found C 54.3%; H 4.7%
C H BrO required C 54.4%; H 4.8%.
EXPERIMENTAL
1
6
17
4
Compound 3f: Yield: 40%, Found C 44.3%; H 3.6%
C H Br O required C 44.4%; H 3.7%.
All Melting points are in degree centigrade and are
1
6
16
2
4
uncorrected. IR spectra were recorded in KBr on a Nicolet 400D
Compound 3g: Yield: 35%, Found C 60.1%; H 5.2%; N
4.3% C H NO required C 60.2%; H 5.3%; N 4.4%.
1
spectrophotometer and H NMR in CDCl on Hitachi R-1500,
3
1
6
17
6
6
0 MHz spectrometer using TMS as an internal standard. High
Compound 3h: Yield: 44%, Found
C
C
C
74.2%; H 6.3%
74.7%; H 5.7%
72.0%; H 6.3%
1
13
resolution NMR H & C of selected compounds were recorded
on Brucker Avance 300 spectrometer using CDCl as solvent
and TMS as an internal standard. Mass spectra of selected
compounds were scanned on Thermo-Finnigan Polaris Q mass-
spectrometer (EI mode).
C H O required C 74.1%; H 6.2%.
2
0
20
4
3
Compound 4a: Yield: 60%, Found
C H O required C 74.9%; H 5.9%.
2
1
20
4
Compound 4b: Yield: 45%, Found
C H O required C 72.1%; H 6.0%.
2
2
22
5

1
702
D. I. Brahmbhatt, J. M. Gajera, C. N. Patel, V. P. Pandya and U. R. Pandya
Vol 43
Compound 4c: Yield: 63%, Found
C H O required C 75.4%; H 6.3%.
C
75.2%; H 6.2%
REFERENCES
22
22
4
Compound 4d: Yield: 55%, Found C 67.8%; H 5.3%
C H ClO required C 68.0%; H 5.1%.
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21
19
4
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Compound 4e: Yield: 59%, Found C 60.5%; H 4.7%
C H BrO required C 60.7%; H 4.6%.
21
19
4
Compound 4f: Yield: 60%, Found C 51.2%; H 3.5%
C H Br O required C 51.0%; H 3.6%.
21
18
2
4
Compound 4g: Yield: 57%, Found C 66.3%; H 4.9%; N
.4% C H NO required C 66.1%; H 5.0%; N 3.6%.
3
21
19
6
[
Compound 4h: Yield: 62%, Found
C H O required C 77.7%; H 5.7%.
C
77.5%; H 5.5%
(
25
22
4
[
Synthesis of Furo[3,4-c]coumarins (5a-h and 6a-h).
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[
M Barker, M.
3
0mL) successively. The chloroform layer was then dried over
[
anhydrous sodium sulphate. The solvent was removed by
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eluent to give 5a-h and 6a-h. In case of compound 5b and 6b the
reaction initially gave the hydroxyl derivatives (OH group at 8-
position) which were converted in to 5b and 6b by methylation of
[
[
[
hydroxyl group using K CO and MeI in acetone.
Compound 5a: White solid (Chloroform-hexane); H nmr:
2
3
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1
(
7
(
(
1
(
(
CDCl 300MHz) ꢀ 2.61 (s, 3H, -CH ), 2.66 (s, 3H, -CH ), 7.18-
3
3
3
13
.27 & 7.57-7.60 (m, 4H, aromatic protons) ;
C nmr: ꢀ 13.52
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CH ), 13.89 (CH ), 108.01 (C), 114.44 (C), 116.09 (C), 117.74
3 3
CH), 123.52 (CH), 124.42 (CH), 128.21 (CH), 144.30 (C),
51.48 (C), 157.63 (C=O), 158.69 (C); ms: m/z 215 (16.6), 214
76.93), 199 (5.19), 185 (8.41), 171 (8.68), 115 (30.15), 89
15.63), 74 (8.15), 63 (17.5), 43 (100).
1
Compound 6a: White solid (Chloroform-hexane); H nmr:
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(
CDCl 300MHz) ꢀ 2.74 (s, 3H, -CH ), 7.22-7.31, 7.41-7.49,
3
3
1
3
7
1
1
(
1
.65-7.68 & 8.31-8.34 (m, 9H, aromatic protons) ; C nmr: ꢀ
4.32 (CH ), 107.42 (C), 115.68 (C), 116.78 (C), 117.57 (CH),
3
[
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2xCH), 128.81 (C), 130.04 (CH), 145.25 (C), 151.28 (C),
56.26 (C=O), 158.04 (C); ms: m/z 276 (1.2), 219 (5.23), 176
10.47), 115 (20.0), 105 (100).
[
(
[
Acknowledgement.
[
The authors are thankful to the Head, Department of
Chemistry, Sardar Patel University for providing research
facilities.
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