Novel heterocyclic compounds from 2-Carboxy-6-methoxybenzofuran-3-acetic acid anhydride

Article abstract of DOI:10.3184/030823408X303231

2-Carboxy-6-methoxybenzofuran-3-acetic acid anhydride is utilised for the synthesis of novel polycyclic heteroaromatic compounds in which the benzofuran ring is fused or bound to pyrido[1,4]benzothiazine, thiazole, pyridine, pyrazolopyridine, pyrazole, pyrano-pyridine, and pyrazolo[1,5-a]pyrido[3,2-e] pyrimidines using versatile reaction strategies.

Full text of DOI:10.3184/030823408X303231

JOURNAL OF CHEMICAL RESEARCH 2008
MARCH, 129–133
RESEARCH PAPER 129
Novel heterocyclic compounds from 2-carboxy-6-methoxybenzofuran-
3-acetic acid anhydride
Jyoti A. Patankar*, Rajiv T. Khombare, Rahul R. Khanwelkar, and Jyoti B. Shet
Department of Chemistry, The Institute of Science, 15, Madam Cama Road, Mumbai 400 032, India
2-Carboxy-6-methoxybenzofuran-3-acetic acid anhydride is utilised for the synthesis of novel polycyclic heteroaromatic
compounds in which the benzofuran ring is fused or bound to pyrido[1,4]benzothiazine, thiazole, pyridine, pyrazolo-
pyridine, pyrazole, pyrano-pyridine, and pyrazolo[1,5-a]pyrido[3,2-e]pyrimidines using versatile reaction strategies.
Keywords: benzofurans, anhydrides, fused pyrones, pyrazoles, pyridines, pyrimidines, 1,4-benzothiazines, aminothiazoles
Benzofurans1-4 and 2-pyridones5-7 are well known for their
broad spectrum of biological activities. This has generated
much interest in the synthesis of heterocycles bearing the
benzofuran and pyridone moieties.
anhydride. Compound 1 reacted with triethyl orthoformate to
give the ethoxymethylene derivative 6. This on reaction with
3-aminopyrazole-4-carbonitrile20 gave the pyridopyrazole
derivative 7 in good yield. The IR spectrum of 7 showed a
characteristic peak for the CN functional group at 2228 cm-1 and
13C NMR spectrum showed a signal at 120.3 ppm for CN carbon.
Compound 7 on fusion with p-anisidine gave by N-insertion the
product 8. When compound 7 was refluxed in ethanolic NaOH
it underwent ring-opening to give the pyridopyrazole derivative
9. This was confirmed by the 1H NMR spectrum which showed
D2O-exchangeable peaks at d 6.80, 11.95 and 12.11 for the
three OH protons, and the disappearance of the CN peak in the
IR spectrum. Further support for structure 9 was provided by
its esterification in acidic methanol, which formed the methyl
diester 10 (Scheme 2).
7-Methoxypyrano[3,4-b][1]benzofuran-1,3(4H)-dione (7-
methoxy-2,9-dioxafluorene-1,3(4H)-dione, or 2-carboxy-
6-methoxybenzofuran-3-acetic acid anhydride) (1) has a
pyranobenzofuran moiety and an active methylene group
at position 4. Its utility is still not much explored in the
literature.8-11 Hence we decided to explore the possibilities of
this compound for the synthesis of novel heterocycles, which
might be useful for biological applications. Therefore, in
continuation of our work on the synthesis of novel heterocyclic
compounds,8,9 we now report the preparation of a number of
novel systems originating from the anhydride 1.
Compound 6 with hydrazine hydrate in ethanol gave
the fused pyrazole derivative 11 in good yield. Which was
confirmed on the basis of H NMR spectrum showing peak
Results and discussion
Compounds
containing
the
pyridobenzothiazine12-14
1
and aminothiazole15,16 nuclei are well known for their
biological activities. Hence, 1 was utilised for the synthesis
of the pyridobenzothiazine 4 and the fused aminothiazole 5
(Scheme 1). Compound 1 on fusion with p-anisidine gave
the N-inserted product 2, which was brominated to give the
monobromo compound 3, both reactions proceeding in high
yield. Compound 3 on heating with o-aminothiophenol and
thiourea, in the presence of triethylamine in ethanol, gave the
expected pyridobenzothiazine derivative 4 and aminothiazole
derivative 5, respectively, in good yields (Scheme 1).
at d 8.11 for NH proton, which was D2O exchangeable, and
absence of peaks for ethyl protons. Compound 11 on fusion
with p-anisidine gave the N-insertion product 12. When lactone
11 was heated in ethanolic NaOH it underwent ring-opening;
acidification formed the acid 13, and this on esterification in
acidic methanol gave its methyl ester 14 (Scheme 3).
Compound 6 on reaction with piperidine in ethanol and p-
anisidine in benzene gave condensation products 15 and 16
respectively. Compound 15 on fusion with p-anisidine gave
the N-insertion product 17, and compound 16 on treatment
with morpholine gave the ring-opening product 18 in good
yield. (Scheme 4)
Since pyrazole derivatives are also well known for their
biological activities,17-19 we explored the utility of 1 for
the synthesis of pyrazole derivatives of the benzofuran
O
O
O
O
OMe
MeO
MeO
a
N
O
MeO
OMe
O
O
2
1
b
O
N
O
O
O
O
S
OMe
S
N
O
H N
2
MeO
c
d
N
H
N
N
O
Br
3
OMe
MeO
4
5
Scheme 1 Reagents: a, p-anisidine, fused at 170-180°C; b, Br2/AcOH, 50°C; c, 2-aminobenzenethiol, Et3N/EtOH, reflux;
d, thiourea/Et3N/EtOH, reflux
* Correspondent. E-mail: ja_patankar@yahoo.co.in
PAPER: 07/4891

130 JOURNAL OF CHEMICAL RESEARCH 2008
O
O
O
O
MeO
MeO
O
O
a
b
1
O
N
N
OMe
OEt
7
6
N
c
d
CN
O
O
O
O
COOMe
N
CO2H
OH
MeO
MeO
OH
NC
N
N
e
N
N
N
N
N
N
N
9
CO2H
OMe
10
COOMe
8
Scheme 2 Reagents: a, CH(OEt)3/Ac2O/C6H6, reflux; b, 3-aminopyrazole-4-carbonitrile/EtOH, reflux; c, p-anisidine,
fused at 170-180°C; d, NaOH/EtOH, reflux; e, MeOH/p-TSA, reflux
O
O
O
O
O
O
OMe
MeO
O
MeO
MeO
N
O
O
a
b
N
O
N
N
H
c
N
H
OEt
11
12
6
O
COOMe
OH
CO H
2
MeO
MeO
OH
d
N
N
N
N
H
H
14
13
Scheme 3 Reagents: a, N2H4.H2O/EtOH, refl; b, p-anisidine, fused, 170-180°C; c, NaOH/EtOH, refl; d, MeOH/p-TSA, refl.
O
O
O
O
O
O
OMe
MeO
MeO
MeO
O
O
N
a
b
O
O
O
N
OEt
O
N
6
15
17
c
O
O
CO2H
N
O
MeO
MeO
O
d
O
O
NH
NH
OMe
OMe
16
18
Scheme 4 Reagents: a, piperidine/EtOH, reflux; b, p-anisidine, fused, 170-180°C; c, p-anisidine/C6H6, reflux; d, morpholine/EtOH,
O
O
O
O
O
O
O
MeO
MeO
O
O
MeO
O
a
b
1
O
O
c
HO2C
O
20
21
21
19
Scheme 5 Reagents: a, b,b–dimethylacryloyl chloride/pyridine, 0-5°C; b, pyridine, reflux; c, as a but heat to reflux
PAPER: 07/4891

JOURNAL OF CHEMICAL RESEARCH 2008 131
Isocoumarins also possess biological activity.21-26
The isocoumarin derivative 21 was synthesised as follows.
Compound 1 reacted with b,b-dimethylacryloyl choride
in pyridine at 0–5°C to give 19. This on reflux with
pyridine gave the isocoumarin analogue 21 in moderate
yield via the rearrangement product 20. Alternatively, 21 was
synthesised in good yield by directly refluxing 1 with b,b-
dimethylacryloyl choride in pyridine (Scheme 5).
J = 2.1, 8.1 Hz), 6.58–6.52 (m, 4H, aromatic protons), 4.34 (s, 1H,
NH, D2O-exchangeable), 3.86 (s, 3H, OCH3), 3.79 (s, 3H, OCH3);
dC 160.3 (CO), 158.8, 158.1, 157.5, 147.3, 146.3, 133.4, 130.5, 130.2,
125.9, 125.4, 122.6, 121.1, 119.6, 118.9, 118.2, 115.3, 114.7, 108.6,
97.8, 91.5 (22 aromatic carbons), 56.0, 55.6 (2 OCH3). MS (EI):
m/z 442 (M+). Found; C, 67.70; H, 4.00; N, 6.17; S, 7.02.
C25H18N2O4S requires C, 67.86; H, 4.10; N, 6.33, S, 7.25%.
2-Amino-8-methoxy-4-(4-methoxyphenyl)[1]benzofuro[3,2-d]thiazolo
[4,5-b]pyridin-5(4H)-one (5): The bromo-compound 3 (4.0 g,
0.01 mol) in ethanol (75 ml) was stirred at 50°C, and triethylamine
(1.0 g, 0.01 mol) and thiourea (0.76 g, 0.01 mol) were added.
The reaction mixture was then heated to reflux for 5 h. Excess of
ethanol was removed under vacuum and the reaction mass was poured
onto 100 g crushed ice and stirred vigorously. This solution was then
neutralised with 2N HCl to afford solid product 5, which was filtered
off, washed with water, air-dried and recrystallised from methanol.
Yield 84%, m.p. 145°C. IR: νmax 3133 (NH), 1618 (C=O), 1511
cm-1 (NH). NMR (CDCl3): dH 7.68–7.65 (d, 2H, H-3',5', J = 8.4 Hz),
7.54–7.51 (d, 1H, H10, J = 8.4 Hz), 7.48–7.47 (d, 1H, H7, J = 1 Hz),
7.34–7.31 (d, 2H, H-2',6', J = 8.4 Hz), 7.05–7.02 (dd, 1H, H9,
J = 2.1, 8.4 Hz), 4.79 (s, 2H, NH2, D2O-exchangeable), 3.82 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3); dC 170.7 (C–NH2), 159.3 (CO), 158.1,
157.2, 155.7, 145.3, 133.0, 130.8, 123.7, 121.1, 120.0, 118.2, 114.1,
108.7, 107.9, 95.4 (16 aromatic carbons), 56.3, 55.7 (2 OCH3). MS
(ESI) m/z 393 (M+). Found; C, 60.88; H, 3.68; N, 10.52; S, 8.02.
C20H15N3O4S requires C, 61.06; H, 3.84; N, 10.68; S, 8.15%.
4-Ethoxymethylene-7-methoxy-1H-pyrano[3,4-b][1]benzofuran-
1,3(4H)-dione (6): The anhydride 1 (4.0 g, 0.01 mol) was stirred
in dry benzene (150 ml) containing triethyl orthoformate (2.22 g,
0.015 mol) and a catalytic amount of acetic anhydride. The reaction
mixture was refluxed for two hours. Excess of benzene was removed
under vacuum and a light pink solid (6) separated from the solution.
This was filtered off, washed with cold benzene, and recrystallised
from chloroform as white needles (85%, m.p. 144°C). IR νmax 1755,
1701 cm-1 (C=O). NMR (CDCl3): dH 8.09 (s, 1H, CH), 7.66–7.63 (d,
1H, H5, J = 8.1 Hz), 7.35–7.34 (d, 1H, H8, J = 2.1 Hz), 6.96–6.93
(dd, 1H, H6, J = 2.1, 8.1 Hz), 4.53 (q, 2H, CH2), 3.84 (s, 3H, OCH3),
1.80 (t, 3H, CH3); dC 161.3, 151.7 (2 CO), 156.7 (C-O), 160.1, 158.1,
143.2, 130.6, 120.3, 118.0, 108.8, 106.8, 97.4, (9 aromatic carbons),
61.3 (OCH2), 55.5 (OCH3), 11.8 (CH3). Found; C, 62.3; H, 4.02.
C15H12O6 requires C, 62.50; H, 4.20%.
9-Methoxy-6-oxo-6H-[1]benzofuro[2',3':5,4]pyrano[3,2-e]pyrazolo
[1,5-a]pyrimidine-1-carbonitrile (7): 3-Aminopyrazole-4-carbo-
nitrile20 (1.08 g, 0.01 mol) was added to a stirred solution of the
enol ether 6 (2.88 g, 0.01 mol) in acetic acid (35 ml). The reaction
mixture was refluxed for 6 hours. Excess of acetic acid was removed
under vacuum and the solution was poured onto crushed ice (100 g)
to afford a solid yellow product (7) (91%), m.p. >250°C, which was
filtered off, washed with warm water, and dried in vacuo. IR: νmax
2228 (CN), 1692 cm-1 (C=O). NMR (DMSO-d6): dH 8.47 (s, 1H),
8.28 (s, 1H), 7.51–7.48 (d, 1H, H11, J = 8.1 Hz), 7.35–7.34 (d, 1H,
H8, J = 2.1 Hz), 6.89–6.86 (dd, 1H, H10, J = 2.1, 8.1 Hz), 3.84 (s,
3H, OCH3); dC 165.3 (CO), 161.4, 160.1, 155.2, 154.2, 145.1, 141.7,
137.3, 132.1, 123.0, 121.1, 113.5, 112.6, 102.2, 95.6 (14 aromatic
carbons), 120.3 (CN), 55.8 (OCH3). Found; C, 61.25; H, 2.22; N,
16.72. C17H8N4O4 requires C, 61.45; H, 2.43; N, 16.86%.
9-Methoxy-5-(4-methoxyphenyl)-6-oxo-5,6-dihydro[1]benzofuro
[2',3':5,4]pyrido[3,2-e]pyrazolo[1,5-a]pyrimidine-1-carbonitrile(8):
The lactone 7 (3.32 g, 0.01 mol) and p-anisidine (1.23 g, 0.01 mol)
were fused in an oil bath at 170–180°C for 45 minutes. A clear
thick solution was obtained, which solidified on cooling to room
temperature. To this solid, acetic acid (20 ml) was added and the
mixture was heated to reflux for 20 minutes. On cooling compound 8
separated as a crystalline solid; it was filtered off, washed with water,
and vacuum-dried (yield 88%, m.p. >250°C. IR: νmax 2227 (CN),
1623 cm-1 (C=O). NMR: dH (DMSO-d6) 8.50 (s, 1H, =CH), 8.26 (s,
1H, =CH), 7.62–7.59 (d, 2H, H-3',5', J = 8.4 Hz), 7.53–7.51 (d, 1H,
H11, J = 7.8 Hz), 7.47–7.44 (d, 2H, H-2',6', J = 8.4 Hz), 7.33–7.32 (d,
1H, H8, J = 2.1 Hz), 6.94–6.91 (dd, 1H, H10, J = 2.1, 8.1 Hz), 3.85
(s, 3H, OCH3), 3.75 (s, 3H, OCH3) dC (CDCl3): 166.2 (CO), 163.2,
158.5, 158.3, 158.1, 157.7, 145.3, 133.0, 130.5, 122.6, 119.6, 118.2,
114.3, 110.3, 105.6, 97.5 (20 aromatic carbons), 120.9 (CN), 56.0,
55.8 (2 OCH3). MS (EI): m/z 437 (M+). Found; C, 65.73; H, 3.36; N,
17.07. C24H15N5O4 requires C, 65.90; H, 3.46; N, 17.19%.
Conclusion
In this paper we report simple and convenient synthetic
routes for the synthesis of novel heterocyclic compounds
containing pyridobenzothiazine, aminothiazole, pyrazole,
and isocoumarin systems starting from the benzofuran
anhydride 1.
Experimental
Melting points were taken in open capillaries. IR spectra were
recorded on Perkin-Elmer 257-FTIR 1600 series spectrometer, using
1
the KBr disc method for solid materials. H and 13C NMR spectra
were recorded at 300 and 75 MHz using a Varian VXR 300 machine
at 25°C (chemical shifts in d ppm). Mass spectra were recorded on
Shimadzu QP 2010 GC MS instrument. Elemental analyses were
obtained using a Thermoquest Flash1112 series instrument.
7-Methoxypyrano[3,4-b][1]benzofuran-1,3(4H)-dione (1): The anhydride
1 was synthesised from 3-carboxymethyl-6-methoxy benzofuran-
2-carboxylic acid using the reported method.8
7-Methoxy-2-(4-methoxyphenyl)[1]benzofuro[2,3-c]pyridine-1,3(4H)-
dione (2): Compound 1 (2.32 g, 0.01 mol) and p-anisidine (1.23 g,
0.01 mol) were fused at 170-180°C in an oil bath for one hour.
A clear thick solution was obtained, which solidified on cooling.
Acetic acid (20 ml) was added and the resulting solution was heated
to reflux for 30 minutes. On cooling, the crystalline solid 2 was
obtained. It was filtered off, washed with water, and vacuum-dried;
yield 85%, m.p. 215°C. IR: νmax 1694, 1625 cm-1 (C=O). NMR
(DMSO-d6): dH 7.54–7.51 (d, 2H, H-3',5', J = 8.4 Hz), 7.49–7.46 (d,
1H, H5, J = 7.8 Hz), 7.45–7.42 (d, 2H, H-2',6', J = 8.4 Hz), 7.35–7.34
(d, 1H, H8, J = 2.1 Hz), 6.94–6.91 (dd, 1H, H6, J = 2.1, 8.1 Hz),
4.87 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 3.78 (s, 3H, OCH3); dC 166.3,
160.3 (2 CO), 158.1, 157.2, 155.7, 145.3, 133.0, 121.1, 120.0, 118.2,
114.7, 113.6, 103.8, 93.5 (14 aromatic C), 56.1, 55.7 (2 OCH3), 20.9
(CH2). Found: C, 67.45; H, 4.27; N, 4.02. C19H15NO3 requires C,
67.45; H, 4.48; N, 4.15%.
4-Bromo-7-methoxy-2-(4-methoxyphenyl)[1]benzofuro[2,3-c]
pyridine-1,3(4H)-dione (3): Compound 2 (3.21 g, 0.01 mol) was
dissolved in acetic acid (50 ml) at 50°C, and a solution of bromine
(0.51 ml, 0.01 mol) in glacial acetic acid (20 ml) was added dropwise
with constant stirring over one hour. After complete addition,
reaction mixture was stirred for one hour at the same temperature.
The reaction mixture was poured onto crushed ice (100 g) and stirred
vigorously to afford the solid product 3 which was filtered off, washed
with water, air-dried and recrystallised from chloroform, yield 87%,
m.p. 95°C. IR: νmax 1695, 1628 cm-1 (C=O). NMR (DMSO d6):
dH 7.55–7.52 (d, 2H, H-3',5', J = 8.4 Hz), 7.50–7.47 (d, 1H, H5,
J = 8.1 Hz), 7.44–7.41 (d, 2H, H-2',6', J = 8.4 Hz), 7.34–7.33 (d, 1H,
H8, J = 2.1 Hz), 6.94–6.91 (dd, 1H, H6, J = 2.1, 8.1 Hz), 5.81 (s, 1H,
CH), 3.84 (s, 3H, OCH3), 3.75 (s, 3H, OCH3); dC 167.1, 161.2 (2 CO),
157.9, 157.7, 157.2, 145.2, 144.8, 133.1, 123.7, 121.3, 119.7, 113.9,
107.9, 97.7 (14 aromatic carbons), 56.0, 55.7 (2 OCH3), 40.5 (CH)
ppm. Found: C, 54.70; H, 3.16; N, 3.17; Br, 19.02. C19H14BrNO5
requires C, 54.83; H, 3.39; N, 3.37; Br, 19.20%.
10-Methoxy-6-(4-methoxyphenyl)-5H-[1]benzofuro[3',2':3,4]
pyrido[3,2-b][1,4]benzothiazin-7(6H)-one
(4):
The
bromo-
compound 3 (4.0 g, 0.01 mol) in ethanol (75 ml) was stirred at 50°C,
and triethylamine (1.0 g, 0.01 mol) and o-aminothiophenol (1.25 g,
0.01 mol) were added. The reaction mixture was refluxed for 5 h.
Excess of ethanol was removed under vacuum and the reaction
mass was poured onto crushed ice (100 g) and stirred vigorously.
The solution was then neutralised with 2N HCl to afford solid product
4. Which was filtered, washed with water, air-dried and recrystallised
using methanol. IR: νmax 3295 (NH), 1616 (C=O), 1513 cm-1 (NH).
NMR (CDCl3): dH 7.63–7.60 (d, 2H, H-3',5', J = 8.4 Hz), 7.55–
7.52 (d, 1H, H12 J = 8.7 Hz), 7.44–7.43 (d, 1H, H9, J = 2.1 Hz),
7.34–7.31 (d, 2H, H-2',6', J = 8.4 Hz), 6.96–6.93 (dd, 1H, H11,
6-(2'-Carboxy-6'-methoxybenzofuran-3'-yl)-7-hydroxypyrazolo
[1,5-a]pyrimidine-3-carboxylic acid (9): The lactone 7 (3.32 g,
0.01 mol) was refluxed in 20% ethanolic NaOH solution for
2.5 h. Excess of ethanol was removed under vacuum and the reaction
mass was poured onto crushed ice (100 g) and stirred vigorously.
PAPER: 07/4891

132 JOURNAL OF CHEMICAL RESEARCH 2008
This solution was then neutralised with 2N HCl to precipitate 9,
which was filtered off, washed with water, air-dried and recrystallised
from methanol:benzene (1:5); yield 78%; m.p. 225°C. IR: νmax
3432 (OH), 1712, 1698 cm-1 (C=O). NMR (DMSO-d6): dH 12.11
(s, 1H, COOH, D2O-exchangeable), 11.95 (s, 1H, COOH, D2O-
exchangeable), 8.57 (s, 1H, =CH), 8.38 (s, 1H, =CH), 7.55–7.52 (d,
1H, H4', J = Hz), 7.44–7.43 (d, 1H, H7', J = 2.1 Hz), 6.96–6.93 (dd,
1H, H5', J = 2.1, 8.1 Hz), 6.80 (s, 1H, OH), 3.85 (s, 3H, OCH3);
Methyl
3-(3-hydroxy-1H-pyrazol-4yl)–6-methoxybenzofuran-
2-carboxylate (14): Compound 13 (2.74 g, 0.01 mol) was heated
to reflux for 3 h in methanol (35 ml) with a catalytic amount of p-
toluenesulfonic acid (60 mg). Excess of methanol was then removed
under vacuum and the reaction mass was poured onto 100 g crushed
ice and stirred vigorously to afford a solid product (14) which was
filtered off, washed with water, air-dried and recrystallised from
methanol:benzene (1:5); yield 90%, m.p. 171°C. IR: νmax 3468
(OH), 3272 (NH), 1742 (C=O), 1596 cm-1 (C=N). NMR (CDCl3):
dH 8.20–8.17 (d, 1H, NH, D2O-exchangeable, J = 9 Hz), 7.61–7.58
(d, 1H, CH, J = 9 Hz), 7.55–7.52 (d, 1H, H4, J = 8.1 Hz), 7.42–7.41
(d, 1H, H7, J = 2.1 Hz), 6.94–6.91 (dd, 1H, H5, J = 2.1, 8.1 Hz), 6.68
(s, 1H, OH), 3.83 (s, 3H, OCH3), 3.92 (s, 3H, OCH3); dC 159.3 (CO),
158.8, 158.1, 142.3, 134.3, 131.9, 131.3, 122.5, 121.1, 109.0, 105.3,
97.8 (11 aromatic carbons), 56.0, 51.7 (2 OCH3). MS (ESI) (m/z):
289 (M+). Found; C, 58.21; H, 4.04; N, 9.53. C14H12N2O5 requires C,
58.33; H, 4.20; N, 9.72%.
7-Methoxy-4-(piperidin-1-ylmethylene)-4H-pyrano[3,4-b][1]
benzofuran-1,3-dione (15): Piperidine (0.95 g, 0.011 mol) in a little
ethanol was added dropwise into a stirred solution of the enol ether 6
(2.82 g, 0.01 mol) in ethanol (50 ml) over 10 min at room temperature.
The solution was then heated to reflux for 3 hr. Excess of ethanol was
removed in vacuo and the residue was poured onto crushed ice (100 g)
and acidified with 2N HCl to afford the enamino-anhydride 15, which
was filtered off, washed with water, air-dried and recrystallised from
ethanol (yield 87%, m.p. 245°C). IR: νmax 3300 (NH), 1725, 1670 cm-1
(C=O). NMR: dH (CDCl3) 7.65–7.62 (d, 1H, H5, J = 8.1 Hz),
7.38–7.35 (d, 1H, H8, J = 2.1 Hz), 6.97–6.94 (dd, 1H, H6,
J = 2.1, 8.1 Hz), 6.91 (s, 1H, CH), 3.74 (m, 4H, N(CH2)2), 1.90 (m,
4H, (CH2)2), 1.79 (m, 2H, CH2); dC (DMSO-d6) 161.5, 154.0 (2
CO), 151.6 C=C–N), 160.0, 157.7, 144.7, 130.6, 121.9, 119.8, 107.9,
96.6 (8 aromatic C), 109.3 (C=C–N), 55.7 (OCH3), 50.1, 26.0, 24.7
(5 CH2). Found; C, 65.94; H, 5.11; N, 4.14. C18H17NO5 requires C,
66.05; H, 5.23; N, 4.28%.
7-Methoxy-4-(4'-methoxyphenylaminomethylene)-4H-pyrano[3,4-b]
[1]benzofuran-1,3-dione (16): p-Anisidine (0.629 g, 5 mmol) in
benzene (20 ml) was added dropwise at room temperature into
a stirred solution of the enol ether 6 (1.44 g, 5 mmol) in benzene
(50 ml). The reaction mixture was then heated to reflux for 3 h.
Removal of excess of benzene under vacuum resulted in precipitation
of yellow solid 16, which was filtered off, washed with benzene
and 2N HCl to remove unreacted anisidine, and recrystallised from
dimethyl formamide (DMF) (yield 87%, m.p. >250°C. IR: νmax 3300
(NH), 1745, 1680 cm-1 (C=O). NMR (CDCl3): dH 11.20 (s, 1H, NH,
D2O-exchangeable), 8.22 (s, 1H, =CH), 7.69–7.66 (d, H5, J = 8.1
Hz), 7.35–7.34 (d, 1H, H8, J = 2.1 Hz), 7.17–7.14 (d, 2H, H-3',5',
J = 8.4 Hz), 6.96–6.93 (dd, 1H, H6, J = 2.1, 8.1 Hz), 6.91–6.88 (d,
2H, H-2',6', J = 8.4 Hz), 3.94 (s, 3H, OCH3), 3.81 (s, 3H, OCH3); dC
160.2, 156.3 (2 CO), 151.7 (C=C–NH), 160.9, 158.0, 144.7, 144.3,
138.7, 130.7, 122.4, 120.7, 115.7, 114.4, 112.3, 97.6 (14 aromatic
carbons), 109.1 (C=C–NH), 56.2, 55.7 (2 OCH3). Found; C, 65.59;
H, 4.01; N, 3.66. C20H15NO6 requires C, 65.75; H, 4.14; N, 3.83%.
7-Methoxy-2-(4-methoxyphenyl)-4-(piperidin-1-ylmethylene)-4H-
[1]benzofuro[2,3-c]pyridine-1,3-dione (17): p-Anisidine (0.629 g,
5 mmol) and the anhydride 15 (1.6 g, 5 mmol) were fused together
at 170–180°C and kept at that temperature for 1 h. A clear thick
melt was produced, which solidified on cooling. Acetic acid (20 ml)
was added and the resulting solution was refluxed for 30 min.
Cooling afforded a bright yellow solid (17), which was filtered off,
washed with water, air-dried and recrystallised from DMF (yield
68%,m.p.>250°C).IR:νmax 3300(NH),1725,1670cm-1 (C=O).NMR:
d
C 177.3, 172.0 (2 COOH), 170.4, 161.3, 155.2, 154.2, 145.1, 141.7,
137.3, 132.1, 127.1, 121.1, 113.5, 105.6, 102.2, 94.9 (14 aromatic C),
54.7 (OCH3). MS (ESI): m/z 369 (M+). Found; C, 55.19; H, 2.887; N,
11.25. C17H11N3O7 requires C, 55.29; H, 3.00; N, 11.38%.
Methyl
6-(6'-Methoxy-2'-methoxylcarbonylbenzofuran-3'-yl)-7-
hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (10): The diacid 9
(3.69 g, 0.01 mol) was heated to reflux for 3 h in methanol (35 ml)
with catalytic p-toluenesulfonic acid (60 mg). Excess of methanol
was removed under vacuum and the reaction mass was poured
onto crushed ice (100 g) and stirred vigorously to afford the solid
product 10. This was filtered off, washed with water, air-dried and
recrystallised from methanol:benzene (1:5); yield 72%, m.p. 159°C.
IR: νmax 3457 (OH), 1746, 1732 cm-1 (C=O). NMR (DMSO-d6):
dH 8.55 (s, 1H, =CH), 8.36 (s, 1H, =CH), 7.54–7.51 (d, 1H, H4',
J = 8.1 Hz), 7.41–7.40 (d, 1H, H7', J = 2.1 Hz), 6.99–6.96 (dd, 1H,
H5', J = 2.1, 8.1 Hz), 6.89 (s, 1H, OH, D2O-exchangeable), 3.84 (s,
3H, OCH3), 3.82 (s, 3H, OCH3), 3.75 (s, 3H, OCH3); dC 169.0, 158.3
(2 CO), 168.4, 158.7, 157.2, 155.0, 141.9, 135.3, 132.6, 132.1, 127.6,
122.1, 121.2, 106.4, 102.7, 95.9 (14 aromatic C), 55.5, 51.2, 48.4 (3
OCH3). Found; C, 57.29; H, 3.70; N, 10.43. C19H15N3O7 requires C,
57.43; H, 3.81; N, 10.58%.
8-Methoxy[1]benzofuro[3',2':4,5]pyrano[2,3-c]pyrazol-5(2H)-
one (11): The enol ether 6 (2.88 g, 0.01 mol) was stirred in ethanol
(50 ml), and hydrazine hydrate (80%, 0.75 ml, 0.015 mol) was added
dropwise over 10 minutes at room temperature. The reaction mixture
was refluxed for 30 min, and on cooling to room temperature a solid
product (11) separated. This was filtered off, washed with ethanol,
air-dried and recrystallised from ethanol; yield 72%, m.p. 149°C. IR:
νmax 3245 (NH), 1684 (C=O), 1570 cm-1 (C=N). NMR (DMSO-d6):
dH 8.11–8.08 (d, 1H, NH, D2O-exchangeable, J = 9 Hz), 7.72–7.69
(d, 1H, CH, J = 9 Hz), 7.51–7.48 (d, 1H, H10, J = 8.1 Hz), 7.32–7.31
(d, 1H, H7, J = 2.1 Hz), 7.00–6.97 (dd, 1H, H9, J = 2.1, 8.1 Hz), 3.85
(s, 3H, OCH3); dC 154.3 (CO), 161.4, 158.2, 142.5, 135.3, 132.5,
132.0, 122.4, 121.1, 107.8, 104.7, 96.0 (11 aromatic C), 55.7 (OCH3).
Found; C, 60.81; H, 3.05; N, 10.79. C13H8N2O4 requires C, 60.94; H,
3.15; N, 10.93%.
8-Methoxy-4-(4-methoxyphenyl)-2,4-dihydro-5H-[1]benzofuro[3,2-d]
pyrazolo[3,4-b]pyridin-5-one (12): Compound 11 (2.56 g, 0.01 mol)
and p-anisidine (1.23 g, 0.01 mol) were fused in an oil bath at
170–180°C for 45 min. A clear thick solution was obtained, which
solidified on cooling. To this solid acetic acid (20 ml) was added
and the mixture was refluxed for 20 min, after which cooling gave
a crystalline solid 12, which was filtered off, washed with water, and
vacuum dried (yield 87%, m.p. 215°C). IR: νmax 3210 (NH), 1620
(C=O), 1590 cm-1 (C=N). NMR: dH (DMSO-d6) d 8.12–8.09 (d, 1H,
NH, D2O-exchangeable, J = 9 Hz), 7.82–7.79 (d, 1H, CH, J = 9 Hz),
7.64–7.61 (d, 2H, H-3',5', J = 8.4 Hz), 7.51–7.48 (d, 2H, H-2',6',
J = 8.4 Hz), 7.42–7.39 (d, 1H, H10, J = 8.1 Hz), 7.28–7.27 (d, 1H,
H7, J = 2.1 Hz), 6.96–6.93 (dd, 1H, H9, J = 2.1, 8.1 Hz), 3.85 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3); dC (CDCl3): 159.7 (CO), 158.5, 158.1,
157.7, 154.0, 145.5, 132.0, 131.3, 122.5, 121.4, 120.1, 114.7, 108.7,
97.4, 92.0 (17 aromatic C), 56.3, 56.0 (2 OCH3). MS (EI): m/z 361
(M+). Found; C, 66.32; H, 4.04; N, 11.51. C20H15N3O4 requires C,
66.48; H, 4.18; N, 11.63%.
d
H (CDCl3) 7.94 (s, 1H, =CH), 7.53–7.50 (d, 2H, H-3',5', J = 8.4 Hz),
3-(3-Hydroxy-1H-pyrazol-4-yl)-6-methoxybenzofuran-2-carboxylic
acid (13): The lactone 11 (2.56 g, 0.01 mol) was refluxed in 20%
ethanolic NaOH for 3 h. Excess of ethanol was removed under
vacuum and the reaction mass was poured onto crushed ice (100 g)
and stirred vigorously. This solution on neutralisation with 2N HCl
afforded the acid 13, which was filtered off, washed with water, air-
dried and recrystallised from methanol:benzene (1:5) (yield: 72%,
m.p. >250°C). IR: νmax 3457 (OH), 3265 (NH), 1700 (C=O), 1585
cm-1 (C=N). NMR: dH (DMSO-d6) d12.12 (s, 1H, -COOH, D2O-
exchangeable), 8.21–8.18 (d, 1H, NH, D2O-exchangeable, J = 9 Hz),
7.66–7.63 (d, 1H, CH, J = 9 Hz), 7.54–7.51 (d, 1H, H4, J = 8.1 Hz),
7.44–7.43 (d, 1H, H7, J = 2.1 Hz), 6.94–6.91 (dd, 1H, H5, J = 2.1,
8.1 Hz), 6.44 (s, 1H, OH, D2O-exchangeable), 3.86 (s, 3H, OCH3);
dC (CDCl3) 161.7 (CO), 161.5, 157.7, 143.5, 135.1, 132.0, 131.3,
121.8, 120.7, 108.3, 105.1, 97.3 (11 aromatic carbons), 55.8 (OCH3).
Found; C, 56.82; H, 3.54; N, 10.09. C131H10N2O5 requires C, 56.94;
H, 3.68; N, 10.22%.
7.49–7.46(d, 1H, H5, J=8.1Hz), 7.44–7.41(d, 2H, H-2',6', J=8.4Hz),
7.33–7.32 (d, 1H, H8, J = 2.1 Hz), 6.94–6.91 (dd, 1H, H6,
J = 2.1, 8.1 Hz), 3.90 (s, 6H, 2 OCH3), 3.76 (m, 4H, N(CH2) 2),
1.93 (m, 4H, 2 CH2), 1.81 (m, 2H, CH2); dC (DMSO-d6) 160.4, 162.0
(2 CO), 155.2 (C=C–N), 154.2, 150.0, 146.1, 141.7, 137.3, 130.1,
127.1, 121.3, 119.1, 113.5, 105.6, 95.1 (14 aromatic carbons), 111.3
(C=C–N), 55.4, 55.2 (2 OCH3), 50.1, 26.1, 24.8 (5 CH2). Found;
C, 69.25; H, 5.43; N, 6.32. C25H24N2O5 requires C, 69.43; H, 5.59;
N, 6.48%.
6-Methoxy-3-[2-(4-methoxyphenylamino)-1-(morpholine-4-carbonyl)
vinyl]benzofuran-2-carboxylic acid (18): Morpholine (0.5 g,
6 mmol) was added dropwise over 10 min to a stirred solution of
16 (1.8 g, 5 mmol) in ethanol (50 ml) at room temperature. Stirring
was continued for 3 hours at the same temperature. Excess of ethanol
was removed under vacuum and the obtained mass was poured onto
crushed ice (100 g) and acidified with 2N HCl to afford the yellow
solid 18. This was filtered off, washed with water, air-dried and
PAPER: 07/4891

JOURNAL OF CHEMICAL RESEARCH 2008 133
recrystallised from ethanol (yield 73%, m.p. 110°C). IR: νmax 3300
(OH), 1740, 1680 cm-1 (C=O). NMR (CDCl3): dH 10.41 (d, 2H, 1
NH, 1 COOH, D2O-exchangeable), 8.23 (s, 1H, =CH), 7.69–7.66 (d,
1H, H4, J = 8.1 Hz), 7.35–7.34 (d, 1H, H7, J = 2.1 Hz), 7.19–7.16
(d, 2H, H-3',5', J = 8.4 Hz), 6.96–6.93 (dd, 1H, H5, J = 2.1, 8.1 Hz),
6.94–6.91 (d, 2H, H-2',6', J = 8.4 Hz), 3.91 (s, 6H, 2 OCH3), 3.80
(t, 4H, 2 CH2), 3.78 (t, 4H, 2 CH2); dC 164.8, 162.3 (2 CO), 152.6
(C=C–NH), 159.8, 158.1, 144.5, 140.4, 139.0, 130.7, 122.5, 121.1,
116.4, 114.3, 113.2, 97.7 (14 aromatic C), 109.0 (C=C–NH), 71.3 (2
OCH2), 56.1, 56.0 (2 OCH3), 50.6 (2 NCH2). MS (EI): m/z 452 (M+).
Found; C, 63.58; H, 5.22; N, 6.03. C24H24N2O7 requires C, 63.71; H,
5.35; N, 6.19%.
7-Methoxy-4-(3-methyl-1-oxobut-2-enyl)pyrano[3,4-b][1]
benzofuran-1,3(4H)-dione(19):b,b-Dimethyacryloylchloride(1.78g,
0.015 mol) was added dropwise at 0–5°C to a stirred solution of
the anhydride 1 (2.32 g, 0.01 mol) in pyridine (25 ml). The reaction
mixture was stirred for 2 h at room temp. It was poured onto crushed
ice (100 g) and acidified with 2N HCl to afford the solid 19, which
was filtered off, washed with water, air-dried, and recrystallised from
ethyl acetate (yield 80%, m.p. 148°C). IR: νmax 1748, 1722, 1688
cm-1 (C=O). NMR (DMSO-d6): dH 7.55–7.52 (d, 1H, H5, J = 8.7 Hz),
7.43–7.42 (d, 1H, H8, J = 2.1 Hz), 7.02–6.99 (dd, 1H, H6, J = 2.1,
8.1 Hz), 6.89 (s, 1H, =CH), 5.64 (s, 3H, CH), 3.83 (s, 3H, OCH3),
2.07 (s, 3H, CH3), 1.85 (s, 3H, CH3); dC 196.5, 166.3, 160.1 (3 CO),
158.7, 155.3, 145.2, 123.1, 122.6, 117.6, 107.5, 95.7 (8 aromatic
C), 147.7 (C(CH3)2), 123.3 ( =CH), 56.1 (OCH3), 50.2 (CH), 24.9,
19.2 (2 CH3). Found; C, 64.78; H, 4.30. C17H14O6 requires C, 64.97;
H, 4.49%.
9-Methoxy-3,3-dimethyl-3,4-dihydropyrano[4',3':2,3]pyrano[3,4-b]
[1]benzofuran-1,6-dione (21): b,b-Dimethylacryloyl chloride (1.78 g,
0.015 mol) was added dropwise to a stirred solution of the anhydride
1 (2.32 g, 0.01 mol) in pyridine (25 ml) at 0–5°C. After complete
addition, the reaction mixture was refluxed for 1 h. It was then
poured onto crushed ice (100 g) and acidified with 2N HCl, affording
the solid lactone 21, which was filtered off, washed with water, air-
dried, and recrystallised using ethyl acetate (yield 67%, m.p. 106°C).
IR: νmax 1689, 1702 cm-1 (C=O). NMR (DMSO-d6): dH 7.55–7.52
(d, 1H, H-11, J = 8.7 Hz), 7.48–7.47 (d, 1H, H8, J = 2.1 Hz), 6.99–
6.96 (dd, 1H, H-10, J = 2.1 8.1 Hz), 3.84 (s, 3H, OCH3), 3.03 (s,
2H, CH2), 1.98 (s, 6H, 2 CH3); dC 191.3, 168.1 (2 CO), 163.3, 158.5,
156.3, 146.3, 128.5, 121.3, 119.2, 105.7, 97.4, 84.1 (10 aromatic C),
58.2 (C(CH3)2), 56.1 (OCH3), 44.7 (CH2), 26.5 (2 CH3). MS (EI):
m/z 314 (M+). Found; C, 64.75; H, 4.32. C17H14O6 requires C, 64.97;
H, 4.49%.
Received 16 October 2007; accepted 19 March 2008
Paper 07/4891
doi: 10.3184/030823408X303231
References
1
2
3
4
L.T. Power and M.P. Merters, J. Med. Chem., 1970, 13, 1102.
F. Bohlman, J. Schutz and V. Bohlman, Tetrahedron Lett., 1969, 4703.
D.R. Rerrin and C.P. Whittle, Tetrahedron Lett., 1971, 1673.
J. Schmitt, M. Suquet, J. Salle, P. Comoy and J. Le Mear, Chem. Ther.,
1966, 305.
5
J.A. Spicer, G.W. Rewcastle, M.D. Kaufman, S.L. Black, M.S. Plummer,
W.A. Denny, J. Quin, A.B. Shahripour, S.D. Barrett, C.E. Whitehead,
J.B.J. Milbank, J.F. Ohren, R.C. Gowan, C. Omer, H.S. Camp, N. Esmaeil,
K. Moore, J.S. Sebolt-Leopold, S. Pryzbranowski, R.L. Merriman,
D.F. Ortwine, J.S. Warmus, C.M. Flamme, A.G. Pavlovsky and H. Tecle, J.
Med. Chem., 2007, 50, 5090.
6
7
J.J. Parlow, R.G. Kurumbail, R.A. Stegeman, A.M. Stevens,
W.C. Stallings and M.S. South, J. Med. Chem., 2003, 46, 4696.
I. Collins, C. Moyes, W.B. Davey, M. Rowley, F.A. Bromidge, K. Quirk,
J.R. Atack, R.M. McKernan, S.A. Thompson, K. Wafford, G.R. Dawson,
A. Pike, B. Sohal, N.N. Tsou, R.G. Ball and J.L. Castro, J. Med. Chem.,
2002, 45, 1887.
8
9
J.A. Patankar, S.S. Athaiye, R.S. Verma and A.A. Dalvi, Indian J. Chem.,
2000, 39B, 548-550.
J.A. Patankar, S.S. Athalye and R.S. Verma, Indian J. Heterocycl. Chem.,
1996, 5, 311-314.
10 M. Cushman and E.J. Madaji, J. Org. Chem., 1987, 52, 907.
11 P. Waykole and R.N. Usgaonkar, Indian J. Chem., 1984, 23B, 478-479.
12 V. Cecchetti, A. Fravolini, P.G. Pagella, A. Savino and O. Tabarrini,
J. Med. Chem., 1993, 36, 3449-3454.
13 V. Cecchetti, A. Fravolini, R. Friguelli, G. Mascellani, P. Pagella,
M. Palmioli, G. Segre and P. Terni, J. Med. Chem., 1987, 30, 465-473.
14 A. Sharma and E. Tyagi, Farmazie, 1991, 46, 746-747.
15 M.D. Chordia, M. Zigler, L.J. Murphree, H. Figler, T.L. Macdonald,
R.A. Olsson and J. Linden, J. Med. Chem., 2005, 48, 5131-5139.
16 Y. Kumar, R. Green, D.S. Wise, LL. Wotring and L.B. Townsend, J. Med.
Chem., 1993, 36, 3849-3852.
17 H. Cheng, M. Kristin, L. DeMello, J. Li, S.M. Sakya, K. Ando,
K. Kawamura, T. Kato, R.J. Rafka, B.H. Jaynes, C.B. Ziegler, R. Stevens,
L.A. Lund, D.W. Mann, C. Kilroy, M.L. Haven, E.L. Nimz, J. K. Dutra,
C. Li, M.L. Minich, N.L. Kolosko, C. Petras, A.M. Silvia and S. B. Seibel,
Bioorg. Med. Chem. Lett., 2006, 16, 2076-2080.
18 B.S. Holla, M. Mahalinga, M.S. Karthikeyan, P.M. Akberali and N.S. Shetty,
Bioorg. Med. Chem., 2006, 14, 2040-2047 and references therein.
19 M.V. Patel, R. Bell, S. Majest, R. Henry and T. Kolasa, J. Org. Chem.,
2004, 69, 7058- 7065 and references therein.
20 R.K. Robins, J. Am. Chem. Soc., 1956, 78, 784-790.
21 J.E. Kerrigan, J. Oleksyszyn, C.M. Kam, J. Selzler and J.C. Powers,
J. Med. Chem., 1995, 38, 544-552.
22 C.M. Kam, J.E. Kerrigan, R.R. Plaskon, E.J. Duffy, P. Lollar, F.L. Suddah
and J.C. Powers, J. Med. Chem., 1994, 37, 1298-1306.
23 M.A. Hernandez, J.C. Powers, J. Glinski, J. Oleksyszyn, J. Vijayalakshmi
and E.F. Mayer, J. Med. Chem., 1992, 35, 1121-1129.
24 V.H. Belgoankar and R.N. Usgoankar, Tetrahedron Lett., 1975, 3849.
25 U.C. Mashelkar, K.V. Walawalkar and C.N. Arvindakshan, J. Indian
Chem. Soc., 1992, 63, 404.
26 U.C. Mashelkar, K.V. Walawalkar, C.N. Arvindakshan and A. Singh,
J. Indian Chem. Soc., 1992, 69, 404.
The help rendered by TIFR, IIT (Mumbai), and Institute of
Science (Mumbai) for IR, NMR, MS measurements and by
UDCT Mumbai for elemental analyses of new compounds is
gratefully acknowledged. We also thank Prof. K. D. Deodhar,
Department of Chemistry, IIT (Mumbai) for their valuable
support.
PAPER: 07/4891