Synthesis of some potentially bioactive compounds from visnaginone

Article abstract of DOI:10.3390/60400396

The reaction of 5-acetyl-6-hydroxy-4-methoxybenzo[b]furan (visnaginone Ia) with 2-diethylaminoethylchloride led to the formation of 5-acetyl-6- diethylamino-ethoxy-4-methoxybenzo[b]furan (II), whereas condensation of compound II with some aromatic aldehydes afforded the corresponding chalcones IIIa-c. Methylation of visnaginone (Ia) gave 5-acetyl-4,6-dimethoxybenzo[b]furan (Ib), which in turn reacted with some aromatic aldehydes to give the corresponding chalcones IIId,e. The reaction of chalcones IIId,e with hydrazine hydrate in alcohol gave the pyrazoline derivatives IVa,b, whereas when the same reaction was carried out in acetic acid it afforded the N-acetylpyrazoline derivatives Va,b. Similarly, the reaction of IIId,e with phenyl hydrazine in acetic acid led to the formation of phenylpyrazoline derivatives VIa,b, whereas condensation of chalcones IIId,e with hydroxyl amine hydrochloride gave the isoxazoline derivatives VIIa,b. The reaction of compound II with phenylhydrazine and 2,4,6-trichlorophenylhydrazine afforded the corresponding phenyl hydrazone derivatives VIIIa,b. Mannich bases IXa,b were synthesized by the reaction of visnaginone (Ia) with piperidine and benzylamine in the presence of formaline.

Full text of DOI:10.3390/60400396

Molecules 2001, 6, 396-405
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Some Potentially Bioactive Compounds From
Visnaginone
O. M. Abdel Hafez*, Kh. M. Ahmed and E. E. Haggag
National Research Centre, Natural Products and Microbiology Department, Cairo, Egypt, Fax:
+2023370931.
*Author to whom correspondence should be addressed; email: mohamed_serry@hotmail.com
Received: 7 November 1999; in revised form 19 February 2001 / Accepted: 2 March 2001/
Published: 31 March 2001
Abstract: The reaction of 5-acetyl-6-hydroxy-4-methoxybenzo[b]furan (visnaginone Ia)
with 2-diethylaminoethylchloride led to the formation of 5-acetyl-6-diethylamino-ethoxy-
4-methoxybenzo[b]furan (II), whereas condensation of compound II with some aromatic
aldehydes afforded the corresponding chalcones IIIa-c. Methylation of visnaginone (Ia)
gave 5-acetyl-4,6-dimethoxybenzo[b]furan (Ib), which in turn reacted with some
aromatic aldehydes to give the corresponding chalcones IIId,e. The reaction of chalcones
IIId,e with hydrazine hydrate in alcohol gave the pyrazoline derivatives IVa,b, whereas
when the same reaction was carried out in acetic acid it afforded the N-acetylpyrazoline
derivatives Va,b. Similarly, the reaction of IIId,e with phenyl hydrazine in acetic acid
led to the formation of phenylpyrazoline derivatives VIa,b, whereas condensation of
chalcones IIId,e with hydroxyl amine hydrochloride gave the isoxazoline derivatives
VIIa,b. The reaction of compound II with phenylhydrazine and 2,4,6-
trichlorophenylhydrazine afforded the corresponding phenyl hydrazone derivatives
VIIIa,b. Mannich bases IXa,b were synthesized by the reaction of visnaginone (Ia) with
piperidine and benzylamine in the presence of formaline.
Keywords: Visnaginone, 6-methoxyvisnaginone, 5-cinnamoylbenzofuran, 5-pyrazoline-
benzofuran, 5-isoxazolinebenzofuran, Mannich base.

Molecules 2001, 6
397
Introduction
Benzofuran derivatives have been reported to possess biological activities [1-5]. Some derivatives
of 6-aminoalkoxy-5-cinnamoyl-4,7-di-methoxybenzofuran have vasodialating and hypotensive
effects [6]. Also, 5-acetyl-6-hydroxy-4-methoxy-7-morpholinomethylbenzofuran has hypotensive and
arrhythimic activities [7]. The biological activity of Mannich bases as antiamoebic and
antiinflammatory agents has also been reported [8]. Some pyrazoline derivatives were used as
bacteriostatic, fungicidal and anticancer agents [9]. Also, isoxazoline compounds have been shown to
have antituberculosis and antibiotic activities [10-12]. Our plan was to incorporate these active
cinnamoyl, pyrazoline and isoxazoline groups and Mannich bases into the structure of the parent
compound visnaginone (Ia), with the aim of increasing its biological activity.
Results and Discussion
As shown in Scheme 1, visnaginone (Ia) was reacted with diethylaminoethyl chloride in acetone
to afford 4-methoxy-5-acetyl-6-diethylamino-ethoxybenzofuran (II). The reaction of II with some
aromatic aldehydes, namely, benzaldehyde, anisaldehyde and 4-chlorobenzaldehyde in dry methanol
in the presence of sodium methoxide afforded the cinnamoyl derivatives IIIa-c. Methylation of
visnaginone (Ia) with methyl iodide in dry acetone led to the formation of 6-methoxy visnaginone
(Ib). The reaction of (Ib) with benzaldehyde and anisaldehyde afforded the corresponding chalcones
IIId,e. The action of hydrazines on chalcones IIId,e was studied and it was found that when
compounds IIId,e were reacted with one equivalent hydrazine hydrate in alcohol, they afforded the
pyrazoline derivatives Iva,b, and when the same reaction was carried out in acetic acid the N-
acetylpyrazolinyl derivatives Va,b were obtained. The reaction of IIId,e with phenyl hydrazine was
carried out in boiling acetic acid to afford the phenyl pyrazolinyl derivatives VIa,b. On the other
hand, the isoxazolinyl derivatives VIIa,b were obtained when chalcones IIId,e were reacted with
hydroxylamine hydrochloride. Visnaginone Ia reacted with phenyl hydrazine and 2,4,6-
trichlorophenyl hydrazine to yield the corresponding hydrazones VIIIa,b. Also, visnaginone was
reacted with piperidine and benzylamine under Mannich conditions to afford the corresponding
Mannich bases IXa,b.
Experimental
General
Melting points are uncorrected. 1H-NMR spectra were run using TMS as internal reference on a Jeol
EX-270 NMR spectrometer. IR spectra were recorded on a FT/IR Jasco 300 E instrument. The
prepared compounds were analyzed for C, H and N and the microanalytical data is in full agreement
with the suggested structures (Table 1). Compound Ia was prepared according to Musante [13].

Molecules 2001, 6
398
Compound Ib was prepared according to Schonberg [14] and compound IXa was prepared according
to Ragab [7]. The biological activity of the prepared compounds is under investigation and will be
published separately in near future.
Scheme 1
OCH3
OCH3
N
C
NH R
CH3
OCH3
COCH3
OH
COCH3
OH
a
b
RNH2
CH2CH3
formalin
O
O
O
CH2 CH2 N
O
CH2CH3
Ia
CH2
R
VIII a, R = Ph
b, R = 2,4,6-Tri Cl-Ph
RNHNH2
N
IX a, R =
MeI,
K CO
acetone
b, R =
HNH2C
2
3
OCH3
OCH3
O
C
COCH3
CH3
d
a
b
CH2CH3
O
OCH3
c
O
O
CH2 CH2 N
Ib
CH2CH3
II
OCH3
N
NH
RCHO
c
NaOCH3
a
b
RCHO
NaOH
O
OCH3
OCH3
OCH3
IVa,b
CO CH=CH R
NH2NH2
EtOH
a
b
CH2CH3
c
d
OCH3
O
O CH2 CH2 N
CH2CH3
CO CH=CH R
OCH3
IIIa-c
O
OCH3
N
N
Ph
IIId,e
NH2NH2
AcOH
R
PhNHNH2
O
OCH3
VIa,b
OCH3
N
N COCH3
R
OCH3
N
O
O
OCH3
R
Va,b
O
OCH3
VIIa,b
III-VII, a,d, R = Ph; b,e, R = C6H4-OCH3 (p); c, R = C6H4-Cl (p)

Molecules 2001, 6
399
Preparation of 5-acetyl-6-diethylaminoethoxy-4-methoxybenzo[b]furan (II).
A mixture of visnaginone (0.2 mole), potassium carbonate (5.4g) and diethylaminoethyl chloride
(0.47 mole) in acetone (340 mL) was refluxed with stirring for 10 hrs. The acetone mixture was
filtered off and filtrate was evaporated under reduced pressure, and extracted with chloroform, the
chloroform washed with sodium hydroxide solution (5%), then with water, the chloroform extract
was dried over anhydrous sodium sulphate and evaporated under reduced pressure to give 5-acetyl-6-
diethylamino-ethoxy benzofuran (II) as yellowish white oil. IR (KBr) cm-1 2950 (CH-alkyl), 1750
1
(C=O), 1225 (C-N) and 1150 (C-O-C); H-NMR (CDCl3) ppm: δ 1.05 (6H, t, CH3-b), 2.45 (3H, s,
COCH3), 2.55 (4H, q, 2CH2-a), 2.8 (2H, t, CH2-c), 2.95 (2H, t, CH2-d), 4.00 (3H, s, OCH3), 6.75 (1H,
s, C-7 aromatic), 6.9 (1H, d, H3-furan) and 7.45 (1H, d, H2-furan).
General procedure for the preparation of 5-substituted cinnamoyl-6-(2-diethylaminoethoxy)-4-
methoxy benzo[b]furans (IIIa-c).
Compound II (0.3 mole) was reacted with a mixture of the appropriate aromatic aldehyde (0.3
mole), dry methanol (30 mL) and sodium methoxide (from 3g Na and 30 mL methanol) with stirring
at room temperature for 4 hrs., then water (750 mL) was added and the mixture extracted with ethyl
acetate. The organic layer washed with water, dried over anhydrous sodium sulphate, concentrated
and crystallized from methanol.
5-cinnamoyl-6-(diethylaminoethoxy)-4-methoxybenzo[b]furan (IIIa): Yield 95%, m.p. 110oC. IR:
(KBr) cm-1, 3000 (C-H), 1730 (C=O), 1615 (cinnamoyl C=C) and 1135 (C-O-C); 1H-NMR (DMSO-
d6) ppm: δ at 1.0 (6H, t, CH3-a), 2.45 (4H, q, CH2-b), 2.7 (2H, t, CH2-c), 3.57 (2H, t, CH2-d), 4.0 (3H,
s, OCH3 aromatic), 4.20 (3H, s, OCH3-C4), 6.9-7.4 (6H, m, benzene ring), 7.55 (1H, d, H3 furan) and
7.7 (1H, d, H2-furan).
5-(4-Methoxycinnamoyl-6-(diethylaminoethoxy)-4-methoxybenzo[b]furan (IIIb): Yield 90%, m.p.
1
116oC. IR: (KBr) cm-1, 3110 (C-H), 1620 (cinnamoyl C=C), 1635 (C=O) and 1130 (C-O-C); H-
NMR (DMSO-d6) ppm: δ 0.9 (6H, t, CH3-a), 2.4 (4H, q, CH2-b), 2.6 (2H, t, CH2-c), 3.5 (2H, t, CH2-
d), 4.00 (3H, s, OCH3-aromatic), 4.10 (3H, s, OCH3-C4), 7.2, 7.9 (1H, dd, 2H-cinnamoyl), 6.95, 7.40
(4H, dd, aromatic protons), 7.45 (1H, s, C-7 aromatic), 7.5 (1H, d, H3-furan), and 7.7 (1H, d, H2-
furan).
5-(4-Chlorocinnamoyl-6-(diethylaminoethoxy)-4-methoxybenzo[b]furan (IIIc): Yield 85%, m.p.
209oC. IR: (KBr) cm-1, 3050 (C-H), 1600 (cinnamoyl C=C), 1700 (C=O), 1120 (C-O-C), 1220 (C-N)
1
and 730 (C-Cl); H-NMR (DMSO-d6) ppm: δ 0.95 (6H, t, CH2-a), 2.4 (4H, q, CH2-b), 2.75 (2H, t,
CH2-c), 3.3 (2H, t, CH2-d), 4.00 (3H, s, OCH3), 6.8-7.3 (6H, m, aromatic protons + aliphatic system),
7.5 (1H, s, H-7), 7.8 (1H, d, H-3, furan) and at 7.9 (1H, d, H-2 furan).

Molecules 2001, 6
400
General procedure for the preparation of 5-substituted cinnamoyl-4,6-dimethoxybenzo[b]furans
(IIId,e).
6-Methoxy visnaginone Ib (0.1 mole) was dissolved in ethyl alcohol (15 mL). The appropriate
aromatic aldehyde (0.1 mole) was added, followed by the addition of a solution of sodium hydroxide
(30%, 12 mL). The mixture was stirred and allowed to stand at room temperature for 24 hrs., then
diluted with water (270 mL) and acidified with dilute solution HCl. The precipitate formed was
filtered off and crystallized from ethyl alcohol.
5-Cinnamoyl-4,6-dimethoxybenzo[b]furan (IIId): Yield 97%, m.p. 106oC. IR: (KBr) cm-1, 3000 (C-
H), 1680 (C=O), 1620 (C=C) and 1165 (C-O-C); 1H-NMR (DMSO-d6) ppm: δ 3.8 (2H, s, OCH3-C4),
3.95 (3H, s, OCH3-C4), 6.8 (1H, d, H3 furan), 6.9, 7.6 (2H, dd, 2H cinnamoyl), 7.1-7.5 (5H, m,
aromatic), 7.8 (1H, d, H-3, furan) and at 7.9 (1H, d, H-2 furan).
5-(4-Methoxycinnamoyl-6-(diethylaminoethoxy)-4-methoxybenzo[b]furan (IIIe): Yield 90%, m.p.
1
108oC. IR: (KBr) cm-1, 3040 (C-H), 1700 (C=O), 1625 (C=C) and 1150 (C-O-C); H-NMR (DMSO-
d6) ppm: δ at 0.90 (6H, t, CH3-a), 2.4 (4H, q, CH2-b), 2.60 (2H, t, CH2-c), 3.5 (2H, t, CH2-d), 4.00
(3H, s, OCH3 aromatic), 4.10 (3H, s, OCH3-C4), 7.2, 7.7 (1H, dd, 2H cinnamoyl), 6.95-7.4 (5H, m,
aromatic protons), 7.45 (1H, s, H-7, aromatic), 7.5 (1H, d, H-3, furan) and at 7.9 (1H, d, H-2 furan).
General procedure for the preparation of 4,6-dimethoxy-5-(aryl-2-pyrazolin-3-yl)benzo[b]furans
(IVa,b).
Chalcones IIId,e (0.01 mole) were dissolved in ethyl alcohol (10 mL) and refluxed with
hydrazine hydrate (0.5 mL) for 10 hrs. The reaction mixture was diluted with water (50 mL) and the
solid formed was filtered off and crystallized from ethyl alcohol.
4,6-Dimethoxy-5-(phenyl-3-pyrazolin-3-yl)benzo[b]furan (Iva): Yield 55%; m.p. 131oC. IR: (KBr)
cm-1, 3230 (NH), 1620 (C=C), 1590 (C=N) and 1150 (C-O-C); 1H-NMR (DMSO-d6) ppm: δ 2.8 (1H,
dd, Ha, Jvic = 8 Hz, Jgem=15 Hz), 3.6 (1H, dd, He, Jvic = 8 Hz, Jgem = 10 Hz), 3.9 (3H, s, OCH3, C-6),
4.00 (3H, s, OCH3-C-4), 5.4 (1H, dd, Hc pyrazolinyl, Jvic = 10 Hz, Jgem = 15 Hz), 6.6 (1H, d, H3-
furan), 6.95-7.40 (4H, m, aromatic), 7.5 (1H, s, C-7), 7.9 (1H, d, H2-furan), and 9.6 (1H, s, NH,
exchangeable with D2O).
4,6-Dimethoxy-5-(4-methoxyphenyl-2-pyrazolin-3-yl)benzo[b]furan (IVb): Yield 60; m.p. 64oC. IR:
1
(KBr) cm-1, 3210 (NH), 1700 (C=O), 1625 (C=C), 1590 (C=N) and 1155 (C-O-C); H-NMR
(DMSO-d6) ppm: δ 2.9 (1H, dd, Ha), 3.6 (1H, dd, He), 3.8 (3H, s, OCH3, aromatic), 3.9 (3H, s,
OCH3-C-6), 4.0 (3H, s, OCH3, C-4), 5.4 (1H, dd, He pyrazolinyl), 6.65 (1H, d, H3-furan), 6.95, 7.65
(4H, dd, aromatic), 7.5 (1H, s, C-7), 7.9 (1H, d, H2-furan), and 9.6 (1H, s, NH, exchangeable with
D2O).

Molecules 2001, 6
401
General procedure for the preparation of 4,6-dimethoxy-5-(1-acetyl-5-aryl-2-pyrazolin-3-
yl)benzo[b]furans (Va,b).
Chalcones IIId,e (0.01 mole) were dissolved in acetic acid (10 mL) and refluxed with hydrazine
hydrate (0.5 mL) for 12 hrs. The reaction mixture was poured onto water. The solid formed was
filtered off and crystallized from ethanol.
4,6-Dimethoxy-5-(1-acetylphenyl-2-pyrazolin-3-yl)benzo[b]furan (Va): Yield 90%; m.p. 170oC. IR:
1
(KBr) cm-1, 1670 (keto amide), 1635 (C=N) and observed disappearance of NH band; H-NMR
(DMSO-d6) ppm: δ 2.2 (3H, s, COCH3), 2.7 (1H, dd, Ha, Jvic = 6 Hz, Jgem= 18 Hz), 3.5 (1H, dd, He,
Jvic = 6 Hz, Jgem = 12 Hz), 3.9, 4.00 (3H, s, OCH3, C-4,6), 6.0 (1H, dd, Hc pyrazolinyl, Jvic = 12 Hz,
Jgem = 18 Hz), 6.9 (1H, d, H3-furan), 7.1-7.3 (5H, m, aromatic), 7.6 (1H, s, C-7) and 7.95 (1H, d, H2-
furan).
4,6-Dimethoxyacetyl-5-(4-methoxyphenyl-2-pyrazolin-3-yl)benzo[b]furan (Vb): Yield 85%; m.p.
170oC. IR: (KBr) cm-1, 1660 (keto amide), 1635 (C=N); 1H-NMR (DMSO-d6) ppm: δ 2.1 (3H, s, N-
COCH3), 2.8 (1H, dd, Ha), 3.6 (1H, dd, Hc), 3.75 (3H, s, OCH3-aromatic), 3.9, 4.00 (3H, s, OCH3,
C-4,6), 5.9 (1H, dd, He), 6.9 (1H, d, H3-furan), 7.1-7.3 (4H, m, aromatic), 7.4 (1H, s, C-7), and 7.95
(1H, d, H2-furan).
General procedure for the preparation of 4,6-dimethoxy-5-(5-aryl-1-phenyl-2-pyrazolin-3-
yl)benzo[b]furans (VIa,b).
Chalcones IIId,e, (0.01 mole) were dissolved in glacial acetic acid (10 mL) and refluxed with
phenyl hydrazine (1.1 mL) for 8 hrs. The reaction mixture was cooled and poured onto water. The
precipitate thus formed was filtered off and crystallized from ethyl alcohol.
1
4,6-Dimethoxy-5-(5-diphenyl-2-pyrazolin-benzo[b]furan (VIa): Yield 75%; m.p. 120oC; H-NMR
(DMSO-d6) ppm: δ 2.8 (1H, dd, Ha, Jvic = 8 Hz, Jgem= 18 Hz), 3.6 (1H, dd, He, Jvic = 12 Hz, Jgem = 18
Hz), 3.8 (3H, s, OCH3, C-6), 400 (3H, s, OCH3, C-4), 5.85 (1H, dd, Hc, Jvic = 8 Hz, Jgem = 18 Hz),
6.95 (1H, d, H3-furan), 7.2-7.5 (10H, m, aromatic), 7.6 (1H, s, C-7) and 7.9 (1H, d, H2-furan).
4,6-Dimethoxy-1-phenyl-5-(4-methoxyphenyl)pyrazolin-3-yl)-benzo[b]furan (VIb): Yield 75%
1
(ethanol), m.p. 120oC. H-NMR (DMSO-d6) ppm: δ 2.9 (1H, dd, Ha), 3.7 (1H, dd, He), 3.75 (3H, s,
OCH3-aromatic), 3.8 (3H, s, OCH3-C-6), 4.00 (3H, s, OCH3-C-4), 5.85 (1H, dd, Hc), 6.9 (1H, d, H3-
furan), 7.1-7.4 (9H, m, aromatic), 7.45 (1H, s, C-7), 7.9 (1H, d, H2-furan).

Molecules 2001, 6
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General procedure for the preparation of 4,6-dimethoxy-5-(5-aryl-2-isoxazolin-3-yl)benzo[b]furans
(VIIa,b).
Chalcones IIId,e (0.01 mole) were dissolved in ethanol (10 mL) and a mixture of hydroxylamine
hydrochloride (0.8g) in ethanol (8 mL) and water (2 mL) was added, followed by few drops of
potassium hydroxide (50%). The reaction mixture was refluxed for 9 hrs. The solid formed was
filtered off and crystallized from ethyl alcohol.
4,6-Dimethoxy-5-(phenyl-2-isoxazolin-3-yl)benzo[b]furan (VIIa): Yield 80%; m.p. 138oC; IR:
1
(KBr) cm-1, 1635 (C=N), 1600 (C=C), and 1030 (C-O-C); H-NMR (DMSO-d6) ppm: δ at 2.45 (1H,
dd, Ha, Jvic = 6 Hz, Jgem= 18 Hz), 3.8, 3.9 (3H, s, OCH3, C-4,6), 4.1 (1H, dd, He, Jvic = 6 Hz, Jgem
=
12 Hz), 5.5 (1H, dd, Hc, Jvic = 12 Hz, Jgem = 18 Hz), 6.9 (1H, d, H3-furan), 7.2-7.4 (5H, m, aromatic),
7.5 (1H, s, C-7) and 7.9 (1H, d, H2-furan).
4,6-Dimethoxy-5-(4-methoxyphenyl)-2-isoxazolin-3-yl)benzo[b]-furan (VIb): Yield 70%; m.p.
70oC. IR: (KBr) cm-1, 1635 (C=N), 1620 (C=C), and 1030 (C-O-C); 1H-NMR (DMSO-d6) ppm: δ 2.4
(1H, dd, Ha), 3.8 (3H, s, OCH3, aromatic), 3.9, 4.00 (3H, s, OCH3-C-4,6), 4.3 (1H, dd, He), 5.5 (1H,
dd, Hc), 6.8 (1H, d, H3-furan), 7.1-7.4 (4H, dd, aromatic, J = 8 Hz), 7.45 (1H, s, C-7), 7.9 (1H, d, H2-
furan).
General procedure for the preparation of 5-(1-arylhydrazono-ethyl)-6-(2-diethylaminoethoxy)-4-
methyl benzo[b]furans (VIIIa,b).
Compound II (0.01 mole) was dissolved in ethyl alcohol (10 mL), 0.1 mole of a hydrazine was
added (phenyl hydrazine in case of VIIIa and 2,4,6-trichlorophenyl hydrazine in case of VIIIb),
followed by the addition of few drops of acetic acid and the reaction mixture was refluxed for 5 hrs.
and then cooled. The solid material was filtered off and crystallized from ethyl alcohol.
5-(2-Phenyhydrazonethyl)-6-diethylaminoethyl)-4-methoxy-benzo[b]furan (VIIIa): Yield 70%;
m.p. 125oC; IR: (KBr) cm-1, 3150 (NH), 1630 (C=C), 1597 (C=N), 1320 (C-N), and 1106 (C-O-C);
1H-NMR (DMSO-d6) ppm: δ 0.9 (6H, t, 2CH3-b), 2.5 (4H, q, 2CH2-a), 3.3 (2H, t, 2CH2-d), 3.9 (3H,
s, OCH3), 7.1 (1H, d, H3-furan), 7.4 (5H, m, aromatic), 7.6 (1H, s, C-7), 7.7 (1H, d, H2-furan), 10.0
(1H, s, NH exchangeable with D2O).
5-(2,4,6-Trichloro-1-phenyhydrazonoethyl)-6-(diethylamino-ethyl)-4-methoxybenzo[b]furan
(VIIIb): Yield 75%; m.p. 130oC; IR: (KBr) cm-1, 3175 (NH), 1630 (C=C), 1597 (C=N), 1320 (C-N),
and 1106 (C-O-C); 1H-NMR (DMSO-d6) ppm: δ 1.00 (6H, t, 2CH3-b), 2.6 (4H, q, 2CH2-a), 3.2 (2H,
t, CH2-d), 3.9 (3H, s, OCH3), 7.2 (1H, d, H3-furan), 7.4 (2H, s, aromatic), 7.6 (1H, s, C-7), 7.7 (1H, d,
H2-furan), 10.0 (1H, s, NH, exchangeable with D2O).

Molecules 2001, 6
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General procedure for the preparation of 5-acetyl-6-hydroxy-4-methoxy-7-substituted methyl
benzo[b]furans (IXa,b).
Visnaginone (Ia, 0.01 mole) was dissolved in ethyl alcohol (20 mL). Formalin (0.5 mL) and the
appropriate amine (0.01 mole) were added. The reaction mixture was refluxed for 3 hrs., and then
cooled. The precipitate formed was filtered off and crystallized from ethyl alcohol.
5-Acetyl-6-hydroxy-4-methoxy-7-piperidinomethylbenzo[b]furan (IXa): Yield 80%; m.p. 105oC; IR:
1
(KBr) cm-1, 3400 (broad OH), 3200 (NH), and 1320 (C-N); H-NMR (DMSO-d6) ppm: δ 2.3 (CH2-
N), 3.9 (3H, s, COCH3), 4.0 (3H, s, OCH3), 4.8-5.2 (10H, m, piperidine), 6.9 (1H, d, H3-furan), 7.9
(1H, d, H2-furan), 12.1 (1H, bs, OH).
5-Acetyl-6-hydroxy-4-methoxy-7-benzylaminoethylbenzo[b]furan (IXb): Yield 90%; m.p. 120oC;
IR: (KBr) cm-1, 3400 (broad OH), 3150 (NH), 1350 (C-N); 1H-NMR (DMSO-d6) ppm: δ at 2.4 (2H,
s, CH2-N), 2.6 (2H, s, CH2-Ph), 3.9 (3H, s, COCH3), 4.00 (3H, s, OCH3), 6.9 (1H, d, H3-furan), 7.1-
7.3 (5H, m, aromatic), 7.9 (1H, d, H2-furan), 12.1 (1H, br.s, OH).
Table 1: Physical data for the prepared benzo[b]furan (IIIa-IXb)
OCH3
X
O
O Y
Z
X
M.P. oC
Mol. Formula
Mol. wt.
CHN Analysis %
Calc.-Found
No.
IIIa
IIIb
IIIc
IIId
Y
(Yield,%)
Z
Cinnamoyl
73.28
6.87
3.56
70.92
6.86
3.31
67.37
6.08
3.27
73.45
110
95
C24H27NO4
393
2-diethylaminoethyl
6.62
3.25
70.73
6.91
3.16
67.13
6.24
3.43
H
p-methoxycinnamoyl
116
90
C25H29NO5
423
2-diethylaminoethyl
H
4-chlorocinnamoyl
190
90
C24H26NO4Cl
427.5
2-diethylaminoethyl
H
cinnamoyl
methyl
H
106
97
C19H16O4
308
74.03
5.19
74.35
5.28

Molecules 2001, 6
p-methoxycinnamoyl
404
108
90
C20H18O5
338
71.06
5.33
70.52
5.17
methyl
IIIe
IVa
IVb
Va
H
5-phenyl-2-pyrazolin-3-yl
70.81
5.59
8.69
68.18
5.68
7.95
69.23
5.49
7.69
67.00
5.58
7.10
75.38
5.53
7.04
70.54
5.36
8.35
68.39
5.79
8.24
69.51
5.61
7.93
67.26
5.36
7.38
75.16
5.29
7.32
131
55
C19H18N2O3
322
methyl
H
4-methoxyphenyl-2-pyrazolin-3-yl
64
60
C20H20N2O4
352
methyl
H
1-acetylphenyl-2-pyrazolin-3-yl
methyl
170
90
C21H20N2O4
364
1-acetyl-5-(4-methoxy-
173
85
C22H22N2O5
394
Vb
phenyl)pyrazolin-3-yl
methyl
1,5-diphenyl-2-pyrazolin-3-yl
121
70
C25H22N2O3
398
VIa
methyl
H
1-phenyl-5-(4-methoxy phenyl)-2-
72.89
5.61
6.54
72.53
5.89
6.98
pyrazolin-3-yl
120
75
C26H24N2O4
428
VIb
VIIa
VIIb
VIIIa
methyl
H
5-phenyl-2-isoxazoline-3-yl
70.59
5.26
4.33
70.28
4.83
4.11
138
80
C19H17NO4
323
methyl
H
5-(4-methoxyphenyl)-2-
67.99
5.38
3.97
67.68
5.21
3.71
isoxazoline-3-yl
102
70
C20H19NO5
353
methyl
H
2-phenylhydrazonoethyl
2-diethylaminoethyl
H
69.87
7.34
69.71
7.26
125
70
C23H29N3O3
395
10.63
10.41
2,4,6-trichloro-1-phenyl-
hydrazonoethyl
2-diethylaminoethyl
H
C23H26N3O3
Cl3
55.37
5.22
8.42
55.51
5.35
8.66
130
75
VIII
b
498.5
acetyl
67.33
6.93
4.62
67.76
6.84
4.38
105
80
C17H21NO4
303
IXa
H
piperidinomethyl

Molecules 2001, 6
405
acetyl
H
70.15
5.85
4.31
75.38
5.98
4.71
120
90
C19H19NO4
325
IXb
benzylaminoethyl
References
1. Fauran, C.; Eberele, J.; Raymaud, G.; Pourrias, B. and Baurgey, G.; Fr. Demande, 2,142 648, 09
Mar, 1973.
2. Khan, M.S.Y and Sharma, P., Indian J. Chem., 1993, 22B, 374.
3. Fauran, C.; Eberele, J. and Berthon, D., Chimie Therapeutique, 1973, No. 4, 475.
4. Bourgerg, G.; Dostert, P.; Lacour, A.; Longlois, M.; Pourrias, B. and Vesailles, J. T.; J. Med.
Chem., 1981, 24, 159.
5. Fauran, C.; Eberele, J.; Raynaud, G. and Dorme, N.; Fr. Demande 2,178,815, 21 Dec. 1973.
6. Fauran, C.; Eberele, J.; Raynaud, G. and Pourrias, B.; Ger. Offen, 2, 238, 115. (C. A. 78,
147775, 1973).
7. Ragab, F. A.; El-Ansary, S. L. and Hassan, A. B.;. Egypt. J. Pharm. Sci., 1992, 33, 931.
8. Burckhalter, J. H.; Tendick, F. H.; Jones, E. M.; Jones, P. A.; Holcomb, W. F. and Rawlins, A.
L. J. Am. Chem. Soc., 1948, 70, 1363.
9. Clinton, R. O.; Manson, A. J.; Stonner, F. W.; Beyler, A. L. and Potts, G. O.;. J. Am. Chem. Soc.,
1995, 81, 1513.
10. Doyle, F. P. and Nayler J. H. C.;. U.S. Pat. 2, 996,501 (1014, 1961), (C. A., 56, 5971h, 1962).
11. Katritzky, A. K.; Advanced Heterocyclic Chemistry, Academic Press, New York and London
1966, vol. 6, pp. 347.
12. Fawzy, N. M.;, Mans. Sci. Bull. 1997, 24, 101.
13. Musante, C.; Fabbrini, L. and Franchi, A.;. Farmaco (Pavia), Ed. Sci., 1962, 17, 526.
14. Schonberg, A; Badran, N. and Starkowsky, N. A.; J. Am. Chem. Soc., 1953, 75, 4992.
Sample Availability: Samples of compounds IIIe, IVa, IVb, Va, VIa, VIb, IXa and IXb are
available from MDPI.
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