Novel 1H-2-benzopyran-1-one and 2,3-benzodiazepin-1-one derivatives

Article abstract of DOI:10.3184/030823408X291514

A number of novel 1H-2-benzopyran-1-one derivatives have been synthesised using the readily obtainable starting material obtained from the Stobbe-type condensation of diethyl homophthalate with p-anisaldehyde. Bromination, followed by hydrazinolysis, produced the tetrahydro-2,3-benzodiazepin-1-one derivative 5.

Full text of DOI:10.3184/030823408X291514

JOURNAL OF CHEMICAL RESEARCH 2008
JANUARY, 59–60
RESEARCH PAPER 59
Novel 1h-2-benzopyran-1-one and 2,3-benzodiazepin-1-one derivatives
Mahmoud R. Mahmouda, Manal M. El-Shahawia* and Samira E. Farahatb
aChemistry Department, Faculty of Science, Ain Shams University, Abbssia 11 566, Cairo, Egypt
b7th of April University, Gharian, Libya
A number of novel 1H-2-benzopyran-1-one derivatives have been synthesised using the readily obtainable starting
material obtained from the Stobbe-type condensation of diethyl homophthalate with p-anisaldehyde. Bromination,
followed by hydrazinolysis, produced the tetrahydro-2,3-benzodiazepin-1-one derivative 5.
Keywords: isocoumarins, isoquinolinones, homophthalic esters, 2-benzopyran-1-ones
1H-2-Benzopyran-1-ones (isocoumarins) and their 3,4-
dihydro derivatives are a class of natural products that occur
as microbial metabolites and exhibit interesting biological
properties.1-12 The authors’ objective was to construct the
desired isocoumarin derivatives and study their behaviour
towards different nucleophilic reagents.
ketone carbonyls, respectively. Moreover, cyclisation of 6
with acetyl chloride yielded (Z)-4-(4-methoxybenzylidene)-
3-oxo-3,4-dihydro-1H-2-benzopyran-1-one (8), and its IR
spectrum shows absorption bands at 1770 cm-1 and 1729 cm-1
expected for a six-membered anhydride (coupled vibrations)
with α,β-conjugation. The same product 8 was obtained in
fairly high yield upon treatment of 1 with acetic anhydride
in the presence of zinc chloride (Scheme 1). Compound 8
is a useful intermediate for the synthesis of heterocyclic
compounds, in particular isocoumarins and isoquinolinones,
as will be revealed in a later paper.
Results and discussion
The condensation of p-anisaldehyde with dimethyl
homophthalate in the presence of sodium hydride in dry
benzene afforded the (Z)-half ester 1 (85%) together with
the (Z)-diester 2 (15%). The preferential formation of the
Z-configuration for the half ester 1 and the diester 2 may be
rationalised by considering the strain associated with the (E)-
isomer due to steric interference between the o-carboxyphenyl
(or o-methoxycarbonylphenyl) and the bulky substituted aryl
group.
4-Bromo-4-methoxycarbonyl-3-(4-methoxyphenyl)-3,4-
dihydro-1H-2-benzopyran-1-one (3) was formed as the
sole product via the treatment of the (Z)-half ester 1 with
a mixture of bromine and acetic acid. The reaction of the
isocoumarin derivative 3 with thiourea in ethanol yielded
the thioisocoumarin derivative 4. The primary element tests
indicated the absence of nitrogen and showed the presence of
sulfur and bromine. The IR spectrum of 4 revealed absorption
bands at 1727 cm-1 and 1138 cm-1 corresponding to C=O ester
and C=S groups, respectively, but no absorption band for the
carbonyl group of a δ-lactone. The reaction of compound 3
with hydrazine hydrate afforded the benzodiazepine derivative
5 (Scheme 1).
Experimental
Melting points were taken on Griffin & George melting point
apparatus. IR spectra were recorded on a Pye-Unicam SP1200
spectrophotometer using the KBr wafer technique. The 1H NMR
spectra were determined on a Varian Gemini 200 MHz, Bruker AC-
200 MHz using TMS as internal standard. The mass spectra were
determined using HP model MS-5988 at electron energy 70 eV.
Elemental analyses were carried out at the Microanalytical Unit,
Faculty of Science, Cairo University using a Perkin-Elmer 2400
CHN Elemental Analyser.
Methyl (Z)-2-(o-carboxyphenyl)-3-(4-methoxyphenyl)prop-2-enoate (1)
and methyl (Z)-2-(o-methoxycarbonylphenyl)-3-(4-methoxyphenyl)
prop-2-enoate (2)
p-Anisaldehyde (8.16 ml, 0.06 mole) was added dropwise to a solution
of dimethyl homophthalate (12.5 g, 0.06 mole) in dry benzene (100 ml)
with stirring, then sodium hydride (1.9 g, 0.08 mole) was added.
The whole mixture was stirred for 10 minutes (TLC). The solid
deposited was filtered off and treated with 10% aqueous sodium
carbonate. The alkaline filtrate was acidified and the solid deposited
was filtered off, dried and recrystallised to give 1. The part insoluble
in sodium carbonate solution (neutral fraction) was separated by
filtration, dried and recrystallised to give 2.
Acid ester 1: Colourless crystals (85%, ethanol), m.p. 145–146°C.
IR: νmax 3468–2960 br (OH), 1719 (C=O ester), 1687 cm-1 (C=O
acid). NMR (CDCl3): δH 11.2 (s, 1H, COOH), 8.3–6.6 (m, 9Harom
+ CH= ), 3.75 (s, 3H, OMe), 3.6 (s, 3H, CO2Me); MS: m/z (%) 312
Mild saponification of 1 and/or 2 yield the (Z)-dibasic
acid 6. Cyclisation of 6 using concentrated sulfuric acid
at 0ºC yielded the ketolactone 7, the IR spectrum of which
shows strong absorption bands at 1748 cm-1 and 1706 cm-1
corresponding to δ-lactone and saturated five-membered
Ar
Ar
H
H
CO Me
2
CO Me
2
Ar
Br
Br
Ar
b
a
d
CO H
2
CO Me
2
H
O
H
O
CO H
CO R
2
2
O
S
6
1, R = H
3
4
e
f
2, R = Me
c
O
CO Me
2
MeO
Ar
Ar
H
Br
H
O
NH
NH
g
1
O
O
O
O
Ar = p-MeOC H
6 4
O
5
8
7
Scheme 1 Reagents: a, Br2/AcOH; b, (H2N)2C=S; c, N2H4.H2O/pyridine; d, NaOH/H2O; e, c.H2SO4, 0°C; f, AcCl; g, Ac2O/ZnCl2
* Correspondent. E-mail: elshahawi31@yahoo.com
PAPER: 07/4750

60 JOURNAL OF CHEMICAL RESEARCH 2008
(M+., 58), 252 (17), 194 (5), 121 (100), 91 (5), 65 (4). Anal. Calcd. for
C18H16O5 (312.33): C, 69.22; H, 5.16, Found: C, 69.09; H, 5.40%.
Diester 2: Pale grey crystals (15%, benzene), m.p. 50–51°C. IR:
νmax 1702 cm-1 (C=O). NMR (CDCl3): δH 8.0-6.85 (m, 8H, arom),
6.6 (s, 1H, =CH), 3.8 (s, 3H, Ar-OMe), 3.7 (s, 3H, CO2Me), 3.65
(s, 3H, CO2Me). MS: m/z (%) 326 (M+, 100), 252 (30), 165 (44), 91
(14), 77 (22), 65 (18). Anal. Calcd. for C19H18O5 (326.36): C, 69.93;
H, 5.56, Found: C, 70.28; H, 5.38%.
(39). Anal. Calcd. for C17H14O5 (298.30): C, 68.45; H, 4.73, Found:
C, 68.28; H, 5.06%.
4b,10b-Dihydro-2-methoxyindeno[1,2-c][2]benzopyran-6,11-
dione (7)
Compound 6 (0.9 g, 3 mmol) was stirred at 0°C with concentrated
sulfuric acid (10 ml) for 30 minutes, then cooled overnight in a
refrigerator. The reaction mixture was poured onto ice/cold water and
the obtained solid was filtered off, dried and recrystallised (ethanol)
to give 7 as buff crystals (86%), m.p. 250–251°C. IR: νmax 1748
(C=O lactone), 1706 cm-1 (C=O ketone). MS: m/z (%) 280 (M+, 38),
279 (12), 235 (28), 207 (17). Anal. Calcd. for C17H12O4 (280.29): C,
72.85; H, 4.32. Found: C, 73.11; H, 4.07%.
Methyl 4-bromo-3,4-dihydro-3-(4-methoxyphenyl)-1-oxo-1H-2-benzo-
pyran-4-carboxylate (3)
To compound 1 (1 g, 3 mmol) in acetic acid (15 ml), bromine
(1 ml) was added dropwise over 5 minutes with continuous stirring
which was continued for a further 10 minutes (TLC). The deposited
colourless crystals were filtered off, washed with acetic acid, dried
and recrystallised (methanol) to give 3 as colourless crystals (82%),
m.p. 180–181°C. IR: νmax 1742 (C=O lactone), 1714 cm-1 (CO ester).
NMR (CDCl3): δH 8.2–6.8 (m, 8H, arom), 5.86 (s, 1H, C3-H), 3.9 (s,
3H, Ar-OMe), 3.8 (s, 3H, Ar-CO2Me). Anal. Calcd. for C18H15BrO5
(391.20): C, 55.27; H, 3.86; Br, 20.42; Found: C, 55.19; H, 4.09; Br,
20.16%.
(Z)-4-(4-Methoxybenzylidene)[2]benzopyran-1,3(4H)-dione (8)
The dicarboxylic acid 6 (1 g, 3 mmol) and acetyl chloride (10 ml) were
heated to reflux for 10 minutes on water bath. The reaction mixture
allowed to cool and the obtained solid was collected by filtration,
washed with petroleum ether (80–100°C), dried and recrystallised
(benzene) to give 8 as orange crystals (79%), m.p.124–125°C.
IR: νmax 1770, 1729 (cyclic anhydride). NMR (CDCl3): δH 8.1–7.0
(m, 8H, arom), 6.9 (s, 1H, olefinic H) and 3.9 (s, 3H, OMe). MS:
m/z (%) 280 (M+, 84), 252 (24), 236 (7), 193 (52), 165 (100). Anal.
Calcd. For C17H12O4 (280.29): C, 72.85; H, 4.32. Found: C, 72.63;
H, 4.42%.
Methyl 4-bromo-3,4-dihydro-3-(4-methoxyphenyl)-1-thioxo-1H-2-benzo-
pyran-4-carboxylate (4)
Compound 3 (1 g, 0.0025 mol) and thiourea (1 g, 0.013 mol) were
added to a solution of sodium ethoxide [sodium metal (0.125 g) in
absolute ethanol (30 ml)] and refluxed for 8 h (TLC). The excess
of alcohol was distilled off, and the reaction mixture was poured on
ice and hydrochloric acid to give the thionolactam 4, yellow crystals
(48%, recrystallised from benzene), m.p. 105–107°C. IR: νmax 1717
(C=O), 1138 cm-1 (C=S). Anal. Calcd. for C18H15BrO4S (407.27):
C, 53.10; H, 3.71; Br, 19.61; S, 7.87. Found: C, 52.96; H, 3.95; Br,
19.85; S, 7.53%.
Received 7 July 2007; accepted 29 December 2007
Paper 07/4750 doi: 10.3184/030823408X291514
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PAPER: 07/4750