Synthesis of some new biologically active coumarin derivatives

Article abstract of DOI:10.1007/s10593-006-0088-0

The reaction of 4-hydroxycoumarin in toluene with a variety of aromatic binucleophilic compounds has been studied. 3-(Dimethylaminomethylene)chromane-2, 4-dione was used as a key intermediate for the preparation of bis[N-(4-oxocoumarinylmethylene)]-1,4-di

Full text of DOI:10.1007/s10593-006-0088-0

Chemistry of Heterocyclic Compounds, Vol. 42, No. 3, 2006
SYNTHESIS OF SOME NEW BIOLOGICALLY
ACTIVE COUMARIN DERIVATIVES
N. Hamdi1, C. Lidrissi2, M. Saoud2, A. Romerosa Nievas2, and H. Zarrouk1
The reaction of 4-hydroxycoumarin in toluene with a variety of aromatic binucleophilic compounds has
been studied. 3-(Dimethylaminomethylene)chromane-2,4-dione was used as a key intermediate for the
preparation of bis[N-(4-oxocoumarinylmethylene)]-1,4-diamines. Alternative synthetic procedures and
antibacterial activity data of some of the new compounds are given.
Keywords: benzodiazepin-2-one, 4-hydroxycoumarin, o-phenylenediamine, antibacterial activity.
Several coumarin derivatives have revealed pronounced medicinal value as antibacterial and antifungal
agents [1-5]. Others have displayed antituber- culosis activity [6] and some have insecticidal properties [7]. This
prompted us to investigate the preparation of a new series of compounds containing coumarin moieties with
different side chains or fused rings.
We have studied the reaction of 4-hydroxycoumarin (1) and 3-(dimethylaminomethylene) chromane-2,4-
dione (2) with aromatic binuclephilic compounds.
Compound 1 was found to react with o-phenylenediamine on refluxing in toluene to give product 3
(Scheme 1). According to the elemental analysis, and IR and NMR spectroscopy data, the structure of
4-(2-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepin-2-one can be ascribed to compound 3.
A mass-spectrometric study was carried out to establish the structure of compound 3. Its mass spectrum
contains the molecular ion peak m/z 252 (16.98%) and a base peak (100%) at m/z 210, corresponding to
2-(2-hydroxyphenyl)benzimidazole (4). A tendency towards decreasing the heterocycle size is characteristic of
the mass-spectrometric behavior of 1,5-benzodiazepin-2-ones [8] and consequently the mass spectra of these
compounds contain intense peaks of the corresponding benzimidazoles. It is also known that the mass-
spectrometric fragmentation of 1,5-benzodiazepines is similar to their thermal or acid decomposition [1, 8]. In
fact, refluxing compound 3 in concentrated sulfuric acid yields benzimidazole 4 as the main product.
According to the 1H NMR spectrum in DMSO-d6 benzodiazepine 3 exists as a 4:1 mixture of tautomers
A and A'. Benzodiazepin-2-one 3 is formed due to the substitution of the hydroxyl group of coumarin 1 by one
of the amino groups of o-phenylenediamine and the C–O bond cleavage in the pyrone ring upon reaction with
the second amino group.
In a similar manner, 4-hydroxycoumarin reacts with equimolar amounts of 4-aminothiophenol and
4-aminophenol to give the corresponding coumarin derivatives 5a,b (Scheme 2).
__________________________________________________________________________________________
1
Institut National de Recherche et d'Analyse physicochimique, Technopole de Sidi Thabet 2020,
2
Tunisie; e-mail: hamdi_naceur@yahoo.fr.
Dpto. Quimica Fisica, Bioquimica y Quimica Inorganica,
Universidad de Almeria, Almeria, Spain. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 3,
pp. 361-366, March, 2006. Original article submitted December 22, 2005.
320
0009-3122/06/4203-0320©2006 Springer Science+Business Media, Inc.

Scheme 1
OH
O
H2N
+
H2N
O
1
PhMe ∆
OH
O
N
OH
N
NH
O
N
H
B
A
OH
OH
N
3
N
H
OH HN
NH
O
OH
N
conc.
H2SO4
N
H
A'
∆
4
Scheme 2
HX
PhMe
HN
∆
HX
O
O
1
+
5
H2N
a X = S, b X = O
OH
N
X
O
5'
321

1
The H NMR spectrum of compound 5a in DMSO-d6 showed the presence of a signal at 12.5 ppm
corresponding to the exchangeable NH proton, the ethylenic proton as a singlet at δ 5.6 ppm, and the aromatic
protons appear between 7.27 and 7.80 ppm. The elemental and spectral analysis was in agreement with the
structures of these compounds.
We also investigated the reaction of 4-hydroxycoumarin with an excess of N,N-dimethylformamide
dimethyl acetal (DMFDMA) which afforded the corresponding 3-(dimethylaminomethylene)chromane-2,4-
dione derivative 2. The structure was confirmed by IR, NMR, and MS analyses.
The possibility that diamines might further react inter- or intramolecularly [9-11] at either of the two
carbonyl groups prompted us to examine the interaction of aromatic diamines with compound 2. The reactions of
equimolar amounts of dione 2 and 4-phenylenediamine or 4-aminothiophenol were carried out by refluxing in
toluene for 4 h (Scheme 3). Thin layer chromatography showed the formation of a single product in both cases.
1
The H NMR spectra of compound 6a showed the presence of two doublets of the same intensity at δ 10-12,
corresponding to two exchangeable protons, the ethylenic protons of the Z- and E-isomers [12] as two doublets
at δ 7-8, and signals corresponding to the expected Ar protons.
Scheme 3
O
H2N
NMe2
+
O
O
NH2
2
PhMe reflux, 4h
O
H
N
O
O
H
N
O
O
O
6a
These observations indicated that an intermolecular double condensation has occurred to give a
bis[N-(4-oxocoumarinylmethylene)]-1,4-disubstituted aromatic diamine. Data from the elemental analysis
indicated that the calculated and observed values were within the acceptable limits (± 0.4%) and in conformity
with the assigned structure. In the addition of molar equivalents of 1,4-aromatic binucleophilic compounds to
compound 6 we did not observe any heterocyclic compound resulting from the further intermolecular
nucleophilic
attack
on
the
single
condensation
product.
Since
the
condensation
of
3-(dimethylaminomethylene)chromane-2,4-dione with aromatic binucleophile is the only route to the new
coumarinic compounds, this represents a useful synthetic method. The reactivity of compound 2 is currently
under investigation.
Some representative examples of the new compounds were tested against a pathogenic bacterial strain
and have shown activity against Staphylococcus aureus ATCC 25923. The benzodiazepin-2-one 3 exhibited the
strongest antibacterial activity. The results are summarized in Table 1.
322

TABLE 1. Antibacterial Screening of Compounds 3 and 5
Compound
Concentration, mg/disk
Inhibition zone, mm
1
2
4
1
2
4
1
2
4
50
58
58
30
33
33
39
41
40
3
5a
5b
EXPERIMENTAL
NMR spectra were recorded in DMSO-d6 or CDCl3 at room temperature on a Bruker AC instrument
1
(300 MHz for H, 75.47 MHz for 13C). Chemical shifts are expressed with positive values downfield from
Me4Si. The IR spectra were recorded on a Bruker FT-IR IFS 28 in the region between 4000 and 400 cm-1. Mass
spectra were obtained with a Hewlett–Packard 5880a spectrometer. In this case electron impact techniques were
employed. Elemental analyses were performed at the National Institute of Research and Physicochemical
Analysis in Tunisia. Melting points were determined on a Buchi apparatus and are uncorrected. TLC was
performed on aluminum-backed plates coated with silica gel 60 with F254 indicator. Column chromatography
was carried out on a silica gel 60.
4-(2-Hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepin-2-one (3). 1,2-Phenylenediamine (1.62 g, 15
mmol) was added to a solution of coumarin 1 (1 g, 6.17 mmol) in toluene (30 ml). The mixture was refluxed for
6 h. The precipitate that formed was filtered off and recrystallized from the corresponding solvent to give
compound 3 as yellow needles, mp 160°C (EtOH); yield 80%. IR spectrum, ν, cm-1 (KBr): 3293 (NH), 1599
(C=C). 1H NMR spectrum (DMSO-d6), δ, ppm: 3.62 (2H, s, CH2); 6.97-7.94 (8H, m, Harom); 10.75 (1H, s, NH);
13
14.09 (1H, s, OH). C NMR spectrum (CDCl3), δ, ppm: 90.9 (CH2); 115.7-154.1 (Carom); 167.3 (C=O); 166.5
(C=N). Mass spectrum, m/z (I, %): 252 [M]+ (16.98). Found, %: C 71.3; H 4.7; N 5.4. C12H12N2O2.
Calculated, %: C 71.42; H 4.76; N 5.55.
Reactions of 2-Aminothiophenol and 2-Aminophenol with 4-Hydroxycoumarin (1). 2-Amino-
thiophenol (1.62 g, 12.96 mmol) or 2-aminophenol (1.62 g, 14.86 mmol) was added to a solution of coumarin 1
(1 g, 6.17 mmol) in toluene (30 ml). The mixture was refluxed for 6 h. The precipitate that formed was filtered
off and recrystallized from the corresponding solvent.
4-(2-Mercaptophenylamino)coumarin (5a). Yield 75%; black needles; mp 190°C (CH2Cl2).
IR spectrum, ν, cm-1 (KBr): 3302 (NH), 1620 (C=C). 1H NMR spectrum (DMSO-d6), δ, ppm: 4.95 (1H, s, =CH);
13
7.02-7.26 (8H, m, Harom); 4.9 (1H, s, NH); 5.8 (1H, s, OH). C NMR spectrum (CDCl3), δ, ppm: 160.2 (C(2));
84.2 (C(3)); 121.5-150.2 (Carom); 154.1 (C(4)). Mass spectrum, m/z (I, %): 269 [M]+ (90.50). Found, %: C 66.8;
H 3.9; N 5.1; S 12.4. C15H11NO2S. Calculated, %: C 66.91; H 4.08; N 5.20; S 11.89.
4-(2-Hydroxyphenylamino)coumarin (5b). Yield 85%; red needles; mp 170°C (CH2Cl2). IR spectrum,
1
ν, cm-1 (KBr): 3345 (NH), 1610 (C=C). H NMR spectrum (DMSO-d6), δ, ppm: 4.86 (1H, s, =CH); 6.73-7.27
13
(8H, m, Harom); 4.8 (1H, s, NH); 5.2 (1H, s, OH). C NMR spectrum (CDCl3), δ, ppm: 160.9 (C(2)); 82.6 (C(3));
115.9-158.5 (Carom); 153.2 (C(4)). Mass spectrum, m/z (I, %): 253 [M]+ (96.50). Found, %: C 71.1; H 4.2; N 5.5.
C15H11NO3. Calculated, %: C 71.14; H 4.34; N 5.53.
323

2-(2-Hydroxyphenyl)benzimidazole (4). A solution of benzodiazepin-2-one 3 (0.5 g, 1.6 mmol) in
conc. H2SO4 (20 ml) was heated at 100ºC for 3 h. The reaction mixture was poured into water (50 ml). The
precipitate that formed was filtered off and dried. After recrystallization from ethanol, benzimidazole 4 was
obtained in 63% yield as white needles; mp 130°C (CH2Cl2). IR spectrum, ν, cm-1 (KBr): 3250 (OH); 1625
1
(C=C). H NMR spectrum (DMSO-d6), δ, ppm: 5.2 (1H, s, OH); 6.73-7.70 (8H, m, Harom); 6.2 (1H, s, NH).
13C NMR spectrum (CDCl3), δ, ppm: 152.9 (C=N); 115.3-158.5 (Carom). Mass spectrum, m/z (I, %): 210 [M]+
(90.50).
Synthesis of 3-(Dimethylaminomethylene)chromane-2,4-dione (2). A solution of coumarin 1 (0.7 g,
0.004 mol) and DMFDMA (5 ml) in toluene (20 ml) was refluxed for 4 h. The solid product formed was filtered,
washed with petroleum ether, and recrystallized from a mixture of dichloromethane and petroleum ether to give
1
red needles. Yield 70%; mp 145°C (CH2Cl2). IR spectrum, ν, cm-1 (KBr): 1714 (C=O); 2995 (C–H). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 8.00 (1H, d, J = 13.6, H-5); 7.53 (1H, d, J = 13.5, H-8); 7.20-7.30 (2H, m,
H
arom); 8.40 (1H, s, CH); 3.42 (3H, s, CH3); 3.52 (3H, s, CH3). 13C NMR spectrum (CDCl3), δ, ppm: 178.4 (C(4));
96.8 (C(3)); 164.9 (C(2)); 163.4 (=CH); 117.6-134.2 (Carom); CH3 (45.3); CH3 (49.1). Mass spectrum, m/z (I, %):
217 [M]+ (100).
Reaction of 1,4-Binucleophilic Compounds with Compound 2. A solution of compound 2 (1 g) and
the 1,4-binucleophilic compounds (1 equivalent) in toluene was heated at reflux for 4 h with stirring. The
progress of the reaction was monitored by thin layer chromatography (eluent dichloromethane–diethyl ether,
10:1). The precipitate formed upon cooling to room temperature or after evaporation of solvents was washed
with methanol and recrystallized.
Bis[N-(4-oxocoumarinylmethylene)]-1,4-phenylenediamine (6a). Yield 65%; yellow needles;
mp 220°C (EtOH). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.46 and 8.50 (1H, dd, J = 13.6, CH, Z- and
E-), 10.38 (1H, m, NH, Z- and E-); 11.58 (1H, m, NH, Z- and E-); 7.23-7.94 (8H, m, Ar). Found, %: C 69.1;
H 3.5; N 6.2. C26H16N2O6. Calculated, %: C 69.02; H 3.53; N 6.19.
Bis[N-(4-oxocoumarinylmethylene)]-4-aminothiophenol (6b). Yield 85%; white needles; mp 210°C
(MeOH). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.52 and 8.62 (1H, dd, J = 13.5, CH, Z- and E-); 10.38
(1H, m, NH, Z- and E-); 11.58 (1H, m, NH, Z- and E-); 7.33-7.84 (8H, m, Ar). Found, %: C 66.20; H 3.40;
N 2.8; S 7.3. C26H16NO6S. Calculated, %: C 66.38; H 3.40; N 2.97; S 6.80.
Biological Assays. The antibacterial activity tests of the coumarin derivatives have been carried out
using the disc diffusion (Bauer) method [13]. This consists in introducing the germ (in our case Staphylococcus
aureus ATCC 25923) at a concentration of 106 CFC/ml on the surface of a Mueller-Hinton gelose plate. Then
one applies sterile filter paper discs (diameter 6 mm) impregnated with the product that one wants to test. The
samples are kept at a temperature of 40ºC during 2 h to permit the diffusion of the product on the gelose. After
24 h of incubation at 37ºC, the diameters of the inhibition zones around the discs are measured (in our case, we
deposited on the same plates 2 to 3 discs containing the same product but with increasing doses of 1, 2, and 4
mg, to see if the inhibition of the bacterial growth is dose dependent or not).
Acknowledgements
We are very grateful to the Tunisian Ministry of Scientific Research, Technology, and Development of
Competences and the Spanish Agency of International Cooperation for generous support of this work through
the project A/2903/05.
324

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