Novel efficient three-component, one-pot synthesis of 3-(α- amidobenzyl)- 4-hydroxycoumarin derivatives

Article abstract of DOI:10.3184/174751912X13518648205073

The three-component reaction between 4-hydroxycoumarin, aromatic aldehydes and amides catalysed by p-toluenesulfonic acid in solvent-free conditions provided a simple and efficient one-pot route for the synthesis of 3-(α- amidobenzyl)-4-hydroxycoumarin derivatives in excellent yields.

Full text of DOI:10.3184/174751912X13518648205073

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 715
DECEMBER, 715–717
Novel efficient three-component, one-pot synthesis of 3-(α-amidobenzyl)-
4-hydroxycoumarin derivatives
Masud Malekpoura, Hossein Anaraki-Ardakanib* and Maziar Noeib
aDepartment of Chemistry, Omidiyeh Branch, Islamic Azad University, Omidiyeh, Iran
bDepartment of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
The three-component reaction between 4-hydroxycoumarin, aromatic aldehydes and amides catalysed by p-toluene-
sulfonic acid in solvent-free conditions provided a simple and efficient one-pot route for the synthesis of 3-(α-
amidobenzyl)-4-hydroxycoumarin derivatives in excellent yields.
Keywords: 4-hydroxycoumarin, aromatic aldehydes, amides, p-toluene sulfonic acid, 3-(α-amidobenzyl)-4-hydroxycoumarins,
solvent-free conditions
Multi-component reactions have attracted considerable atten-
tion in organic synthesis as they can produce target products
in a single operation without isolating the intermediates and
thus reducing the reaction times and energy input.1,2 Coupled
with high-throughput library screening, this strategy was an
important development in drug discovery, in the context of
rapid identification and optimisation of biologically active lead
compounds.3
The synthesis of coumarins and their derivatives has attracted
considerable attention from organic and medicinal chemists
for many years as a large number of natural products contain
this heterocyclic nucleus. They are widely used as additives
in food, perfumes, cosmetics, pharmaceuticals4 and optical
brighteners5 and dispersed fluorescent and laser dyes.6 Among
the various substituted coumarins, 3-(benzyl)-substituted 4-
hydroxycoumarins represent a significant class of biologically
active compounds (Fig. 1)7,8 and useful scaffolds, which can be
used for the synthesis of 3,4-substituted derivatives.9–12 The
existing methods for the synthesis of 3-substituted 4-hydroxy-
coumarins include direct synthesis of the target compound13–16
or C3-alkylation/substitution of 4-hydroxycoumarin.17
Recently, we reported the reaction of 4-hydroxycoumarin,
aromatic aldehydes, and acetonitrile in the presence of chloro-
sulfonic acid produced 3-(acetamidoalkyl)-4-hydroxycoumarin
derivatives.18,19 The reaction proceeds through the in situ
formation of 3-benzylidenechroman-2,4-diones, and acetoni-
trile acted as a nucleophile. We describe here a practical and
inexpensive method for the preparation of 3-(α-amidobenzyl)-
4-hydroxycoumarin derivatives via a three-component con-
densationreactionbetweenarylaldehydes,4-hydroxycoumarin,
and amides in the presence of p-toluenesulfonic acid (p-TSA)
as catalyst under thermal and solvent-free conditions. A
similar procedure has been recently used for the synthesis of
1-amidoalkyl-2-naphthols by three-component reaction of aryl
aldehydes, 2-naphthols and amides or urea.20,23
solvent-free conditions at 115 ºC; the results are listed in
Table 1 (Scheme 1). p-TSA was found to show better catalytic
activity among these catalysts. When p-TSA was used, the
reaction was completed after 5 h (the reaction progress was
monitored by TLC) and 3-(α-acetamidobenzyl)-4-hydroxy-
coumarin 4a was obtained in 85% yield (Table 1, entry 5).
Moreover, we found that the yields were obviously affected by
the loading of p-TSA. When 5 mol %, 10 mol %, 20 mol %,
and 30 mol % of p-TSA were used, the yields were 42%, 50%,
55%, and 85%, respectively (Table 1, entries 5–8). Therefore,
30 mol % of p-TSA was sufficient and a larger excess of cata-
lyst did not increase the yields significantly (Table 1, entry 8).
In addition, no product was detected in the absence of the
catalyst. Furthermore, it was found that increasing the reaction
time over 5 h or reaction temperature over 115 ºC did not
improve the yields.
The above reaction was also examined in various solvents
(Table 2). The results indicated that different solvents affected
the efficiency of the reaction. Acetone, dichloromethane and
THF afforded moderate yields (Table 2, entries 1–3), while
when 1,2-dichloroethane and toluene were used, better results
were obtained (Table 2, entries 4 and 5. However, the best
result was obtained when the reaction was carried out under
solvent-free conditions at 115 ºC (Table 2, entry 6).
To study the scope of the reaction, a series of aldehydes
and amides were employed. The results are shown in Table 3.
In all cases, aromatic aldehydes substituted with either elec-
tron-donating or electron-withdrawing groups underwent the
reaction smoothly and gave the products in good yields. It
could also be concluded that the aldehydes bearing electron-
withdrawing groups required shorter reaction times and gave
higher yields (Table 3). In addition, 4-hydroxycoumarin
reacted with aromatic aldehydes and other amides, such as
propionamide (Table 3, entry 4j) to afford the corresponding
4-hydroxy-3-(α-propionamidobenzyl)coumarin derivative in
excellent yield.
Results and discussion
Initially, we studied the reaction of 4-hydroxycoumarin,
benzaldehyde, and acetamide using different catalysts under
Compounds 4a–i were known and their structures were
deduced by comparison of melting points and spectral data
with authentic samples.18,19 Compound 4j was new and its
Fig. 1 Structures of three 3-(benzyl)-substituted 4-hydroxycoumarins.
* Correspondent. E-mail: hosseinanaraki@yahoo.com

716 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 1 Reaction between 4-hydroxycoumarin, benzaldehyde and acetamide catalysed by p-TSA.
Table 1 Acid catalysed one-pot condensation reaction between
structure was deduced by elemental and spectral analysis. For
example, the H NMR spectrum of compound 4j exhibited a
4-hydroxycoumarin, benzaldehyde and acetamidea
1
Catalyst Catalyst Temp/oC
/mol %
Time/h
Yield/%b
triplet signal at 0.91 ppm and a quartet at δ = 1.9 ppm for the
protons of the ethyl group. The methine and NH protons are
coupled and two doublets were observed for them at 7.1 and
8.7 ppm, respectively. When the 1H NMR spectrum was
recorded after addition of some D2O to the DMSO-d6 solution
of 4j the doublet due to the NH proton disappeared and the
doublet corresponding to the methine proton was converted to
a singlet. The hydroxy group proton resonated at 10.01 ppm
as a broad singlet. The 13C NMR spectrum of compound 4j
showed 17 distinct signals consistent with the proposed
structure.
Entry
1
2
NH4Cl
ZrCl4.6H2O
ZnCl2
10
10
10
10
5
10
20
30
20
40
115
115
115
115
115
115
115
115
100
115
5
5
5
3
5
3
5
5
5
6
20
30
41
40
42
50
55
85
65
85
3
4
FeCl3·3H2O
p-TSA
5
6
p-TSA
7
p-TSA
8
p-TSA
9
p-TSA
10
p-TSA
The reaction of 4-hydroxycoumarin with aromatic alde-
hydes in the presence of an acid catalyst is proposed to give
3-benzylidenechroman-2,4-diones. These 3-benzylidene-chro-
man-2,4-diones, generated in situ, react with amide to form the
3-(acetamidoalkyl)-4-hydroxycoumarin products (Scheme 2).
In conclusion, we have developed a highly efficient synthe-
sis of 3-(amidoalkyl)-4-hydroxycoumarin from aryl aldehydes,
4-hydroxycoumarin and an amide respectively under solvent-
free conditions. The advantages of the reported method are
inexpensive and easily available starting materials, simple
reaction conditions, high yields, single-product reaction and
simple workup procedure.
a Reaction conditions: 4-hydroxy coumarin (1.0 mmol), acet-
amide (1.1 mmol), benzaldehyde (1.0 mmol), neat 115 °C.
b Isolated yield.
Table 2 Solvent effect on the reaction between 4-hydroxy-
coumarin (1equiv.), benzaldehyde (1 equiv.) and acetamide
(1.1 equiv.) catalysed by p-TSA (0.3 equiv.)
Entry
Solvent
Temp/°C
Time/h
Yield/%
1
2
3
4
5
6
Acetone
Dichloromethane
THF
Reflux
Reflux
Reflux
Reflux
Reflux
115
5
5
5
5
5
5
50
52
50
65
60
85
Experimental
1,2 Dicholoroehane
Toluene
Melting points were determined with an Electrothermal 9100 appara-
tus. Elemental analyses were performed using a Heraeus CHN-O-
Rapid analyser. Mass spectra were recorded on a FINNIGAN-MAT
8430 mass spectrometer operating at an ionisation potential of 70 eV.
Neat
1
IR spectra were recorded on a Shimadzu IR-470 spectrometer. H
and 13C NMR spectra were recorded on a Bruker DRX-500 Avance
spectrometer at 500 and 125 MHz respectively for DMSO-d6 solu-
tions using TMS as internal standard. The chemicals used in this work
purchased from Fluka (Buchs, Switzerland) and were used without
further purification.
Table 3 Three-component reaction of aromatic aldehydes,
4-hydroxycoumarin and amides catalysed by p-TSA
Entry
R
Ar
Time/h Yield/%
M.p. /°CLit.
4a
4b
4c
4d
4e
4f
CH3
C6H5
5
85
88
90
89
87
90
78
80
82
80
182–185 (184–186)18,19
177–179 (175–177)18,19
209 (208–210)18,19
174 (172–174)18,19
196 (195–196)18,19
179–183 (179–182)18,19
202–204 (203–206)18,19
192 (190–191)18,19
147–148(146–148)18,19
184–186
Synthesis of compounds 4a–j; general procedure
CH3 4-Cl-C6H4
CH3 2-Cl-C6H4
CH3 4-Br-C6H4
CH3 3-NO2-C6H4
CH3 4-NO2-C6H4
5
A mixture of the appropriate amide (1.1 mmol) aldehyde (1.0 mmol),
4-hydroxycoumarin (1 mmol) and p-TSA (0.1 mmol) was stirred in
an oil bath at 115 ºC and the reaction was followed by TLC. After
completion, ethyl acetate (10 mL) was added to the reaction mixture
and the product was filtered and washed with ethyl acetate (10 mL).
N-[(4-Hydroxy-2-oxo-2H-chromen-3-yl)phenylmethyl]propionami
5
5
4.5
4.5
4g
4h
4i
CH3 3-CH3O-C6H4 5.5
CH3 2-CH3O-C6H4 5.5
CH3 2-HO-C6H4
C2H5 C6H5
o
de (4j): White powder, m.p. 184–186 C, IR (KBr) (νmax cm−1): 3320
5
5
(NH), 1674, 1629 (2 C=O). Analyses: Calcd for C19H17NO4: C, 70.58;
H, 5.30; N, 4.33. Found: C, 70.31; H, 5.36; N, 4.51%. MS (m/z, %):
4j
Scheme 2 Suggested pathway for the formation of compounds 4a–j.

JOURNAL OF CHEMICAL RESEARCH 2012 717
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Received 14 August 2012; accepted 19 September 2012
Paper 1201461 doi: 10.3184/174751912X13518648205073
Published online: 5 December 2012
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