Synthesis of biscoumarin derivatives by the reaction of aldehydes and 4-hydroxycoumarin using ruthenium(III) chloride hydrate as a versatile homogeneous catalyst

Article abstract of DOI:10.2298/JSC110427189T

The one-pot domino Knoevenagel-type condensation/Michael reaction of aromatic, heteroaromatic and aliphatic aldehydes with 4-hydroxycoumarin in aqueous media in the presence of ruthenium salt as homogeneous catalyst was investigated. It was found that 5 m

Full text of DOI:10.2298/JSC110427189T

J. Serb. Chem. Soc. 77 (4) 407–413 (2012)
UDC 546.963’131+547.587.4+547–316:544.4
JSCS–4278
Original scientific paper
Synthesis of biscoumarin derivatives by the reaction of
aldehydes and 4-hydroxycoumarin using ruthenium(III)
chloride hydrate as a versatile homogeneous catalyst
*
KHALIL TABATABAEIAN , HANNANEH HEIDARI, ALIREZA KHORSHIDI,
MANOUCHEHR MAMAGHANI and NOSRAT O. MAHMOODI
Department of Chemistry, Faculty of Sciences, University of Guilan,
P. O. Box 41335-1914, Iran
(Received 27 April, revised 6 October 2011)
Abstract: The one-pot domino Knoevenagel-type condensation/Michael reac-
tion of aromatic, heteroaromatic and aliphatic aldehydes with 4-hydroxy-
coumarin in aqueous media in the presence of ruthenium salt as homogeneous
catalyst was investigated. It was found that 5 mol % of RuCl3·nH2O catalyzes
biscoumarin synthesis in high yields (70–95 %) under optimized, mild, green
and environmentally benign reaction conditions in short times (25–35min).
Keywords: ruthenium; biscoumarin; aldehyde; 4-hydroxycoumarin; homoge-
neous catalyst; condensation reaction.
INTRODUCTION
Coumarin derivatives have received considerable attention because of their
biological importance and numerous pharmacological activities. Some coumarin
derivatives, in general, and biscoumarins, in particular, are known for their anti-
fungal, anti-HIV, anticancer, antithrombotic, anticoagulant, antimicrobial and
1–4
5
6
antioxidant,
urease inhibitory, cytotoxicity and enzyme inhibitory activities.
In addition, their optical and fluorescence emission properties have already been
7,8
studied.
Although some types of these compounds could be isolated from
plants, for example 7,7’-dihydroxy-6,6’-dimethoxy-3,3’-biscoumarin from Ery-
9
cibe obtusifolia, attempts have been made to use alternative catalysts for biscou-
marin synthesis. In 1999, Hagiwara et al. reported the use of Et AlCl as a Lewis
2
acid for the condensation of 4-hydroxycoumarin and aldehydes in acetonitrile or
10
dichloromethane at room temperature in moderate to good yields (40–80 %).
5
Later, other researchers reported a similar reaction using piperidine, molecular
iodine, tetrabutylammonium bromide (TBAB), heteropolyacids, phospho-
11
12
13
*Corresponding author. E-mail: Taba@guilan.ac.ir
doi: 10.2298/JSC110427189T
407
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TABATABAEIAN et al.
14
15
tungstic acid and sodium dodecyl sulfate (SDS) as catalysts. A number of
catalyst-free condensation reactions under thermal and microwave irradia-
1d,16–18
tion,
heating in ionic liquid 1-butyl-3-methylimidazolium tetrafluoro-
19
20
borate ([bmim]BF ) and sonochemical condition were also developed. How-
4
ever, each of the above procedures has its own disadvantages, such as long
reaction time, the use of large excess of reagents, low yield and so forth. Due to
their wide application, further development of an efficient and useful method for
the synthesis of biscoumarin derivatives was considered advantageous.
On the other hand, transition metal and especially ruthenium compounds are
favorable materials having useful characteristics, including low redox potential,
high electron transfer ability and high coordination ability to heteroatoms. They
21,22
have been employed as catalyst for various organic syntheses.
RuCl ⋅nH O
3 2
has shown suitable homogenous catalytic activity in diverse organic transforma-
23
tions, such as in the generation of hydrogen from isopropanol, deoxygenation
24
25
of aromatic N-oxides, direct arylation of arenes, etc. Hence, investigation of
26–31
ruthenium chemistry has attracted the interest of our group.
To the best of our knowledge, Ru(III) salts have never been used as a water-
soluble transition metal catalyst for the condensation reaction of 4-hydroxycou-
marins with aromatic, heteroaromatic and aliphatic aldehydes for the synthesis of
biscoumarin compounds.
RESULTS AND DISCUSSION
Details of the condensation reaction between 4-hydroxycoumarin and va-
rious aldehydes are summarized in Scheme 1. In order to optimize the reaction
conditions, the effect of various parameters were studied.
Scheme 1. RuCl3·nH2O catalyzed synthesis of biscoumarins.
Upon treatment of 4-hydroxycoumarin and 3,4-dimethoxybenzaldehyde as a
model reaction in the presence of RuCl ·nH O (5 mol %) in refluxing EtOH,
3
2
3,3’-(3,4-dimethoxybenzylidene)-bis(4-hydroxycoumarin) (2a) was formed within
30 min as a white precipitate in 46 % yield (Table I, reaction conditions 2). When
water was used as the solvent, surprisingly, the yield improved and the best re-
sults were obtained using 5 mol % RuCl ·nH O in this solvent; other polar sol-
3
2
vents such as EtOH, MeOH and CH CN gave lower yields. As is shown in Table
3
II, the temperature had a critical effect on the reaction yield and at room tem-
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RUTHENIUM (III)-CATALYZED BISCOUMARIN SYNTHESIS
409
perature, no reaction occurred even after four hours of stirring the reaction mix-
ture. However, heating the reaction mixture at 80 °C afforded the product in 84
% yield (reaction conditions 3). For yield improvement, the effect of the catalyst
loading was also studied (Table III). Increasing the catalyst loading from 5 to 10
mol % did not significantly affect the yield, while the reaction in the absence of
14
RuCl ·nH O in water at 80 °C, gave the product in only 30 % yield after 10 h.
3
2
TABLE I. Optimization of the solvent for the synthesis of 3,3’-(3,4-dimethoxybenzylidene)-
-bis(4-hydroxycoumarin); reaction conditions: 4-hydroxycoumarin, 2 mmol, 3,4-dimethoxy-
benzaldehyde, 1 mmol, RuCl3·nH2O, 5 mmol, solvent, 5 mL, temperature: 80 °C
Reaction condition
Solvent
τ / min
Yield, %
1
2
3
4
H2O
EtOH
CH3OH
CH3CN
30
30
30
30
84
46
50
30
TABLE II. Optimization of the temperature for the synthesis of 3,3’-(3,4-dimethoxybenzyl-
idene)-bis(4-hydroxycoumarin); reaction conditions: 4-hydroxycoumarin, 2 mmol, 3,4-dime-
thoxybenzaldehyde, 1 mmol, RuCl3·nH2O, 5 mmol, water, 5 mL
Reaction condition
t / °C
τ / min
Yield, %
1
2
3
4
RT
50
80
30–240
30
30
30
–
42
84
84
100
TABLE III. Optimization of the amount of RuCl3·nH2O for the synthesis of 3,3’-(3,4-di-
methoxybenzylidene)-bis(4-hydroxycoumarin); reaction conditions: 4-hydroxycoumarin, 2
mmol, 3,4-dimethoxybenzaldehyde, 1 mmol, 80 °C, water, 5 mL
Reaction condition
Amount of catalyst, mol %
τ / min
Yield, %
1
2
3
4
2
5
10
15
30
30
30
30
80
84
82
84
With the optimized conditions in hand, an array of aldehydes were treated
with 4-hydroxycoumarin using 5 mol % RuCl ·nH O at 80 °C whereby the de-
3
2
sired products were afforded in good to excellent yields (75–95 %) (Table IV).
Aromatic aldehydes, however, provided better yields in comparison with their
aliphatic counterparts. With regard to the substituents, both aldehydes with elec-
tron withdrawing and electron donating groups participated in the reaction, but
the former were better. It should be mentioned that the reaction with amides such
as N-formylpiperidine failed. Even after several modifications such as a four-fold
increase in the catalyst loading, prolonged reaction times and changing solvent,
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410
TABATABAEIAN et al.
no traceable amount of the desired product was obtained (Table IV, reaction
condition 6).
TABLE IV. Ru(III)-catalyzed synthesis of biscoumarins by condensation of 4-hydroxycou-
marin and aldehydes (all products were characterized by 1H-NMR, 13C-NMR and IR data)
Reaction condition
1
2
3
4
5
6
7
8
9
10
11
12
13
R
τ / min
Product Yielda, % M.p.b, °C
3,4-(CH3O)2C6H3
2-NO2,CH=CHC6H4
2-OH,3-CH3OC6H3
3F,4-FC6H3
2-Cl,6-FC6H3
N-Formylpiperidine
3-C6H5OC6H4
3-Indolyl
30
30
33
25
25
60
30
30
25
25
30
35
25
2a
2b
2c
2d
2e
2f
84
90
84
90
92
NRc
90
90
84
85
92
75
95
264–266c
190–192
268–270
262–264
288–290
–
2g
2h
2i
2j
2k
2l
218–220
238–240c
227–229c
252–254c
242–244c
144–146
240–242
Ph
4-ClC6H4
4-CH3OC6H4
CH3CH2
4-CNC6H4
2m
a
b
Isolated yields; m.p. are matched as given in the literature;25,28 cno reaction
The condensation products 2a and 2h–k (Table IV) are known compounds
and their spectroscopic data were consistent with those reported in the litera-
5,14,16,17a
ture.
Selected characterization data for the newly synthesized com-
pounds (2c–e, 2g and 2l–m) are given in the Supplementary material to this paper.
A proposed mechanistic route for the condensation of aldehydes and 4-hyd-
roxycoumarin that rationalizes the formation of the products is exhibited in
Scheme 2. As is shown, nucleophilic attack of 4-hydroxycoumarin to the acti-
vated aldehyde (by Ru coordination), followed by H O elimination provides in-
2
termediate “A” that is further activated by Ru. This in turn, undergoes a second
nucleophilic attack by another 4-hydroxycoumarin to provide the final product.
In order to evaluate the reusability of the catalyst, after the first run, the pro-
duct was separated from the reaction mixture by filtration and substrates were
added to the filtrate and tested again. It was found that the reused catalyst main-
tained its activity after successive runs, as is shown in Table V; after six runs, the
reused catalyst showed only 8 % decrease in the yield of the biscoumarin pro-
duct. Thus, the operational simplicity and reusability of the catalyst cover the ex-
pensive cost of ruthenium chloride hydrate.
EXPERIMENTAL
All reactions were followed by thin layer chromatography (TLC) with detection by UV
light. The IR spectra were obtained in KBr discs on a Shimadzu IR-470 spectrometer. The 1H-
-NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer and the 13C-NMR
spectra were obtained on a Bruker DRX-125 or DRX-100 Avance spectrometers. Samples
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RUTHENIUM (III)-CATALYZED BISCOUMARIN SYNTHESIS
411
were analyzed in CDCl3 or DMSO-d6, and the chemical shift values are reported in ppm re-
lative to TMS (tetramethylsilane) as the internal reference. Melting points were measured on
an electrothermal apparatus and are uncorrected. Elemental analyses were realized using a
Carlo-Erba EA1110 CNNO-S analyzer and agreed with the calculated values. The mass spec-
tra of representative compounds were recorded on a HP 5973 network mass selective detector.
Scheme 2. Proposed mechanism for the Ru(III)-catalyzed synthesis of biscoumarins.
TABLE V. Reusability of RuCl3·nH2O in successive runs
Run No.
Yield, %
1
2
3
4
5
6
84
84
82
78
76
76
Materials
4-Hydroxycoumarin, the aldehydes, RuCl3·nH2O and solvents were purchased from
Merck and used without further purification.
General procedure for the synthesis of biscoumarins
The catalytic process was performed in a liquid phase. In a typical reaction, 4-hydro-
xycoumarin (2.0 mmol, 324 mg), the corresponding aldehyde (1.0 mmol), H2O (5.0 ml) and
RuCl3·nH2O (5.0 mmol, 10.7 mg) were taken in a 50 mL round-bottom flask. The reaction
mixture was heated at 80 °C in an oil bath and stirred magnetically. After completion of the
reaction, as shown by TLC, the mixture was cooled until a solid appeared. The precipitate was
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TABATABAEIAN et al.
filtered and washed with aqueous ethanol. The crude products were recrystallized from EtOH
to yield the pure products. When testing the reusability of the catalyst, hot ethanol was added
after completion of the reaction. As the product was insoluble in the cool reaction media, after
separation of the solid product, the excess solvent was evaporated from the filtrate. The same
substrates were again added to the filtrate including the aqueous medium and catalyst without
further purification and reused in the next run.
CONCLUSION
In summary, this study presents a simple experimental procedure under mild
reaction conditions, which provides the desired products in short reaction times
and high yields. Easy working up, use of water as an eco-friendly solvent, re-
usability of the catalyst, and availability of the Ru(III) salt are other highlights of
this work. This protocol extends the applications of RuCl ·nH O to clean synthe-
3
2
tic methodologies for preparation of pharmaceutically important biscoumarins.
SUPPLEMENTARY MATERIAL
Selected characterization data of the newly synthesized compounds are available elec-
tronically from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgement. The authors thank the Research Council of University of Guilan for
the partial support of this study.
И З В О Д
СИНТЕЗА ДЕРИВАТА БИСКУМАРИНА РЕАКЦИЈОМ АЛДЕХИДА И
4-ХИДРОКСИКУМАРИНА ПОМОЋУ ХИДРАТИСАНОГ РУТЕНИЈУМ(III)-ХЛОРИДА
КАО УНИВЕРЗАЛНОГ ХОМОГЕНОГ КАТАЛИЗАТОРА
KHALIL TABATABAEIAN, HANNANEH HEIDARI, ALIREZA KHORSHIDI, MANOUCHEHR MAMAGHANI
и NOSRAT O. MAHMOODI
Department of Chemistry, Faculty of Sciences, University of Guilan, P. O. Box 41335-1914, Iran
Испитивана је секвенција домино реакција Knoevenagel-ова кондензација/Michael-ова
адиција ароматичних, хетероароматичних и алифатичних алдехида са 4-хидроксикумари-
ном, у воденој средини, у присуству рутенијумових соли као хомогених катализатора. Утвр-
ђено је да 5 mol % RuCl3·nH2O катализује синтезу бискумарина у високом приносу (70–95
%) под оптимизованим, благим и еколошки прихватљивим условима, у кратком реакционом
времену (25–35 min).
(Примљено 27 априла, ревидирано 6. октобра 2011)
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