Sulfated titania catalyzed water mediated efficient synthesis of dicoumarols - A green approach

Article abstract of DOI:10.1016/j.tetlet.2012.06.024

An efficient, mild, and environmental friendly method has been developed for the synthesis of dicoumarols in water over Lewis and Bronsted acid catalyst sulfated titania (TiO₂/SO₄^2-). The method involves the condensation of various aromatic and aliphatic aldehydes with 4-hydroxycoumarin. It affords the corresponding product in high yield with short reaction times employing a very low loading of catalyst. The catalyst was reused several times without significant change in activity.

Full text of DOI:10.1016/j.tetlet.2012.06.024

Tetrahedron Letters 53 (2012) 4343–4346
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sulfated titania catalyzed water mediated efficient synthesis
of dicoumarols—a green approach
Bikash Karmakar a,b, Anupam Nayak b, Julie Banerji b,
⇑
a Gobardanga Hindu College, Department of Chemistry, Khantura, North 24, Parganas 743273, India
b Centre of Advances Studies on Natural Products Including Organic Synthesis, Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, mild, and environmental friendly method has been developed for the synthesis of dicouma-
rols in water over Lewis and Bronsted acid catalyst sulfated titania (TiO2/SO42ꢀ). The method involves the
condensation of various aromatic and aliphatic aldehydes with 4-hydroxycoumarin. It affords the corre-
sponding product in high yield with short reaction times employing a very low loading of catalyst. The
catalyst was reused several times without significant change in activity.
Received 21 April 2012
Revised 1 June 2012
Accepted 5 June 2012
Available online 15 June 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Dicoumarol
Aldehydes
Sulfated titania
Aqueous medium
Reusable
Throughout the last decade, the concept of ‘Green Chemistry’
has been globally adopted in science and technology to protect hu-
man health and environment. In organic chemistry, the impetus
has been made on the search for alternate chemical pathways to
accomplish the desired chemical conversions with minimal expo-
sure of toxic wastes to environment.1 Following this connection,
removal of organic solvents has become an important factor
toward developing benign chemical technologies due to the haz-
ards involved and their high toxicity. As a result, organic reactions
in aqueous media have come into prominence in view of the green
methodology involved.2 The use of water is also preferred due to
its abundance, being economical, and high polarity. It shows higher
reactivity and selectivity compared to other organic solvents due
to its strong hydrogen bonding ability.
Multicomponent reactions (MCRs) have drawn the attention of
synthetic organic chemists for constructing highly functionalized
organic motifs and biologically important heterocycles in an one
pot and atom-economical way.3 Coumarins are an important class
of organic compounds which are used as additives to food, in cos-
metics, and as optical brightening agents.4 Many of them are highly
biologically active.5 Dicoumarol is an important class of naturally
occurring coumarin derivative which is an anticoagulant and also
functions as a vitamin K antagonist.6 Further, lanthanum (III)
complexes of dicoumarol are observed to show effective cytotoxic
activity.7 Its synthetic derivative warfarin sodium (coumadin) is
used for the treatment of a variety of cancers and improves tumor
response rates and survival in patients with several types of can-
cer.8 Dicoumarol in combination with taxol has been reported to
show a synergistic inhibition of cell division of sea urchin embryos.
This combination drug markedly reduces the high toxicity of taxol.
Dicoumarols are generally synthesized by combination of two
equivalents of 4-hydroxycoumarin and different aldehydes. In the
recent few years several methods have been reported for this syn-
thesis which includes the use of different catalysts like molecular
iodine,9 DBU,10 MnCl2,11 POCl3 in dry DMF,12 Et2AlCl3,13 SO3H func-
tionalized ionic liquids,14 [bmim][BF4],15 TBAB,16 Zn(Proline)2,17
SDS,18 refluxing in ethanol or acetic acid19 thermal solvent-free
microwave condition20 etc. However, keeping in mind of their
own intrinsic worth, we decided to carry out further development
of the procedure in view of simplicity, greenness, and economic
viability, as many of the reported methods suffer from drawbacks
like refluxing in organic solvents for prolonged time, harsh condi-
tions, use of expensive and toxic catalysts, and low product yields.
In continuation of our ongoing research on the use of heteroge-
neous catalysts in organic synthesis,21 we report herein a green
and expedient synthesis of dicoumarols over sulfated titania
(TiO2/SO42ꢀ) in water for the first time.22 In the recent past sulfated
titania has emerged as a promising solid acid catalyst in many
organic transformations.23 The advantages of using this catalyst
are non hazardous, very selective, easier work-up to separate it,
and reusability. The reaction proceeded in short time with high
yields of the products (Scheme 1). The catalyst has been recycled
several times with no substantial loss in activity.
⇑
Corresponding author. Tel.: +91 33 2350 8386; fax: +91 33 2351 9755.
E-mail address: juliebanerji47@gmail.com (J. Banerji).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.024

4344
B. Karmakar et al. / Tetrahedron Letters 53 (2012) 4343–4346
R
OH
OH
O
CHO
OH
O
2-
TiO2/SO4
+
o
H2O, 80 C
O
O O
O
R
Scheme 1. Synthesis of dicoumarol derivatives over sulfated titania.
Table 1
Screening of catalysts in the synthesis of dicoumarol (3af) in watera
Table 2
Solvents effect in the synthesis of dicoumarol (3af) over TiO2/SO4 (15%) catalysta
Entry
Catalyst
Time
Yield (%)
2ꢀ
1
2
3
4
5
—
24 h
12 h
12 h
12 h
2 h
Trace
45
52
67
72
Entry
Solvent
Temperature (°C)
Time
Yielda (%)
NH4Cl
PTSA
ZnCl2
1
2
3
4
5
H2O
80
45
110
78
15 min
12 h
12 h
2 h
96
38
52
75
88
CH2Cl2
Toluene
CH3CN
MeOH
L-Proline
6
7
8
9
Unsulfated TiO2
TiO2/SO4 (5%)
TiO2/SO4 (10%)
TiO2/SO4 (15%)
2 h
75
85
90
96
2ꢀ
65
2 h
15 min
15 min
15 min
2ꢀ
a
Reaction condition: 4-Chlorobenzaldehyde:4-hydroxycoumarin = 0.5:1, cata-
lyst 10 wt%, isolated yield.
2ꢀ
a
Reaction condition: 4-Chlorobenzaldehyde:4-hydroxycoumarin = 0.5:1, cata-
lyst 10 wt%, water bath (80 °C), isolated yield.
Table 3
Synthesis of the dicoumarols by condensation of 4-hydroxycoumarin and different aldehydes in water over TiO2/SO4 (15%) catalysta
2ꢀ
OH
R
OH
OH
2-
TiO2/SO4
RCHO
+
o
H2O, 80 C
O
O
O
O O
O
1
2
3
Entry
R
Product
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
C6H5
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
15
15
12
30
15
15
20
15
12
15
15
20
25
15
12
20
25
15
12
25
15
20
30
25
15
15
15
15
15
12
92
90
90
88
92
96
91
94
89
95
84
96
85
88
92
89
85
90
94
82
96
89
86
85
90
88
90
90
92
95
2-NO2 C6H4
3-NO2 C6H4
4-NO2 C6H4
3-Cl C6H4
4-Cl C6H4
3-Br C6H4
4-Br C6H4
4-Me C6H4
2-OH C6H4
3-OH C6H4
4-OH C6H4
2-OMe C6H4
3-OMe C6H4
4-OMe C6H4
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3at
3au
3av
3aw
3ax
3ay
3az
3ba
3bb
3bc
3bd
4-OH-3-OMe C6H3
3-OH-4-OMe C6H3
3,4-DiOMe C6H3
3,4,5-TriOMe C6H2
4-OBn-3-OMe C6H3
4-CN C6H4
4-NMe2 C6H4
–CH@CH C6H5
1-Naphthyl
2-Furyl
Ethyl
Propyl
iPropyl
–CH@CH CH3
H
a
2ꢀ
Reaction condition: Aldehyde:4-hydroxycoumarin = 0.5:1, 15 wt% TiO2/SO4 catalyst (10 wt%), water bath (80 °C), isolated yield.

B. Karmakar et al. / Tetrahedron Letters 53 (2012) 4343–4346
4345
Bronsted acid site
Lewis acid site
O
O
O
Ti
O
O
Ti
O
O
Ti
S
S
OH
Ti
O
O
+
+
TS
O
Ti
Ti
Ti
O
O
O
O
O
O
O
TS
O
OH
O
O
OH
O
TS
-H2O
O
R
+
+
R
H
O
O
-H+/+H+
OH
O
R
OH
OH
R
O
O
enolisation
H
OO
OO
O
O
Scheme 2. Active catalytic sites of sulfated titania and the plausible reaction pathway toward the formation of dicoumarols.
interact with each other for the smooth conversion to the desired
product. Further, the optimum ratio of 4-hydroxycoumarin and
aldehyde was found to be 1.0:0.5.
Table 4
2ꢀ
Reusability study of TiO2/SO4 catalyst in the condensation of 4-hydroxycoumarin
and 4-chlorobenzaldehyde at optimum conditions
Subsequently, a range of dicoumarols were synthesized using
different aldehydes and 4-hydroxycoumarin under the standard-
ized reaction. The results have been summarized in Table 3.
Regardless of the nature of the substitution (electron donating
and electron withdrawing) of the aromatic aldehydes, the products
were obtained in excellent yields (entries 1–24). Similar results
were obtained with the heteroaromatic and aliphatic aldehydes
(entries 25–30). All the reactions were completed within
10–30 min. In these reactions there was no need for column puri-
fication of the products. The solid products obtained were just
filtered off the reaction mixture, dissolved in hot ethanol and again
filtered to separate any contaminated catalyst with the product
and finally recrystallized from the filtrate to obtain pure
dicoumarols.
Cycles
4-Hydroxycoumarin (gm)
Catalyst (mg)
Yielda (%)
Fresh
0.5
0.4
0.3
0.2
0.1
50
40
35
25
10
96
94
93
90
88
1
2
3
4
a
Isolated yield.
At the outset, we tried the condensation of 4-chlorobenzalde-
hyde and 4-hydroxycoumarin as a probe reaction over 5 wt%
TiO2/SO4 catalyst in water at water bath (80 °C). To our delight,
it afforded the corresponding dicoumarol (3af) in 85% yield within
15 min. The reaction was optimized further to obtain the best
result. In an effort to develop the best catalytic system, a screening
of catalysts was carried out with the probe reaction. As shown in
2ꢀ
Regarding the mechanism, the transformation involves
a
Knoevenagel condensation of 4-hydroxycoumarin with the alde-
hydes followed by a Michael addition with another molecule of
4-hydroxycoumarin (Scheme 2). The catalyst possesses as many
Lewis acid sites as Bronsted acid sites. The superacidity can be
attributed to the Bronsted acidic hydroxyl groups attached to Ti
atom, being generated by interaction with water and also already
existing. The acidity is enhanced by the generation of Lewis acid
Table 1, different catalysts like NH4Cl, PTSA, ZnCl2, L-Proline,
unsulfated TiO2, and TiO2/SO42ꢀ with different SO42ꢀ loadings were
treated with the starting materials in water at 80 °C. It clearly re-
vealed that sulfated titania catalysts were superior to others in
terms of reaction and yields. The 15 wt% loaded catalyst was found
to be the best affording 96% yield of the desired product in 15 min.
The other catalysts required much longer time and in some cases
the reaction remained incomplete. The product yield was also
low to moderate in most of the cases. Only a trace of the product
was obtained in the absence of any catalyst.
2ꢀ
sites due to –I effect exerted by attached SO4 ions to Ti atoms.
These factors promote the overall reaction by activating the alde-
hydes and the Michael acceptor.
Reusability of the catalyst was performed in order to satisfy the
green chemistry criteria. The reaction between 4-hydroxycouma-
rin and 4-chlorobenzaldehyde was chosen as the model. The reac-
Our next investigation was to find the best reaction media to
discern whether any other solvent could provide better results
compared to water using 15 wt% sulfated titania as catalyst. The
results have been summarized in Table 2. Different conventional
organic solvents like dichloromethane, acetonitrile, toluene, and
methanol were used along with water in the reaction. The outcome
of the reaction was found to depend on the nature of the solvent.
The solvent with low polarity like dichloromethane and toluene
afforded the product in low yields. Moderate yield was obtained
with the more polar acetonitrile. Although, the polar and protic
solvent methanol provided high yield it took much longer time.
The best result was obtained in water in which 96% of the
dicoumarol derivative was obtained. The hydrophobicity of the
organic starting materials in water might associate them to
2ꢀ
tants were mixed in 2:1 molar ratio with 10 wt% TiO2/SO4 (15%
loaded) catalyst in water and heated for appropriate time. After
completion (by TLC), the reaction mixture was shaken with dichlo-
romethane and was filtered to separate the catalyst. The isolated
catalyst was washed thoroughly with acetone and dried at 80 °C
for 2 h before reuse. The catalyst was so efficient that we could
use it for a successive 5 times without much change in catalytic
activity as indicated in the nominal change in yield of the product
(Table 4).
In conclusion, the present method demonstrates an operation-
ally simple and clean procedure for the synthesis of dicoumarols
using a catalytic amount of sulfated titania. In addition, low cost,
recyclability, low toxicity, high Bronsted and Lewis acidity and

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B. Karmakar et al. / Tetrahedron Letters 53 (2012) 4343–4346
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Acknowledgments
B.K. and A.N. thank UGC, New Delhi for financial assistance. J.B.
thanks Instrumentation laboratory, University of Calcutta, for
providing technical help.
References and notes
2ꢀ
A mixture of 4-hydroxycoumarin (2 mmol), aldehyde (1 mmol), TiO2/SO4
(10 wt%), and water (5 mL) was taken in a round bottomed flask and heated on
a water bath at 80 °C for specified time (Table 3). The progress of the reaction
was monitored by thin-layer chromatography (TLC). Upon completion of the
reaction, the mixture was cooled to room temperature. The crude product was
extracted with dichloromethane, dried over anhydrous Na2SO4, and
concentrated to furnish the product.
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The sulfated titania catalyst was synthesized by simply sulfating the
commercially available titania powder (anatase). TiO2 was dispersed in
distilled water under stirring condition and quantitative amount of 0.5 (M)
2ꢀ
H2SO4 was added drop wise at room temperature with varying the SO4
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Characteristic spectroscopic data:
3,30-(Phenylmethylene)bis-(4-hydroxy-2H-chromen-2-one) (3aa):
White solid; mp 230 °C; IR (KBr): 3080, 1675, 1567 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d 6.21 (s, 1H), 7.08–7.31 (m, 11H), 7.51 (t, 2H, J = 7.8 Hz), 7.9 (d, 2H,
J = 7.5 Hz); 13C NMR (75.5 MHz, CDCl3): d 35.6, 104.2, 116.0, 116.2, 123.7,
124.2, 126.1, 128.05, 128.6, 132.5, 136.0, 151.9, 167.2, 166.5; Anal. Calcd for
C
25H16O6: C, 72.81; H, 3.91%. Found: C, 72.72; H, 3.83%.
3,30-(2-Nitrophenylmethylene)bis-(4-hydroxy-2H-chromen-2-one) (3ab):
Pale yellow solid; mp 204 °C; IR (KBr): 3054, 1668, 1562 cmꢀ1 1H NMR
;
(300 MHz, CDCl3): d 6.6 (s, 1H), 6.72–7.94 (m, 12H), 11.24 (br s, 2H); 13C NMR
(75.5 MHz, CDCl3): d 33.7, 102.5, 115.8, 116.4, 119.2, 123.9, 124.7, 126.6, 129.6,
131.54, 131.8, 152.1, 168.02, 172.4; Anal. Calcd for C25H15NO8: C, 65.65; H,
3.31; N, 3.06%. Found: C, 65.71; H, 3.41; N, 3.11%.
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