A facile and practical p-toluenesulfonic acid catalyzed route to dicoumarols containing an aroyl group

Article abstract of DOI:10.17159/0379-4350/2015/v68a8

New and known dicoumarols may be efficiently synthesized employing p-toluenesulfonic acid (p-TSA) as a solid acid catalyst from the reaction of 4-hydroxycoumarin with aryl glyoxal in water. This method offers direct access to structurally diverse coumarin derivatives in moderate to good yields (up to 65%). A total of five new compounds were synthesized.

Full text of DOI:10.17159/0379-4350/2015/v68a8

RESEARCH ARTICLE
S. Khodabakhshi, B. Karami, K. Eskandari and A. Rashidi,
S. Afr. J. Chem., 2015, 68, 53–56,
53
<http://journals.sabinet.co.za/sajchem/>.
A Facile and Practical p-Toluenesulfonic Acid Catalyzed
Route to Dicoumarols Containing an Aroyl group
b
b,
a
Saeed Khodabakhshi,a, Bahador Karami, Khalil Eskandari and Alimorad Rashidi
*
*
aNanotechnology Research Center, Research Institute of Petroleum Industry, Tehran, Iran.
bDepartment of Chemistry, Yasouj University, P.O. Box 353, Yasouj, 75918-74831, Iran.
Received 6 May 2014, revised 29 January 2015, accepted 2 February 2015.
ABSTRACT
New and known dicoumarols may be efficiently synthesized employing p-toluenesulfonic acid (p-TSA) as a solid acid catalyst
from the reaction of 4-hydroxycoumarin with aryl glyoxal in water. This method offers direct access to structurally diverse
coumarin derivatives in moderate to good yields (up to 65%). A total of five new compounds were synthesized.
KEYWORDS
Dicoumarol, p-toluenesulfonic acid, aryl glyoxal, 4-hydroxycoumarin.
1. Introduction
Among the analogues of vitamin K antagonists, dicoumarol,
which may be considered as bridge substituted dimers of
4-hydroxycoumarin, is a naturally occurring anticoagulant.1
This compound is used for the prevention and treatment of
thrombosis. Furthermore, dicoumarol derivatives exhibit bio-
activity as inhibitor of reductases.2 The chemistry of coumarin
derivatives has recently gained much attention from chemists
owing to some interesting biological properties.3–5
Dicoumarol was firstly discovered in moldy wet sweet-clover
hay subsequent to which several methods have been reported
for the development of its chemistry and synthesis of deriva-
Scheme 1
tives. Traditionally, the most popular strategies towards the
Synthesis of dicoumarols catalyzed by p-TSA.
synthesis of dicoumarols start from salicylaldehyde and formal-
dehyde6 and involve the biosynthesis of dicoumarol using
micro-organisms such as Penicillium jenseni,7 or require the
Knoevenagel condensation of 4-hydroxycoumarins with
carbonyl compounds using several catalysts.8–10
that the reaction did not go to completion in the absence of
catalyst even after extended reaction times. Higher loadings of
catalyst did not afford a marked influence on the product yield
nor reaction rate. In another experiment, in order to illustrate the
effect of solvent or media on the reaction progress, several different
solvents were employed, the results of which are illustrated in
Table 1.
It may be concluded that protonic solvents such as EtOH,
MeOH, and H20 can accelerate the condensation reaction.
Finally, it was found that this reaction is enhanced using p-TSA
(10 mol%) as catalyst under reflux in H2O in 70 min.
For many years, chemical reactions in water have attracted the
attention of chemists.11 From an environmental and economic
point of view, water as a solvent or media has many advantages
and usually results in excellent efficiency and selectivity.12 Accord-
ingly, we describe an ecofriendly method for the synthesis of
some new and known dicoumarols containing an aryloyl group
in water as solvent.
2. Results and Discussion
After determining the optimal reaction conditions, attention
Recently, we have been involved in studies involving the was focused on the extension of the scope of the method. For
synthesis of new coumarin derivatives.13 In this regard, we this, various aryl glyoxals 2 and 4-hydroxycoumarin (1) were
found that the condensation between 4-hydroxycoumarin reacted. Results are given in Table 2 in which it is apparent
(1) and aryl glyoxals 2 in the presence of catalytic amounts of that aryl glyoxals, including those bearing electron-poor and
p-toluenesulfonic acid (p-TSA) in water under reflux produces electron-rich substituents, were able to undergo this reaction.
new and known dicoumarols 3 (Scheme 1). p-TSA is well known Compared with a previously reported method which has used
as catalyst because of its advantages, such as low corrosivity, AcOH as reaction media,9 the present method provides environ-
simple handling and it is inexpensive. It has been widely used as mentally safe conditions using water as solvent and p-TSA as
an efficient catalyst in several organic reactions.14–16
catalyst to obtain the desired products with better yields than
In order to establish the best conditions for the synthesis of 3 previous reported. Recently, organic synthesis on water has also
using p-TSA as catalyst, reaction between 4-hydroxycoumarin (1) been reviewed by Fokin and co-workers.17 Based on their study,
and phenyl glyoxal was selected as a model. Results indicated it would appear that this reaction type may be placed in the
category of ‘on-water’ synthetic reactions.
Based on the common mechanistic pathway of the Knoevenagel
* To whom correspondence should be addressed. E-mail: saeidkhm@yahoo.com /
khalileskandari@yahoo.com
ISSN 0379-4350 Online / ©2015 South African Chemical Institute / http://saci.co.za/journal
DOI: http://dx.doi.org/10.17159 /0379-4350/2015/v68a8

RESEARCH ARTICLE
S. Khodabakhshi, B. Karami, K. Eskandari and A. Rashidi,
S. Afr. J. Chem., 2015, 68, 53–56,
54
<http://journals.sabinet.co.za/sajchem/>.
Table 1 Effect of catalyst amount and various solvents on the synthesis of 3a at reflux temperature.
Entry
Catalyst amount/mol%
Solvent
Time/min
Yield/%*
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
–
MeOH (50 mL)
EtOH (50 mL)
THF (50 mL)
CH2Cl2 (50 mL)
EtOH/H2O (1/1) (50 mL)
H2O (50 mL)
H2O (50 mL)
H2O (50 mL)
H2O (50 mL)
50
45
50
120
60
70
180
180
50
78
80
75
50
82
80
30
75
77
5
20
* Values provided are the average of three experiments.
Table 2 Synthesis of dicoumarols using p-TSA (10 mol%) under reflux in
H2O
Knoevenagel condensation between 4-hydroxycoumarin
(oxonium ions not depicted in mechanism) and the aryl glyoxal
generates the non-isolable a,b-unsaturated carbonyl com-
pound 4. Attack of the next 4-hydroxycoumarin molecule
(1) through a Michael-type addition to 4 and subsequent, the
enolization of adduct 5, gives the final product 3.
Entry
Ar
Time (min)
70
Yield/% a [Lit.]
82 (74) 9
Mp/°C [Lit.]
3a
C6H5
197–199
(200–202) 9
273–235
3b
3c
4-F-C6H4
4-Br-C6H4
65
70
78
81 (79) 9
240–242
3. Experimental
(236–238) 9
243–245
80 (76) 9
3.1. General
3d
4-NO2-C6H4
60
(240–242) 9
265–267
All chemicals were purchased from Merck and Aldrich. Aryl
gloxals were synthesized in accord with our previous method.20
The reactions were monitored by thin layer chromatography
(TLC; silica-gel 60 F254, n-hexane: ethyl acetate). IR spectra
3e
3f
3g
4-MeO-C6H4
3-MeO-C6H4
4-Cl-C6H4
55
75
70
78
70
75
205–207
250–252
1
were recorded on a FT-IR JASCO-680 and the H NMR and
13C NMR spectra were recorded on a Bruker Avance Ultra Shield
spectrometer respectively at 400, 300, 100, and 75 MHz. The Vario
EL-III CHNS elemental analyzer from Isfahan Industrial Univer-
sity was used for elemental analysis. The structures and purity of
the products were deduced from their IR, elemental analysis,
and NMR spectral data.
3h
60
84
255–257
a Isolated yields.
and Michael reaction,18,19 we propose a reasonable mechanism
involving the protonic acid-catalyzed reaction of aryl glyoxal 2
with 4-hydroxycoumarin (1), as depicted in Scheme 2. Firstly,
3.2. Preparation of Dicoumarols 3
A mixture of 4-hydroxycoumarin 1 (20 mmol, 3.2 g), aryl
glyoxals 2 (10 mmol) and p-TSA (10 mol%) in H2O (50 mL) was
Scheme 2
Plausible mechanism for p-TSA-catalyzed condensation of 4-hydroxycoumarin with aryl glyoxal (H+ transfers not depicted).

RESEARCH ARTICLE
S. Khodabakhshi, B. Karami, K. Eskandari and A. Rashidi,
S. Afr. J. Chem., 2015, 68, 53–56,
55
<http://journals.sabinet.co.za/sajchem/>.
refluxed for an appropriate time mentioned in Table 2. The 2H, J = 6.0 Hz), 7.72 (d, 2H, J = 5.2 Hz), 7.62–7.52 (m, 4H),
progress of the reaction was monitored by TLC (EtOAc/hexane, 7.31–7.25 (m, 4H), 6.28 (s, 1H); 13C NMR (DMSO-d6, 100 MHz):
1:1). After completion, the mixture was poured on ice and the d = 196.1, 165.9, 163.3, 152.2, 135.9, 131.6, 131.2, 129.3, 125.9, 123.8,
precipitate was filtered and purified by recrystallization from 123.4, 118.0, 115.8, 101.6, 42.9. Anal. Calcd. for C26H15ClO7: C,
EtOH/THF (2:1). In some cases, column chromatography is 65.76; H, 3.18. Found: C, 65.91; H, 3.03.
needed (EtOAc/hexane, 1:1).
2-Naphthoyl[bis(4-hydroxycoumarin-3-yl)]methane (3h): Recrys-
tallized from EtOH/THF (TLC n-hexane:ethyl acetate, 1:1, Rf =
0.11); M.p. 255–257 °C; IR (KBr) n = 3550–3300, 1694, 1653, 1617,
1565, 1454, 1280 cm–1; 1H NMR (CDCl3, 300 MHz): d = 11.24 (s,
2H), 8.27 (s, 1H), 8.01 (dd, 2H, J1 = 8.2, J2 = 1.6 Hz), 7.83–7.72 (m,
4H), 7.54–7.43 (m, 4H), 7.33–7.23 (m, 4H), 6.19 (s, 1H). 13C NMR
(DMSO-d6, 75 MHz): d = 177.3, 166.6, 163.6, 152.3, 134.4, 134.3,
131.8, 131.5, 129.1, 127.9, 127.5, 126.7, 124.1, 123.9, 123.3, 118.5,
115.7, 101.6, 43.1. Anal. Calcd. for C30H18O7: C, 73.47; H, 3.70.
Found: C, 73.68; H, 3.75.
Benzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3a): Recrystallized
from EtOH/THF (TLC n-hexane:ethyl acetate, 1:1, Rf = 0.12);
M.p. 197–199 °C (Lit.9 200–202 °C); IR (KBr) n = 3400–2900, 3073,
1
1698, 1659, 1618, 1566, 1271, 1100 cm–1; H NMR (DMSO-d6,
400 MHz): d = 10.95 (s, 2H), 7.92 (dd, 2H, J1 = 7.8, J2 = 2.8 Hz),
7.63–7.58 (m, 2H), 7.43 (d, 2H, J = 7.2 Hz), 7.39–7.31 (m, 7H), 6.31
(s, 1H).
4-Flourobenzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3b): Recrys-
tallized from EtOH/THF (TLC n-hexane:ethyl acetate, 1:1, Rf =
0.15);M.p. 235–237 °C; IR (KBr) n = 3500–3300, 3066, 2887, 1695,
4. Conclusion
1
1650, 1619, 1600, 1567, 1271, 1225, 1107 cm–1; H NMR (CDCl3,
An improved route for the synthesis of dicoumarols contain-
ing an aryloyl group from simple substrates and p-TSA catalyst
has been achieved with a very high atom economy for the
preparation of pharmaceutically relevant heterocyclic systems.
Importantly, use of water as a cheap and clean media for reaction
should place this chemistry in the category of Green Chemistry.
A total of five new compounds were obtained.
300 MHz): d = 11.15 (s, 2H), 7.89 (dd, 2H, J1 = 8.2, J2 = 1.6 Hz),
7.79–7.75 (m, 2H), 7.56–7.50 (m, 2H), 7.33–7.24 (m, 4H), 6.94 (t, 2H,
J = 8.6 Hz). 13C NMR (CDCl3, 75 MHz): d= 192.9, 165.4, 152.4,
133.2, 132.0, 130.7, 130.6, 125.0, 124.5, 116.7, 116.3, 115.9, 115.6,
42.8. Anal. Calcd. for C26H15FO7: C, 68.12; H, 3.30. Found: C, 68.30;
H, 3.22.
4-Bromobenzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3c): Recrys-
tallized from EtOH/THF (TLC n-hexane:ethyl acetate, 1:1, Rf =
0.11); M.p. 240–242 °C (Lit.9 236–238 °C); IR (KBr) n = 3400–2900,
1711, 1651, 1614, 1564, 1497, 1267, 1099 cm–1; 1H NMR (DMSO-d6,
400 MHz): d = 10.56 (s, 2H), 7.89 (d, 2H, J = 7.6 Hz), 7.59 (t, 2H, J =
7.6 Hz), 7.40–7.29 (m, 6 H), 7.11 (d, 2H), 6.28 (s, 1H).
Supplementary material
The 1H and 13C spectra of all the novel compounds are given in
the online supplement.
Acknowledgement
The authors are grateful to Yasouj University for partial
support.
4-Nitrobenzoyl[bis(4-hydroxycoumarin-3-yl)]methane (3d): Recrys-
tallized from EtOH/THF (TLC n-hexane:ethyl acetate, 1:1, Rf =
0.12); M.p. 243–245 °C (Lit.9 240–242 °C); IR (KBr) n = 3400–2900,
2883, 1715, 1650, 1614, 1565, 1518, 1341, 1266, 1102 cm–1; 10.95 (s,
2H), 7.92 (dd, 2H, J1 = 7.8 Hz, J2 = 2.8 Hz), 7.63–7.58 (m, 2H), 7.43
(d, 2H, J = 7.2 Hz), 7.39–7.31 (m, 7H), 6.31 (s, 1H).
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Supplementary Information, S. Afr. J. Chem., 2015, 68, 53–56
A Facile and Practical p-Toluenesulfonic Acid Catalyzed Route to Dicoumarols Containing an
Aroyl group
1,
Saeed Khodabakhshi *, Bahador Karami , Khalil Eskandari * and Alimorad Rashidi
2
2,
1
1
Nanotechnology Research Center, Research Institute of Petroleum Industry, Tehran, Iran
2
Department of Chemistry, Yasouj University, P. O. Box 353, Yasouj, 75918-74831, Iran
Table of contents
1
13
H NMR and C NMR spectra of products 3b, 3e, 3f, 3g, 3h
1

O
HO
O
O
O
HO
O
F
3b
Figure 1 1H NMR spectrum of 3b
2

O
HO
O
O
O
HO
O
F
3b
Figure 2 13C NMR spectrum of 3b
3

O
HO
O
O
O
HO
O
MeO
3e
Figure 3 1H NMR spectrum of 3e
4

O
HO
O
O
O
HO
O
MeO
3e
Figure 4 13C NMR spectrum of 3e
5

O
HO
O
O
O
HO
O
OMe
3f
Figure 5 1H NMR spectrum of 3f
6

O
HO
O
O
O
HO
O
OMe
3f
Figure 6 13C NMR spectrum of 3f
7

O
HO
O
O
O
HO
O
Cl
3g
Figure 7 1H NMR spectrum of 3g
8

O
HO
O
O
O
HO
O
Cl
3g
Figure 8 13C NMR spectrum of 3g
9

O
HO
O
O
O
HO
O
3h
Figure 9 1H NMR spectrum of 3h
10

O
HO
O
O
O
HO
O
3h
Figure 10 13C NMR spectrum of 3h
11

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