An efficient procedure for the synthesis of coumarin derivatives using TiCl4 as catalyst under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2005.03.124

The ability of titanium(IV) chloride as a catalyst to promote the Pechmann condensation reaction with a range of phenols and β-keto esters is described.The reaction was carried out by addition of TiCl₄ to a mixture of the phenol and the β-keto ester with thorough stirring in the absence of a solvent and represents an improvement on the classical Pechmann conditions. The yields of coumarins obtained via this novel protocol were significantly higher than those using the conventional method and the reaction duration was reduced to a few minutes or even a few seconds.

Full text of DOI:10.1016/j.tetlet.2005.03.124

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3501–3503
An efficient procedure for the synthesis of coumarin derivatives
using TiCl4 as catalyst under solvent-free conditions
Hassan Valizadeha,* and Abbas Shockravib
aDepartment of Chemistry, Faculty of Science, Azarbaydjan University of Tarbiat-Moallem, PO Box 53714-161, Tabriz, Iran
bFaculty of Chemistry, Teacher Training University of Tehran, Tehran, Iran
Received 14 January 2005; revised 9March 2005; accepted 15 March 2005
Available online 8 April 2005
Abstract—The ability of titanium(IV) chloride as a catalyst to promote the Pechmann condensation reaction with a range of phenols
and b-keto esters is described.The reaction was carried out by addition of TiCl4 to a mixture of the phenol and the b-keto ester with
thorough stirring in the absence of a solvent and represents an improvement on the classical Pechmann conditions. The yields of
coumarins obtained via this novel protocol were significantly higher than those using the conventional method and the reaction
duration was reduced to a few minutes or even a few seconds.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Coumarins can be synthesised by various methods
including the Perkin,15 Pechmann,16 Knoevenagel,17
Reformatsky18 and Wittig19 reactions. Among these,
the Pechmann reaction has been the most widely used
method since it proceeds from very simple starting mate-
rials and gives good yields of variously substituted cou-
marins. Substituted phenols are condensed with b-keto
esters in the presence of an acid to afford coumarins.
Various acids have been used to carry out this reac-
tion.20 In some methods, several hours or even days
are required to complete the reaction even when
heated above 150 °C. Undesired by-products such as
chromones are sometimes formed.21 Recently, cation
exchange resins22 and solid acid catalysts23 have been
used, however, such reactions require, either a reaction
temperature of about 150 °C or higher or long reaction
times and in some cases give low yields. More recently,
there have been reports on the use of microwave irradi-
ation24 for accelerated synthesis of different coumarins.
Coumarins have been both widely studied and widely
used but still generate much interest. Coumarins are well
known as natural products and many exhibit high levels
of biological activity.1 Coumarins are also used as food
additives, in cosmetics,2 as optical brightening agents3
and dispersed fluorescent and laser dyes.4 In addition,
some coumarins are of interest because of their toxicity,5
carcinogenity6 and photodynamic effects.7 Coumarins
also act as intermediates for the synthesis of furocouma-
rins, chromenes, coumarones and 2-acylresorcinols.8
The drive towards clean technology has encouraged the
application of solvent-free conditions.9 A move away
from the use of solvents in organic synthesis has led in
some cases to improved results and more benign syn-
thetic procedures.10 Adopting the principles of ÔGreen
ChemistryÕ, we have established that using solvent-free
conditions for Knoevenagel11 and Wittig12 reactions re-
sults in a dramatic improvement in yields. Our approach
reduces the use of organic solvents, which are potentially
toxic and hazardous13 and uses simple and mild condi-
tions, with inherently lower costs.14
In view of the current emphasis on solid state synthesis25
and on Ôgreen chemistryÕ26 we set out to develop a sol-
vent-free preparation of coumarins using an inexpensive
˚
and non-polluting catalyst. We have recently used 3 A
molecular sieves as promoting agents in the synthesis
of coumarins.27 In continuation of our interest in organ-
ic synthesis in solvent-free systems12,28 we report here a
method for the preparation of coumarins 3 and 5 using
TiCl4 as the catalyst in the Pechmann reaction of a neat
mixture of a phenol and a b-keto ester (Scheme 1).
Keywords: Pechmann condensation; Titanium(IV) chloride; Coumarin;
Solvent-free system.
*
Corresponding author. Tel.: +98 411 6561188; fax: +98 412
4524991; e-mail: h-valizadeh@azaruniv.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.124

3502
H. Valizadeh, A. Shockravi / Tetrahedron Letters 46 (2005) 3501–3503
R2
plete after addition of the TiCl4 (up to 80 s). The reac-
tion mixture was poured onto crushed ice and the
resulting crude product was filtered off and recrystal-
lised from hot ethanol/water (9/1) to give the pure
product.
OH
R2
TiCl4
EtO2C
EtO2C
+
+
r.t.
O
O
O
O
R1
R1
solvent-free
3
1
2
Me
OH
2.1. Selected spectroscopic data
Me
TiCl4
1
Compound 3a: H NMR d (DMSO-d6): 2.65 (s, 3H,
O
O
r.t.
Me), 6.41 (s, 1H, C@CH), 6.91–7.72 (m, 3H, ArH),
solvent-free
OH not observed, IR, m (KBr): 3260–3080, 1690 cmÀ1
.
5
4
EIMS: m/z: 176 (M+). Compound 3b: 1H NMR d
(CDCl3): 2.59(s, 3H, Me), 4.22 (s, 3H, OMe), 6.51 (s,
1H, C@CH), 7.01–7.51 (m, 3H, ArH), IR, m (KBr):
Scheme 1.
+
1
Attempted TiCl4-catalysed reactions in the presence of
solid supports and MW irradiation proved to be unsuc-
cessful, the reactions were sluggish and considerable
amounts of starting materials were recovered even after
prolonged exposure to microwave irradiation. After
some experimentation with respect to the molar ratios
of reagents, we developed the conditions that generally
gave the coumarins in good to excellent yields (Table
1). These conditions employed a 1:1.5 ratio of the phe-
nol and the b-keto ester using TiCl4 as catalyst. As
shown in Table 1 the time of reaction was reduced to
a few minutes or even a few seconds. The work-up
involved simply quenching with water then filtration
and recrystallisation from a suitable solvent.
1685 cmÀ1. EIMS: m/z: 19 0 (M). Compound 3c: H
NMR d (CDCl3): 2.62 (s, 3H, Me), 2.80 (s, 3H, Me),
6.41 (s, 1H, C@CH), 7.10–7.60 (m, 3H, ArH), IR, m
(KBr): 1685 cmÀ1. EIMS: m/z: 174 (M+). Compound
3d: 1H NMR d (CDCl3): 1.71 (t, J = 6.98, 3H, Me),
2.64 (s, 3H, Me), 4.30 (q, J = 6.98, 2H, OCH2), 5.35
(s, 2H, OCH2), 6.45 (s, 1H, C@CH), 7.20–7.81 (m,
3H, ArH), IR, m (KBr): 1730, 1650 cmÀ1. EIMS: m/z:
1
262 (M+). Compound 3e: H NMR d (CDCl3): 2.65 (s,
3H, Me), 5.50 (s, 2H, CH2), 6.51 (s, 1H, C@CH),
7.01–8.20 (m, 8H, ArH), IR,
m
(KBr): 1700,
+
1630 cmÀ1. EIMS: m/z: 29 4 (M). Compound 3f: 1H
NMR d (CDCl3): 1.90 (d, J = 6.65, 3H, Me), 2.60 (s,
3H, Me), 2.91 (s, 3H, Me), 5.10 (q, J = 6.65, 1H, CH),
6.60 (s, 1H, C@CH), 7.10–7.81 (m, 3H, ArH), IR, m
(KBr): 1730, 1668 cmÀ1. EIMS: m/z: 230 (M+). Com-
In conclusion, we have demonstrated an efficient and
simple alternative for the preparation of substituted
coumarins via the TiCl4-catalysed Pechmann reaction
in solvent-free conditions. Prominent among the
advantages of this new method are operational sim-
plicity, good yields, short reaction times and an easy
work-up.
1
pound 3g: H NMR d (DMSO-d6): 2.65 (s, 3H, Me),
6.25 (d, J = 2.61, 1H, ArH), 6.35 (d, J = 2.61, 1H,
ArH), 6.40 (s, 1H, C@CH), OH not observed, IR, m
+
(KBr): 3160, 1670 cmÀ1. EIMS: m/z: 19 2 (M). Com-
1
pound 3h: H NMR d (DMSO-d6): 6.24 (d, J = 2.62,
1H, ArH), 6.34 (d, J = 2.62, 1H, ArH), 6.50 (s, 1H,
C@CH), OH not observed, IR,
m (KBr): 3158,
1665 cmÀ1. EIMS: m/z: 246 (M+). Compound 3i: 1H
NMR d (DMSO-d6): 5.11 (s, 2H, CH2Cl), 6.25 (d,
J = 2.60, 1H, ArH), 6.29(d, J = 2.60, 1H, ArH), 6.35
(s, 1H, C@CH), OH not observed, IR, m (KBr): 3157,
1655 cmÀ1. EIMS: m/z: 226 (M+). Compound 3j: 1H
NMR d (DMSO-d6): 2.65 (s, 3H, Me), 2.95 (s, 3H,
Me), 6.25 (d, J = 2.60, 1H, ArH), 6.35 (d, J = 2.60,
2. General procedure
The phenol (20 mmol) and the b-keto ester (30 mmol)
were mixed thoroughly and titanium(IV) chloride
(10 mmol) was added to the mixture with stirring at
room temperature. The reaction was essentially com-
Table 1. Titanium(IV) chloride-catalysed Pechmann condensations in the absence of solvent
Product
R1
R2
Time (s)
Mp (°C)
Yield (%)a
3a
3b
3c
3d
3e
3f
7-OH
7-OMe
7-Me
Me
Me
Me
Me
Me
Me
Me
CF3
CH2Cl
Me
Me
Me
Me
50
40
184–186
156–158
131–132
98–100
173–174
231–233
283–285
250–252
242–244
243–245
83–84
97
96
92
89
87
90
96
97
95
92
60
—
—
90
60
55
7-OCH2CO2Et
7-OCH2COPh
7-OCHMeCOMe
5,7-Di OH
5,7-Di OH
5,7-Di OH
7-OH–5-Me
H
70
80
3g
3h
3i
50
60
60
50
3j
3k
3l
70
4-NO2
4-Cl
No reaction
No reaction
70
—
—
3m
5
155–157
a After recrystallisation.

H. Valizadeh, A. Shockravi / Tetrahedron Letters 46 (2005) 3501–3503
3503
11. Shockravi, A.; Sharghi, H.; Valizadeh, H.; Heravi, M. M.
Phosphorus, Sulfur, Silicon Relat. Elem. 2002, 177, 2555–
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12. Shockravi, A.; Valizadeh, H.; Heravi, M. M.; Ghadim, H.
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1H, ArH), 6.41 (s, 1H, C@CH), OH not observed, IR, m
+
(KBr): 3159, 1665 cmÀ1. EIMS: m/z: 19 0 (M). Com-
1
pound 3k: H NMR d (CDCl3): 2.62 (s, 3H, Me), 6.48
(s, 1H, C@CH), 7.30–7.65 (m, 4H, ArH), IR, m (KBr):
1665, 1610, 1450, 1400 cmÀ1. EIMS: m/z: 160 (M+).
1
Compound 5: H NMR d (CDCl3): 2.71 (s, 3H, Me),
6.51 (s, 1H, C@CH), 7.50–8.91 (m, 6H, ArH), IR, m
(KBr): 1675 cmÀ1. EIMS: m/z: 210 (M+).
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