G Model
CRAS2C-3762; No. of Pages 5
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N. Azizi et al. / C. R. Chimie xxx (2013) xxx–xxx
Table 1
Investigation of the chemoselectivity of deep eutectic solvents (DES).
HO
O
O
Ph
Ph
O
O
O
DES
2 h
+
PhCHO
2
+
O
O
OH
1
2
4
3
Entry
DES
Yields (%)
3
4
1
2
3
4
Choline chloride:urea (2:1)
1 mL
92
00
Choline chloride:malonic acid (1:1)
00
85
00
60
00
88
1 mL
Choline chloride:SnCl2 (1:2)
1drop
Choline chloride:ZnCl2 (1:2)
1 drop
5
6
Choline chloride:ZnCl2:SnCl2 (1:1:1) 1 drop
00
60
85
30
Choline chloride:LaCl3 (1:2)
1 drop
7
8
Choline chloride:PTSA (1:1)
20
75
60
10
1 mL
Choline chloride:glycerol(1:2)
1 mL
compounds in the presence of acid or alkaline catalysts are
widely used as important versatile precursors for the
synthesis of tetraketones [2]. Because of their great
practical importance, several methods have been pro-
posed, employing different catalysts and promoters, such
as NaOH [13], KOH [14], piperidine [15], proline [16], and
cetyltrimethylammonium bromide (CTMAB) [17]. Further-
more, catalyst-free reactions in pure water [18], in the
solid state, and in melts have been reported [19].
control in xanthenes and tetraketones synthesis by
changing the DES component.
2. Results and discussions
As part of our continuous interest in developing green
reaction media for the synthesis of useful compounds, we
recently succeeded in developing the deep eutectic solvent
as a green solvent and catalyst in organic synthesis [32–
35]. Encouraged by these successful efforts and aiming to
demonstrate the efficiency and generality of DES, we
present in this paper a mild, reliable, efficient, and scalable
synthesis of xanthene and tetraketone derivatives in a
choline chloride-based deep eutectic solvent.
Choline chloride-based DESs were prepared according
to the reported procedure and were used without further
purification. Our initial effort was focused on the evalua-
tion of choline chloride-based DESs systems for the model
reaction of benzaldehyde 1 and dimedone 2 to optimize
the reaction conditions and selectivity. The catalytic
activities of various DESs were evaluated for this model
reaction, and the results are summarized in Table 1. We
found that all DESs catalyze this simple condensation
reaction and provide the desired tetraketones 3 and
xanthenes 4 in different proportions.
Natural products with xanthene heterocyclic motives
have a great deal of importance because of their diverse
ubiquitous pharmacological properties, such as antibac-
terial [20], antiviral and antinociceptive activities [21], In
addition, due to their spectroscopic properties [22], they
are used as fluorescent compounds in laser technology and
in the monitoring of biomolecules. Considerable efforts
have been made toward the one-pot, three-component
synthesis of xanthenes annulated heterocyclic derivatives
due to their wide applications. Among the numerous
methods for the synthesis of xanthene, the condensation of
aldehydes with active methylene in the presence of an
acidic catalyst or a promoter is reported in the literature
[23–32]. Some of these methods suffer from prolonged
reaction times, high cost, or the catalysts’ sensitivity to
moisture. Therefore, the development of simple and
efficient procedures for the synthesis of xanthenes in
the novel reaction media is a challenging task. Herein, we
report an efficient three-component tandem synthesis of
xanthenes and tetraketones from aldehydes and active
methylene compounds in choline chloride-based deep
eutectic solvents (DESs). To the best of our knowledge, this
represents one of the first examples of the use of DES
The DES-based choline chloride–urea and choline
chloride–SnCl2 provided tetraketones 3 in higher yields
and shorter reaction times than methods using other DESs
(Table 1, entry 8 vs entries 1–5). On the other hand, in
choline chloride–ZnCl2 and choline chloride–malonic acid
mixtures, the reaction proceeded selectively to generate
xanthene derivatives 4.
Please cite this article in press as: Azizi N, et al. Chemoselective synthesis of xanthenes and tetraketones in a choline