Imidazol-1-yl-acetic acid as a novel green bifunctional organocatalyst for the synthesis of 1,8-dioxooctahydroxanthenes under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2013.12.011

Imidazol-1-yl-acetic acid is introduced as a new, efficient and recyclable green bifunctional organocatalyst for the synthesis of 1,8- dioxooctahydroxanthenes under solvent-free conditions. This catalyst is water soluble and can be separated from the prod

Full text of DOI:10.1016/j.cclet.2013.12.011

Chinese Chemical Letters 25 (2014) 317–320
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Imidazol-1-yl-acetic acid as a novel green bifunctional organocatalyst
for the synthesis of 1,8-dioxooctahydroxanthenes under solvent-free
conditions
a
b,
b
c
Simin Nazari , Mosadegh Keshavarz *, Bahador Karami , Nasir Iravani ,
c
Masoumeh Vafaee-Nezhad
a
Department of Chemistry, Sousangerd Branch, Islamic Azad University, Sousangerd 44181-6189, Iran
b
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
c
Department of Chemistry, Gachsaran Branch, Islamic Azad University, Gachsaran 75818-63876, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Imidazol-1-yl-acetic acid is introduced as a new, efficient and recyclable green bifunctional
Received 19 July 2013
organocatalyst for the synthesis of 1,8-dioxooctahydroxanthenes under solvent-free conditions. This
catalyst is water soluble and can be separated from the products by simple filtration. The filtrate can be
evaporated to dryness and recrystallized from cool methanol to give the recovered catalyst. This
organocatalyst was used for the synthesis of 1,8-dioxooctahydroxanthenes under solvent-free
conditions and recycled up to 8 consecutive runs without any losing of its efficiency.
ß 2013 Mosadegh Keshavarz. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received in revised form 28 November 2013
Accepted 29 November 2013
Available online 8 December 2013
Keywords:
Bifunctional catalyst
Organocatalyst
Solvent-free
1
,3-Dicarbonyl compounds
1
,8-Dioxooctahydroxanthenes
1
. Introduction
Xanthenes and benzoxanthenes compounds have received
conditions. Therefore, there is a focus on developing an alternative,
facile and green method for the synthesis of xanthenes derivatives.
Organocatalytic reactions are becoming dominant tools for the
production of complex molecular skeletons [18]. Organocatalysts
are organic molecules that do not contain any metal which
accelerate reactions in substoichimetric amounts. Bifunctional
organocatalysts are organocatalysts with dual action. Imidazol-1-
yl-acetic acid is an example of a bifunctional organocatalysts. This
amino acid has two forms: a neutral and an ionized form. It is
almost always in the ionized form (a in Scheme 1), except in the
gaseous phase and in aprotic solvents (b in Scheme 1). Herein, we
report imidazol-1-yl-acetic acid as a new, efficient and recyclable
green bifunctional organocatalyst for the synthesis of 1,8-
dioxooctahydroxanthenes under solvent-free conditions.
great attention from many pharmaceutical and organic chemists
because of their broad spectrum of biological and pharmaceutical
properties, such as antibacterial [1], anti-inflammatory, and
antiviral [2] properties. Moreover, these compounds are used as
dyes [3], as fluorescent materials for visualization of biomolecules
[
4] and in laser technologies [5] because of their photochemical
and photophysical properties. Various synthetic procedures have
been developed for the preparation of xanthenediones. For
example, copper iodide nanoparticles on poly(4-vinylpyridine)
[
6], trichloroisocyanuric acid and cyanuric chloride [7,8], carbon-
based solid acid [9], Fe and ZnO nanoparticles [10,11],
functionalized mesoporous materials [12], cellulose sulfuric acid
and succinimide-N-sulfonic acid [13,14], I [15], P /Al [16]
3 4
O
2
2
O
5
2 3
O
2. Experimental
and DABCO-bromine [17] have been used as catalysts for the
synthesis of xanthenediones. However, some of these methods
involve the use of expensive reagents, toxic solvents, tedious
workup, low yields, long reaction times and harsh reaction
All of the products were prepared by our own procedures; their
spectroscopic and physical data were compared with those of
authentic samples [6,10,21]. NMR spectra were recorded in CDCl
3
on Bruker AC 400 MHz instrument spectrometers using TMS as the
internal standard. IR spectra were recorded on a BOMEMMB-Series
1998 FT-IR spectrometer. Elemental analyses were performed on a
Thermo Finnigan CHNS-O analyzer, 1112 series. Chemicals were
*
Corresponding author.
E-mail address: chem.mosadegh@gmail.com (M. Keshavarz).
1
001-8417/$ – see front matter ß 2013 Mosadegh Keshavarz. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.12.011

3
18
S. Nazari et al. / Chinese Chemical Letters 25 (2014) 317–320
1
3
4
(
.84 (s, 1H), 7.44 (d, 2H, J = 8.0 Hz,), 7.53 (d, 2H, J = 8.0 Hz); C NMR
100 MHz, CDCl ): 20.2, 27.1, 32.3, 36.8, 110.2, 115.8, 119.10,
129.4, 132.0, 149.7, 164.5, 196.5. Elem. Anal. Calcd. for C20 : C,
4.06%; H, 6.21%; Found: C, 74.05%; H, 6.22%.
-(3-Bromophenyl)-3,3,6,6-tetramethyl-2,3,4,5,6,7,8,9-octahy-
N
OH
H
N
O
N
3
d
N
O
20 4
H O
O
7
a
b
9
Scheme 1. The two forms of imidazol-1-yl-acetic acid.
dro-1H-1,8-xanthenedion (Table 1, entry 17): White solid, mp
À1
2
81–282 8C [6]; IR (KBr, cm ):
n
max 3070, 2910, 2890, 1660, 1620,
1
purchased from Fluka, Merck and Aldrich Chemical companies.
Yields refer to isolated pure products.
1560, 1470, 1420, 1358, 1200, 1170, 1122, 957, 800, 680; H NMR
(400 MHz, CDCl ): 1.95–2.1 (m, 4H), 2.30–2.44 (m, 4H), 2.55–2.63
(m, 2H), 2.66–2.73 (m, 2H), 4.79 (s, 1H), 7.11 (t, 1H, J = 7.6 Hz),
3
d
To a mixture of 5,5-dimethyl-1,3-cyclohexanedione or 1,3-
cyclohexanedione (4 mmol) and aldehyde (2 mmol), imidazol-1-
yl-acetic acid (1.2 mmol) was added and the reaction mixture was
stirred at 60 8C for 7–15 min (Table 1). The progress of the reaction
was monitored by TLC (eluent:EtOAc/n-hexane = 5/1, v/v). After
completion of the reaction, the mixture was cooled to room
temperature, water (20 mL) was added and the mixture was stirred
for 10 min. The mixture was filtered and the solid residue was
recrystallized from ethanol to afford the pure product. Evaporation
of the filtrate gave the recovered catalyst which purified by
recrystallization in cool methanol (30 mL), dried at 50 8C and used
in the next consecutive runs.
1
3
7.26–7.36 (m, 3H); C NMR (100 MHz, CDCl ):
3
d 20.3, 27.2, 31.6,
36.9, 116.3, 122.3, 127.7, 129.6, 131.0, 146.6, 164.3, 196.4. Elem.
Anal. Calcd. for C20H17NO : C, 75.22%; H, 5.37%; N, 4.39; Found: C,
3
75.22%; H, 5.39%; N, 4.39%.
3. Results and discussion
Imidazol-1-yl-acetic acid contains both acidic and basic
functionalities. The existence of such functionalities makes this
molecule an ideal bifunctional organocatalyst for condensation
reactions [19]. In fact the bifunctional catalytic activities of
imidazol-1-yl-acetic acid arise from its ionized form (a in Scheme
1). To the best of our knowledge there is only one report that has
investigated the catalytic activity of this simple and interesting
bifunctional organocatalyst [20]. Consequently, we decided to
study the potential catalytic activity of this simple bifunctional
catalyst for the preparation of 1,8-dioxooctahydroxanthenes under
solvent-free conditions.
In an initial attempt, a mixture of 1,3-cyclohexadione (4 mmol)
and benzaldehyde (2 mmol) in the presence of imidazol-1-yl-
acetic acid (0.6 mmol, 75 mg) was stirred at room temperature.
After 30 min, 48% of the expected product 3 (Scheme 2) was
obtained. Another run was performed using 1.2 mmol (150 mg) of
imidazol-1-yl-acetic acid which led to 88% of the title compound
after 30 min. To improve the yield and rate of the reaction, the
same reaction was carried out under solvent-free conditions using
9
-(3-Methoxyphenyl)-3,3,6,6-tetramethyl-2,3,4,5,6,7,8,9-octa-
hydro-1H-1,8-xanthenedion (Table 1, entry 15): White solid, mp
À1
1
1
(
(
92–194 8C [6]; IR (KBr, cm ):
nmax 3070, 2950, 1650, 1605, 1580,
1
450, 1360, 1265, 1220, 1200, 1180, 1130, 1050, 960; H NMR
): 1.99–2.1 (m, 4H), 2.3–2.45 (m, 4H), 2.54–2.71
m, 4H), 3.81 (s, 3 H), 4.83 (s, 1H), 6.69–6.71 (dd, 1H, J = 8.0 Hz,
3
400 MHz, CDCl d
1
13
J
2
= 1.6 Hz), 6.89–6.95 (m, 2H), 7.17 (t, 1H, J = 8.0 Hz); C NMR
100 MHz, CDCl ): 20.3, 27.2, 31.5, 37.0, 55.2, 111.5, 114.5, 116.8,
21.0, 129.0, 146.0, 159.4, 164.0, 196.5. Elem. Anal. Calcd. for
: C, 74.06%; H, 6.21%; Found: C, 74.05%; H, 6.22%.
-(4-Cyanophenyl)-3,3,6,6-tetramethyl-2,3,4,5,6,7,8,9-octahy-
(
1
C
3
d
20 20 4
H O
9
dro-1H-1,8-xanthenedion (Table 1, entry 16): White solid, mp 270–
À1
2
1
72 8C [6]; IR (KBr, cm ):
n
max 3070, 2950, 2900, 2220, 1652, 1619,
1
356, 1200, 1173, 1125, 958, 830, 610, 550; H NMR (400 MHz,
): 1.95–2.11 (m, 4H), 2.30–2.42 (m, 4H), 2.57–2.73 (m, 4H),
CDCl
3
d
Table 1
Imidazol-1-yl-acetic acid catalyzed synthesis of 1,8-dioxooctahydroxanthenes under solvent-free conditions.
O
H
O
Ar
O
O
Imidazol-1-yl-acetic acid
Solvent-free, 60 o
ArCHO
+
2
R
R
R
C
O
R
R
R
R= CH or H
3
Entry
Aldehyde
R
Time (min)
Yield (%)
Mp (8C)
Found
Reported
a
b
b
1
2
3
4
5
6
7
8
9
PhCHO
PhCHO
H
8
10
12
15
15
15
15
7
95 , 90
266–268
203–204
217–218
189–191
241–243
176–178
202–203
222–224
225–227
227–228
215–217
248–250
284–286
283–285
192–194
273–275
281–283
267–269 [21]
202–204 [10]
215–216 [10]
188–190 [10]
242–243 [10]
175–176 [10]
200–201 [10]
223–225 [10]
226–227 [10]
226–227 [10]
217–218 [10]
247–248 [10]
286–288 [10]
284–286 [21]
192–194 [6]
270–272 [6]
281–282 [6]
a
CH
CH
CH
CH
CH
H
3
88 , 86
a
4-MeC
6
H
4
CHO
3
3
3
3
87
a
2-MeOC
4-MeOC
6
H
H
4
CHO
CHO
87
a
6
4
89
a
3,4-(MeO)
4-MeOC
4-NO
2-ClC
4-FC
4-CNC
4-OHC
4-ClC
4-BrC
3-MeOC
4-CNC
3-BrC
2
C
6
H
3
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
86
a
6
H
4
88
a
2
C
6
H
4
CH
CH
CH
CH
CH
H
3
3
3
3
3
90
a
b
6
H
4
8
89 , 86
a
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
6
H
4
8
87
a
6
H
4
10
15
8
85
a
b
b
6
H
4
89 , 85
a
6
H
4
92 , 89
a
6
H
4
CHO
CHO
CHO
CHO
H
9
89
a
6
H
4
H
15
10
8
90
a
b
6
H
4
H
93 , 90
a
6
H
4
H
90
a
Refer to pure and isolated yield in the first run.
Refer to pure and isolated yield in the eighth run.
b

S. Nazari et al. / Chinese Chemical Letters 25 (2014) 317–320
Ar
319
H
O
Ar
O
H
O
H
O
O
Ar
O
H
-
H O
2
H
H
O
O
O
O
H
O
O
3
H
O
N
N
O
N
N
O
O
N
H
N
O
O
H
O
N
H
Ar
H
O
N
OH
H
O
1
N
N
O
O
H
O
O
H
O
O
N
O
H
N
O
O
O
H
O
N
H
H
O
N
O
N
O
O
O
H
O
H
H
H H
Ar
N
-
H O
H
2
H
Ar
O
O
O
O
Ar
2
Scheme 2. The proposed mechanism for the synthesis of xanthene derivatives using imidazol-1-yl-acetic acid as bifunctional organocatalyst.
1
.2 mmol of imidazol-1-yl-acetic acid at 60 8C. A significant
pure 1,8-dioxooctahydroxanthenes. In order to recover the
catalyst, the filtrate was evaporated to dryness and recrystallized
from cool methanol. The obtained precipitate was filtered and
dried at 50 8C. The recovered catalyst was reused in the next
consecutive similar runs (7 runs). No appreciable yield decrease
was observed during reusing processes. Typically, the yield
difference between the first and 8th runs of the reaction between
benzaldehyde and 1,3-cyclohexadione (Table 1, entry 1) was only
5%. These observations indicate that the efficiency and catalytic
activity of the title catalyst is almost completely maintained over 8
runs. In all cases, the corresponding 1,8-dioxooctahydroxanthene
was isolated in typically good to high yields (85–93%). The catalytic
activity of imidazol-1-yl-acetic acid most probably arises from its
dual action participating in acid catalyzed as well as base catalyzed
activation during the reaction progress. The suggested mechanism
is illustrated in Scheme 2.
improvement in the rate of the reaction was observed and the
reaction time was decreased to 8 min. Moreover, the yield of the
title compound was increased to 95%. Greater amounts of the
catalyst did not clearly improve the reaction rate. When the same
reaction was performed in the absence of the catalyst, only trace
amount of corresponding product was obtained even after a long
reaction time (1 h).
To extend the scope of the reaction and to generalize the
procedure, a variety of electronically divergent aromatic alde-
hydes, 5,5-dimethyl-1,3-cyclohexanedione or 1,3-cyclohexane-
dione, were examined under optimized reaction conditions and
the results are summarized in Table 1.
In all cases, aromatic aldehydes carrying either an electron-
withdrawing group or an electron-donating group in the ortho,
meta and para positions reacted effectively and gave the products
in good to excellent yields. It is observed that substituents in the
aromatic ring of aldehydes have a mild effect on the reaction times.
Aromatic aldehydes with electron-withdrawing groups reacted
faster than those with electron-donating groups.
During the reaction progress, the two forms of imidazol-1-yl-
acetic acid (a and b in Scheme 1) are in equilibrium with each
other. Form a of the catalyst plays two roles, works both as acid
and base. These activities allow it to be
a bifunctional
A simple and clean procedure was used for the separation of the
catalyst from the reaction mixture. After completion of the
reaction (Table 1), the mixture was cooled and water was added
then stirred for 10 min. The undissolved solid was filtered and
washed with water. Recrystallization from hot ethanol afforded
organocatalyst for the preparation of 1,8-dioxooctahydrox-
anthenes. The advantages of the introduced catalyst are its
cheapness, green nature and ease of workup and catalyst
recovery. More importantly, its bifunctional activity can
efficiently catalyze this typical condensation reaction by

3
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