A combination of green solvent and ultrasonic irradiation promotes the catalyst-free reaction of aldehydes, indoles and Meldrum’s acid

Article abstract of DOI:10.1007/s11164-016-2675-8

Abstract: A facile and practical approach for the preparation of 3-indole derivatives was performed by the Yonemitsu condensation of indoles with Meldrum’s acid and aldehydes in a mixture of solvent from glycerol and water under ultrasonic irradiation at

Full text of DOI:10.1007/s11164-016-2675-8

Res Chem Intermed
DOI 10.1007/s11164-016-2675-8
A combination of green solvent and ultrasonic
irradiation promotes the catalyst-free reaction
of aldehydes, indoles and Meldrum’s acid
1
1
1
•
Cheng-Wei Lu¨
Wen-Juan Shan
•
Jia-Jing Wang
1
•
Yan-Hang Liu
1
1
•
Qi Sun
•
Lei Shi
Received: 20 May 2016 / Accepted: 22 July 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A facile and practical approach for the preparation of 3-indole derivatives
was performed by the Yonemitsu condensation of indoles with Meldrum’s acid and
aldehydes in a mixture of solvent from glycerol and water under ultrasonic irradiation at
room temperature without catalyst. A series of aromatic aldehydes representative of
various electronic and steric conditions were employed to examine the scope of sub-
strates for this protocol in moderate to good yields. No catalyst, clean reaction condi-
tions, tolerating the substrates with diverse functional groups and an environmentally
acceptable medium are the best features in this process.
Graphical Abstract
Keywords Yonemitsu condensation Á 3-Indole derivatives Á Catalyst-free Á Ultrasonic
irradiation Á Aqueous glycerol
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2675-8)
contains supplementary material, which is available to authorized users.
&
Cheng-Wei Lu¨
chengweilv@126.com
1
School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029,
People’s Republic of China
123

C.-W. L u¨ et al.
Introduction
The efficient and high-throughput synthesis of complex organic molecules with a
lower impact on the environment is one of the most important objectives in modern
synthetic organic and green chemistry [1, 2]. As the pressure to produce the myriad
of substances required by society in an environmentally benign fashion has
continued to increase, it is now essential for chemists to develop new greener
synthetic pathways under natural conditions as many as possible [3]. Green
chemistry utilizes a set of principles that optimize the synthetic methodologies to
reduce pollution, cost, and tedious work-ups [4–6]. One of the key areas of green
chemistry is the reduction or elimination of expensive catalysts in chemical
processes and the replacement of hazardous solvents with environment-friendly
solvents [7–9]. Glycerol is the only green solvent like water that can combine at a
low price with a low toxicity and has been recently proposed as an effective
promoting medium for organic transformation [10, 11]. Many reactions can be
performed under catalyst-free conditions in the presence of glycerol as a reaction
medium [12, 13]. Despite these promising features, much effort has to be made in
the future to extend the use of glycerol as a green solvent [10]. On the other hand,
application of ultrasound in organic transformation has been proved to be a green-
synthetic approach and a fantastic tool. Compared with conventional methods, this
technique is more efficient, innocuous, convenient, and easily controlled. A large
number of organic reactions can be efficiently carried out with high yields under
ultrasonic irradiation [14–17].
The indole nucleus is an important structural unit that is present in many drugs
currently on the market [18]. Most of these belong to the 3-substituted indole
family, which is an important intermediate for chemical synthesis and widely
distributed in many important natural products [19–21]. Consequently, several
research groups have turned their attention to access those 3-substituted indoles by
simple synthetic methods [22–24]. The Yonemitsu trimolecular reaction of indole
with Meldrum’s acid and aldehyde for the construction of 3-substituted indole
frameworks has recently been the subject of numerous investigations [25, 26]. A
plethora of improved Yonemitsu condensations involving the solid phase reaction
without catalyst [27], the reaction in ethanol without catalyst [28], and the reaction
in deep eutectic solvent [29] has been elaborated in order to develop green
technology for this reaction. However, the development of simple, efficient, and
environmentally benign synthetic approaches for 3-substituted indole derivatives
via a Yonemitsu type reaction still remains an active research area [30–36]. Thus,
the synthetic utility of such protocols is further made more attractive when the
reactions are promoted by glycerol under catalyst-free and ultrasonic irradiation
conditions. In continuation of our efforts to develop green chemistry methods as
well as our interest in the application of Meldrum’s acid to synthesis of useful
organic molecules [37–40], in this manuscript the Yonemitsu condensation using
glycerol as green medium without catalyst under ultrasonic irradiation at room
temperature is described (Scheme 1). Compared to the catalyst-free methods
1
23

A combination of green solvent and ultrasonic irradiation…
Scheme 1 The approach for the preparation of 3-indole derivatives
reported in the literature [27, 28], various aromatic aldehydes have been applied for
this reaction, and moderate to good yields have been obtained.
Experimental
General
Unless otherwise stated, all reagents were obtained from commercial sources and
were used without further purification. Melting points were determined on a Beijing
Tech X-5 melting point detector and were uncorrected. The IR spectra were
1
measured with a Bruker Shimadzu IR-460 spectrometer. H NMR spectra were
recorded on a Bruker Avance III 400 MHz or a Bruker Avance III 500 MHz. The
chemical shifts (d) were reported in parts per million (ppm) and coupling constants
(J) in Hertz. A commercially available Kunshan KQ 2200DB, 80 W ultrasonic
cleaner (220 V, 40 kHz, 3 L capacity) was utilized for reactions.
Typical experimental procedure for synthesis of 4
A mixture of indole (0.5 mmol), Meldrum’s acid (0.55 mmol), and 2 mL
glycerol:H O (1.3:0.7 v/v) was added in a 10 mL Schlenk tube, then aldehyde
2
(
0.5 mmol) was added, and the mixture was placed in an ultrasonic bath at r.t.
0 kHz for 20 min three times (with a 5 min rest). The temperature of the process
4
was maintained at 25 ± 3 °C by means of supply of water to the reactor used for the
synthesis. After completion of reaction, the product stood for 4 h at room
temperature. The precipitate was separated by filtration and washed with aqueous
ethanol. The crude products were recrystallized from an appropriate solvent to
obtain the corresponding adducts.
Results and discussion
As a starting point for the development of our methodology, we commenced our
work to optimize the reaction condition by carrying out the three-component
condensation of indole, Meldrum’s acid, and benzaldehyde in equimolecular
amounts of 0.5 mmol. The effects of reaction parameters were studied. Initially,
123

C.-W. L u¨ et al.
3
mL glycerol was used as the solvent without catalyst. After ultrasonic 20 min for
three times at room temperature, the product was collected in 81 % yield (Table 1,
entry 1). As we know, water could promote the condensation of Meldrum’s acid
with aldehydes avoiding the addition of any catalyst [41, 42] and also exhibits
unique reactivity in this multicomponent reaction [30, 38]. In another attempt, we
employed 2 mL glycerol and 1 mL H O as solvent. To our delight, the required
2
product was formed in 89 % yield (Table 1, entry 2). In order to improve the yield,
various volumes and ratios of the water and glycerol were screened (Table 1, entries
2
–6). The reaction showed a surprising dependence on the solvent, with 1.3 mL
glycerol and 0.7 mL water giving the best yield and purity of the desired product
Table 1, entry 6). The reaction in water was also investigated and afforded the
(
corresponding adduct in moderate yield due to the formation of homodimeric by-
products (Table 1, entry 7). On the basis of the above results, we examined the
effects of the reaction temperature and time. As shown in Table 1, the reaction at r.t.
was a feasible option. Further elevating or lowering the temperature failed to
improve the yield (Table 1, entries 8, 9). The effect of the reaction time was also
surveyed, and a similar result as for entry 6 was achieved as the time was prolonged
to 80 min (Table 1, entry 11). Decreasing the reaction time to 40 min was
detrimental to the result (Table 1, entry 10).
In addition, we have also investigated the fate of varying the molar ratio of each
substrate (Table 2, entries 1–3). It is clear that, when increased the reagent’s loading
of Meldrum’s acid to 0.55 mmol, a better outcome to afford the desired product in
9
6 % yield was observed. To show the role of ultrasound, the control experiment
was investigated without ultrasonic irradiation at the same temperature under
traditional stirring conditions. It was observed that the use of ultrasound leads to the
faster reaction and higher yields (Table 2, entries 3, 4).
Table 1 The screening of reaction conditions
a
b
Yield (%)
Entry
Solvent
Volume (mL)
Temp. (°C)
Time (min)
1
2
3
4
5
6
7
8
9
Glycerol
3.0
rt
60
60
60
60
60
60
60
60
60
40
80
81
89
78
69
78
93
66
90
89
86
92
Glycerol/H
Glycerol/H
Glycerol/H
Glycerol/H
Glycerol/H
2
2
2
2
2
O
O
O
O
O
2.0/1.0
2.5/0.5
1.5/1.5
2.7/1.3
1.3/0.7
3.0
rt
rt
rt
rt
rt
H
2
O
rt
Glycerol/H
Glycerol/H
Glycerol/H
Glycerol/H
2
2
2
2
O
O
O
O
1.3/0.7
1.3/0.7
1.3/0.7
1.3/0.7
35
20
rt
1
1
a
0
1
rt
The reactions were carried out with benzaldehyde, indole, and Meldrum’s acid in equimolecular
amounts of 0.5 mmol without catalyst under ultrasound conditions
b
Isolated yield
1
23

A combination of green solvent and ultrasonic irradiation…
Table 2 The screening of reaction conditions
a
b
Yield (%)
Entry
Condition
Benzaldehyde/indole/Meldrum’s acid
Time (min)
1
2
3
4
a
US
0.5 mmol/0.55 mmol/0.5 mmol
0.55 mmol/0.5 mmol/0.5 mmol
0.5 mmol/0.5 mmol/0.55 mmol
0.5 mmol/0.5 mmol/0.55 mmol
60
60
87
85
96
90
US
US
60
Vigorously stirred
480
The reactions were carried out at rt
Isolated yield
b
The optimal result was achieved when the transformation was sonicated in a
mixture solvent from 1.3 mL glycerol and 0.7 mL water at r.t. for twenty minutes
and for three times under catalyst-free conditions. A substrate scope evaluation
showed that the method is compatible with many substituted benzaldehydes, and all
the substrates that were tested (see Table 3) afforded moderate to good yields. As
shown in Table 3, the presence of electron withdrawing or electron donating
substituents in the same position on the ring of various aromatic aldehydes had
different influences on the procedure to furnish the desired products. When
introducing methoxy group in the para- or meta-position on the benzene ring, the
Table 3 Substrate scope for the synthesis of product 4
a
1
R
2
R
b
Yield (%)
Entry
Product
M.p. (°C)
1
2
C
6
H
5
H
4a
4b
4c
4d
4e
4f
96
82
65
78
37
59
92
70
76
66
61
92
91
93
Trace
36
80
140–142 (140–142 [27])
130–132 (137–139 [38])
120–122 (115–117 [38])
139–141 (136–138 [39])
122–124 (125–127 [38])
130–132 (139–141 [38])
155–157 (160–162 [38])
133–135 (131–133 [38])
138–140 (138–139 [38])
140–142 (134–136 [38])
136–138 (142–144 [38])
139–141 (138–141 [38])
145–147 (142–144 [27])
157–159 (157–159 [27])
–
4-MeC
3-MeC
2-MeC
6
6
6
H
H
H
4
4
H
c
3
H
4
5
4
H
4-MeOC
3-MeOC
2-MeOC
6
6
6
H
4
4
4
H
c
6
H
H
H
7
8
H
4g
4h
4i
4-ClC
3-ClC
2-ClC
6
6
6
H
H
H
4
4
4
H
c
9
H
1
1
1
1
1
1
1
1
a
0
1
2
3
4
5
6
7
H
4j
4-BrC
6
6
H
4
H
4k
4l
3-BrC
H
4
H
4-NO
2
C
6
H
4
H
4m
4n
4o
4p
4q
3-NO
2
C
6
H
4
H
(CH
3
)
2
CH
H
C
6
H
5
CH
CH
3
3
148–150 (152–153 [38])
143–145 (143–145 [38])
2 6
4-NO C H
4
The reactions were carried out with benzaldehyde/indole/Meldrum’s acid (0.5 mmol/0.5 mmol/
.55 mmol) at rt without catalyst under ultrasound conditions
0
b
Isolated yield
c
Reacted at 40 °C
123

C.-W. L u¨ et al.
lowest yield was observed (Table 3, entries 5, 6). High yields were obtained when
the strong electron withdrawing substituents were present in the meta- and para-
positions on the ring of aromatic aldehydes. For example, 3-nitrobenzaldehyde and
4
-nitrobenzaldehyde gave the best results (Table 3, entries 13, 14). On the other
hand, when employing ortho-substituted aromatic aldehyde as substrate, the steric
hindrance was dominant than other factors in the product formation. Poor yields or
no products were obtained for the ortho-substituted benzaldehydes, such as
2
-chlorobenzaldehyde, 2-bromobenzaldehyde, and 2-nitrobenzaldehyde. Unexpect-
edly, 2-tolualdehyde and 2-methoxybenzaldehyde gave 78 and 92 % yields in this
three-component reaction (Table 3, entries 4, 7). Unfortunately, aliphatic aldehyde
had a low reactivity in this reaction (Table 3, entry 15). Finally, when 1-methylin-
dole was used as starting material, a lower yield than indole was obtained (Table 3,
entries 16, 17).
Conclusions
A glycerol and water-mediated procedure for the synthesis of 5-[(indol-3-yl)-
arylmethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione derivatives from the condensation
of indole with Meldrum’s acid and aldehyde under ultrasonic irradiation has been
developed. This green synthetic pathway has many advantages, such as using
inexpensive green solvents, catalyst-free, mild reaction conditions and tolerant the
substrates with diverse functional groups.
Acknowledgments We are grateful for financial support from the National Natural Science Foundation
of China (21403100, 21576128) and Liaoning Province, and the Doctoral Scientific Research Foundation
(20141100).
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