Choline chloride and lactic acid: A natural deep eutectic solvent for one-pot rapid construction of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridines]

Article abstract of DOI:10.1016/j.molliq.2019.01.065

The application of natural eutectic solvent (NDDES) in organic synthesis has received more and more attention. In this work, a green protocol for one-pot synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridines] via three-component reactions of 1H-pyrazo

Full text of DOI:10.1016/j.molliq.2019.01.065

Accepted Manuscript
Choline chloride and lactic acid: A natural deep eutectic solvent
for one-pot rapid construction of spiro[indoline-3,4′-
pyrazolo[3,4-b]pyridines]
Wei-Hong Zhang, Meng-Nan Chen, Yi Hao, Xin Jiang, Xiao-Lin
Zhou, Zhan-Hui Zhang
PII:
S0167-7322(18)32559-5
DOI:
Reference:
https://doi.org/10.1016/j.molliq.2019.01.065
MOLLIQ 10296
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
18 May 2018
23 October 2018
12 January 2019
Please cite this article as: Wei-Hong Zhang, Meng-Nan Chen, Yi Hao, Xin Jiang, Xiao-
Lin Zhou, Zhan-Hui Zhang , Choline chloride and lactic acid: A natural deep eutectic
solvent for one-pot rapid construction of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridines].
Molliq (2018), https://doi.org/10.1016/j.molliq.2019.01.065
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ACCEPTED MANUSCRIPT
Choline chloride and lactic acid: A natural deep eutectic solvent for one-pot
rapid construction of spiro[indoline-3,4'-pyrazolo[3,4-b]pyridines]
Wei-Hong Zhang, Meng-Nan Chen, Yi Hao, Xin Jiang, Xiao-Lin Zhou, Zhan-Hui Zhang*
Key Laboratory of Inorganic Nanomaterials of Hebei Province, National Demonstration Center for Experimental
Chemistry Education, College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024,
P. R. China
ABSTRACT
The application of natural eutectic solvent (NDDES) in organic synthesis has received more and more attention. In
this work, a green protocol for one-pot synthesis of spiro[indoline-3,4'-pyrazolo[3,4-b]pyridines] via
three-component reactions of 1H-pyrazol-5-amin, isatin and enolizable C−H activated compound is achieved by
the combination of microwave irradiation with choline chloride and lactic acid based NDDES. This novel method
is clean, cheap, simple, high yield, chromatography-free and scalable. The use of choline chloride and lactic acid as
a biodegradable, recycled and reusable media meets most of the criteria to be considered as a sustainable and
environmentally benign process.
Keywords:
Natural deep eutectic solvents, Choline chloride/lactic acid, Multicomponent reaction, Isatin, Spirooxindoles,
Pyrazolo[3,4-b]quinoline
____________________________________________________________________________
*Corresponding
author.
Fax:
+86
31180787431.
E-mail
address:
zhanhui@hebtu.edu.cn,
zhanhui@mail.nankai.edu.cn (Z.-H. Zhang)
1

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1. Introduction
Solvents occupy a strategic place in the chemical industry. Developing new green solvents to replace current
harsh organic solvents is one of the key subjects. In recent years, deep eutectic solvents (DES) have attracted
attention due to their excellent biodegradability, low volatility, non-toxicity, ease of preparation, and low cost
[1-3]. DESs are conveniently prepared by mixing two or more components that are inexpensive, easily degradable,
and environmentally friendly. Most DESs are liquids at room temperature, mainly because these components are
capable of self-association through strong hydrogen bonding interactions to generate an eutectic mixture with a
much lower melting point than that of any of its individual components [4-6]. When the compound that constitutes
DES is primary metabolite, such as polyols, amino acid, organic acid, sugar, urea or choline derivatives, DESs are
called natural deep eutectic solvents (NADESs) [7-9]. So far, these solvents have been applied to many chemical
processes such as extraction and separation [10], biomass processing [11], polymerization and materials science
[12] as well as organic synthesis [13-26]. Thus, the development of new NADESs and extension of research on
the use of these solvents to replace harmful traditional solvents in organic reaction is highly desirable.
Pyrazolo[3,4-b]pyridines represent an important class of heterocyclic compounds and have found in many
active biological products, natural products, and functional materials. Structures embedded with
pyrazolo[3,4-b]pyridine units display potential medicinal properties such as antiplatelet [27], antifungal [28],
anticancer [29], antimicrobial and antiproliferative [30]. They have also been found to behave as potent dual
orexin receptor antagonists [31], c-Met [32], and selective FGFR kinase inhibitors [33]. Moreover, spirooxindole
are also attractive structural units and are encountered in the core structure of bioactive naturally alkaloids as well
as they were considered as privileged scaffolds for antiviral drug development [34-36]. According to current
research, merging pyrazolo[3,4-b]pyridine backbones and spirooxindole motif into one molecular structure may
result in a series of structural and biologically interesting compounds that will have all the properties of the moiety
and enhance the pharmacological activity. For these reasons, there have been some methods for the synthesis of
spiro[indoline-3,4'-pyrazolo[3,4-b]pyridines] via three-component reactions of isatins with aminpyrazoles and
reactive dicarbonyls [37-41], β-ketonitriles [42-43] or enol derivatives [44]. Despite these advances, there are only
a few reports about the synthesis of spirooxindole derivatives in deep eutectic solvents [45-47].
Given these considerations and as a part of our constant interest in developing efficient and environmentally
friendly synthetic methods [48-50], we herein focus on the development of a highly efficient, clean, quick, and
scalable protocol for the preparation of spiro[indoline-3,4'-pyrazolo[3,4-b]pyridines] and other similar
2

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spiroheterocycles via three-component one-pot reaction of 1H-pyrazol-5-amin, isatin and enolizable C−H
activated compound by combining the microwave-assisted organic synthesis (MAOS) with natural deep eutectic
solvent (Scheme 1).
Scheme 1. Synthesis of pyrazolo[3,4-b]quinoline spirooxindoles in ChCl/Lac
2. Experimental section
2.1 General
All reagents were commercially available and used without further purification. Melting points were
determined on an X-5 digital melting point apparatus and are uncorrected. IR spectra were recorded on a Thermo
1
Scientific Nicolet iS50 spectrometer using KBr disks. H NMR and 13C NMR (500 MHz and 125 MHz,
respectively) spectra were recorded on a Bruker DRX-500 spectrometer using DMSO-d6 as the solvent with
tetramethylsilane (TMS) as an internal standard at room temperature. The mass spectra were obtained on a 3200
Qtrap instrument (ESI). High-resolution mass spectroscopy (HRMS) was recorded on Thermo Scientific LTQ FT
Ultra FT-MS.
2.2. Preparation of choline chloride (ChCl) and lactic acid (Lac) based natural deep eutectic solvent
A mixture of ChCl (100 mmol) and Lac (100 mmol or 200 mmol)) were ground with a mortar and pestle in
an argon-filled glove box, transferred to a round bottom flask and heated at 60 oC to give a clear liquid.
2.3. General procedure for preparation of pyrazolo[3,4-b]quinoline spirooxindoles
A mixture of 1H-pyrazol-5-amin (1 mmol), isatin (1 mmol) and enolizable C−H activated compound (1
mmol) in NDDES (1.5 ml) was stirred under microwave irradiation at 60 °C for an appropriate time. The progress
of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled to room
temperature and cold water was added to the reaction mixture. The precipitated solid was isolated by filtration,
washed with water and purified by recrystallization from ethanol.
3. Results and Discussion
In this work, ChCl/Lac systems were prepared by mixing ChCl and Lac at different molar ratios 1:1 and 1:2
in an argon-filled glove box. The mixture was kept under constant stirring and at 60 °C until a homogeneous
3

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liquid was formed. Then, the mixture was cooled to room temperature, and the resulting NDDES was used
directly in the organic reaction without further purification.
Subsequently, the NDDES-promoted three-component reaction of 1,3-diphenyl-1H-pyrazol-5-amine, isatin
and 5,5-dimethylcyclohexane-1,3-dione was evaluated under microwave irradiation. Control experiments showed
that no reaction was observed when the reaction was performed in the absence of solvent or catalyst at 60 °C for 1
h (Table 1, entry 1). Reaction was performed in H2O or N,N-dimethylformamide (DMF), only trace of product
was formed (entry 2 and 3). Switching the solvent to PEG 400 or EtOH, the desired product 4a was isolated in
15% and 18%, respectively (Table 1, entries 4 and 5). The use of ethyl lactate (EL) as solvent resulted in 25%
yield (Table 1, entry 6). In EL/H2O only 20% yield was observed (Table 1, entry 7). Because ChCl is a low
toxicity, biodegradable, inexpensive and ton-scale available substance, DESs derived from ChCl with several
classes of hydrogen bond donor (HBD) such as renewable polyols, carbohydrates, alcohols, amides and
carboxylic acids are liquids at room temperature and can be used as solvent and catalyst in different organic
synthsis processes, we decided to optimize the reaction conditions using DESs. It was found that ChCl/ZnCl2,
ChCl/ZnBr2, ChCl/ glycerol (G), and ChCl/ proline (Pro) gave the low yield of product (entries 8-11). The use of
ChCl/malonic acid (MA), ChCl/ethylene glycol (EG), ChCl/1,3-dimethylurea (DU), ChCl/tartaric acid (TA)
increased the yield of the desired 4a (entries 12-15). Further exploration showed when the reaction was carried out
in ChCl/Lac (1:1), product 4a was formed in 86% yield (entry 16). Encouraged by these result, we further carried
out this reaction with varied rations of ChCl and Lac. It was found high yield (95%) could be achieved in
ChCl/Lac (1:2) (entry 17). Notably, the reaction can proceed in pure ChCl or Lac, but only low yield of the
product was formed (Table 1, entry 18 and 19).
The reaction was also monitored under different amount of ChCl/Lac and the results revealed that 1.5 ml
ChCl/Lac was the optimum amount for completing the reaction. Moreover, slight decrease in the product yield
was observed when the reactions were performed at lower temperature (entries 20 and 21). In addition, we also
studied the effect of microwave irradiation on this reaction. It was found that the reaction required a longer
reaction time under simple heating conditions, and the yield of product is relatively lower than under microwave
irradiation (entry 27). The effect of microwave power on the reaction was also tested. The results showed that 500
W was the proper power for this three-component reaction. These results indicated that microwave irradiation
effectively accelerated the progress of this reaction. It should be pointed out that low yield was obtained when
HCl was used in the absence of ChCl/Lac (entry 31). In addition, the reaction time is not shortened and the yield
4

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is not increased when 1 drop of HCl was added in ChCl/Lac (entry 32). It was indicated that the formation of HCl
during the preparation of DDES has little effect on the reaction [2].
To further showcase the practical utility of this newly developed system, the model reaction was evaluated
on a larger scale. Reassuringly, the reaction was found to proceed smoothly on a 100-mmol scale and the excellent
yield of 4a was maintained (entry 33). On the same scale, the recovery and recyclability of NDDES were also
investigated. After the reaction is completed, the reaction mixture was cooled to room temperature and then cold
water was added, shacked vigorously and solid was separated by simple filtration followed by washing with water.
The soluble NDDES in water could be easily recovered through evaporating the water at 80 oC under vacuum and
was reused for the next batch. After eight consecutive recycles, it still afforded target product 4a in 78% yield
(entry 34). A slight decrease in the yield of the target product may be a little loss of deep eutectic solvent during
the work-up process.
Table 1
Optimization of the reaction conditionsa
Entrysolvent
Temperature (oC)
60
MW (W) Time (min)
Yield (%)b
0
1
2
3
4
5
6
7
8
9
No
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
60
60
60
60
60
60
60
20
20
20
20
20
20
20
20
20
H2O
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
trace
trace
15
DMF
PEG 400
EtOH
18
EL
25
EL/H2O (1:1)
ChCl/ZnCl2 (1:2)
ChCl/ZnBr2 (1:2)
20
21
28
10 ChCl/G (1:1)
11 ChCl/Pro(1:2)
12 ChCl/MA (1:2)
13 ChCl/EG (1:1)
14 ChCl/DU (1:1)
15 ChCl/TA (2:1)
16 ChCl/Lac (1:1)
20
30
50
56
58
64
86
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17 ChCl/Lac (1:2)
18 ChCl
60
60
60
60
60
60
60
40
50
70
60
60
60
60
60
60
60
500
500
500
500
500
500
500
500
500
500
0
20
60
60
20
20
20
20
20
20
20
120
40
40
20
20
20
20
95
35
19 Lac
20
20c ChCl/Lac (1:2)
21d ChCl/Lac (1:2)
22e ChCl/Lac (1:2)
23f ChCl/Lac (1:2)
24 ChCl/Lac (1:2)
25 ChCl/Lac (1:2)
26 ChCl/Lac (1:2)
27 ChCl/Lac (1:2)
28 ChCl/Lac (1:2)
29 ChCl/Lac (1:2)
30 ChCl/Lac (1:2)
31g no
30
71
93
91
81
90
93
82
300
400
600
500
500
500
91
93
95
12
32h ChCl/Lac (1:2)
33i ChCl/Lac (1:2)
95
94
93, 90, 88, 86,
83, 80, 80, 78
34j ChCl/Lac (1:2)
60
500
20
a
Reaction
conditions:
1,3-diphenyl-1H-pyrazol-5-amine
(1
mmol),
isatin
(1
mmol),
o
5,5-dimethylcyclohexane-1,3-dione (1 mmol) in solvent (1.5 ml) at 60 C under microwave irradiation (500 W)
unless otherwise specified in the table.
b Isolated yield.
c The reaction was performed in 0.50 ml ChCl/Lac.
d The reaction was performed in 0.75 ml ChCl/Lac.
e The reaction was performed in 1.25 ml ChCl/Lac.
f The reaction was performed in 1.75 ml ChCl/Lac.
g1 ml HCl (1 mol/l) was used.
h1 Drop of HCl was added.
i The reaction was carried out in 100 mmol scale.
j ChCl/Lac was reused for 8 times.
After the optimal reaction conditions were identified, the scope and generality of this domino process were
evaluated. As shown by the results in Table 2, various isatins reacted with 1,3-diphenyl-1H-pyrazol-5-amine and
5,5-dimethylcyclohexane-1,3-dione to produce the expected products in excellent yields, no matter the presence of
substituents bearing electron-rich or electron-poor groups in various positions. Various functional groups were
well tolerated on the isatin moiety including methyl (4b, 4f and 4i), fluoro (4g), chloro (4h), bromo (4c and 4e),
6

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and nitro (4d) groups. Additionally, diversified 1H-pyrazol-5-amines were also surveyed. Regarding the upper
aromatic ring, various substituents, including electron-donating methyl group, and electron-withdrawing groups
such as chloro and nitro groups were tolerated. Moreover, 1H-pyrazol-5-amine with benzo[d]thiazole ring
behaved quite well in this domino process to afford the corresponding products 4p and 4q in high yields, thereby
expanding the range of functional groups tolerated with this novel method.
Table 2
Synthesis of spiro[indoline-3,4'-pyrazolo[3,4-b]quinoline]-2,5'(6'H)-diones in ChCl/Lac
Entry
1
R1
R2
R3
Product
4a
Time (min)
Yield (%)a
Ph
Ph
H
20
15
20
25
20
18
16
17
20
20
15
20
16
15
16
95
94
93
95
94
95
94
93
92
95
94
93
93
94
93
2
Ph
Ph
5-Me
5-Br
5-NO2
6-Br
7-Me
7-F
4b
4c
3
Ph
Ph
4
Ph
Ph
4d
4e
5
Ph
Ph
6
Ph
Ph
4f
7
Ph
Ph
4g
8
Ph
Ph
7-Cl
1-Me
H
4h
4i
9
Ph
Ph
10
11
12
13
14
15
Ph
4-FC6H4
Ph
4j
4-MeC6H4
3-ClC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
H
4k
4l
Ph
H
Ph
H
4m
4n
4o
Ph
5-Me
7-Me
Ph
16
17
Ph
Ph
H
22
18
92
91
4p
4q
5-Me
a Isolated yield.
To further investigate the scope of this reaction, various enolizable C−H activated compounds such as
barbituric acid, cyclopentane-1,3-dione, cyclohexane-1,3-dione, and 1,3-indanedione were assessed in this
three-component reaction. Gratifyingly, these reactions proceeded smoothly, leading to the formation of the
7

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anticipated pyrazolo[3,4-b]quinoline spirooxindoles 6a–6ah in excellent yields. The above results clearly
demonstrated that the present procedure can be extended to a wide variety of substrates to construct a library of
diversified orientations of functionalized spirooxindoles.
Table 3
Synthesis of pyrazolo[3,4-b]quinoline spirooxindoles in ChCl/Lac.
Entry
1
2
3
4
5
6
7
8
9
10
11
R1
Ph
Ph
Ph
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R3
H
5-Me
7-Cl
H
1,3-Dicarbonyl
Product
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
Time (min)
Yield (%)a
20
20
18
25
20
15
20
20
20
19
25
95
95
93
94
92
95
95
94
93
93
94
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
3-FC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
4-MeC6H4
4-NO2C6H4
H
5-Me
7-Cl
H
H
H
2,6-Me2C6H3 Ph
Ph
4-FC6H4
H
12
13
Ph
Ph
H
30
30
94
93
5a
5a
6l
5-Me
6m
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph
Ph
Ph
3-ClC6H4
3-ClC6H4
3-ClC6H4
Ph
Ph
Ph
3-ClC6H4
3-ClC6H4
4-NO2C6H4
4-NO2C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
H
7-Me
7-Cl
H
5-Me
7-Cl
H
H
5-Me
H
5-Me
H
5-NO2C6H4
H
17
13
15
14
15
15
20
20
20
20
20
18
18
25
94
93
95
95
95
94
93
94
93
94
95
94
95
93
5b
5b
5b
5b
5b
5b
5b
5c
5c
5c
5c
5c
5c
5c
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
6x
6y
6z
4-FC6H4
6aa
28
29
Ph
Ph
H
30
30
94
90
5c
5c
6ab
6ac
5-Me
30
31
32
33
Ph
Ph
Ph
3-ClC6H4
Ph
Ph
Ph
Ph
H
21
25
20
20
93
91
94
92
5d
5d
5d
5d
6ad
6ae
6af
6ag
5-OMe
7-Cl
H
8

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34
3-ClC6H4
Ph
5-Me
20
94
5d
6ah
a Isolated yield.
To illustrate the advantages and limitations of this work, we summarize some of the results for the synthesis
of 6a and compare them with other reported methods in the literatures. As can be seen from this Table 4, the
present work is an equally or more efficient than those previously reported.
Table 4
Comparison of different methods for synthesis of 6a
Entry
Reaction condition
Yield (%)
Ref.
1
2
3
4
p-Toluenesulfonic acid, H2O, reflux, 24 h
Alum, [Bmim]PF6, 100 oC, 30 min
90
95
83
95
39
40
A tin complex immobilized on silica gel, H2O, reflux, 90 min
ChCl/Lac (1:2), microwave irradiation, 60 oC, 20 min
41
This work
The
tentative
reaction
mechanism
for
the
NDDES-based
formation
of
7',7'-dimethyl-1',3'-diphenyl-1',7',8',9'-tetrahydrospiro[indoline-3,4'-pyrazolo[3,4-b]quinoline]-2,5'(6'H)-dione
(4a) is well established (Scheme 2). With the understanding from the literatures [37, 39] and based on the results
obtained, the first step involved Knoevenagel condensation of isatin and 5,5-dimethylcyclohexane-1,3-dione to
give intermediate I in the presence of a NDDES. The subsequent a Michel-type addition of
1,3-diphenyl-1H-pyrazol-5-amine to the C=C bond of intermediate I occurred, resulting in the formation of the
adduct II. Afterwards, an intramolecular cyclic condensation between the amino and the carbonyl groups of the
Michael adduct II took place to produce intermediate III, which upon elimination of water to provide the
expected product 4a. The NDDES acts as the solvent as well as participates as a hydrogen-bonding catalyst, the
strong hydrogen bond interaction of NDDES with carbonyl group is responsible for formation of Knoevenagel
condensation product as well as for assisting to enhance electrophilic character of carbonyl carbons in both
intermediate I and intermediate II.
9

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Scheme 2. A plausible mechanism for the formation of product 4a
4. Conclusion
In summary, we have disclosed a novel, general, highly efficient, economical method for the fast and
divergent assembly of a new class of pyrazolo[3,4-b]quinoline spirooxindoles via a three-component reaction
involving 1H-pyrazol-5-amin, isatin and enolizable C−H activated compound under microwave irradiation in ChCl
and Lac based NDDES for the first time. This environmentally friendly process features broad substrate scope,
high yield, short reaction time, easy scalability with the use of NDDES as a biodegradable, recycled and reusable
media and catalyst.
Acknowledgments
We are grateful for financial support from the Nature Science Foundation of Hebei Province (B2015205182), the
National Natural Science Foundation of China (21272053), the Science and Technology Research Foundation of
Hebei Normal University (L2018Z06) and National Undergraduate Training Programs for Innovation and
Entrepreneurship (201810094027).
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Graphical abstract
Choline chloride and lactic acid: A natural deep eutectic solvent for one-pot rapid construction of
spiro[indoline-3,4'-pyrazolo[3,4-b]pyridines]
Wei-Hong Zhang, Meng-Nan Chen, Yi Hao, Xin Jiang, Xiao-Lin Zhou, Zhan-Hui Zhang*
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Highlights
 The synthetic procedure of choline chloride and lactic acid based on the natural eutectic
solvents is very simple.
 The NDDES plays dual role as medium and catalyst for synthesis of spirooxindole derivatives.
 This new method is clean, inexpensive, high yield, chromatography-free and scalable.
 NDDES is easy to recycle and reuse.
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