The selective condensation of pyrazolones to isatins in aqueous medium

Article abstract of DOI:10.1016/j.tet.2019.130916

The selective condensation of pyrazolones with isatins using water as the reaction medium is presented. This strategy provides an environmentally benign synthetic route to synthesize various potentially bioactive pyrazolone substituted oxindoles.

Full text of DOI:10.1016/j.tet.2019.130916

Journal Pre-proof
The selective condensation of pyrazolones to isatins in aqueous medium
Yong Zhang, Long-Jun Nie, Liang Luo, Jia-Xin Mao, Jin-Xiang Liu, Guo-Hai Xu,
Deliang Chen, Hai-Qing Luo
PII:
S0040-4020(19)31335-3
https://doi.org/10.1016/j.tet.2019.130916
TET 130916
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 October 2019
Revised Date: 20 December 2019
Accepted Date: 23 December 2019
Please cite this article as: Zhang Y, Nie L-J, Luo L, Mao J-X, Liu J-X, Xu G-H, Chen D, Luo H-Q, The
selective condensation of pyrazolones to isatins in aqueous medium, Tetrahedron (2020), doi: https://
doi.org/10.1016/j.tet.2019.130916.
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Graphical Abstract
The Selective Condensation of Pyrazolones
with Isatins in Aqueous Medium
Yong Zhang a,*, Long-Jun Nie a, Liang Luo a, Jia-Xin Mao a, Jin-Xiang Liu a, Guo-Hai Xu a, Deliang Chen a,
and Hai-Qing Luo a,*

Tetrahedron
1
Tetrahedron
journal homepage: www.elsevier.com
The Selective Condensation of Pyrazolones to Isatins in Aqueous Medium
Yong Zhang a,*, Long-Jun Nie a, Liang Luo a, Jia-Xin Mao a, Jin-Xiang Liu a, Guo-Hai Xu a, Deliang Chen
a, and Hai-Qing Luo a,*
a Key Laboratory of Organo-pharmaceutical Chemistry, Gannan Normal University, Ganzhou 341000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The selective condensation of pyrazolones with isatins using water as the reaction medium is
presented. This strategy provides an environmentally benign synthetic route to synthesize
various potentially bioactive pyrazolone substituted oxindoles.
2019 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
Water
Condensation
Pyrazolones
Oxindoles
The discovery and development of environmentally benign
protocols for the diversity-oriented synthesis of heterocyclic
compounds is of great significance to chemical and
pharmaceutical research.1 Water, the solvent of choice for
Nature, is cheaper, safer, and cleaner than conventional organic
solvents.2 In addition to being a green reaction medium, water
has special physical and chemical properties, such as high heat
capacity, high dielectric constant, amphoteric nature and
extensive H-bonding ability.3 These special properties allow
chemists to realize reactivities and selectivities that cannot be
achieved in common organic solvents.4 Therefore, extensive
efforts have focused on the use water as a reaction medium, and
great success has been achieved in modern organic synthesis.5
However, pursuing practical organic reactions in water for the
synthesis of biologically relevant heterocycles is still in early
stages and more research is needed.6
nucleophilic addition of antipyrine to carbonyl compounds is the
most convenient strategy for the construction of antipyrine-
substituted alkanol products. However, to the best of our
knowledge, no report was found in literature on the selective
condensation of antipyrine with carbonyl compounds, and most
of these reactions resulted in the formation of diantipyrine-
substituted products.13 Herein, we report that the selective
condensation of N-substituted pyrazolones with isatins can be
realized in water (Scheme 1).
Pyrazolone, a unique five-membered heterocycle featuring
two adjacent nitrogen atoms, is identified
a significant
pharmacophore because of its prevalence in bioactive natural
alkaloids and pharmaceuticals.7 In particular, antipyrine (1-
phenyl-2,3-dimethylpyrazol-5-one) and its derivatives have been
widely used for a long time in medicine as antipyretic, analgesic,
sedative, antimicrobial, antiviral, antioxidant, anticancer, and
anti-inflammatory drugs (Figure 1).8 Thus, considerable attention
has been directed towards the synthesis of antipyrine analogues
for drug discovery.9 Although several of methods, such as
electrophilic
substitutions10
and
metal-catalyzed
C-H
functionalization11 have been used for the synthesis of antipyrine
analogues, the existing synthetic routes to antipyrine-substituted
alkanol products are limited to the nucleophilic addition of
aldehyde with Grignard reagent and the reduction of the
corresponding ketone.12 These methods suffer from many
disadvantages, such as narrow substrate tolerance, harsh reaction
conditions and low atom economy. Theoretically, the direct
Figure 1 Examples of pharmaceutically active pyrazolones

2
Tetrahedron
Table 1 Optimization of the reaction conditionsa
O
Ph
O
Ph
N
O
N
N
N
N
N
H
HO
1a
N
Ph
O
Additive
Solvent
+
+
O
O
O
N
N
Ph
O
H
N
H
3a
N
4a
2a
Entry Solvent Temp. Additive
[oC]
t
3a
4a
[h] Yield[%]b Yield[%]b
Organic
solvents
H2O
25
none
48
-
-
1
25
65
65
65
65
65
65
65
65
80
100
80
80
80
80
80
80
80
80
80
80
none
none
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
-
58
-
-
nd
-
2
H2O
DMF
DMSO
Toluene
Dioxane
CHCl3
MeOH
MeCN
H2O
3
none
4
none
-
-
5
none
-
-
6
none
-
-
7
none
-
-
8
none
trace
trace
55
24
37
34
40
51
65
46
86
38
67
73
-
9
none
-
10
11
12
13
14
15
16
17
18
19
20
21c
22d
Scheme 1 Synthetic routes to pyrazolone-substituted alkanol
none
21
68
8
products
H2O
none
Initially, we investigated the reaction of isatin with antipyrine,
leading to the formation of 3-antipyrine substituted 3-hydroxy-2-
oxindole, as a model for optimizing the reaction condition (Table
1). Different solvents including water, DMF, DMSO, Toluene,
Dioxane, CHCl3, MeOH and MeCN were studied at various
temperatures. No product was formed when the reaction was
performed at room temperature. Elevating the reaction
H2O
NaHCO3
K2CO3
DABCO
DMAP
DBU
H2O
10
8
H2O
H2O
17
9
H2O
H2O
Et2NH
imidazole
TMG
18
-
o
temperature from rt to 65 C, the desired product was obtained
H2O
with 58% yield in water, while no product or only traces of
product were observed in other organic solvents. Increasing the
H2O
<5
20
10
o
o
H2O
imidazole
imidazole
reaction temperature in water from 65 C to 80 C and further to
o
H2O
100 C did not improve the yield of the desired product, but led
a Unless otherwise noted, the reaction was performed with 0.4 mmol of 1,
to the formation of a further nucleophilic substitution product 4a
(bis-antipyrinyl oxindole). We speculated that the increased
acidity of water at elevated temperature is the reason of further
nucleophilic substitution process.14 To suppress this competitive
process, a series of base additives were then screened. To our
delight, when 20 mol % imidazole was tested, it resulted in 86%
of the 3-antipyrine substituted 3-hydroxy-2-oxindole product 3a,
and no bis-antipyrinyl oxindole product 4a was observed. Other
bases, such as NaHCO3, K2CO3, DABCO, DMAP, DBU, Et2NH
and TMG, gave inferior results. When the amount of imidazole
was reduced to 10 and 5 mol %, 10% and 20% of 4a was isolated
respectively in 48 h, which suggests the key role of imidazole for
this protocol.
0.2 mmol of 2a and 20 mol % additive in 1 mL water.
b Isolated yield.
c 5 mol % of the catalyst was used.
d 10 mol % of the catalyst was used.
Interestingly, di-substituted isatin (4,7-dichloroisatin as an
example) was also applicable for this reaction even in the
absence of imidazole, affording the desired product 3m in 88%
yield. The scope of this nucleophilic addition reaction was further
extended to N-protected isatins. It is shown that N-methyl isatins,
N-ethyl isatin, N-allyl isatin and N-phenyl isatin were also
compatible substrates with the formation of the corresponding
products in 67–84% yields. However, poor result was obtained
when N-benzyl isatin was employed, presumably due to its poor
dispersibility in water. Moreover, it is recognized that the
electronic nature of N-aryl substituted pyrazolones has no
pronounced on the reaction yields. Pyrazolones with different
groups, such as fluoro, chloro, bromo, methyl, and methoxyl
were proceeded smoothly to afford the corresponding products
(3t–3x) in moderate to good yields. However, almost no
conversions were observed when the aryl group in 2 was replaced
with methyl group or hydrogen atom. The structure of the
product was unambiguously confirmed on the basis of single-
crystal X-ray diffraction analysis of compound 3d.15
Having optimized the reaction conditions, we then examined
the substrate scope of this nucleophilic addition reaction, and the
results are shown in Table 2. The procedure serves as a general
approach to structurally diverse product 3. Various isatins and N-
substituted pyrazolones could engage in the process, providing
the corresponding products in moderate to good yields.
Generally, the reaction worked well with electron-withdrawing
groups on the 5-position of isatins, providing 3-antipyrine
substituted 3-hydroxy-2-oxindole products in 60–82% yields,
whereas electron-donating groups underwent moderate
conversion into the products. 7-fluoro-, 7-chloro- and 7-bromo
isatins reacted well with antipyrine in 29–48 h to furnish the
desired products in 74–84% yields.

Tetrahedron
3
Table 2 The substrate scope of direct nucleophilic addition reactiona
a Unless noted, reactions were performed with 0.4 mmol of 1 and 0.2 mmol of 2 in 1 mL water with 20 mol % imidazole as the catalyst. Yield refers to the
isolated product.
b Without the addition of imidazole.

4
Tetrahedron
Most importantly, the present method could be used for
Table 3 Synthesis of 3,3-di-antipyrine substituted oxindolesa
preparative synthesis, as demonstrated by a scale up reaction
using 6.0 mmol of 1a and 4.0 mmol of 2a under the similar
reaction conditions described above. After completion of the
reaction, the desired product 3a (> 99% purity) was obtained in
1.154 grams with 86% yield by simple filtration and washing
with water. (scheme 2a). This strategy provided a direct, step-
economic and environmentally benign access to various 3-
pyrazolone substituted 3-hydroxy-2-oxindole products with
important biological.16 Moreover, compound 3a displays
excellent synthetic application in diversity-oriented synthesis. As
shown in scheme 2b, various nucleophiles such as indole, N-
methyl indole, pyrrole, 2-methylfuran, and p-toluenethiol reacted
well with 3a in the presence of DBSA (4-
Dodecylbenzenesulfonic acid) to furnish di-substituted 2-
indolinones 6 in high yields.
a Unless noted, reactions were performed with 0.2 mmol of 1 and 0.45
mmol of 2a in 1 mL water. Isolated yield by washing process.
In conclusion, the selective condensation of pyrazolones with
isatins could be realized in water. Various mono-pyrazolone
substituted 3-hydroxy oxindoles were achieved in the presence
o
of imidazole under hot water condition (80–100 C), while di-
antipyrine substituted oxindoles were obtained under high
o
temperature water condition (120 C). This process provides a
highly efficient and environmentally benign approach for the
diversity-oriented synthesis of Antipyrine derivatives,
structural scaffold for various pharmaceutical agents.
a
Acknowledgments
Financial support from the Jiangxi Provincial Department of
Science and Technology Fund 20192BAB213007), the
(
Education Department of Jiangxi Province (GJJ170835) and the
National Natural Science Foundation of China (Nos. 21865003
and 21763002) is gratefully acknowledged.
Supplementary Material
Supplementary data associated with this article can be
found, in the online version, at
Scheme 2 Synthetic utility of this “On water” process
In addition, without the addition of imidazole, the reaction
between isatins with antipyrine resulted in the formation of di-
antipyrine substituted oxindoles under high temperature (120 oC)
water. As shown in Table 3, isatins with various substituents on
the benzene ring were all found to be suitable for the reaction
and gave 4a–4l in 65–90% yields. Di-substituted isatin (5,7-
dimethylisatin as an example) and N-methyl isatin were also
well tolerated and afforded the target compounds with good
yields. It should be noted that all of the desired products were
isolated by simple filtration and does not require any column
chromatographic purification. The structure of 4d was confirmed
by an X-ray crystallographic analysis.15
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Highlights
The synthesis of both mono-antipyrine and di-antipyrine substituted oxindoles.
The selective condensation of pyrazolones with isatins in water.
Works well with a wide range isatins.

Declaration of interests
☐ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: