Mild and efficient synthesis of isoindigo derivatives catalyzed by Lewis acid

Article abstract of DOI:10.1016/j.tetlet.2016.11.053

A mild and efficient ZrCl₄-catalyzed synthesis of isoindigo derivatives from isatins and indolin-2-ones in refluxing ethanol is described. A variety of new functionalized isoindigo derivatives are obtained by simple filtration. Lewis acid was f

Full text of DOI:10.1016/j.tetlet.2016.11.053

Accepted Manuscript
Mild and efficient synthesis of isoindigo derivatives catalyzed by Lewis acid
Meilin Liu, Shaozhong Qiu, Yu Ye, Guodong Yin
PII:
S0040-4039(16)31521-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.053
TETL 48339
Reference:
Tetrahedron Letters
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Revised Date:
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29 September 2016
8 November 2016
14 November 2016
Please cite this article as: Liu, M., Qiu, S., Ye, Y., Yin, G., Mild and efficient synthesis of isoindigo derivatives
catalyzed by Lewis acid, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.053
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Tetrahedron Letters
Mild and efficient synthesis of isoindigo derivatives catalyzed by Lewis acid
Meilin Liu, Shaozhong Qiu, Yu Ye and Guodong Yin*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis and Reuse Technology, Hubei Normal University,
Huangshi 435002, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A mild and efficient ZrCl4-catalyzed synthesis of isoindigo derivatives from isatins and indolin-
2-ones in refluxing ethanol is described. A variety of new functionalized isoindigo derivatives
are obtained by simple filtration. Lewis acid was first used as catalyst in the synthesis of
isoindigo derivatives.
Available online
Keywords:
Isoindigo
Isatins
2015 Elsevier Ltd. All rights reserved.
Indolin-2-ones
Lewis acid
Zirconium (IV) tetrachloride
1. Introduction
Isoindigo, as a structural isomer of the famous indigo pigment is an important bis-indole heterocyclic molecule, which has
attracted much attention in drug development.1 For example, meisoindigo has been employed for the treatment of chronic myeloid
leukemia in China2 and Natura is proved to be an excellent inhibitor for cyclin-dependent kinases (CDKs) (Fig. 1).3 Moreover,
isoindigo is becoming a popular electron acceptor unit for organic electronic materials4,5 and can be used as the key intermediate for
the synthesis of natural products.6
The most commonly used approach to structural diverse isoindigo derivatives is based on the condensation of isatins and
indolin-2-ones in refluxing acetic acid in the presence of concentrated hydrochloric acid7 or p-toluene sulphonic acid system.8,9 In
recent years, a large number of isoindigo-based functionalized polymers and drug candidates have been prepared by this route. In
addition, many symmetrically substituted isoindigos can be synthesized by the homocoupling of isatins10 or indolin-2-ones.11
o
Apparently, the substrate scope is often limited by the strong acid reaction media and high reaction temperature (above 120 C).
More notably, the work-up procedure is a little tedious and purification by column chromatography is required in some cases.1b,1c,12
Accordingly, new approach to isoindigo derivatives with wide substrate scope, easy work-up procedure as well as enhanced
reaction efficiency is still highly desirable. Zirconium (IV) tetrachloride (ZrCl4) as a green Lewis acid is widely employed in
organic synthetic chemistry due to the low toxicity, moisture stability, low cost and excellent efficiency.13 In a continuation of our
effort to obtain valuable heterocycles from isatins,14 we herein would like to report a ZrCl4-catalyzed efficient synthesis of
isoindigos from isatins and indolin-2-ones in refluxing ethanol.
Figure 1 Structures of indigo and isoindigo derivatives.
———
*Corresponding author. Tel./fax: +86 0714 6515602; e-mail address: gdyin@hbnu.edu.cn (G. Yin)

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2. Results and discussion
Initially, (1a, 1.0 mmol) and
(2a, 1.0 mmol) were stirred in refluxing ethanol in the presence of a catalytic
amount of iodine (0.2 mmol), and a red solid precipitated. The structure was confirmed as isoindigo (3a) with 73% isolated yield.
Meanwhile, a trace amount of undehydrated product 3-hydroxy-3,3'-biindoline-2,2'-dione (3a’) was also observed (Table 1, entry
1). Next, the reaction conditions were further optimized by screening various catalysts, solvents and temperature. When the
commonly used L-Proline, ZnCl2 and AcOH were examined, the reactions gave 3a’ as the main product (entries 2 4). In the
absence of any catalyst, only 3a’ was obtained in excellent yield (entry 5).15 Satisfyingly, InCl3 and ZrCl4 were efficient catalysts for
the formation of 3a, and the latter gave a slightly higher yield (entries 6, 7). Reducing the loading of ZrCl4 did not significantly
o
decrease the yield (entries 8, 9). Decreasing the reaction temperature to 40 C resulted in 3a in 60% yield (entry 10). MeCN was
also an efficient solvent, but the reaction gave a lower yield in MeOH and THF (entries 11 13). Finally, the optimized reaction
conditions were identified as the reaction of 1a with 1.0 equivalent of 2a in refluxing ethanol in the presence of 10 mol% ZrCl4.
Table 1
Optimization of reaction conditions for the synthesis of 3aa
Catalyst
(equiv)
I2 (0.2)
L-Proline (0.2)
ZnCl2 (0.2)
AcOH
Solvent
(mL)
Yieldb
(%, 3a/3a’)
73/trace
trace/96
20/76
Entry
Temp. (oC)
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
MeOH
THF
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
40
3
4c
5
21/70
0/96
None
6
7
8
9
10
11
12
13
InCl3 (0.2)
ZrCl4 (0.2)
ZrCl4 (0.1)
ZrCl4 (0.05)
ZrCl4 (0.1)
ZrCl4 (0.1)
ZrCl4 (0.1)
ZrCl4 (0.1)
88/trace
92/trace
91/trace
89/trace
60/30
90/trace
74/<5
10/32
reflux
reflux
reflux
a All the reactions were carried out using isatin (1a, 1.0 mmol) and
b Isolated yield.
(2a, 1.0 mmol) in solvent (5 mL) for 9 h, unless otherwise specified.
c0.5 mL AcOH was used.
With the optimized
isatins with
(2a) were examined, and the results were summarized in Table 2. Methoxy and halogenated (-F, -Cl, -Br)
isatins
gave the
meisoindigo (3f) was obtained in
86% yield
. Other
-CH2C6H5, -
isatins
isatin resulted in the deacetylated product isoindigo (3a) as the main product
in 69% yield
.
halogenated
valuable derivatives
isatins to give the
. To our delight,
5’-/6’-chloro- and 5’-bromo-
3d, 3i o and 3e 81 95% yields
isoindigos
isoindigo using
Table 2
The scope of substratesa

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Entry
1
2
3
4
R1
H
5-OMe
7-F
5-Cl
5-Br
H
R2
H
H
H
H
H
Me
R3
H
H
H
H
H
H
R4
H
H
H
H
H
H
Product
3a
3b
3c
Yieldb (%)
91
85
94
86
87
3d
3e
3f
5
6
86
7
8
9
H
H
H
H
CH2C6H5
CH2COOEt
COMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
86
84
69
95
82
88
92
94
81
86
83
95
91
85
91
85
3g
3h
3a
3d
3i
3j
3k
3l
3m
3n
3o
3e
3p
3q
3r
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
5’-Cl
5’-Cl
5’-Cl
5’-Cl
5’-Cl
6’-Cl
6’-Cl
6’-Cl
5’-Br
H
H
H
H
H
H
H
H
5-OMe
5-Cl
5-Br
H
H
H
H
Me
H
H
H
H
H
H
5-Cl
7-F
H
H
H
H
H
H
Me
i-Pr
CH2C6H5
CH2COOEt
CH2C6H5
n-Bu
3-Octyl
3s
3t
3u
3v
3w
88
83
87
86
5-Br
5-Br
5-Br
a All of the reactions were carried out with 1 (1.0 mmol), 2 (1.0 mmol), ZrCl4 (0.01 mmol) in anhydrous EtOH (5 mL) under reflux for 8 12 h, unless
otherwise specified.
b Isolated yields.
Scheme 1. N-alkylation reaction of 3e
In summary, we have developed a ZrCl4-catalyzed efficient synthesis of isoindigo derivatives from isatins and indolin-2-ones
in refluxing ethanol. Lewis acid was used as catalyst in the synthesis of isoindigo derivatives for the first time. This method has the
advantages of mild reaction conditions, highly reaction efficiency, functional group tolerance and easy work-up procedure. A
number of new functionalized isoindigos are obtained by simple filtration. All these unknown compounds were characterized by
1
means of H NMR, 13C NMR, HRMS and IR spectra. Further investigations on the applications of isoindigos to other valuable
nitrogen-containing heterocycles16 are currently underway in our laboratory.
Acknowledgments
We gratefully acknowledge support from the National Natural Science Foundation of China (21542009).

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Supplementary data
Supplementary data related to this article can be found, in the online version at:
References and notes
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Mild and efficient synthesis of isoindigo
derivatives catalyzed by Lewis acid
Leave this area blank for abstract info.
Meilin Liu, Shaozhong Qiu, Yu Ye, and Guodong Yin*
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis
and Reuse Technology, Hubei Normal University, Huangshi 435002, China

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Research highlights
 This method allows the facile approach
to new functionalized isoindigos under
mild conditions.
 The products can be obtained only by
simple filtration.
 Lewis acid is used as catalyst in the
synthesis of isoindigo derivatives for the
first time.