Synthesis of symmetrical and unsymmetrical 3,3-di(indolyl)indolin-2-ones under controlled catalysis of ionic liquids

Article abstract of DOI:10.1016/j.tet.2010.02.017

Three ionic liquids, [BMIM][BF₄] doped with 60 mol % of LiCl ([BMIM][BF₄]-LiCl), N,N,N,N-tetramethylguanidinium trifluoroacetate (TMGT), and N,N,N,N-tetramethylguanidinium triflate (TMGT_f) were found useful as catalyst solvents for controlled 3-indolylation of isatins. Our investigation revealed that the reaction between isatin and indoles in [BMIM][BF₄]-LiCl or TMGT_f media stops at the step of addition of the two components providing 3-indolyl-3-hydroxyindolin-2-ones while the ionic liquid TMGT runs the reaction further through accompanying Friedel-Crafts substitution to afford symmetrical 3,3-di(indol-3-yl)indolin-2-ones. To take advantage of the difference between the effects of these ionic liquids on?the reaction progress, we planned a two-step protocol for the efficient synthesis of unsymmetrical 3,3-di(indol-3-yl)indolin-2-ones.

Full text of DOI:10.1016/j.tet.2010.02.017

Tetrahedron 66 (2010) 2316–2321
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of symmetrical and unsymmetrical 3,3-di(indolyl)indolin-2-ones under
controlled catalysis of ionic liquids
*
Kurosh Rad-Moghadam , Masoumeh Sharifi-Kiasaraie, Homayun Taheri-Amlashi
Chemistry Department, University of Guilan, PO Box 41335-19141, Rasht, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Three ionic liquids, [BMIM][BF ] doped with 60 mol % of LiCl ([BMIM][BF ]–LiCl), N,N,N,N-tetrame-
4
4
Received 18 October 2009
Received in revised form 28 December 2009
Accepted 1 February 2010
Available online 6 February 2010
thylguanidinium trifluoroacetate (TMGT), and N,N,N,N-tetramethylguanidinium triflate (TMGT
found useful as catalyst solvents for controlled 3-indolylation of isatins. Our investigation revealed that
the reaction between isatin and indoles in [BMIM][BF ]–LiCl or TMGT media stops at the step of addition
of the two components providing 3-indolyl-3-hydroxyindolin-2-ones while the ionic liquid TMGT runs
the reaction further through accompanying Friedel–Crafts substitution to afford symmetrical 3,3-di(in-
dol-3-yl)indolin-2-ones. To take advantage of the difference between the effects of these ionic liquids
on the reaction progress, we planned a two-step protocol for the efficient synthesis of unsymmetrical
f
) were
4
f
Keywords:
Indole
Isatin
Oxindole
Ionic liquid
3,3-di(indol-3-yl)indolin-2-ones.
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
considerable attention because such ‘liquid phase’ synthesis retains
the advantages of homogenous catalysis, and still permits the fairly
facile purification of the products and recycling of the catalysts.
In continuation of our studies directed toward the use of ionic
The versatile properties and the variety of available ionic liquids
have made them promising substances for application in most
chemistry areas.1
–3
Ionic liquids are new generation solvents
liquids as catalysts in synthesis of organic compounds, herein we
13
composed of bulky organic cations having liquid range at/or close
to room temperature, hence they are well positioned to fill the
polarity gap between molecular liquids and the molten metal salts.
The unique nature of ionic liquids allows virtually all possible in-
teractions between the solutes and the ions thus have an ability to
dissolve both organic and inorganic materials. On other hand, the
high polarity of ionic liquids ensures immiscibility with many
organic solvents, offering unique opportunities for phase separa-
tion and recycling. An important feature of ionic liquids is the
possibility to tune their chemical properties and also to adjust their
solubility to enable phase separation. Today, ionic liquids have been
shown to be more than simple solvents, showing significant roles in
describe the efficiencies of three ionic liquids, [BMIM][BF
with 60 mol % of LiCl ([BMIM][BF ]–LiCl), N,N,N,N-tetramethylgua-
nidinium trifluoroacetate (TMGT), and N,N,N,N-tetramethylguani-
dinium triflate (TMGT ) for the promotion of the reaction between
isatin and indoles providing the catalytic controlled syntheses of
3-(indol-3-yl)-3-hydroxyindolin-2-ones and symmetrical or un-
symmetrical 3,3-di(indol-3-yl)indolin-2-ones.
4
] doped
4
f
Isatin is a privileged lead molecule for designing potential bio-
active agents, and its derivatives have been shown to possess
a broad spectrum of bioactivity as many of which were assessed
1
4
15
16–18
19,20
anti-HIV, antiviral, anti-tumor,
antifungal,
anti-angio-
21
22
23
genic, anticonvulsants, anti-Parkinson’s disease therapeutic,
and effective SARS coronavirus 3CL protease inhibitor. These in-
4
,5
24
controlling reactions as catalysts. The early use of ionic liquids as
catalysts was merely based on their role as polar media to facilitate
organic reactions having polar transition states. The application
now is extended by the so-called task-specific ionic liquids either
through immobilization of the effective ionic catalysts in ionic
teresting properties prompted many efforts toward the synthesis
and pharmacological screening of isatin derivatives. During these
investigations, the indolin-2-one (oxindole) moiety has been rec-
2
5,26
ognized as a biologically active framework.
tegral constituent of many natural products.
Oxindole is an in-
6
,7
27–31
liquids or by incorporating a functional group responsible for
Thus, it is not
8
–10
catalysis in their ionic partners.
Synthesis by the aid of immo-
surprising that access to several members of this class may be the
goal of many research laboratories. Oxindole derivatives have been
prepared by the reaction of isatin or its derivatives with barbituric
11,12
bilized metal catalysts in ionic liquids
recently has received
3
2
33
34
35–38
acid, aromatics in triflic acid, pyrazolones, and other routes.
The 3,3-di(indol-3-yl)indolin-2-ones can be formed by the reaction of
isatin and indoles in acidic conditions and several methods have been
*
Corresponding author. Fax: þ98 131 3220066.
E-mail address: radmm@guilan.ac.ir (K. Rad-Moghadam).
0
040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.017

K. Rad-Moghadam et al. / Tetrahedron 66 (2010) 2316–2321
2317
developed for the synthesis of these compounds.39–41 On the other
hand, a number of oxindole alkaloids having a hydroxyl substituent at
Table 2
Synthesis of 3-(indol-3-yl)-3-hydroxyindolin-2-ones 3a–f in TMGT
LiCl ionic liquids
f
or [BMIM][BF
4
]–
4
2,43
the C-3 position possess various bioactivities,
and were synthe-
3
8,44,45
R1
R2
sized by a variety of methods.
. Result and discussion
The 3-indolylation of isatin, which was found very sluggish in
Entry
Product
Yield (%)
BMIM]BF
[
4
–LiCl
TMGT
f
1
2
3
4
5
6
H
Me
H
Me
H
Me
H
H
Br
Br
F
3a
3b
3c
3d
3e
3f
90
92
88
90
89
91
92
93
89
87
90
89
2
nature is essentially a Friedel–Crafts reaction. This recognition
implies that the reaction could be assisted by enhancing the nu-
cleophilic character of indoles in basic media, or by activating the
carbonyl group of isatin with the aid of acidic species. In this view,
we envisaged that the acid–base guanidinium ionic liquids could be
suitable choices for performing the dual role. Our initial trials on
F
out in N,N,N,N-tetramethylguanidinium trifluoroacetate (TMGT), in
place of TMGT , at room temperature. Monitoring of this reaction by
TLC revealed a rather slow disappearance of the reactants,
compared to the reaction in TMGT or [BMIM]BF –LiCl, and still
f
f
the model reaction between indole and isatin in TMGT was very
encouraging as it proceeds smoothly at room temperature and
stops at the stage of monoindolylation of isatin to afford 3-(indol-3-
yl)-3-hydroxyindolin-2-one 3a in fairly high yield. We have also
performed the model reaction in either of the neutral ionic liquids,
f
4
signifying an efficient conversion giving both 3-(indol-3-yl)-3-
hydroxyindolin-2-one 3a and 3,3-di(indol-3-yl)indolin-2-one 4a in
about an hour. Formation of 3,3-di(indol-3-yl)indolin-2-one 4a as
a by-product obviously accounts for the capability of TMGT to
catalyze the Friedel–Crafts reaction between 3-(indol-3-yl)-3-
hydroxyindolin-2-one 3a and another indole molecule, meanwhile
showing a need for optimization of conditions to gain better yield
of 4a. In order to optimize the reaction conditions, we performed
the model reaction using different quantities of reactants and the
ionic liquid. The best results were obtained with 1:2 mmol ratios of
isatin and indoles in the presence of 1 mL of TMGT at room tem-
perature. Therefore, we set out a method comprising the room
temperature reaction of a 2:1 mixture of indole 1 and isatin 2
without using any solvent or additional catalyst in TMGT and
[
BMIM]Cl and [BMIM]BF
4
or in the absence of ionic liquids to re-
is responsible for
spond the issue if the high polarity of TMGT
f
catalysis of the reaction. Of note, the model reaction has not pro-
ceeded in either of the above imidazolium ionic liquids or absence
of them, confirming the functional role of TMGT
f
in catalysis of the
reaction. To learn more about this function and on expectation that
þ
þ
Li could play the same role as H in TMGT
model reaction in [BMIM]BF doped with LiCl. As expected, the LiCl
contained in [BMIM]BF efficiently catalyzed the addition of indole
f
we intended to test our
4
4
onto isatin to provide 3-(indol-3-yl)-3-hydroxyindolin-2-one 3a in
a few minutes (Table 1).
Table 1
Optimization of reaction conditions
HN
R1
R2
O
R2
Ionic Liquid
rt
OH
N
H
R1
N
H
O
N
H
O
1
2
3
Entry
R1
R2
Ionic liquid
[BMIM]Cl
Product
Reaction time
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
H
d
d
3a
3a
d
d
3b
3b
12 h
12 h
20 min
10 min
12 h
12 h
20 min
10 min
d
d
90
92
d
d
92
93
[BMIM]BF
[BMIM]BF
4
4
–LiCl
TMGT
f
[BMIM]Cl
[BMIM]BF
[BMIM]BF
4
4
–LiCl
TMGT
f
Several indoles and isatin derivatives, having electron donor and
electron withdrawing substituents, likewise underwent the same
thereby 3,3-di(indol-3-yl)indolin-2-ones 4a–f were obtained in
fairly high yields (Table 3). Here again both electron donor as well
as electron withdrawing substituents exert no considerable effects
on reactivity of reactants under catalysis of TMGT.
reaction efficiently in both ionic liquids, TMGT
LiCl.
f 4
and [BMIM]BF –
The results are summarized in Table 2. All the compounds 3a–f
are formed solely under these conditions and were not contami-
nated with the production of 3,3-di(indol-3-yl)indolin-2-ones 4
even when 3 equiv of indoles were employed in the reactions.
Delighted by this result, we intended to examine the effect of
another guanidinium ionic liquid. For this purpose the reaction
involving a 1:1 mmol ratio of isatin and indole was similarly carried
The condensation of indoles with isatin derivatives is better
rationalized by an initial nucleophilic addition of the indole
onto the ketonic carbonyl group of isatin to yield the corresponding
3-(indol-3-yl)-3-hydroxyindolin-2-one 3. Dehydration of this
adduct gives the intermediate 6, which subsequently undergoes
nucleophilic addition of the second indole molecule to provide the
final products 3,3-di(indol-3-yl)indolin-2-ones 4 (Scheme 1).

2318
K. Rad-Moghadam et al. / Tetrahedron 66 (2010) 2316–2321
Table 3
Synthesis of symmetrical 3,3-di(indolyl)indolin-2-ones from indoles and isatin derivatives in TMGT
R1
N
R3
O
R2
TMGT
R3
N
N
R2
N
H
O
R1
N
H
O
R2
R1
1
2
4
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
H
H
H
H
Me
H
H
OMe
Br
H
NO
2
4a
4b
4c
4d
4e
93
91
86
90
88
Me
Me
H
Me
X
X
H
[
BMIM]BF -LiCl
E = Li
E = H
N
HN
4
H
E
O
H
O
E
OH
X
or TMGT
f
+
O
O
O
N
H
N
or TMGT
E = H
N
H
N
H
H
3
TMGT
X
H
N
H
N
X
X
NH
X
N
H
O
O
N
H
N
H
4
TMGT
6
Scheme 1. Proposed mechanism for the reaction between isatin and indole derivatives in the ionic liquids.
In the next phase of this investigation we planned to take ad-
vantage of the difference between catalytic activities of TMGT and
TMGT for the synthesis of unsymmetrical 3,3-di(indol-3-yl)indo-
f
lin-2-ones in a more controlled manner. In this protocol the initially
synthesized 3-(indol-3-yl)-3-hydroxyindolin-2-ones 3, on reaction
f 4
of an isatin derivatve with an indole in TMGT or [BMIM]BF –LiCl
ionic liquids, was treated with 1 equiv of another indole derivate in
TMGT to give the desired unsymmetrical 3,3-di(indol-3-yl)indolin-
2-one 5. The results of the application of this procedure are sum-
marized in Table 4.
Table 4
Synthesis of unsymmetrical 3,3-di(indolyl)indolin-2-ones from indoles and isatin in TMGT
R4
R4
R2
H
N
H
N
R2
TMGT
OH
N
R1
N
N
O
N
O
R1
R3
R3
1
3
5
Entry
R1
R2
R3
R4
Yield (%)
Product
1
2
3
4
5
H
H
H
H
H
H
H
Br
H
H
H
H
Me
H
H
5a
5b
5c
5d
5e
90
88
88
87
91
CN
Br
H
Me
H

K. Rad-Moghadam et al. / Tetrahedron 66 (2010) 2316–2321
2319
3
. Conclusion
residue was washed with 2ꢀ15 mL of cold water to extract the ionic
liquids. The solid residues were recrystallized from ethanol (95.5%)
to afford pure products 3a–f. The ionic liquids were recovered from
the aqueous extracts by evaporation of water in reduced pressure
and reused in the next cycles. All the known products have spectral
and physical data consistent with those reported in literatures as
well as the samples prepared from previously reported methods.
We have demonstrated the application of three ionic liquids in
the synthesis of 3-(indol-3-yl)-3-hydroxyindolin-2-ones, symmet-
rical and unsymmetrical 3,3-di(indol-3-yl)indolin-2-ones of bi-
ological interests at room temperature. The reaction of an indole
and an isatin derivative even in 3:1 mole ratio under catalysis of
f 4
either TMGT or [BMIM]BF –LiCl ionic liquids gave solely the 1:1
adduct, 3-(indol-3-yl)-3-hydroxyindolin-2-ones 3a–f, in fairly high
yields at room temperature, while similar reaction in TMGT favored
to form solely symmetrical 3,3-di(indol-3-yl)indolin-2-ones 4a–e.
We have also devised the reaction between the adducts 3 and
indoles in TMGT to synthesize some unsymmetrical 3,3-di(indol-3-
yl)indolin-2-ones 5a–e at room temperature. Experimental
simplicity associated with the high yield of products, recyclability
of the ionic liquids, and short reaction times render the methods
presented here highly competitive compared to existing pro-
cedures. We believe that the simple and novel methods presented
here could be of broad interest for synthetic and medicinal
chemists.
4.3.1. 3-Hydroxy-3-(1H-indol-3-yl)indolin-2-one (3a). White solid
ꢁ
44
ꢁ
(0.243 g, 92%), mp 293–295 C, lit. mp 294–296 C;
n
max (KBr)
ꢂ1
3457, 3261, 1702, 1618, 1476, 1182 cm
H
; d (300 MHz, DMSO) 6.32
(1H, s, OH), 6.85 (1H, t, J 8.0 Hz), 6.90 (1H, d, J 7.6 Hz), 6.96 (1H, t,
J 6.7 Hz), 7.02 (1H, t, J 7.0 Hz), 7.06 (1H, d, J 2.6 Hz), 7.23 (1H, d,
J 6.0 Hz), 7.25 (1H, t, J 6.5 Hz), 7.32 (1H, d, J 8.2 Hz), 7.34 (1H, d,
J 9.4 Hz), 10.32 (1H, s, amidic N–H), 10.97 (1H, br s, N–H).
4.3.2. 3-Hydroxy-3-(2-methyl-1H-indol-3-yl)indolin-2-one
ꢁ
44
(3b). Dark red solid (0.259 g, 93%), mp 181–183 C, lit. mp 178–
ꢁ
ꢂ1
; d
180 C;
DMSO) 2.41 (3H, s, CH
.97 (4H, m), 7.18–7.26 (3H, m),10.34 (1H, s, amidic N–H), 10.87 (1H,
br s, N–H).
n
max (KBr) 3398, 3352, 3297, 1705, 1617 cm
H
(300 MHz,
3
), 6.27 (1H, s, OH), 6.73 (1H, t, J 7.5 Hz), 6.89–
6
4
4
. Experimental section
.1. General
4.3.3. 5-Bromo-3-hydroxy-3-(1H-indol-3-yl)indolin-2-one
ꢁ
(
3c). White solid (0.306 g, 89%), mp 200 C (dec). Found: C, 56.16;
All of the solvents and reagents were purchased from Fluka or
H, 3.31; N, 8.08. C16
H
11BrN
2
O
2
requires C, 56.00; H, 3.23; N, 8.16%;
ꢂ1
Merck chemical companies. Melting points were measured on an
Electrothermal apparatus and are uncorrected. IR spectra were
n
max (KBr) 3457, 3261, 1703, 1615, 1472, 1168 cm
;
d
H
(300 MHz,
0
DMSO) 6.55 (1H, br s, OH), 6.88–6.96 (2H, m), 7.05 (1H, t, J 7.7 Hz, 5 -
H), 7.12 (1H, d, J 2.3 Hz, 2 -H of indole), 7.33 (1H, d, J 2.0 Hz, 4-H),
7.36 (2H, d, J 8.3 Hz), 7.44 (1H, dd, J 8.2 and 2.0 Hz, 6-H), 10.30 (1H,
C
br, N–H), 11.07 (1H, s, N–H); d (100.62 MHz, DMSO) 75.4 (C-3),
1
0
obtained in KBr discs on a Shimadzu IR-470 spectrometer. H and
13
C NMR spectra were measured with Brucker DRX-500, DRX-400
1
13
or DRX-300 AVANCE spectrometers. Chemical shifts of H and
C
NMR spectra were expressed in parts per million downfield from
tetramethylsilane. Mass spectra were recorded on a Shimadzu
QP1100EX mass spectrometer operating at an ionization potential
of 70 eV. Elemental analyses for C, H, and N were performed using
a Foss Heraus CHN-O-rapid analyzer.
112.1, 112.3, 113.8, 115.1, 119.2, 120.5, 121.7, 124.1, 125.2, 127.8, 132.2,
136.3, 137.3, 141.4, 178.4 (C]O).
4.3.4. 5-Bromo-3-hydroxy-3-(2-methyl-1H-indol-3-yl)indolin-2-one
ꢁ
(3d). Brown solid (0.321 g, 90%), mp 136–138 C. Found: C, 57.22;
H, 3.72; N, 7.68. C17
H
13BrN
2
O
2
requires C, 57.17; H, 3.67; N, 7.84%;
ꢂ1
4
.2. Procedure for preparation of [BMIM]BF
4
–LiCl
n
max (KBr) 3387 (br), 1721, 1615, 1465, 1178 cm
;
d
H
(300 MHz,
0
DMSO) 2.41 (3H, s, CH
3
), 6.47 (1H, s, OH), 6.77 (1H, t, J 7.5 Hz, 5 -H),
1
-Methylimidazole (5.1 g, 62.1 mmol) was added to 32 mL of
6.86–6.98 (3H, m,), 7.21 (1H, d, J 8.1 Hz, 7-H), 7.24 (1H, d, J 2.0 Hz, 4-
H), 7.41 (1H, dd, J 8.1 and 2.0 Hz, 6-H), 10.54 (1H, s, amidic N–H),
1
-chlorobutane. The mixture was heated to reflux for 24 h and then
cooled to room temperature, the obtained oily product was sepa-
C 3
10.95 (1H, s, N–H); d (100.62 MHz, DMSO) 13.7 (CH ), 76.4 (C-3),
rated from reaction mixture by decanting, washed with EtOAc (2ꢀ
109.1, 110.9, 112.3, 113.8, 118.9, 119.3, 120.4, 126.8, 127.9, 132.1, 134.0,
135.3, 137.0, 141.3, 178.6 (C]O).
2
0 mL), and the solvent of the collected organic phase was removed
under reduced pressure to give 1-butyl-3-methylimidazolium
chloride ([BMIM]Cl). In second step, to [BMIM]Cl (9.3 g, 53 mmol)
4.3.5. 5-Fluoro-3-hydroxy-3-(1H-indol-3-yl)indolin-2-one
ꢁ
44
dissolved in anhydrous acetone (40 mL) was added LiBF
4
(5 g,
(3e). White solid (0.254 g, 90%), mp 194–196 C, lit. mp 196–
ꢁ
ꢂ1
; d
5
3 mmol). The mixture was then stirred for 48 h at room temper-
198 C;
n
max (KBr) 3425, 3355, 1720, 1623, 1484, 1189 cm
H
ꢁ
ature to get a solution and then stored at 4 C over 2 days in re-
frigerator giving the excess of the dissolved LiCl crystals to
precipitate. After separation of the precipitated LiCl crystals (0.87 g,
(300 MHz, DMSO) 6.50 (1H, br s, OH), 6.80–6.91 (2H, m), 7.01–7.12
0
(3H, m), 7.11 (1H, br s, 2 -H of indole), 7.35 (2H, t, J 7.8 Hz),10.38 (1H,
C
s, amidic N–H), 11.04 (1H, s, N–H); d (75.47 MHz, DMSO) 75.6 (C-3),
3
2
2
0.5 mmol) the solvent of the filtered solution was removed under
110.9 (d, JC–F 7.9 Hz, C-7), 112.0, 112.7 (d, JC–F 25.0 Hz), 115.2, 115.7
2
3
reduced pressure thereby the ionic liquid 1-butyl-3-methyl-
imidazolium tetrafluoroborate doped with 60 mol % of LiCl
(d, J 23.0 Hz), 119.0, 120.6, 121.6, 124.0, 125.2, 135.6 (d, JC–F 7.6 Hz,
C-3a), 137.2, 138.2, 156.9 (d, JC–F 24.8 Hz, C-5), 178.8 (C]O); m/z (EI)
1
þ
þ
þ
(
[BMIM]BF
4
–LiCl) was obtained as a yellow oil.
282 (24, M ), 253 (14, M ꢂ[HC]O]), 237 (100, M ꢂ[OHþC]O]),
1
44 (14), 117 (45), 89 (13).
4
3
.3. General procedure for preparation of 3-(indol-3-yl)-
-hydroxyindolin-2-ones (3a–f)
4.3.6. 5-Fluoro-3-hydroxy-3-(2-methyl-1H-indol-3-yl)indolin-2-one
ꢁ
44
(
3f). White solid (0.269 g, 91%), mp 212–213 C, lit. mp 212–
ꢁ
ꢂ1
; d
A mixture of the indole (1 mmol) and an isatin derivative
214 C;
n
max (KBr) 3340, 3199, 1713, 1625, 1485, 1461, 1188 cm
H
(
1 mmol) was added to a vial containing a magnetic stir bar and the
ionic liquid (TMGT or [BMIM][BF ]–LiCl, 1 mL). The reaction mix-
ture was sealed and stirred at room temperature until disappear-
ance of the starting materials (20 min for [BMIM][BF ]–LiCl, 10 min
for TMGT ), as monitored by TLC on silica gel using 1:2 mixture of
ethyl acetate/n-hexane. After completion of the reaction, the
(300 MHz, DMSO) 2.42 (3H, s, CH
7.2 Hz, 5 -H), 6.90–7.00 (4H, m), 7.08 (1H, t, J 8.1 Hz, 6-H), 7.20 (1H,
d, J 7.8 Hz, 4-H), 10.40 (1H, s, amidic N–H), 10.93 (1H, s, N–H of
3
), 6.43 (1H, br s, OH), 6.75 (1H, t, J
0
f
4
4
indole);
111.0 (d,
C 3
d (75.47 MHz, DMSO) 13.8 (CH ), 76.6 (C-3), 109.2, 110.8,
JC–F 7.8 Hz, C-7), 112.8 (d, JC–F 24.0 Hz), 115.7 (d, J
C–F
3
2
2
f
3
22.7 Hz), 118.8, 119.3, 120.4, 126.8, 134.1, 135.3, 136.4 (d, JC–F 7.7 Hz,

2320
K. Rad-Moghadam et al. / Tetrahedron 66 (2010) 2316–2321
1
C-3a), 138.2, 158.6 (d, JC–F 252 Hz, C-5), 179.1 (C]O); m/z (EI) 296
7.5 Hz), 6.88 (1H, t, J 7.1 Hz), 6.89 (1H, t, J 7.2 Hz), 6.94 (1H, d, J
7.7 Hz), 7.14 (1H, d, J 7.3 Hz), 7.20–7.23 (3H, m), 10.50 (1H, s, amidic
N–H), 10.82 (1H, br s, N–H), 10.85 (1H, br s, N–H).
þ
þ
(
15, M ), 288 (18), 251 (46, M ꢂ[OHþC]O]), 237 (58, 251ꢂ[CH
2
]),
1
30 (100, N-methylindole), 109 (60), 82 (60).
4
2
.4. Synthesis of symmetrical 3,3-di(indol-3-yl)indolin-
-ones (4a–e)
4.4.5. 5-Nitro-3,3-di(1-methyl-1H-indol-3-yl)indolin-2-one
(4e). Pale brown solid (0.384 g, 88%), mp>300 C. Found: C, 71.64;
ꢁ
H, 4.73; N, 12.70. C26
H
20
N
4
O
3
requires C, 71.56; H, 4.62; N, 12.83%;
A mixture of the indole 1 (1 mmol) and an isatin derivative 2
0.5 mmol) was added to a vial containing a magnetic stir bar and
n
max (KBr) 3230, 3105, 3055, 1715, 1608, 1465, 1325, 1158, 730; d
H
0
(
(500 MHz, DMSO) 3.72 (6H, s, 2ꢀCH
3
), 6.89 (2H, t, J 7.5 Hz, 5 -H of
0
0
the ionic liquid (TMGT, 1 mL). The reaction mixture was sealed and
stirred at room temperature until the isatin derivative was com-
pletely consumed (about 1 h, as monitored by TLC on silica gel
using a 4:3 mixture of ethyl acetate/n-hexane). After completion of
the reaction, the resulting paste was washed with 2ꢀ15 mL of cold
water to extract the ionic liquid. The remained crude products 4a–e
were crystallized from ethanol (95.5%). To recover the ionic liquid,
the aqueous filtrate was evaporated under reduced pressure. TMGT,
which remained as nonvolatile oil in the evaporating vessel was
collected and reused. All the novel products were characterized by
indoles), 7.02 (2H, s, 2 -H of indoles), 7.11 (2H, t, J 7.5 Hz, 6 -H of
indoles), 7.21 (1H, d, J 8.6 Hz, 7-H), 7.26 (2H, d, J 8.1 Hz), 7.40 (2H, d, J
8.2 Hz), 8.00 (H, s, 4-H), 8.25 (1H, d, J 8.6 Hz, 6-H), 11.36 (1H, s,
amidic N–H);
d
C
(125.8 MHz, DMSO) 33.2 (2ꢀCH
3
), 53.2 (C-3), 110.8,
110.9, 112.8, 119.6, 121.0, 121.4, 122.2, 126.4, 126.6, 129.6, 136.0,
138.3, 143.1, 148.6, 179.6 (C]O); m/z (EI) 436 (86, M ), 422 (22,
þ
þ
þ
M ꢂ[CH
2
]), 407 (100, M ꢂ[HC]O]), 393 (25, 422ꢂ[CH
2
]), 361
þ
(28), 306 (21, M ꢂ[N-methylindole]), 278 (22, 306ꢂ[HC]O]), 232
(18), 131 (33).
1
13
their IR, H NMR, C NMR, and mass spectral data, as well as ele-
mental analysis. Partial assignments of the spectral data are given
in the following sections.
4.5. Synthesis of unsymmetrical 3,3-di(indol-3-yl)indolin-
2-ones (5a–e)
A mixture of oxindoles 3a–f (1 mmol) and an indole derivative
(1 mmol) was added to a vial containing a magnetic stir bar and
TMGT (1 mL). The reaction mixture was sealed and stirred at room
temperature until the disappearance of the starting materials (1 h,
monitored by TLC on silica gel using 4:3 mixture of ethyl acetate/n-
hexane). After completion of the reactions, the residues were
washed with 2ꢀ15 mL of cold water to extract TMGT. The remained
crude products 5a–e were recrystallized from ethanol (95.5%).
TMGT was recovered from the aqueous extracts by evaporation of
water in reduced pressure and reused in the next cycles. Partial
assignment of spectral data to the structure of previously un-
reported products 5 is given in the following sections.
4
.4.1. 3,3-Di(1H-indol-3-yl)indolin-2-one
(4a). White
solid
ꢁ
39
ꢁ
(
0.338 g, 93%), mp>300 C, lit. mp 311–313 C;
n
max (KBr) 3420,
ꢂ1
0
3
300, 1704, 1610, 1105, 737 cm
H
; d (500 MHz, DMSO) 6.79 (2H, t, J
7
6
(
.7 Hz), 6.84 (2H, d, J 2.2 Hz, 2 -H of indoles), 6.92 (1H, t, J 7.5 Hz),
.97–7.02 (3H, m), 7.22 (4H, d, J 7.8 Hz), 7.35 (2H, d, J 8.1 Hz), 10.58
1H, s, amidic N–H), 10.94 (2H, br s, N–H); (125.8 MHz, DMSO)
d
C
5
3.4 (C-3), 110.4, 112.4, 115.2, 119.1, 121.6, 121.8, 122.3, 125.1, 125.8,
þ
126.6, 128.7, 135.5, 137.8, 142.2, 179.6 (C]O); m/z (EI) 363 (57, M ),
þ
þ
3
34 (69, M ꢂ[HC]O]), 248 (64, M ꢂ[indole]), 219 (95, 334ꢂ[in-
dole]), 117 (64), 86 (100).
4
.4.2. 5-Methoxy-3,3-di(1-methyl-1H-indol-3-yl)indolin-2-one
ꢁ
(4b). Pale pink solid (0.383 g, 91%), mp 279–281 C. Found: C,
4.5.1. 3,3-Di(1H-indol-3-yl)indolin-2-one (5a). Compound 5a is
identical with 4a (0.327 g, 90%).
7
9
7.02; H, 5.59; N, 9.89. C27
.97%;
H
23
N
3
O
2
requires C, 76.94; H, 5.50; N,
ꢂ1
n
max (KBr) 3200, 3100, 1702, 1603, 1486, 1200, 740 cm
; d
H
(
(
(
500 MHz, DMSO) 3.61 (3H, s, OCH
4H, m), 6.92 (1H, d, J 7.8 Hz, 6-H), 6.93 (2H, s, 2 -H of indoles), 7.09
2H, t, J 7.4 Hz), 7.28 (2H, d, J 8.0 Hz), 7.38 (2H, d, J 8.3 Hz), 10.47 (1H,
3
), 3.70 (6H, s, N–CH
3
), 6.81–6.87
4.5.2. 3-(1H-Indol-3-yl)-3-(5-cyano-1H-indol-3-yl)indolin-2-one
(5b). Light pink solid (0.341 g, 88%), mp>300 C. Found: C, 77.25;
0
ꢁ
H, 4.17; N,14.41. C25
(KBr) 3360, 3254, 3100, 2220, 1675, 1618, 1467, 1200, 740 cm
(500 MHz, DMSO) 6.82 (1H, t, J 7.4 Hz), 6.91 (1H, d, J 1.8 Hz, 2 -H),
6.97 (1H, t, J 7.6 Hz), 7.02–7.04 (2H, m), 7.07 (1H, d, J 1.8 Hz, 2 -H),
16 4 max
H N O requires C, 77.31; H, 4.15; N,14.42%. n
ꢂ1
s, amidic N–H);
5
1
4
d
C
(125.8 MHz, DMSO) 33.2 (N–CH
3
), 53.7 (C-3),
; d
H
0
6.2 (O–CH
3
), 110.6, 110.8, 113.0, 114.3, 119.3, 121.8, 122, 126.9, 129.4,
þ
00
35.5, 136.7, 138.2, 155.6 (C-5), 179.3 (C]O); m/z (EI) 421 (78, M ),
þ
þ
07 (7, M ꢂ[CH
2
]), 392 (100, M ꢂ[HC]O]), 348 (14), 291 (12,
7.15 (1H, d, J 8 Hz), 7.26 (2H, d, J 7.4 Hz), 7.35–7.42 (2H, m), 7.56 (2H,
þ
0
M ꢂ[N-methylindole]), 263 (16, 392ꢂ[N-methylindole]), 211 (10),
d, J 8.5 Hz), 7.72 (1H, s, 4 -H), 10.72 (1H, s, amidic N–H), 11.02 (1H, br
1
31 (10).
s, N–H), 11.62 (1H, br s, N–H);
C
d (125.8 MHz, DMSO) 53.2 (C-3),
101.2, 110.7, 112.7, 114.1, 114.9, 116.3, 119.4, 120.8, 121.6, 122, 122.6,
4
.4.3. 5-Bromo-3,3-di(1-methyl-1H-indol-3-yl)indolin-2-one
124.5, 125.2, 125.8, 126.3, 126.4, 127.6, 127.7, 129.0, 134.7, 137.8,
ꢁ
þ
(4c). Pale pink solid (0.405 g, 86%), mp>300 C. Found: C, 66.52; H,
139.7, 142.1, 179.4 (C]O); m/z (EI) 388 (44, M ), 359 (57,
þ
þ
4
.36; N, 8.86. C26
H20BrN
3
O requires C, 66.40; H, 4.28; N, 8.93%;
n
max
M ꢂ[HC]O]), 334 (24), 273 (63, M ꢂ[indole]), 244 (75, 359ꢂ[in-
dole]), 219 (45, 359ꢂ[5-cyanoindole]), 142 (44), 117 (100), 94 (66),
71 (42).
ꢂ1
(
(
(
KBr) 3390, 3120, 3050, 1738, 1610, 1480, 1337, 1075, 739 cm
500 MHz, DMSO) 3.72 (6H, s, N–CH
2H, s, 2 -H of indoles), 7.11 (2H, t, J 7.4 Hz), 7.20 (1H, d, J 8.6 Hz, 7-
; d
H
3
), 6.88 (2H, t, J 7.4 Hz), 7.01
0
H), 7.25 (2H, d, J 8.0 Hz), 7.41 (2H, d, J 8.2 Hz), 7.99 (1H, s, 4-H), 8.24
1H, d, J 8.6 Hz, 6-H), 11.35 (1H, s, amidic N–H); (125.8 MHz,
DMSO) 33.2 (CH ), 53.5 (C-3), 110.8, 112.6, 113.5, 114.1, 119.5, 121.6,
22.1, 126.7, 128.2, 129.4, 131.6, 137.7, 138.2, 141.5, 178.9 (C]O); m/z
4.5.3. 3-(1H-Indol-3-yl)-3-(5-bromo-1H-indol-3-yl)indolin-2-one
(5c). Pale brown solid (0.389 g, 88%), mp 284–286 C. Found: C,
65.07; H, 3.73; N, 9.42. C24H16BrN O requires C, 65.18; H, 3.64; N,
3
ꢁ
(
d
C
3
1
9.50%;
1330, 1100, 740 cm
n
max (KBr) 3390, 3310, 3104, 3050, 1680, 1660, 1468, 1450,
þ
81
þ
79
ꢂ1
(
4
EI) 471 (2, M , Br), 470 (4), 469 (2, M , Br), 468 (4), 442 (10),
11 (26), 285 (26), 223 (35), 149 (73), 57 (100).
H
; d (500 MHz, DMSO) 6.83 (1H, t, J 7.6 Hz),
6.90 (1H, d, J 1.6 Hz), 6.91 (1H, d, J 1.5 Hz), 6.96 (1H, t, J 7.6 Hz), 7.01–
.05 (2H, m), 7.16 (1H, d, J 8.6 Hz), 7.21 (2H, t, J 7.9 Hz), 7.25 (1H, t, J
7
0
4
.4.4. 3,3-Di(2-methyl-1H-indol-3-yl)indolin-2-one
(4d). White
7.6 Hz), 7.37 (2H, t, J 8.8 Hz), 7.48 (1H, s, 4 -H), 10.68 (1H, s, amidic
N–H), 10.97 (1H, br s, N–H), 11.22 (1H, br s, N–H); (125.8 MHz,
ꢁ
39
ꢁ
solid (0.352 g, 90%), mp>300 C, lit. mp 300–301 C;
n
max (KBr)
d
C
ꢂ1
3
(
7
370, 3119, 3050, 1705, 1615, 740 cm
3H, s, CH ), 2.06 (3H, s, CH
.1 Hz), 6.63 (1H, d, J 7.8 Hz), 6.69 (1H, d, J 8.0 Hz), 6.85 (1H, t, J
;
d
H
(500 MHz, DMSO) 1.93
DMSO) 53.3 (C-3), 110.6, 111.8, 112.6, 114.6, 114.9, 115, 119.3, 121.1,
3
3
), 6.45 (1H, d, J 8.2 Hz), 6.60 (1H, t, J
121.9, 122.5, 124.2, 124.4, 125.2, 125.8, 126.4, 126.7, 128.4, 128.9, 135,
þ 81
136.6, 137.8,142.2, 179.5 (C]O); m/z (EI) 443 (40, M , Br), 441 (40,

K. Rad-Moghadam et al. / Tetrahedron 66 (2010) 2316–2321
2321
þ 79
M , Br), 414 (43, 443ꢂ[HC]O]), 412 (42, 441ꢂ[HC]O]), 363 (49),
34 (62), 299 (25, 414ꢂ[indole]), 297 (20, 412ꢂ[indole]), 248 (74),
19 (100, 414ꢂ[5-bromoindole]), 195 (55), 193 (55), 117 (80).
11. Dupont, J.; de souza, R. F.; Suarez, P. A. Z. Chem. Rev. 2002, 102, 3667–3692.
2. Virtanen, P.; Karhu, H.; Toth, G.; Kordas, K.; Mikkola, J.-P. J. Catal. 2009, 263,
09–219.
3. Rad-Moghadam, K.; Sharifi-Kiasaraie, M. Tetrahedron 2009, 65, 8816–8820.
4. Ratan Bal, T.; Anand, B.; Yogeeswari, P.; Sriram, Dh. Bioorg. Med. Chem. Lett.
005, 15, 4451–4455.
5. Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.;
1
3
2
2
1
1
2
4
.5.4. 1-Methyl-3-(1H-indol-3-yl)-3-(5-bromo-1H-indol-3-yl)indo-
lin-2-one (5d). Pale brown solid (0.397 g, 87%), mp>300 C. Found:
1
ꢁ
Tuntland, T.; Zhang, K.; Karanewsky, D.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
C, 65.67; H, 4.05; N, 9.28. C25
H
18BrN
3
O requires C, 65.81; H, 3.98; N,
2109–2112.
1
6. Tripathy, R.; Reiboldt, A.; Messina, P. A.; Iqbal, M.; Singh, J.; Bacon, E. R.;
Angeles, Th. S.; Yang, Sh. X.; Albom, M. S.; Robinson, C.; Chang, H.; Ruggeri, B.
A.; Mallamo, J. P. Bioorg. Med. Chem. Lett. 2006, 16, 2158–2162.
17. Cane, A.; Tournaire, M.-C.; Barritault, D.; Crumeyrolle-Arias, M. Biochem. Bio-
phys. Res. Commun. 2000, 276, 379–384.
9
.20%; max (KBr) 3350, 3106, 1662, 1604, 1460, 1445, 1087,
n
ꢂ1
7
7
7
40 cm
.5 Hz), 6.89 (1H, d, J 2.1 Hz), 6.90 (1H, d, J 2.1 Hz), 7.01–7.09 (3H, m),
.14–7.20 (2H, m), 7.27 (1H, d, J 7.3 Hz), 7.30–7.37 (4H, m), 7.47 (1H,
H 3
; d (500 MHz, DMSO) 3.27 (3H, s, N–CH ), 6.81 (1H, t, J
1
8. Silveira, V. Ch; Luz, J. S.; Oliveira, C. C.; Graziani, I.; Ciriolo, M. R.; Costa Ferreira,
A. M. J. Inorg. Biochem. 2008, 102, 1090–1103.
0
s, 4 -H), 11.00 (1H, br s, N–H), 11.24 (1H, br s, N–H);
DMSO) 27.1 (CH ), 52.8 (C-3), 109.7, 111.8, 112.6, 114.6, 114.8, 119.4,
20.8, 122, 123.2, 123.5, 124.3, 124.4, 125.3, 125.4, 126.3, 126.7, 128.3,
C
d (125.8 MHz,
3
19. Amal Raj, A.; Raghunathan, R.; Sridevikumaria, M. R.; Raman, N. Bioorg. Med.
Chem. 2003, 11, 407–419.
20. Rodriguez-Arguelles, M. C.; Mosquera-Vazaquez, S.; Touron-Touceda, P.; San-
martin-Matalobos, J.; Garcia-Deibe, A. M.; Belicchi-Ferraris, M.; Pelosi, G.;
Pelizzi, C.; Zani, F. J. Inorg. Biochem. 2007, 101, 138–147.
21. Maskell, L.; Blanche, E. A.; Colucci, M. A.; Whatmore, J. L.; Moody, Ch. J Bioorg.
Med. Chem. Lett. 2007, 17, 1575–1578.
2. Verma, M.; Nath Pandeya, S.; Nand Singh, K.; Stables, J. P. Acta Pharm. 2004, 54,
1
þ
29.1, 134.1, 136.6, 137.8, 143.6, 177.6 (C]O); m/z (EI) 457 (19, M ,
1
8
1
þ
79
þ
Br), 456 (66), 455 (18, M , Br), 454 (60), 429 (5, M ꢂ[C]O]),
4
3
28 (18, 456ꢂ[C]O]), 426 (17, 454ꢂ[C]O]), 414 (18, 428ꢂ[CH
2
]),
þ
92 (100), 377 (15, M ꢂ[Br]), 364 (75), 348 (23), 214 (22), 115 (36).
2
49–56.
4
.5.5. 3-(1H-Indol-3-yl)-3-(1-methyl-1H-indol-3-yl)indolin-2-one
23. Igosheva, N.; Lorz, C.; O’Conner, E.; Glover, V.; Mehmet, H. Neurochem. Int. 2005,
47, 216–224.
ꢁ
39
(5e). White solid (0.344 g, 91%), mp 299–301 C, lit. mp 298–
2
4. Chen, L.-R.; Wang, Y.-Ch.; Lin, Y. W.; Chou, Sh.-Y.; Chen, Sh.-F.; Liu, L. T.; Wu, Y.-T.;
Kuo, Ch.-J.; Chen, T. Sh.-Sh.; Juang, Sh.-H Bioorg. Med. Chem. Lett. 2005, 15,
3058–3062.
ꢁ
ꢂ1
;
3
00 C;
(500 MHz, DMSO) 3.70 (3H, s, CH
t, J 7.7 Hz), 6.87 (2H, s, 2-H of indoles), 6.93 (1H, t, J 7.4 Hz), 6.98–7.03
2H, m), 7.08 (1H, t, J 7.4 Hz), 7.22–7.26 (4H, m), 7.36 (2H, t, J 8.4 Hz),
0.61 (1H, s, amidic N–H), 10.97 (1H, br s, N–H); (125.8 MHz,
DMSO) 33.2 (CH ), 53.4 (C-3), 110.4, 110.6, 112.5, 114.4, 115.1, 119.1,
19.2, 121.5, 121.8, 121.9, 122.0,122.4, 125.2, 125.8,126.5,126.9, 128.7,
nmax (KBr) 3310, 3190,1683,1615,1469,1330,1100, 740 cm
d
H
3
), 6.80 (1H, t, J 7.5 Hz), 6.84 (1H,
2
2
2
2
2
5. Shimazawa, R.; Kuriyama, M.; Shirai, R. Bioorg. Med. Chem. Lett. 2008, 18,
3350–3353.
(
1
6. Abadi, A. H.; Abou-Seri, S. M.; Abdel-Rahman, D. E.; Klein, Ch.; Lozach, O.;
Meijer, L. Eur. J. Med. Chem. 2006, 41, 296–305.
7. Yamada, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2008, 64,
d
C
3
7690–7694.
1
8. Kogure, N.; Kobayashi, H.; Ishii, N.; Kitajima, M.; Wongseripipatana, S.;
Takayama, H. Tetrahedron Lett. 2008, 49, 3638–3642.
9. Zhang, Zh.; Di, Y.-T.; Wang, Y.-H.; Zhang, Zh.; Mu, Sh.-Zh.; Fang, X.; Zhang, Y.;
Tan, Ch.-J.; zhang, Q.; Yan, X.-H.; Guo, J.; Li, Ch.-sh.; Hao, X.-J. Tetrahedron 2009,
þ
129.3,135.4,137.8,138.2,142.2,179.5 (C]O); m/z (EI) 379 (4, M ), 377
þ
(
90, M ꢂ2), 348 (100), 332 (13), 261 (13), 219 (21).
65, 4551–4556.
Acknowledgements
30. Kam, T.-S.; Choo, Y.-M. Tetrahedron 2000, 56, 6143–6150.
3
1. Wu, Y.; Kitajima, M.; Kogure, N.; Zhang, R.; Takayama, H. Tetrahedron Lett. 2008,
9, 5935–5938.
2. Jursic, B. S.; Stevens, E. D. Tetrahedron Lett. 2002, 43, 5681–5683.
4
We gratefully acknowledge the financial support from the Re-
search Council of University of Guilan.
3
33. Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 1998, 63,
481–4484.
4
34. Sharma, I.; Saxena, A.; Ojha, C. K.; Paradasani, C. K. P.; Paradasani, R. T.; Mu-
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. Chowdhury, Sh.; Mohan, R. S.; Scott, J. L. Tetrahedron 2007, 63, 2363–2389.
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