Three-component synthesis of new unsymmetrical oxindoles via Friedel-Crafts type reaction

Article abstract of DOI:10.1016/j.tet.2011.02.054

The synthesis of 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H- indene-1,3(2H)-diones as new unsymmetrical oxindoles via a Friedel-Crafts type three-component reaction of 1,3-indandion, N,N-dimethylaniline and isatins in ethanol in the presence of

Full text of DOI:10.1016/j.tet.2011.02.054

Tetrahedron 67 (2011) 3954e3958
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Three-component synthesis of new unsymmetrical oxindoles via FriedeleCrafts
type reaction
*
Somayeh Ahadi, Leila Moafi, Afsaneh Feiz, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, Evin, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-indene-1,3(2H)-diones as
new unsymmetrical oxindoles via a FriedeleCrafts type three-component reaction of 1,3-indandion,
N,N-dimethylaniline and isatins in ethanol in the presence of LiClO4 is reported.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 23 November 2010
Received in revised form 29 January 2011
Accepted 21 February 2011
Available online 9 March 2011
Keywords:
Isatin
Indandion
Friedelecraft reaction
Oxindole
1. Introduction
indolin-2-one(oxindole)moietyhas been recognizedasa biologically
active framework.17 Oxindole is an integral constituent of many
Multi-component reactions (MCRs) have offered many fasci-
nating and challenging transformations in organic synthesis.1 The
atom-economy, convergent character, operational simplicity,
structural diversity, and complexity of the molecules are the major
advantages associated with multi-component reactions. Besides
this multi-component reactions are emerging as a powerful tool in
the synthesis of biologically important compounds.2
natural products.18 Thus, it is not surprising that access to several
members of this class may be the goal of many research laboratories.
Recently, LiClO4 has emerged as a powerful promoter in many
chemical processes and in different organic media.19 The develop-
ment of method, which allows the reaction under essentially mild
and neutral conditions should heighten the synthetic potential of the
reaction. The LiClO4 medium provides a convenient procedure to
carry out reactions under simple and neutral conditions.
Although several isatin-based reactions have been reported by
our20 or other research groups21 for the synthesis of new oxindoles,
the synthesis of 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-
indene-diones 4 has not been reported yet. In this paper, for the first
time we report an efficient synthesis of new unsymmetrical oxindoles
4 based on a FriedeleCrafts type three-component reaction of 1,3-
indandione 1, isatins 2 and N,N-dimethylaniline 3 in the presence of
LiClO4 as an inexpensive and available catalyst (Scheme 1).
FriedeleCrafts reaction3 is one of the oldest carbonecarbon
bond forming processes, and is still an attractive method to
introduce substituents on aromatic rings. Initial works concerned
FriedeleCrafts acylation from acyl chlorides or alkylation from alkyl
halides. To perform acylations, Lewis acids are needed. More than
stoichiometric amounts of AlCl3 or BF3 are required, whereas cat-
alytic amounts of rare-earth triflates,4 more specially scandium
triflate,5 perfluorinated rare-earth metals,6 gallium triflate7 or
bismuth triflate,8 allow the formation of the expected products.
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 anti-HIV,9
antiviral,10 anti-tumor,11 antifungal,12 anti-angiogenic,13 anticonvul-
sants,14 anti-Parkinson’s disease therapeutic,15 and effective SARS
coronavirus 3CL protease inhibitor.16 These interesting properties
prompted many efforts toward the synthesis and pharmacological
screening of isatin derivatives. During these investigations, the
Me
Me N
O
Me Me
O
O
O
N
X
+
EtOH (Reflux)
X
O
O
+
N
O
LiClO4 (10 mol%)
R
N
R
1
2a-i
3
4a-i
* Corresponding author. Fax: þ98 21 22431661; e-mail address: a_bazgir@
Scheme 1. Synthesis of unsymmetrical oxindoles 4.
sbu.ac.ir (A. Bazgir).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.054

S. Ahadi et al. / Tetrahedron 67 (2011) 3954e3958
3955
2. Results and discussion
To study the generality of this protocol, a library of nine
substituted 2-(3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-
1H-indene-1,3(2H)-diones 4aei were built using 1,3-indandione 1,
isatins 2aei, and N,N-dimethylaniline 3 (Table 3). All compounds
are stable solids whose structures were established by IR, 1H and
13C NMR spectroscopy, and elemental analysis.
Our initial experiments were focused on the three-component re-
action of 1,3-indandione 1 (1 mmol), isatin 2a (1 mmol), and N,N-di-
methylaniline 3 (1 mmol) as a simple model substrate using different
catalysts in refluxing EtOH, and the results are listed in Table 1.
Table 1
Screening of catalysts
(Me)2N
(Me)2N
N(Me)2
O
N(Me)2
O
O
O
EtOH (Reflux)
Catalyst
+
O
+
+
O
N
O
O
H
N
N
H
H
1
2a
3
4a
5
Entry
Catalyst (mol %)
Time (h)
Yields 4a (%)
Yields 5a (%)
1
2
3
4
5
6
7
8
9
LiClO4 (5)
LiClO4 (10)
LiClO4 (15)
p-TSA (10)
HOAc (10)
AlCl3 (10)
ZnCl2 (10)
CAN (10)
InCl3
3
3
3
3
3
3
3
3
3
7
80
95
96
30
25
55
37
32
<10
Trace
Trace
35
43
27
46
37
49
Trace
35
Trace
10
None
a
Isolated yield based on precipitation.
It was observed that when HOAc, p-TSA, ZnCl2, CAN, and InCl3
were used, it led to the formation of 5 as major product and desired
product 4a as a minor product in a low yield (Table 1). AlCl3 showed
better selectivity for 4a in comparison to 5. LiClO4 was found to be
the best catalyst for the synthesis of unsymmetrical oxindole 4a. As
can be seen from Table 1, when the amount of the LiClO4 increased
from 5 to 10, and 15 mol %, the yields increased from 80 to 95 and
96%, respectively. It was found that 10 mol % LiClO4 in EtOH is
sufficient to push this reaction forward (Table 1, entry 2). More
amounts of the LiClO4 (15 mol %) did not improve the yields and
decreasing the amount of LiClO4 (5 mol %) resulted in a decrease in
the yield of 4a and increase in the yield of 5. When this reaction was
carried out without LiClO4 the yield of the product was Trace even
after 7 h (entry 10).
Table 3
Synthesis of unsymmetrical oxindoles 4
Product 4
R
X
Yields (%)
Timea (h)
a
b
c
d
e
f
g
h
i
H
H
H
H
Br
NO2
Me
F
Br
NO2
95
90
87
90
91
94
98
90
85
3
4.5
6
4
3.5
4
4
6
7
Me
Et
H
H
H
H
Me
Et
a
Isolated yields.
Then, we examined the solvent effect on the LiClO4-catalyzed
model reaction. The results of Table 2 demonstrate that solvent
affected the efficiency of the reaction and EtOH was the best choice
of solvent (Table 2). In other solvents, such as CH3CN, CH2Cl2, THF,
H2O, and CHCl3, low yield of 4a was obtained with significant for-
mation of 5. Therefore, the use of the commercially available, in-
expensive, and easily handled LiClO4 in EtOH provides a convenient
procedure for the synthesis of unsymmetrical oxindole 4a under
neutral and simple conditions.
The plausible mechanism of this FriedeleCrafts type reaction is
given in Scheme 2. Aromatic amine 3 reacts with isatin 2 to gen-
erate an intermediate 6, followed by a nucleophilic addition with
1,3-indandione 1 to afford unsymmetrical oxindole 4. Compound
5 was also formed by the attack of another molecule of 3 on
intermediate 6.
To further explore the potential of the reaction, we investigated
the reaction of acenaphthylene-1,2-dione 7 and ninhydrin 8 in-
stead of isatin 2 and obtained 2-(1-(4-(dimethylamino)phenyl)-
2-oxo-1,2-dihydroacenaphthylen-1-yl)-1H-indene-1,3(2H)-dione
Table 2
Solvent effect on the reactiona
9
and
2-(4-(dimethylamino)phenyl)-1H,10H-2,20-biindene-
Yield 5b (%)
1,10,3,30(2H,20H)-tetraone 10 in 73% and 60% yield, respectively
(Scheme 3).
Entry
Solvent (Reflux)
Yield 4a (%)
1
2
3
4
5
6
CH3CN
CH2Cl2
THF
H2O
EtOH
CHCl3
33
52
37
63
52
Trace
49
Trace
<20
Trace
95
It is notable, when we carried out the reaction with another
cyclic 1,3-dicarbonyl compounds 11, the TLC and 1H NMR spectra of
the reaction mixture showed a combination of starting materials
and numerous products; low yields of desired products 12 were
obtained and compound 5 was produced as a major product
(Scheme 4).
<20
a
Reaction time¼3 h, LiClO4 (10 mol %).
b
Isolated yield.

3956
S. Ahadi et al. / Tetrahedron 67 (2011) 3954e3958
O
O
O
HO
Me
Me
NH
NH
Me
Me
LiClO4
N
Me
+
N
O
N
N
Me
H
6
3
2
3
1
(Me)2N
(Me)2N
N(Me)2
O
O
O
O
5
N
H
N
4
H
Scheme 2. Proposed mechanism of the reaction.
and 75.47 MHz, respectively. 1H and 13C NMR spectra were obtained
on solutions in DMSO-d6. IR spectra were recorded using an FTIR
apparatus. Elemental analyses were performed using a Heracus
CHN-O-Rapid analyzer.
Me
Me
O
N
O
O
O
7
The chemicals used in this work were obtained from Fluka and
Merck and were used without purification.
O
Me
Me
9
73%
O
O
N
EtOH (Reflux)
4.1.1. 2-(3-(4-(Dimethylamino)phenyl)-2-oxoindolin-3-yl)-1H-in-
dene-1,3(2H)-dione (4a). A mixture of 1,3-indandione (1 mmol),
isatin (1 mmol), N,N-dimethylaniline (1 mmol), and LiClO4 (10 mol %)
in refluxing ethanol (5 mL) was stirred for 3 h (the progress of the
reaction was monitored by TLC). After completion, the reaction
mixture was filtered and the precipitate washed with diethyl ether
(10 ml) to afford the pure product 4a as greenish powder (0.396 g,
95%); mp 240 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3357, 3080,1737,1706.1H
NMR (300 MHz, DMSO-d6): dH¼2.86 (6H, s, 2CH3), 4.71 (1H, s, CH),
6.64e7.89 (12H, m, HeAr), 10.47 (1H, s, NH). 13C NMR (75 MHz,
DMSO-d6): dC¼40.6, 55.5, 57.2, 110.3, 112.5, 121.6, 123.0, 124.8, 128.1,
129.1,129.5,136.5,143.3,144.2,149.2,178.0,179.4,197.7,198.0. MS (EI,
70 eV) m/z: 396 (Mþ). Anal. Calcd for C25H20N2O3: C, 75.74; H, 5.08; N,
7.07. Found: C, 75.65; H, 5.03; N, 7.01%.
O
+
O
LiClO4 (10 mol%)
12 h
O
O
O
1
3
8
O
O
Me
N
Me
10
60%
Scheme 3. Examining acenaphthylene-1,2-dione and ninhydrin instead of isatin.
Me
N
Me
N
Me
N
Me
Me
Me
O
Me Me
N
O
O
O
Reflux EtOH
+
+
O
O
O
LiClO4
N
N
N
H
4.1.2. 2-(3-(4-(Dimethylamino)phenyl)-1-methyl-2-oxoindolin-3-
yl)-1H-indene-1,3(2H)-dione (4b). Yellow powder (0.41 g, 90%); mp
230 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3425, 3043, 1742, 1706. 1H NMR
(300 MHz, DMSO-d6): dH¼3.00 (6H, s, CH3), 3.13 (3H, s, CH3), 4.78
(1H, s, CH), 6.62e7.90 (12H, m, HeAr).13C NMR (75 MHz, DMSO-d6):
dC¼26.8, 40.5, 54.8, 57.5,109.4,112.4,122.3,123.1,124.5,128.2,128.6,
129.3,136.4,136.6,141.7,142.4, 143.0, 144.8,176.5,197.5,197.6,197.8.
MS (EI, 70 eV) m/z: 410 (Mþ). Anal. Calcd for C26H22N2O3: C, 76.08;
H, 5.40; N, 6.82. Found: C, 75.97; H, 5.47; N, 6.74%.
H
H
O
5 h
11
2a
3
5
12
<20 %
40-50 %
O
O
OH
O
O
OH
O
O
O
O
O
O
11:
O
O
O
O
O
Scheme 4. Examining different CH-acids instead of 1,3-indandione.
3. Conclusion
4.1.3. 2-(3-(4-(Dimethylamino)phenyl)-1-ethyl-2-oxoindolin-3-yl)-
1H-indene-1,3(2H)-dione (4c). Yellow powder (0.42 g, 87%); mp
243 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3415, 3045, 1718, 1605. 1H NMR
(300 MHz, DMSO-d6): dH¼1.17 (3H, t, J¼5.7 Hz, CH3), 2.86 (6H, s,
CH3), 3.58e3.76 (2H, m, CH2), 4.80 (1H, s, CH), 6.46e7.91 (12H, m,
HeAr). 13C NMR (75 MHz, DMSO-d6): dC¼12.4, 34.7, 40.5, 54.8, 57.5,
109.4, 112.4, 122.1, 123.0, 123.1, 124.7, 125.0, 128.1, 129.0, 129.3,
136.4, 136.6, 141.7, 143.0, 143.8, 149.9, 176.1, 197.5, 197.8. MS (EI,
70 eV) m/z: 424 (Mþ). Anal. Calcd for C27H24N2O3. C, 76.39; H, 5.70;
N, 6.60. Found: C, 76.45; H, 5.66; N, 6.69%.
In conclusion, we have developed an efficient three-component
reaction of 1,3-indandione, isatins, and N,N-dimethylaniline using
LiClO4 as a catalyst. The reaction is operationally simple and offers
high yields of the new unsymmetrical oxindole derivatives. Prom-
inent among the advantages of this new method are novelty,
operational simplicity and easy work-up procedures employed.
4. Experimental
4.1. General
4.1.4. 2-(5-Bromo-3-(4-(dimethylamino)phenyl)-2-oxoindolin-3-yl)-
1H-indene-1,3(2H)-dione (4d). Cream powder (0.474 g, 90%); mp
250 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3190, 3111, 1711, 1617. 1H NMR
(300 MHz, DMSO-d6): dH¼2.87 (6H, s, 2CH3), 4.83 (1H, s, CH),
Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13

S. Ahadi et al. / Tetrahedron 67 (2011) 3954e3958
3957
6.66e7.92 (11H, m, HeAr), 10.66 (1H, s, NH). 13C NMR (75 MHz,
DMSO-d6): dC¼40.4, 55.9, 57.0, 112.3, 112.5, 113.1, 123.0, 124.8, 127.4,
127.9, 131.8, 136.6, 141.9, 142.5, 142.7, 149.9, 177.6, 197.2, 197.9. MS
(EI, 70 eV) m/z: 476 (Mþ), 474 (Mþ). Anal. Calcd for C25H19BrN2O3: C,
63.17; H, 4.03; N, 5.89. Found: C, 63.10; H, 4.11; N, 5.98%.
143.2, 149.8, 198.2, 201.0. MS (EI, 70 eV) m/z: 431 (Mþ). Anal. Calcd
for C29H21NO3: C, 80.72, H, 4.91; N, 3.25. Found: C, 80.65; H, 4.99;
N, 3.32%.
4.1.11. 2-(4-(Dimethylamino)phenyl)-1H,10H-2,20-biindene-
1,10,3,30(2H,20H)-tetraone (10). Yellow powder (0.41 g, 60%); mp
291 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3243, 3078, 1716, 1702. 1H NMR
(300 MHz, DMSO-d6): dH¼2.86 (6H, s, 2CH3), 4.76 (1H, s, CH),
6.64e7.99 (12H, m, HeAr). 13C NMR (75 MHz, DMSO-d6): dC¼40.4,
57.7, 109.7, 112.6, 120.0, 123.3, 123.8, 126.6, 127.9, 130.6, 135.8, 136.8,
141.6, 142.4, 142.7, 149.8, 150.1, 197.0, 197.4, 198.3, 199.9. MS (EI,
70 eV) m/z: 409 (Mþ). Anal. Calcd for C26H19NO4: C, 76.27, H, 4.68;
N, 3.42. Found: C, 76.16; H, 4.60; N, 3.51%.
4.1.5. 2-(3-(4-(Dimethylamino)phenyl)-5-nitro-2-oxoindolin-3-yl)-
1H-indene-1,3(2H)-dione (4e). Cream powder (0.44 g, 91%); mp
215 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3451, 3184, 1742, 1706, 1612. 1H
NMR (300 MHz, DMSO-d6): dH¼2.88 (6H, s, 2CH3), 5.00 (1H, s,
CH), 6.66e8.15 (11H, m, HeAr), 11.29 (1H, s, NH). 13C NMR
(75 MHz, DMSO-d6): dC¼40.5, 56.4, 57.3, 110.5, 112.6, 120.3, 123.2,
124.3, 126.6, 127.9, 131.3, 136.8, 141.7, 142.1, 142.7, 149.7, 150.0,
178.4, 197.1, 197.6. MS (EI, 70 eV) m/z: 441 (Mþ). Anal. Calcd for
C25H19N3O5: C, 68.02; H, 4.34; N, 9.52. Found: C, 67.91; H, 4.28; N,
9.43%.
Acknowledgements
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
4.1.6. 2-(3-(4-(Dimethylamino)phenyl)-5-methyl-2-oxoindolin-3-
yl)-1H-indene-1,3(2H)-dione (4f). Cream powder (0.41 g, 94%); mp
239 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3362, 3190, 1742, 1721, 1690. 1H
NMR (300 MHz, DMSO-d6): dH¼1.96 (3H, s, CH3), 2.87 (6H, s, 2CH3),
4.69 (1H, s, CH), 6.47e7.90 (11H, m, HeAr), 10.36 (1H, s, NH). 13C
NMR (75 MHz, DMSO-d6): dC¼21.0, 40.5, 55.6, 57.2, 110.0, 112.4,
122.9, 125.5, 128.1, 129.3, 129.7, 130.2, 136.3, 136.4, 140.8, 141.9,
149.8, 178.0, 198.0. MS (EI, 70 eV) m/z: 410 (Mþ). Anal. Calcd for
C26H22N2O3: C, 76.08, H, 5.40; N, 6.82. Found: C, 75.99; H, 5.46; N,
6.77%.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.02.054.
References and notes
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1. (a) Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Wein-
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Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (d) Simon, C.; Constantieux, T.;
Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
4.1.7. 2-(3-(4-(Dimethylamino)phenyl)-5-fluoro-2-oxoindolin-3-yl)-
1H-indene-1,3(2H)-dione (4g). Cream powder (0.41 g, 98%); mp
252 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3398, 1737, 1711, 1705. 1H NMR
(300 MHz, DMSO-d6): dH¼2.87 (6H, s, 2CH3), 4.78 (1H, s, CH),
6.53e7.91 (11H, m, HeAr), 10.54 (1H, s, NH). 13C NMR (75 MHz,
DMSO-d6): dC¼40.5, 56.2, 56.9, 111.1, 112.1, 112.5, 115.3, 123.1, 124.8,
128.0, 136.6, 139.4, 141.9, 142.8, 149.9, 177.9, 197.3, 197.8. MS (EI,
70 eV) m/z: 414 (Mþ). Anal. Calcd for C25H19FN2O3: C, 72.45, H, 4.62;
N, 6.76. Found: C, 72.55; H, 4.68; N, 6.69%.
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8. (a) Desmurs, J.-R.; Labrouillere, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.;
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4.1.8. 2-(5-Bromo-3-(4-(dimethylamino)phenyl)-1-methyl-2-ox-
oindolin-3-yl)-1H-indene-1,3(2H)-dione (4h). Cream powder (0.49 g,
90%); mp 220 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3420,1742,1715,1701. 1H
NMR (300 MHz, DMSO-d6): dH¼2.50 (6H, s, 2CH3), 3.12 (3H, s, CH3),
4.91 (1H, s, CH), 6.65e8.31 (11H, m, HeAr).13C NMR (75 MHz, DMSO-
d6): dC¼26.9, 40.4, 55.1, 57.5, 111.4, 112.5, 113.9, 123.1, 123.2, 127.1,
128.0, 131.7, 132.0, 136.7, 141.7, 142.7, 150.6, 176.0, 197.2, 197.7. MS (EI,
70 eV) m/z: 490 (Mþ), 488 (Mþ). Anal. Calcd for C26H21BrN2O3: C,
63.81, H, 4.33; N, 5.72. Found: C, 63.70; H, 4.25; N, 5.61%.
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4.1.9. 2-(3-(4-(Dimethylamino)phenyl)-1-ethyl-5-nitro-2-ox-
oindolin-3-yl)-1H-indene-1,3(2H)-dione (4i). Yellow powder (0.47 g,
85%); mp 220 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3085, 1748, 1732, 1711.
1H NMR (300 MHz, DMSO-d6): dH¼1.19 (3H, t, J¼6.8 Hz, CH3), 2.87
(6H, s, 2CH3), 3.77e3.81 (2H, m, CH2), 5.09 (1H, s, CH), 6.65e8.23
(11H, m, HeAr). 13C NMR (75 MHz, DMSO-d6): dC¼12.3, 35.4, 40.4,
54.6, 57.7, 109.7, 112.6, 120.0, 123.3, 123.6, 126.6, 127.9, 130.6, 136.8,
136.8, 141.6, 142.4, 142.7, 149.8, 150.1, 176.6, 197.0, 197.4. MS (EI,
70 eV) m/z: 469 (Mþ). Anal. Calcd for C27H23N3O5: C, 69.07, H, 4.94;
N, 8.95. Found: C, 69.13; H, 4.99; N, 8.87.
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4.1.10. 2-(1-(4-(Dimethylamino)phenyl)-2-oxo-1,2-dihydroacenaph-
thylen-1-yl)-1H-indene-1,3(2H)-dione (9). Yellow powder (0.43 g,
73%); mp 284 ꢀC dec; IR (KBr) (nmax, cmꢁ1): 3278, 3075, 1717, 1654.
1H NMR (300 MHz, DMSO-d6): dH¼2.81 (6H, s, 2CH3), 5.19 (1H, s,
CH), 6.58e8.21 (14H, m, HeAr). 13C NMR (75 MHz, DMSO-d6):
dC¼40.4, 58.3, 60.0, 112.4, 121.9, 122.9, 123.1, 125.3, 125.5, 128.3,
128.9, 129.4, 130.6, 131.9, 132.2, 136.4, 136.7, 138.9, 141.2, 141.6,

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