Ultrasound promoted clay catalyzed efficient and one pot synthesis of substituted oxindoles

Article abstract of DOI:10.1016/j.ultsonch.2011.03.023

A simple facile, one-pot synthesis of oxindoles in reasonable purity is reported via intramolecular Friedal-Craft cyclization. Clay KSF is an inexpensive, efficient and mild catalyst for the synthesis of substituted oxindoles by the reaction of chloroacetyl chloride and various anilines under the influence of ultrasonic irradiation under solvent-free conditions. The remarkable advantages of this method are the simple experimental procedures, short reaction times, high yields of products, suitability for a wide variety of substituents, and the green aspects through the avoidance of toxic catalyst and solvents.

Full text of DOI:10.1016/j.ultsonch.2011.03.023

Ultrasonics Sonochemistry 18 (2011) 1143–1147
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound promoted clay catalyzed efficient and one pot synthesis of substituted
oxindoles
⇑
A. Dandia , D.S. Bhati, A.K. Jain, G.N. Sharma
Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur 302 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 May 2010
Received in revised form 18 March 2011
Accepted 18 March 2011
Available online 30 March 2011
A simple facile, one-pot synthesis of oxindoles in reasonable purity is reported via intramolecular Frie-
dal–Craft cyclization. Clay KSF is an inexpensive, efficient and mild catalyst for the synthesis of substi-
tuted oxindoles by the reaction of chloroacetyl chloride and various anilines under the influence of
ultrasonic irradiation under solvent-free conditions. The remarkable advantages of this method are the
simple experimental procedures, short reaction times, high yields of products, suitability for a wide vari-
ety of substituents, and the green aspects through the avoidance of toxic catalyst and solvents.
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Clay catalyzed reaction
Sonication
Oxindoles
1
. Introduction
rhodium-catalyzed carbonylations of 2-alkynylanilines [18], rho-
dium- and Nafion-H-catalyzed cyclizations of
a-diazoamides
Indole and its derivatives are known as an important class of
[19], copper catalyzed amidation of N-substituted 2,6-bromophe-
nyl acetamide [20], intramolecular Heck couplings of 2-haloacry-
loylanilides [21], as well as some photochemical methods which
have also been reported [22]. Although these methods are very
useful for the construction of the oxindoles, the majority of these
methods lead to 3-monosubstituted or 3,3-di-substituted oxin-
doles. Straightforward approaches to the less stable 3-unsubstitut-
ed oxindoles, which are important synthons for various indole
heterocycles [23] exist, but these methods also suffer from several
limitations, including longer reaction times, unsatisfactory yields,
harsh reaction conditions, and excessive use of reagents and cata-
lyst. Many of the other methods are also limited by the types of
oxindoles that may be prepared because of the specifically func-
tionalized precursors required or because the starting materials
are not available conveniently. Friedel–Craft cyclization of N-acetyl
anilines (the Stolle synthesis) [16] is one of the most generally used
methods for the synthesis of monosubstituted oxindoles. Some
limitations are also associated with this method, such as tedious
work up processes and the requirement for high temperature
and strong acidic conditions (AlCl ), which further limits the range
3
of functional group tolerated. In order to overcome these limita-
tions, a nontrivial synthetic methodology is required.
The use of clays as inorganic solid catalysts or as reaction media
in various organic transformations has become widespread in the
last two decades [24]. Such environmentally benign heterogeneous
reactions often involve minimal waste, efficient catalyst recycling,
increased yield or selectivity, and easier setup and workup proce-
dures compared to conventional liquid phase homogeneous reac-
tions. In addition, mineral clays benefit from practical features
heterocyclic compounds in the pharmaceutical industry as well
as in synthetic chemistry [1]. The oxindole skeleton can be found
in the most ubiquitous of the known bioactive alkaloids and herbi-
cides (e.g., Horsfiline, paraherquamide, rhyncophylline, and the
gelsemium alkaloids) [2], and its derivatives play an important role
as intermediates in the synthesis of indole alkaloids (e.g., physo-
stigmine) [3,4]. The biological importance of this family is demon-
strated by the fact that many drugs are already marketed (e.g.,
ropinirole, ziprasidone) [5], and several new and promising oxin-
dole derivatives are used in various therapeutic fields, including
P-glycoprotein mediated multiple drug resistance inhibitors [6],
non-opioid nociceptin receptor ligands [7], CDKs inhibitors [8]
and AChE and BChE inhibitors [9].
Three unsubstituted oxindoles are important starting materials
for further functionalization [10]. As a consequence, the develop-
ment of efficient synthetic method for the synthesis of 3-unsubsti-
tuted oxindoles is of great importance.
There are many methods that have been developed for the syn-
thesis of oxindoles both in solution phase and on solid supports,
such as derivatization of other heterocycles [11], cyclization of o-
aminophenylacetic acid derivatives [12], reduction of isatins [13],
radical cyclizations [14], Pummerer cyclizations [15], Gassman sul-
fonium yield reactions, and Friedel–Crafts reactions (Stolle synthe-
sis) [16]. Some Metal-catalyzed routes to oxindoles include
palladium-catalyzed cyclocarbonylations of 2-aminostyrenes [17],
⇑
Corresponding author.
E-mail address: dranshudandia@yahoo.co.in (A. Dandia).
1
350-4177/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2011.03.023

1
144
A. Dandia et al. / Ultrasonics Sonochemistry 18 (2011) 1143–1147
such as stability, ease of handling, lack of corrosiveness and low
cost. For example, acid-treated montmorillonite (commercially
known as mont KSF) shows high activity as a solid support in many
organic reactions. [25]
bath (Bandelin Sonorex) operating at 230 V with a 33 kHz output
frequency.
2
2
.1. Synthesis of 1,3-Dihydro-indole-2-one (4a)
Ultrasound irradiation has been considered as a clean and use-
ful protocol in organic synthesis in the last three decades [26]. Son-
ochemistry can be extremely efficient and it is applicable to a
broad range of practical syntheses [27]. The prominent features
of the ultrasound approach are enhanced reaction rates, formation
of purer products in high yields, easier experimental procedures,
increased selectivities, and cleaner reactions. Many ultrasound-in-
duced organic transformations offer additional convenience in the
field of synthetic organic chemistry due to cavitation. Cavitation is
a physical process that creates, enlarges, and implodes gaseous and
vaporous cavities in an irradiated liquid, thus enhancing the mass
transfer and allowing chemical reactions to occur [28]. A search of
the literature indicates that a number of researchers have demon-
strated the efficacy of sonication even under solvent-free condi-
tions [29].
.1.1. Conventional synthesis
Involves two steps.
2.1.1.1. Synthesis of a-chloroacetanilide (3a). Chloroacetyl chloride
(
0.01 mol) in dry benzene (10 mL) was added drop wise to a stirred
and cooled solution of the aniline (1a) (0.01 mol) in dry benzene
25 mL) and anhydrous pyridine (0.01 mol). The mixture was al-
(
lowed to stand overnight at room temperature and then heated
on water bath. After cooling, the product was treated with water
(
20 mL) to dissolve precipitated salts, and the benzene layer was
separated and extracted with 1.5% HCl (5 mL), followed by the
addition of successive quantities of water (15 mL) until the aque-
ous layer was neutral. The benzene layer was dried (MgSO
4
), fil-
tered and evaporated under reduced pressure to yield crude 3a.
As a part of our interest in the synthesis of a wide range of het-
erocyclic systems and in a continuation of the use of green chem-
istry tools in heterocyclic synthesis [30], we wish to report a one-
pot efficient approach for the clay-catalyzed synthesis of 3-unsub-
stituted oxindoles under sonication, with no need for the prior syn-
2
.1.1.2. Cyclization of
chloroactanilide derivative (3a) (0.01 mol) and finely powdered
anhydrous AlCl (0.02 mol) was warmed at 50 °C for 10 min and
a-chloroacetanilide (3a). A mixture of the a-
3
subsequently heated at 200 °C for 2 h. After cooling, the black solid
was decomposed with ice (20 g), and the crude product removed
by filtration and recrystallized (ethanol) to form oxindole (4a).
thesis of
a-chloroacetanilide in the first step. The synthetic
approach presented here may be considered a processing aid in
terms of energy conservation and waste minimization in compar-
ison to traditional methods, and this technique is more convenient
when taking green chemistry concepts into account. The reaction
of substituted anilines with chloroacetyl chloride and intramolec-
2.1.2. Reaction under sonication
2.1.2.1. Using Clay catalyst (one pot synthesis). A mixture of aniline
(1a) (0.01 mol) and solid catalyst (4 g) (Clay KSF/acidic Al O /silica
ular Friedel–Craft cyclization of the
a-chloroactanilide generated
2
3
in situ under ultrasound irradiation leads to the facile synthesis
of wide variety of substituted oxindoles, while avoiding harsh reac-
tion conditions. (Scheme 1)
gel) were placed in a conical flask which was immersed in the
water bath of an ultrasonic cleaner. The flask was positioned
0.5 cm above the bottom of the bath at room temperature followed
by the drop wise addition of chloroacetyl chloride (1b) (0.01 mol)
over a period of 10 min. The resulting mixture was then sonicated
for the periods indicated in Table 1. The progress of the reaction
was monitored by TLC. After completion, the reaction mixture
was desorbed from the solid support with ethanol. The resulting
solution was kept at room temperature to afford the final product
with no need for further purification.
2
. Experimental
The melting points of all compounds were determined on a
Toshniwal apparatus. The purity of the compounds was checked
by TLC using silica Gel–G coated glass plates with benzene: ethyl
acetate (8:2) as the solvent. IR spectra were recorded on a Shima-
1
13
dzu FT IR-8400S spectrophotometer using KBr pellets. H and
C
NMR spectra were recorded on a Bruker DRX-300 using CDCl
3
at
2.1.2.2. Using Tween 80 as phase transfer catalyst. An equimolar
mixture (0.01 mol) of (1a) and (2b) was dissolved in 5 mL
Tween-80 and the mixture was placed in a conical flask, which
was immersed in the water bath of an ultrasonic cleaner for the
appropriate time (indicated TLC, Table 1) using method (a). After
completion of the reaction, 50 mL of distilled water was added to
the reaction mixture and extracted three times with 10 mL portion
3
00.15 and 75.47, respectively. TMS was used as an internal refer-
ence. The mass spectrums of representative compounds were re-
corded using a JEOL SX-102 spectrometer at 70 eV. Elemental
microanalyses were carried out on a Carlo- Erba 1108 CHN ana-
lyzer. Sonication was carried out with the help of an ultrasonic
2
of CH Cl
2
. The extract was dried over anhydrous MgSO
4
, concen-
Cl
Mont KSF
X
+
ClCH COCl
2
X
)
))))
Table 1
Comparative study of synthesis of compound 4a.
NH
C
(
2)
(
1)
N
R
O
R
(3)
S.
No.
Reaction media
Method Time
(min)
Yield
(%)
X=H Zn Dust
a
1
2.
3
4
5.
6.
.
Mont. KSF
US Bath 45 min
US Bath 75 min
US Bath 85 min
US Bath 90 min
US Bath 85 min
93
63
60
52
65
O
Acidic Al O3
2
.
.
Silica gel
Zn dust
Tween-80
Mont. KSF
Dry benzene and anhydrous pyridine/
anhydrous AlCl3
Cl
O
X
X
NH
Cl
C
b
N
O
D
D
4 h
25 h
Nil
N
R
c
7.
38
(
5)
R
(4)
R
(3)
a
b
c
Major product
Minor product
Isolated yield.
Intermediate
4a was synthesized in two steps; time and yield refer to the complete reaction.
a
-chloroacetanilide (3a) is formed.
Scheme 1.

A. Dandia et al. / Ultrasonics Sonochemistry 18 (2011) 1143–1147
1145
trated to 5 mL, The resulting solution was kept at room tempera-
ture to obtain the final product and recrystallized with methanol.
2.8. 5-Trifluoromethyl-1,3-dihydro-indole-2-one (4g)
À1
IR (KBr) (
m
max cm ) 3308 (NH str.) 3082 (aromatic CH str.) 1710
1
(
C@O); H NMR (300 MHz, CDCl
J = 8.2 Hz) 7.68 (1H, s), 6.96 (1H, d, J = 8.2 Hz), 3.48 (s, 2H, CH
NMR (75.47 MHz, CDCl ) d : 172, 144.7–120.3, 122.3, 37.2. Anal.
Calc. for C NO: C, 53.74; H, 3.01; N, 6.96. Found: C, 53.57; H,
.07; N, 6.88.
3 H
) d : 9.98 (s, 1H, NH) 7.82 (1H, d,
2.1.2.3. Using Zn Dust. Zn powder (0.01 mol) was added to an equi-
13
molar mixture (0.01 mol) of (1a) and (2b) and placed in a conical
flask, the reaction mixture was mixed with a glass rod and soni-
cated for the appropriate time. After completion of the reaction
2
),
C
3
c
9 6 3
H F
3
(
TLC), the mixture was extracted with methanol. After drying the
extract over anhydrous Na SO , resultant solution was kept at
2
4
room temperature to afford the product, which was recrystallized
with methanol.
2.9. 1-Methyl-1,3-dihydro-indole-2-one (4h)
max cm ) 3088 (aromatic CH str.) 1705 (C@O); 1
À1
H
IR (KBr) (
m
2
.2. 1,3-Dihydro-indole-2-one (4a)
NMR (300 MHz, CDCl
3
) d
H
: 7.44 (m, 2H), 7.26 (t, J = 7.42 Hz, 1H),
13
7
.04 (d, J = 7.58 Hz, 1H), 3.94 (s, 2H, CH
2
), 3.32 (s, 3H, CH
: 176.24, 142.52–127.0, 41.51, 37.96.
9 9
MS (m/z): 147.08 (M ). Anal. Calc. for C H NO: C, 73.45; H, 6.16;
3
),
C
À1
IR (KBr) (
m
max cm ) 3280 (NH str.) 3080 (aromatic CH str.) 1698
NMR (75.47 MHz, CDCl
3 c
) d
1
+
(
C@O); H NMR (300 MHz, CDCl
3
) d
H
: 9.45 (s, 1H, NH) 7.22 (m, 2H),
6
.89 (t, J = 7.38 Hz, 1H), 6.78 (d, J = 7.48 Hz, 1H), 3.53 (s, 2H, CH
2
)
N, 9.52. Found: C, 73.64; H, 6.24; N, 9.42.
1
3
C NMR (75.47 MHz, CDCl
3
) d
z): 133 (M ). Anal. Calc. for C
Found: C, 72.35; H, 5.36; N, 10.58.
c
: 178.3, 142.7–109.9, 36.3. MS (m/
+
8
H
7
NO: C, 72.16; H, 5.30; N, 10.52.
2.10. 1-Ethyl-1,3-dihydro-indole-2-one (4i)
À1
IR (KBr) (
m
max cm ) 3092 (aromatic CH str.) 1708 (C@O); 1
H
2
.3. 5-Methyl-1,3-dihydro-indole-2-one (4b)
NMR (300 MHz, CDCl
3
) d
H
: 7.40 (m, 2H), 7.22 (t, J = 7.49 Hz, 1H),
), 3.28 (q, 2H, CH ), 1.46
), C NMR (75.47 MHz, CDCl ) d : 180.20,
11NO: C,
6
.99 (d, J = 7.62 Hz, 1H), 3.88 (s, 2H, CH
2
2
À1
13
IR (KBr) (
m
max cm ) 3305 (NH str.) 3079 (aromatic CH str.) 1708
C@O); H NMR (300 MHz, CDCl ) d : 9.76 (s, 1H, NH) 7.12 (1H, s)
.92 (1H, d, J = 7.8 Hz), 6.75 (1H, d, J = 7.8 Hz), 3.41 (s, 2H, CH ),
: 176.5, 140.3–
NO: C, 73.45; H, 6.16; N,
(t, J = 7.22 Hz 3H, CH
148.22–132.42, 47.24, 44.26, 42.62. Anal. Calc. for C10
74.51; H, 6.88; N, 8.69. Found: C, 74.73; H, 6.82; N, 8.60.
3
3
c
1
(
3
H
H
6
2
1
9
2
1
3
.28 (s, 3H, CH
24.4, 35.6, 20.3. Anal. Calc. for C
.52. Found: C, 73.77; H, 6.09; N, 9.60.
3
)
3 c
C NMR (75.47 MHz, CDCl ) d
H
9 9
2.11. 1-Phenyl-1,3-dihydro-indole-2-one (4j)
À1
IR (KBr) (
m
max cm ) 3094 (aromatic CH str.) 1706 (C@O); 1
H
2
.4. 5-Chloro-1,3-dihydro-indole-2-one (4c)
NMR (300 MHz, CDCl
J = 7.32 Hz, 1H), 7.0 (d, J = 7.83 Hz, 1H), 3.84 (s, 2H, CH
NMR (75.47 MHz, CDCl ) d : 178.92, 146.22–114.30, 43.58. Anal.
Calc. for C14 11NO: C, 80.36; H, 5.30; N, 6.69. Found: C, 80.12; H,
5.22; N, 6.79.
3 H
) d : 7.26–8.42 (m, 7H, Ar-H), 7.34 (t,
13
2
),
C
À1
IR (KBr) (
m
max cm ) 3315 (NH str.) 3082 (aromatic CH str.) 1696
3
c
1
(
C@O); H NMR (300 MHz, CDCl
J = 8.2 Hz) 7.28 (1H, s), 6.68 (1H, d, J = 8.2 Hz), 3.54 (s, 2H, CH
NMR (75.47 MHz, CDCl ) d : 178, 142–127, 38.2. Anal. Calc. for
ClNO: C, 57.33; H, 3.61; N, 8.36. Found: C, 57.16; H, 3.64; N,
.28.
3
H
) d : 9.62 (s, 1H, NH) 7.42 (1H, d,
H
1
3
2
),
C
3
c
C
8
H
8 6
2.12. 1-Benzyl-1,3-dihydro-indole-2-one (4k)
À1
IR (KBr) (
m
max cm ) 3086 (aromatic CH str.) 1702 (C@O); 1
H
2
.5. 5-Bromo-1,3-dihydro-indole-2-one (4d)
NMR (300 MHz, CDCl
3
) d
H
: 7.28–8.24 (m, 7H, ArAH), 7.08 (t,
), 4.94
: 174.52, 144.66–
13NO: C, 80.69; H, 5.87;
N, 6.27. Found: C, 80.93; H, 5.97; N, 6.20.
J = 7.62 Hz, 1H), 6.60 (d, J = 7.82 Hz, 1H), 3.76 (s, 2H, CH
2
À1
13
IR (KBr) (
m
max cm ) 3289 (NH str.) 3082 (aromatic CH str.) 1695
(m, 2H, CH
2
)
3 c
C NMR (75.47 MHz, CDCl ) d
1
(
C@O); H NMR (300 MHz, CDCl
J = 7.8 Hz) 7.22 (1H, s), 6.59 (1H, d, J = 7.8 Hz), 3.46 (s, 2H, CH
NMR (75.47 MHz, CDCl ) d : 179.8, 142–129, 35.2. Anal. Calc. for
BrNO: C, 45.31; H, 2.85; N, 6.61. Found: C, 45.17; H, 2.93; N,
.69.
3
H
) d : 9.52 (s, 1H, NH) 7.36 (1H, d,
107.12, 40.28,35.59. Anal. Calc. for C15H
1
3
2
),
C
3
c
C
6
8 6
H
3
. Result and discussion
In order to get the best experimental reaction conditions, the
2.6. 5-Fluoro-1,3-dihydro-indole-2-one (4e)
reaction of aniline (1a) and chloroacetyl chloride (1b) has been
considered as a standard model reaction (Table 1). We have
investigated the model reaction using a low-intensity ultrasonic
À1
IR (KBr) (
m
max cm ) 3310 (NH str.) 3084 (aromatic CH str.) 1694
1
(
C@O); H NMR (300 MHz, CDCl
J = 9.1 Hz) 7.44 (1H, s), 6.80 (1H, d, J = 9.1 Hz), 3.49 (s, 2H, CH
NMR (75.47 MHz, CDCl ) d : 177.0, 159.9–113.7, 36.4. Anal. Calc.
for C FNO: C, 63.57; H, 4.00; N, 9.27. Found: C, 63.77; H, 4.10;
N, 9.19.
3 H
) d : 9.92 (s, 1H, NH) 7.88 (1H, d,
(
LIU) laboratory cleaning bath by using different inorganic sup-
1
3
2
),
C
ports such as clay KSF, acidic alumina and silica gel. Results indi-
cate that the reaction proceeds under all conditions investigated,
resulting in the formation of the same product (4a), but that the
yield and reaction times are different. The best result was ob-
tained by using mont. KSF clay. Mont. KSF is the most adaptable
solid support for the synthesis of (4a), and it eliminates the
necessity for an acidic catalyst as required under conventional
conditions. It produces comparatively higher yields in relatively
short reaction time.
In the course of our investigations to develop new synthetic
reaction media, we have also studied the model reaction using
Tween-80 as a phase transfer catalyst [31]. Tween-80 is certainly
effective as a phase transfer catalyst for this reaction under ultra-
3
c
8 6
H
2.7. 5-Nitro-1,3-dihydro-indole-2-one (4f)
À1
IR (KBr) (
m
max cm ) 3304 (NH str.) 3078 (aromatic CH str.) 1708
1
(
C@O); H NMR (300 MHz, CDCl
J = 9.2 Hz) 7.40 (1H, s), 6.82 (1H, d, J = 9.2 Hz), 3.41 (s, 2H, CH
NMR (75.47 MHz, CDCl ) d : 171.8, 143.7–118.3, 36.6. Anal. Calc.
for C : C, 53.94; H, 3.39; N, 15.73. Found: C, 53.79; H,
.32; N, 15.80.
3 H
) d : 9.82 (s, 1H, NH) 7.72 (1H, d,
1
3
2
),
C
3
c
8 6 2 3
H N O
3

1
146
A. Dandia et al. / Ultrasonics Sonochemistry 18 (2011) 1143–1147
sound irradiation, but the isolated yield of products is low due to
tedious work up. Attempts were also made to carry out the reac-
tion using Zn dust as a catalyst, because the literature indicates
that Zn dust effectively catalyzes the acylation process [32]. How-
ever, in the present case, when 1a and 2a are mixed with Zn dust,
the title reaction at room temperature gave a mixture of acylated
Table 2
Physical data of 4a–k.
S.
No.
Compounds
X
R
Time
Yield M.P. (°C)
(min)
(%)
Found Literature
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
H
H
45
48
46
52
55
58
54
45
50
55
52
93
85
82
78
88
78
82
92
88
76
76
123–
24
172–
174
199–
200
216–
218
142–
144
239–
241
191–
200
88–
120–126
[16a]
172–175
[9a]
198–199
[34]
215–217
[9a]
143–144
[9a]
241–242
[35]
188–200
[9a]
87–88
[8a]
1
(
62% yield) and N-acetylated (38% yield) products respectively.
5-
CH
5-
Cl
5-
Br
H
For the intramolecular cyclization required in next the step, a te-
dious work up and purification process is required, which reduces
the yield of the desired oxindoles.
3
H
H
The intermediate
reaction of aniline with chloroacetyl chloride. The preferential for-
mation of -chloroactanilide occurs via N-acylation instead of
a-chloroacetanilide is formed in situ by the
5-F
H
a
5-
NO
5-
CF3
H
H
acylation at the benzene ring, which subsequently undergo intra-
molecular cyclization, resulting in the desired oxindoles. The pres-
ent protocol proceeds smoothly under similar reaction conditions
and in one pot, obviating the need for separation and purification
of a-chloroactanilide in the first step and the necessity of the use
of an environmentally unacceptable catalyst for cyclization in the
2
4g
4h
4i
H
CH
3
90
H
H
H
C
C
2
H
H
5
5
97–
95–96
[36]
123–124
[36]
60–62
[37]
98
second step.
10
4j
6
122–
124
59–
In order to check the utility of this method, we have carried out
the model reaction under conventionally reported conditions [16].
The reaction was completed in two steps, with the requirements of
high temperatures, long reaction times, strongly acidic conditions,
and a tedious work up procedure, which resulted in poor yields.
One the other hand, a yield of 93% was found with short reaction
times in the case of sonication using clay KSF as the catalyst. Thus,
the best current approach for the synthesis of oxindoles based on
this study is an ultrasound-facilitated Stolle process with a simple
work up methodology, which resulted in decreased reaction time
and an increased yield of products. In addition, the clay KSF was
simply recovered by Buchner filtration, washed with methanol,
and air-dried. It was reused for five times to prepare 4a-k without
significant loss of activity.
11
4k
ACH
2
C
6
H
5
61
The structures of all of the synthesized compounds (4a–k) were
established by their spectral characteristics and by comparison
with reported melting points.
4
. Conclusion
We have described an efficient method for the synthesis of
substituted oxindole derivatives with general applicability for a
wide variety of substituted products. The reactions are catalyzed
by clay KSF using ultrasound irradiation. The reaction methodolo-
gies are superior in terms of scope, starting material availability,
brevity, and reproducibility. This new method has the advantages
of higher yields, mild reaction conditions, shorter reaction times,
convenience of procedure and environmental friendliness.
In order to determine the specific effect of ultrasound on this
reaction, we performed the model reaction using clay KSF in the
absence of sonication. It was observed that the reaction was
stopped at the formation of the intermediate
a-chloroactanilide
and could not proceed to the next step of cyclization even after a
long heating time. Thus, ultrasonic irradiation not only facilitated
the reaction to completion, but also significantly increased the
yield of the required oxindole derivatives.
Acknowledgements
When one of the phases is a solid, ultrasonic irradiation has sev-
eral enhancement effects, which are particularly convenient when
the solid acts as catalyst (in this case, the clay–catalyst). Cavitation
generates microinjects of liquid which bombard the solid surface.
This effect causes the exposition of unreacted surfaces on the solid,
increasing the interphase surface which is able to react. Sonication
thus presents beneficial effects with regard to chemical reactivity,
including reaction acceleration, a reduction in the induction peri-
od, and to the ability to enhance catalyst efficiency [33]. Thus, clay
KSF seems to improve its catalytic activity under sonication and to
facilitate intramolecular cyclization in the second step, which is
critical in this reaction, which could otherwise not occur using
classical heating.
After optimization of the conditions, this methodology was
evaluated by using a wide range of anilines to produce the corre-
sponding oxindoles in good to excellent yields (Table 2). In addi-
tion, this method was found to tolerate both electron
withdrawing and electron donating substituents. The last four en-
tries show that the reaction also tolerates significant functionaliza-
tion on the oxindoles by using N-substituted anilines. Both alkyl
and aryl groups can also be accommodated successfully. Overall,
we have found that this process is not only an excellent method
for the synthesis of the corresponding N-substituted oxindoles,
but has a general applicability for a wide variety of anilines.
Financial assistance from the CSIR (01/2248/08/EMR-II) and
UGC (34-349/08/SR) New Delhi are gratefully acknowledged. We
are also thankful to the Central Drug Research Institute (CDRI), Luc-
know, for the elemental and spectral analyses.
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