A Facile Method for the Synthesis of 3-Alkyloxindole

Article abstract of DOI:10.2174/157017812800167420

Benzylamine in combination with acetic acid was identified as a powerful catalyst for the condensation of oxindole with aldehydes, acetone or cyclic ketones. A variety of 3-alkyloxindoles could be readily prepared in 10 mmol scale via the sequential benzylamine acetate catalyzed condensation of oxindoles with aldehydes (or ketones) and conjugate reduction by NaBH₄.

Full text of DOI:10.2174/157017812800167420

Letters in Organic Chemistry, 2012, 9, 225-232
225
A Facile Method for the Synthesis of 3-Alkyloxindole
Tai-Ping Dua, Gang-Guo Zhu*,a and Jian Zhou*,b
aDepartment of Chemistry, Zhejiang Normal University, Jinhua, Zhejiang, P.R. China
bShanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal
University, Shanghai, P.R. China
Received September 07, 2011: Revised October 31, 2011: Accepted December 19, 2011
Abstract: Benzylamine in combination with acetic acid was identified as a powerful catalyst for the condensation of
oxindole with aldehydes, acetone or cyclic ketones. A variety of 3-alkyloxindoles could be readily prepared in 10 mmol
scale via the sequential benzylamine acetate catalyzed condensation of oxindoles with aldehydes (or ketones) and
conjugate reduction by NaBH4.
Keywords: 3-alkenyloxindoles, 3-alkyloxindoles, benzylamine, conjugate reduction, carbonyl compounds, Knoevenagel
condensations.
INTRODUCTION
alcohols catalyzed by RuCl3·xH2O/PPh3 is recently
developed, but limited to unsubstituted oxindoles [13]. 3-
Alkyloxindoles could also be accessed by Cu(II)-mediated
intermolecular coupling reactions, but the use of protecting
groups and a further decarboxyalkylation step were needed
[14].
The direct functionalization of 3-substituted oxindoles
has been established as a fruitful strategy to prepare 3,3-
disubstituted oxindoles [1], which are present in a number of
natural products and medicinal targets [2]. Based on this
strategy, a series of carbon-carbon and carbon-heteroatom
bond forming reactions has been developed, including aldol
[3], Mannich [4], Michael [5], alkylation [6], hydroxylation
[7], fluorination [8], amination [9], and arylation [10],
reactions. Accordingly, a practical method for the synthesis
of 3-substituted oxindoles is highly desirable.
We are interested in the synthesis of 3-alkyloxindoles via
sequential condensation and conjugate reduction [5a], which
is attractive for increasing the diversity of 3-alkyloxindoles
because many oxindoles and carbonyl compounds are easily
available. Furthermore, it is needless to isolate 3-
alkenyloxindoles, obtained from the initial Knoevenagel
condensation of oxindoles and carbonyl compounds, for the
following reduction by NaBH4 [15]. The condensation
reaction is the key step of this sequence, which was typically
run by refluxing the mixture of oxindole 1a, aldehyde (1.1
eq) and piperidine (2.0 eq) in ethanol [5a]. Considering that
recent advances in the iminium catalysis revealed that the
structure of amine catalysts and acid co-catalysts had great
influence on the Knoevenagel condensations [16], we wish
to use acid co-catalyst and optimize the amine-acid
combination to develop a highly efficient condensation of
oxindoles and carbonyl compounds, which is also the most
often-used method for the synthesis of 3-alkenyloxindoles
that are not only useful in building blocks [1] but also
privileged framework in many bioactive natural products and
pharmaceutically active compounds [17].
Because of our interests in the catalytic asymmetric
synthesis of 3,3-disubstituted oxindoles for biological
evaluation [11], we needed a simple and efficient method to
prepare unprotected 3-substituted oxindoles in gram scale
with sufficient diversity. After evaluating the literature
methods, we found that unprotected 3-aryloxindoles could be
readily prepared according to the reported procedure [10a],
but it is necessary to improve the synthesis of unprotected 3-
alkyloxindoles.
For example, the alkylation of oxindole 1 using alkyl
bromide was significantly influenced by the electronic effect
of the substituents on the isatins. While the alkylation of 5-
methoxyoxindole 1f using 1-bromo-3-methyl-2-butene, after
deprotonation by n-BuLi, was reported to give the desired
product in 79% yield [12], we found the alkylation of
unsubstituted oxindole 1a by the same procedure in a
mixture of 3-prenyl or 3,3-diprenyloxindoles. After several
trials, the desired product 4s was still obtained in less than
40% yield after intensive column chromatography
purification. The mono-alkylation of oxindole 1a using
RESULTS AND DISCUSSION
The reaction of oxindole 1a and acetone 2a was chosen
for condition optimization (Scheme 1). The corresponding
product 3a could be obtained by Trost’s modified procedure
using acetone as the solvent in the presence of 10 equivs of
con.HCl [18]. But this procedure is not suitable for
expensive ketones and the use of excess acid should be
avoided. We began the study of solvent effects by running
the reaction at 60 oC using three equivs of acetone relative to
oxindole 1a, in the presence of 30 mol% of piperidine and
*Address correspondence to these authors at the Department of Chemistry,
Zhejiang Normal University, Jinhua, Zhejiang, P.R. China Tel: +86-579-
82283702; Fax: +86-579-82282610; E-mail: gangguo@zjnu.cn
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, Shanghai, P.R.
China; Tel: +86-21-62234560; Fax: +86-21-62234560;
E-mail: jzhou@chem.ecnu.edu.cn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

226 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Du et al.
O
Amine (30 mol%)
Acid (30 mol%)
Solvent, 50 oC
O
O
N
H
N
H
1a (1.0 eq)
2a (3.0 eq)
Scheme 1. The reaction of oxindole 1a and acetone 2a for condition optimization.
Table 1. The Effect of Amine, Acid and Solvent on the Condensation of Oxindole with Acetone
Entrya
Amine
Acid
Solvent
Time (h)
Con. b (%)
1
2
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
PMP-NH2
Morpholine
Piperidine
BnNH2
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
TfOH
THF
MeOH
Toluene
EtOAc
i-PrOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
24
24
24
24
24
16
16
16
16
16
8.5
8.5
8.5
1
70
79
3
85
4
94
5
95
6
97
7
22
8
TFA
71
9
PhCO2H
o-NO2PhCO2H
HOAc
HOAc
HOAc
HOAc
-
85
10
11
12
13
14
15
96
67
85
89
>99 (95)c
BnNH2
3
95
aRun on a 0.2 mmol scale. bDetermined by 1H NMR analysis of the crude mixtures; cIsolated yield.
acetic acid. Ethanol turned out to be the most suitable
solvent, and almost full conversion of 1a could be realized
within 16 hours (Table 1, Entries 1-6). Next, we examined
the effect of the acid co-catalysts. The acid indeed had great
influence on the reaction rate (Table 1, Entries 6-10), but it is
hard to draw a conclusion on the relationship between the
pKa value of the acid co-catalyst and reaction rate. Acetic
acid was chosen as the ideal co-catalyst for its cheapness and
effectiveness. Finally, several typical amine catalysts were
examined (Table 1, Entries 11-14), and the benzyl amine was
found to be the most effective, which in combination with
acetic acid could promote the reaction to almost full
conversion within one hour, affording the product in 95%
isolated yield (Table 1, Entry 14). To confirm that the
addition of acid co-catalyst could accelerate the condensation
reaction, we also tried the use of only 30 mol% of benzyl
amine as catalyst, it turned out that the reaction indeed
proceeded much slower than that catalyzed by 30 mol% of
benzylamine in combination of 30 mol% of acetic acid
(Table 1, Entries 15 vs 14).
With the above results, we further optimized the usage of
carbonyl compounds and catalyst loading in the reaction of
oxindole 1a and cyclopentanone 2b which has higher boiling
point than acetone (Scheme 2). It was found that when the
usage of cyclopentanone was decreased from 3.0 eq to 1.1 eq
in the presence of 30 mol% of BnNH2/HOAc the reaction
was finished within 23 hours (Table 2, Entries 1-3). The
catalyst loading could be decreased to 10 mol%, affording
93% conversion after 81 hours (Table 2, Entries 3-5). If
further lowering the catalyst amount to 5 mol%, the reaction
time was very long (Table 2, Entry 6).
O
BnNH2 (y mol%)
HOAc (z mol%)
O
O
N
H
EtOH, 60 oC
N
H
1a (1.0 eq)
2b (x eq)
3b
Scheme 2. The condensation of oxindole with cyclopentanone.

A Facile Method for the Synthesis of 3-Alkyloxindole
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
227
Table 2. The Optimization of the usage of Carbonyl Compounds and Catalyst loading in the Reaction of Oxindole and
Cyclopentanone
Entrya
2b (x equiv)
BnNH2 (y mol%)
HOAc (z mol%)
Time (h)
Con. (%) b
1
2
3
4
5
6
3.0
2.0
1.1
1.1
1.1
1.1
30
30
30
20
10
5
30
30
30
20
10
5
2
94
>95
92
5.5
23
33
93
81
93
120
83
aRun on a 0.2 mmol scale. bDetermined by 1H NMR analysis of the crude mixtures.
Based on the above results, a sequential condensation-
conjugate reduction procedure was developed for the
synthesis of 3-alkyloxindoles. The best condition for the
condensation step was to run the reaction in ethanol at 60 oC
in the presence of 10 mol% of benzyl amine in combination
with acetic acid. Of course, if one wishes the condensation to
finish as soon as possible, the use of more catalyst was
recommended. To examine the practicability of this method,
all the reactions were run on 10.0 mmol scale using 10 mol%
of catalyst for the initial condensation. It should be noted
that after the initial condensation, the removal of
benzylamine acetate by extraction was necessary for a clean
conjugate reduction using NaBH4 (1.1 eq) as the reducing
reagent.
substituted oxindole with acetone. The desired products 4n-r
could be obtained in high to excellent yield (Table 3, Entries
14-18).
We further examined whether ꢀ,ꢁ-unsaturated aldehydes
could be used for this sequential reaction to introduce
substituted allyl group at the C3 position of oxindole. When
3-methylbut-2-enal 2n was used, both the condensation and
conjugate reduction worked well to afford the desired
product 4s in 58% yield, and no over reduced product was
observed. However, in the case of cinnamaldehyde 2o,
although the condensation step worked well, both the desired
product 4t and over reduced product 5 were obtained. This
result is not unexpected and product 5 was obtained because
the 1,6-reduction of the intermediate 3-alkenyloxindole took
place first, followed by one more reduction. We tried to
improve the ratio of 4t and 5 by lowering the temperature for
the conjugate reduction and adding NaBH4 in small portions.
The best result was that products 4t and 5 were obtained in a
ratio of 7:1.
By this sequential procedure, a series of carbonyl
compounds, including ketones and aldehydes, could readily
react with oxindoles to afford the desired 3-alkyloxindoles
(Scheme 3). Since the 3-cycloheptyl was found to be
important for the bioactivity of 3,3-disubstituted oxindoles
[2d], acetone and several cyclic ketones were first tried, and
the corresponding products could be obtained in high to
excellent yield (Table 3, Entries 1-4). Diphenyl ketone was
also tried, but the condensation proceeded very slowly. Even
using 100 mol% of benzyl amine with acetic acid as the
CONCLUSION
In conclusion, benzylamine in combination with acetic
acid was identified as a powerful catalyst for the synthesis of
3-alkenyloxindoles, which is also very useful in organic
chemistry. An efficient procedure for the synthesis of 3-
alkyloxindoles via the sequential condensation of oxindoles
with aldehydes (or ketones) and conjugate reduction by
NaBH4 was then developed, which could be run on a 10.0
mmol scale without the isolation of the intermediate 3-
alkenyloxindoles, operationally very simple.
o
catalyst at 100 C, the condensation did not finish within ten
days (Table 3, Entry 5). After reduction, the desired product
3e was obtained in only 32% yield. A variety of aldehydes,
including aromatic and aliphatic aldehydes, afforded the
desired 3-alkyloxindoles 4f-m in good to excellent yield
(Table 3, Entries 6-13). It should be noted that no aldol
reaction took place when aliphatic aldehydes such as 2k and
2l were used.
For example, no self-aldolization of aldehyde 2l took
place by H NMR analysis of the crude mixture from the
EXPERIMENTAL
1
Reactions were monitored by thin layer chromatography
using UV light to visualize the course of reaction.
Purification of reaction products was carried out by flash
chromatography on silica gel. Chemical yields refer to pure
condensation of aldehyde 2l with oxindole 1a. The
substituent effect on the oxindole framework was also
checked, and whether electron-withdrawing or electron-
donating groups had no obvious effect on the reaction of
R3
R4
R1
O
1) BnNH2/HOAc (10 mol%)
R1
O
EtOH, 60 oC
O
R3
R4
NH
2) NaBH4 (1.1 eq)
NH
R2
1 (1.0 eq)
R2
2 (1.1 eq)
4
Scheme 3. The synthesis of 3-substitued oxindoles.

228 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Du et al.
Table 3. The Synthesis of 3-Substituted Oxindole Derivatives Catalyzed by Benzylamine and Acetic Acid
Entry a
1
2
4
Yield b (%)
1
2
1a R1 = H, R2 = H
1b R1 = H, R2 = H
1c R1 = H, R2 = H
1d R1 = H, R2 = H
1e R1 = H, R2 = H
1f R1 = H, R2 = H
1g R1 = H, R2 = H
1h R1 = H, R2 = H
1i R1 = H, R2 = H
1j R1 = H, R2 = H
1k R1 = H, R2 = H
1l R1 = H, R2 = H
1m R1 = H, R2 = H
1n R1 = F, R2 = H
1o R1 = Cl, R2 = H
1p R1 = Br, R2 = H
1q R1 = Me, R2 = Me
1r R1 = OMe, R2 = H
2a R3 = Me, R4 = Me
2b R3, R4 = (CH2)4
4a
4b
4c
4d
4e
4f
95
88
77
83
32c
91
95
66
90
98
90
86
90
91
83
82
86
95
3
2c R3, R4 = (CH2)5
4
2d R3, R4 = (CH2)6
5
2e R3 = Ph, R4 = Ph
2f R3 = H, R4 = Ph
6
7
2g R3 = H, R4 = o-ClC6H4
2h R3 = H, R4 = m-ClC6H4
2i R3 = H, R4 = p-ClC6H4
2j R3 = H, R4 = p-MeOC6H4
2k R3 = H, R4 = n-Bu
2l R3 = H, R4 = i-Bu
2m R3 = H, R4 = i-Pentyl
2a R3 = Me, R4 = Me
2a R3 = Me, R4 = Me
2a R3 = Me, R4 = Me
2a R3 = Me, R4 = Me
2a R3 = Me, R4 = Me
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
4j
4k
4l
4m
4n
4o
4p
4q
4r
aRun on a 10.0 mmol scale. bIsolated yield. cThe condensation was run at 100 oC for 10 d using 100 mol% of catalyst.
isolated substances. The low-resolution mass spectra were
recorded on Agilent Technologies 5970C, and the high-
resolution mass spectra were recorded on Waters GCT
over anhydrous CaSO4 and stored over MS 4Å. All
aldehydes and ketones were commercially available and
freshly distilled before use. Benzylamine and acetic acid
were commercially available and freshly distilled before use.
All oxindoles were commercially available or prepared
according to literatures [19].
1
Premier. H and 13C NMR spectra were obtained using a
Bruker DPX-400 spectrometer. Chemical shifts are reported
in ppm from tetramethylsilane with the solvent resonance as
the internal standard. The following abbreviations were used
to designate chemical shift multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, h = heptet, m = multiplet, br
= broad.
General Procedure for the Synthesis of 3-alkyloxindoles
4a-r
To a 100 mL screw-capped pressure tube was added
oxindole 1 (10.0 mmol), 20.0 mL of absolute ethanol and
Absolute ethanol was prepared by distillation from
magnesium prior to use. Anhydrous acetone was distilled
Me
O
O
+
a, b
O
N
H
Me
H
58%
N
H
4s
2n (1.1 eq)
1a (1.0 eq)
Ph
Ph
O
O
+
a, b
O
+
O
Ph
H
N
H
N
H
N
H
4t 63%
5 9%
2o (1.1 eq)
1a (1.0 eq)
Scheme 4. The reaction of oxindole with ꢀ,ꢁ-unsaturated aldehydes.
Reagents and conditions: (a) BnNH2 (10 mol%), HOAc (10 mol%), 60 oC; (b) NaBH4 (1.0 eq.), 0 oC-r.t.

A Facile Method for the Synthesis of 3-Alkyloxindole
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
229
carbonyl compound 2 (11.0 mmol), followed by the addition
of benzylamine (1.0 mmol) and acetic acid (1.0 mmol). The
tube was sealed and was heated to 60 °C till almost full
conversion of 1 (monitored by a thin-layer chromatography,
TLC). After the solvent was removed, the resulting crude
mixture was dissolved in 20 mL of CH2Cl2 and washed by
20 mL of water to remove benzylamine acetate. The aqueous
phase was extracted with CH2Cl2 (20 mL), and the organic
phase was combined and concentrated. The crude mixture
was dissolved in 30 mL of EtOH, and NaBH4 (10.0 mmol)
3-Benzhydrylindolin-2-one (4e)
o
Yield 32%; yellow solid; Mp: 187-189 C; IR (KBr):
3029, 1703, 1615, 1492, 1469, 1335, 1233, 754, 698, 671. 1H
NMR (400 MHz, CDCl3): ꢀ 8.62 (s, br, 1H), 7.32-7.24 (m,
5H) , 7.17-7.13 (m, 4H), 7.04-7.03 (m, 2H), 6.86-6.82 (m,
1H), 6.74-6.72 (m, 1H), 6.66-6.64 (m, 1H), 4.92 (d, J = 4.0
Hz, 1H), 4.32 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): ꢀ 178.4, 141.8, 141.4, 139.6, 129.4, 128.5, 128.3,
128.1, 128.1, 127.9, 126.9, 126.6, 125.3, 121.9, 109.7, 51.5,
50.7; MS (EI): 299 (M+, 1), 167 (100), 165 (44), 152 (22), 77
(17), 168 (16), 166 (14), 132 (13), 51 (13); HRMS (EI):
Exact mass calcd for C21H17NO: 299.1310, Found: 299.1313.
o
was added at 0 C in one portion. The resulting mixture was
naturally warmed to room temperature and vigorously stirred
till almost full conversion of the intermediate 3-
alkenyloxindoles (monitored by TLC). The reaction is
quenched by addition of 20 mL of saturated aq. NH4Cl and
then extracted with CH2Cl2. The organic phase was dried by
anhydrous Na2SO4, filtered and concentrated in vacuo and
the residue was purified by flash chromatography over silica
gel, using ethyl acetate in CH2Cl2 (from 0% to 5%) as eluent
to afford the title compounds.
3-benzylindolin-2-one (4f) [15]
1
Yield 91%; yellow solid; H NMR (400 MHz, CDCl3): ꢀ
8.51 (s, br, 1H), 7.25-7.14 (m, 6H), 6.91-6.83 (m, 2H), 6.75-
6.73 (m, 1H), 3.76-3.74 (m, 1H), 3.52-3.48 (m, 1H), 2.97-
2.91 (m, 1H); 13C NMR (100 MHz, CDCl3): ꢀ 179.6, 141.4,
137.8, 129.4, 129.0, 128.3, 127.9, 126.7, 124.8, 122.0, 109.7,
47.5, 36.6; MS (EI): 223 (M+, 100), 146 (98), 91 (95), 132
(90), 104 (86), 51 (46), 89 (43).
The spectra data of the compounds 4a-r are as follows.
3-isopropylindolin-2-one (4a) [20]
3-(2-chlorobenzyl)indolin-2-one (4g) [13]
1
Yield 95%; white solid: H NMR (400 MHz, CDCl3): ꢀ
Yield 95%; yellow solid; 1H NMR (400 MHz, CDCl3): ꢀ
9.43 (s, br, 1H), 7.41-7.40 (m, 1H), 7.22-7.16 (m, 4H), 6.94-
6.84 (m, 2H), 6.61-6.59 (m, 1H), 3.91 (m, 1H), 3.66-3.62 (m,
1H), 2.99-2.93 (m, 1H); 13C NMR (100 MHz, CDCl3): ꢀ
180.0, 141.5, 136.0, 134.4, 131.8, 129.7, 128.8, 128.3, 128.0,
126.6, 124.9, 121.9, 109.9, 45.3, 34.8; MS (EI): 257 (M+,
11), 222 (100), 125 (87), 132 (76), 127 (28), 77 (17), 223
(17), 104 (13), 89 (12).
8.44 (s, br, 1H), 7.25-7.20 (m, 2H), 7.04-7.00 (m, 1H), 6.90-
6.88 (m, 1H), 3.41 (m, 1H), 2.53-2.50 (m, 1H), 1.14-1.12 (d,
J = 7.2 Hz, 3H ), 0.92 (d, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3): ꢀ 180.7, 142.3, 128.3, 127.8, 124.5, 122.0,
109.8, 52.3, 30.7, 19.9, 17.9; MS (EI): 175 (M+, 52), 133
(100), 104 (93), 132 (68), 77 (63), 105 (62), 51 (30), 43 (29),
78 (27).
3-(3-Chlorobenzyl)indolin-2-one (4h)
3-cyclopentylindolin-2-one (4b) [21]
o
Yield 88%; pale yellow solid; 1H NMR (400 MHz,
CDCl3): ꢀ 8.70 (s, br, 1H), 7.28-7.26 (m, 1H), 7.22-7.19 (m,
1H), 7.02-6.98 (m, 1H), 6.90-6.88 (m, 1H), 3.53 (d, J = 4.8
Hz, 1H), 2.48-2.47 (m, 1H), 1.93-1.92 (m, 1H), 1.75 (m,
1H), 1.64-1.53 (m, 5H), 1.37-1.26 (m, 1H); 13C NMR (100
MHz, CDCl3): ꢀ 180.1, 141.8, 129.2, 127.7, 124.7, 122.0,
109.5, 49.1, 41.9, 29.9, 28.3, 25.1, 25.0; MS (EI): 201 (M+,
98), 133 (100), 77 (96), 104 (95), 41 (94), 132 (93), 135
(85), 130 (80), 69 (64).
Yield 66%; pink solid; Mp: 123-124 C; IR (KBr): 2922,
1
1703, 1616, 1596, 1468, 1230, 1102, 753, 688, 664; H
NMR (400 MHz, CDCl3): ꢀ 8.68 (s, br, 1H), 7.26-7.18 (m,
4H), 7.06-7.05 (m, 1H), 6.95-6.92 (m, 1H), 6.86-6.79 (m,
2H), 3.74 (m, 1H), 3.46-3.42 (m, 1H), 2.98-2.93 (m, 1H); 13C
NMR (100 MHz, CDCl3): ꢀ 179.2, 141.4, 139.8, 134.1,
129.5, 129.5, 128.5, 128.2, 127.6, 126.9, 124.7, 122.2, 109.8,
47.2, 36.2. MS (EI): 257 (M+, 16), 132 (100), 125 (73), 77
(59), 43 (43), 41 (36), 89 (36), 91 (30), 104 (30); HRMS
(EI): Exact mass calcd for C15H1235ClNO: 257.0607, Found:
257.0609.
3-cyclohexylindolin-2-one (4c) [21]
Yield 77%; pale yellow solid; 1H NMR (400 MHz,
CDCl3): ꢀ 8.10 (s, br, 1H), 7.26-7.18 (m, 2H), 7.03-7.00 (m,
1H), 6.93-6.91 (m, 1H), 3.38 (m, 1H), 2.17-2.11 (m, 1H),
1.78-1.17 (m, 10H); 13C NMR (100 MHz, CDCl3): ꢀ 180.4,
142.1, 128.6, 127.6, 124.6, 121.9, 109.6, 52.1, 40.8, 30.3,
28.3, 26.6, 26.2, 26.0; MS (EI): 215 (M+, 100), 55 (99), 133
(98), 77 (93), 104 (92), 105 (91), 134 (90), 132 (90), 41 (89).
3-(4-chlorobenzyl)indolin-2-one (4i) [13]
Yield 90%; yellow solid; 1H NMR (400 MHz, CDCl3): ꢀ
9.67 (s, br, 1H), 7.16-7.14 (m, 3H), 7.06-7.05 (m, 2H), 6.93-
6.79 (m, 3H), 3.70 (m, 1H), 3.41-3.37 (m, 1H), 2.97-2.92 (m,
1H); 13C NMR (100 MHz, CDCl3): ꢀ 179.8, 141.6, 136.0,
132.3, 130.6, 128.5, 128.3, 128.0, 124.4, 122.0, 109.9, 47.3,
35.6; MS (EI): 257 (M+, 100), 125 (98), 128 (96), 126 (96),
132 (96), 89 (95), 77 (93), 104 (87), 146 (80).
3-cycloheptylindolin-2-one (4d) [15]
1
Yield 83%; orange solid; H NMR (400 MHz, CDCl3): ꢀ
3-(4-methoxybenzyl)indolin-2-one (4j) [22]
9.20 (s, br, 1H), 7.29-7.27 (m, 1H) , 7.22-7.19 (m, 1H), 7.02-
6.99 (m, 1H), 6.91 (m, 1H), 3.45 (m, 1H), 2.32 (m, 1H),
1.77-1.26 (m, 12H); 13C NMR (100 MHz, CDCl3): ꢀ 180.5,
142.1, 128.8, 127.7, 124.4, 122.0, 109.7, 53.2, 42.2, 32.6,
30.3, 27.7, 27.4, 27.3, 26.9; MS (EI): 229 (M+, 92), 133
(100), 104 (92), 132 (81), 77 (62), 105 (60), 41 (50).
Yield 98%; pale yellow solid; 1H NMR (400 MHz,
CDCl3): ꢀ 9.55 (s, br, 1H), 7.16-7.12 (m, 1H), 7.07-7.05 (m,
2H), 6.90-6.84 (m, 2H), 6.76-6.74 (m, 3H), 3.72-3.69 (m,
4H), 3.43-3.40 (m, 1H), 2.91-2.86 (m, 1H); 13C NMR (100
MHz, CDCl3): ꢀ 180.1, 158.2, 141.6, 130.3, 129.6, 129.0,
127.8, 124.6, 121.8, 113.6, 109.8, 55.0, 47.7, 35.6; MS (EI):

230 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Du et al.
253 (M+, 92), 121 (100), 122 (99), 77 (96), 78 (87), 91 (73),
123 (51), 51 (36), 132 (27).
2H), 6.84-6.81 (m, 1H), 3.41 (m, 1H), 2.49-2.48 (m, 1H),
1.11 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): ꢀ 180.1, 141.2, 130.6, 130.4, 127.5,
114.6, 111.2, 52.3, 30.6, 19.6, 17.9; MS (EI): 253 (M+, 27),
43 (100), 213 (93), 211 (93), 41 (85), 76 (36), 51 (35), 50
(30), 103 (30); Exact mass calcd for C11H1279BrNO:
253.0102, Found: 253.0101.
3-butylindolin-2-one (4k) [23]
Yield 90%; yellow solid; 1H NMR (400 MHz, CDCl3): ꢀ
9.82 (s, br, 1H), 7.25-7.17 (m, 2H), 7.03-6.93 (m, 2H), 3.48
(m, 1H), 2.00-1.96 (m, 2H), 1.36-1.26 (m, 4H), 0.88-0.86
(m, 3H); 13C NMR (100 MHz, CDCl3): ꢀ 181.4, 141.9,
129.9, 127.6, 123.9, 122.0, 109.8, 46.2, 30.2, 27.8, 22.6,
13.7; MS (EI): 189 (M+, 88), 146 (100), 133 (98), 134 (96),
132 (93), 104 (83), 77 (77), 117 (44), 105 (38).
3-Isopropyl-5,7-dimethylindolin-2-one (4q)
Yield 86%; pale yellow solid; Mp: 186-187 oC; IR (KBr):
3162, 2924, 1695, 1623, 1477, 1220, 858, 757, 720, 667; 1H
NMR (400 MHz, CDCl3): ꢀ 7.76 (s, br, 1H), 6.91 (s, 1H),
6.84 (s, 1H), 3.36 (m, 1H), 2.47-2.46 (m, 1H), 2.30 (s, 3H),
2.21 (s, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3): ꢀ 181.0, 138.7, 131.2,
129.5, 128.0, 122.6, 118.8, 52.6, 30.6, 21.1, 19.8, 17.9, 16.4;
MS (EI): 203 (M+, 36), 162 (100), 160 (54), 41 (40), 203
(36), 43 (32), 77 (16), 132 (15), 162 (12); Exact mass calcd
for C13H17NO: 203.1310, Found: 203.1312.
3-Isobutylindolin-2-one (4l) [24]
1
Yield 86%; reddish brown oil; H NMR (400 MHz,
CDCl3): ꢀ 8.79 (s, br, 1H), 7.26-7.19 (m, 2H), 7.03-7.00 (m,
1H), 6.92-6.91 (m, 1H), 3.48 (t, J = 6.8 Hz, 1H), 2.08-2.02
(m, 1H), 1.91-1.84 (m, 1H), 1.75-1.66 (m, 1H), 1.01-0.96
(m, 6H);13C NMR (100 MHz, CDCl3): ꢀ 181.0, 141.4, 130.3,
127.7, 124.4, 122.1, 109.7, 44.3, 40.0, 25.3, 22.9, 22.1; MS
(EI): 189 (M+, 24), 133 (100), 146 (32), 132 (26), 134 (25),
104 (21), 77 (20), 118 (12), 128 (12).
3-Isopropyl-5-methoxyindolin-2-one (4r)
Yield 95%; pale yellow solid; Mp: 143-144 oC; IR (KBr):
3173, 2926, 1689, 1607, 1489, 1469, 858, 763, 716, 667; 1H
NMR (400 MHz, CDCl3): ꢀ 8.69 (s, br, 1H), 6.87 (s, 1H),
6.81-6.73 (m, 2H), 3.79 (s, 3H), 3.38 (m, 1H), 2.50-2.48 (m,
1H), 1.11 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3): ꢀ 179.8, 155.4, 135.6, 129.8,
112.2, 112.0, 109.7, 55.8, 52.6, 30.7, 19.7, 18.0; MS (EI):
205 (M+, 34), 41 (100), 43 (77), 55 (38), 45 (37), 205 (34),
57 (31), 119 (29), 77 (27); Exact mass calcd for C12H15NO2:
205.1103, Found: 205.1101.
3-isopentylindolin-2-one (4m) [25]
Yield 90%; yellow solid; 1H NMR (400 MHz, CDCl3): ꢀ
8.91 (s, br, 1H), 7.26-7.19 (m, 2H), 7.05-7.01 (m, 1H), 6.92-
6.90 (m, 1H), 3.47 (m, 1H), 2.04-1.90 (m, 2H), 1.58-1.52 (m,
1H), 1.33-1.16 (m, 2H), 0.88-0.86 (m, 6H); 13C NMR (100
MHz, CDCl3): ꢀ 180.7, 141.6, 129.9, 127.7, 124.1, 122.2,
109.6, 46.2, 34.6, 28.4, 28.1, 22.4; MS (EI): 203 (M+, 100),
133 (99), 146 (98), 147 (96), 132 (95), 104 (92), 77 (87), 117
(64), 128 (59).
General Procedure for the Synthesis of 3-alkyloxindoles
4s-t
5-Fluoro-3-isopropylindolin-2-one (4n)
Yield 91%; pale yellow solid; Mp: 119-120 oC; IR (KBr):
3047, 1698, 1631, 1608, 1483, 1468, 1205, 819, 774, 653; 1H
NMR (400 MHz, CDCl3): ꢀ 10.1 (s, br, 1H), 7.01-6.99 (m,
1H), 6.94-6.89 (m, 2H), 3.41 (m, 1H), 2.51-2.50 (m, 1H),
1.13 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): ꢀ 180.6, 159.9, 157.5, 138.2, 138.2,
129.9, 129.8, 114.1, 113.8, 112.4, 112.2, 110.2, 110.1, 52.6,
30.6, 19.6, 17.7; MS (EI): 193 (M+, 18), 151(100), 41 (84),
43 (71), 122 (50), 150 (47), 95 (36), 75 (33), 51 (19); HRMS
(EI): Exact mass calcd for C11H1219FNO: 193.0903, Found:
193.0910.
To a 5 mL vial was added oxindole 1a (1.0 mmol), 1.0
mL of absolute ethanol and carbonyl compound 2 (1.0
mmol), followed by the addition of benzylamine (0.1 mmol)
and acetic acid (0.1 mmol). The tube was sealed and was
heated to 60 °C till almost full conversion of 1a (monitored
by TLC). After the solvent was removed, the resulting crude
mixture was dissolved in 5 mL of CH2Cl2 and washed by 5
mL of water to remove benzylamine acetate. The aqueous
phase was extracted with CH2Cl2 (5 mL), and the organic
phase was combined and concentrated. The crude mixture
was dissolved in 5 mL of EtOH, and NaBH4 (1.0 mmol) was
5-Chloro-3-isopropylindolin-2-one (4o)
o
added at -10 C in small portions. The resulting mixture was
Yield 83%; pale yellow solid; Mp: 164-165 oC; IR (KBr):
3106, 1704, 1671, 1622, 1477, 1240, 817, 780, 738, 690; 1H
NMR (400 MHz, CDCl3): ꢀ 9.83 (s, br, 1H), 7.23-7.18 (m,
2H), 6.87-6.85 (m, 1H), 3.41 (m, 1H), 2.50-2.49 (m, 1H),
1.12 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): ꢀ 180.3, 140.7, 130.0, 127.7, 127.3,
124.8, 110.7, 52.4, 30.6, 19.7, 17.8; MS (EI): 209 (M+, 23),
167 (100), 43 (58), 41 (47), 169 (29), 209 (23), 166 (23), 75
(20), 138 (20); Exact mass calcd for C11H1235ClNO:
209.0607, Found: 209.0613.
naturally warmed to room temperature and vigorously stirred
till almost full conversion of the intermediate 3-
alkenyloxindoles (monitored by TLC). The reaction is
quenched by addition of 5 mL of saturated aq. NH4Cl and
then extracted with CH2Cl2. The organic phase was dried by
anhydrous Na2SO4, filtered and concentrated in vacuo and
the residue was purified by flash chromatography over silica
gel, using ethyl acetate in CH2Cl2 (from 0% to 5%) as eluent
to afford the title compounds.
5-Bromo-3-isopropylindolin-2-one (4p)
Data for Compounds 4s-t
Yield 82%; pale yellow solid; Mp: 163-164 oC; IR (KBr):
3107, 1702, 1620, 1476, 1321, 1239, 816, 775, 682, 644; 1H
NMR (400 MHz, CDCl3): ꢀ 9.98 (s, br, 1H), 7.36-7.32 (m,
3-(3-Methylbut-2-enyl)indolin-2-one (4s) [26]
1
Yield 58%; pale yellow solid: H NMR (400 MHz,
CDCl3): ꢀ 8.82 (s, br, 1H), 7.23-7.18 (m, 2H), 7.01-6.97 (m,

A Facile Method for the Synthesis of 3-Alkyloxindole
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
231
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1H), 6.90-6.88 (m, 1H), 5.14 (s, 1H), 3.47-3.46 (m, 1H),
2.75-2.71 (m, 1H), 2.62-2.54 (m, 1H), 1.67 (s, 3H), 1.58 (s,
3H); 13C NMR (100 MHz, CDCl3): ꢀ 180.2, 141.6, 134.7,
129.8, 127.8, 124.3, 122.1, 119.6, 46.2, 29.3, 25.7, 18.0; MS
(EI): 201 (M+, 8), 133 (100), 69 (29), 41 (24), 104 (14), 134
(12), 77 (11), 132 (8), 105 (7).
[4]
3-Cinnamylindolin-2-one (4t)
Yield 63%; pale yellow solid; Mp: 148-149 oC; IR (KBr):
3027, 2844, 1699, 1619, 1469, 1232, 782, 746, 693, 668; 1H
NMR (400 MHz, CDCl3): ꢀ 8.66 (s, br, 1H), 7.28-7.21 (m,
7H), 7.02-6.99 (m, 1H), 6.91-6.89 (m, 1H), 6.49-6.45 (m,
1H), 6.21-6.15 (m, 1H), 3.60 (m, 1H), 3.03-2.99 (m, 1H),
2.74-2.67 (m, 1H); 13C NMR (100 MHz, CDCl3): ꢀ 179.5,
141.4, 137.1, 133.2, 129.1, 128.5, 128.0, 127.3, 126.2, 125.5,
124.5, 122.3, 109.7, 46.0, 34.2; MS (EI): 249 (M+, 3), 115
(100), 117 (76), 91 (64), 77 (60), 132 (60), 104 (40), 51 (39)
; Exact mass calcd for C17H15NO: 249.1154, Found:
249.1156.
[5]
ACKNOWLEDGMENTS
The financial support from the National Natural Science
Foundation of China (20902084, 20902025), Shanghai
Pujiang Program (10PJ1403100), Specialized Research Fund
for the Doctoral Program of Higher Education
(20090076120007), the Fundamental Research Funds for the
Central Universities (East China Normal University 11043),
and 973 Program (2011CB808600) is highly appreciated.
[6]
(a) Trost, B. M.; Frederiksen, M. U. Palladium-catalyzed
asymmetric allylation of prochiral nucleophiles: Synthesis of 3-
allyl-3-aryl oxindoles. Angew. Chem. Int. Ed., 2005, 44, 308-312.
(b) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Organocatalytic
asymmetric allylic alkylation of oxindoles with Morita–Baylis–
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Ohmatsu, K.; Kiyokawa, M.; Ooi, T. Chiral 1,2,3-triazoliums as
new cationic organic catalysts with anion-recognition ability:
Application to asymmetric alkylation of oxindoles. J. Am. Chem.
Soc., 2011, 133, 1307-1309.
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
CONFLICT OF INTEREST
Declared none.
[7]
(a) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. Lewis acid-catalyzed enantioselective hydroxylation
reactions of oxindoles and ꢁ-keto esters using DBFOX ligand. J.
Am. Chem. Soc., 2006, 128, 16488-16489. (b) Sano, D.; Nagata, K.;
Itoh, T. Catalytic asymmetric hydroxylation of oxindoles by
molecular oxygen using a phase-transfer catalyst. Org. Lett., 2008,
10, 1593-1595. (c) Bui, T.; Candeias, N.R.; Barbas III, C.F.
Dimeric quinidine-catalyzed enantioselective aminooxygenation of
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