A novel acid-catalyzed C5-alkylation of oxindoles using alcohols

Article abstract of DOI:10.1039/c0ob01144d

A novel C5-alkylation of oxindoles using alcohols as alkylating agents under acid catalysis is described for the first time. The reactions of various benzylic, allylic and propargylic alcohols are studied to obtain the corresponding 5-substituted oxindoles in good yields.

Full text of DOI:10.1039/c0ob01144d

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 3940
www.rsc.org/obc
PAPER
A novel acid-catalyzed C5-alkylation of oxindoles using alcohols†
Chada Raji Reddy,*a Enukonda Jithender,a Gaddam Krishna,a Gunreddy Venkat Reddyb and
Bharatam Jagadeeshb
Received 9th December 2010, Accepted 7th March 2011
DOI: 10.1039/c0ob01144d
A novel C5-alkylation of oxindoles using alcohols as alkylating agents under acid catalysis is described
for the first time. The reactions of various benzylic, allylic and propargylic alcohols are studied to
obtain the corresponding 5-substituted oxindoles in good yields.
Introduction
In recent years, alcohols have been gaining prominence as alky-
lating agents towards green and atom-economic practices since
they generate only water as a by-product in the reaction.1–4 The
availability and ease of preparation also makes them an attractive
source. Amongst these, benzylic, allylic and propargylic alcohols
have received significant attention from synthetic organic chemists
due to the stability of their carbocations. The utility of these
alcohols as alkylating agents in several C–C bond,2 C–N bond3
and C–O bond4 formations has been demonstrated under different
reaction conditions. We also have successfully established the
efficacy of alcohols for the alkylation of sulfonamides, 4-hydroxy
coumarins, hydrazones and 1,3-dicarbonyl compounds under acid
catalysis.5 As a part of the ongoing program on the use of alcohols
as alkylating agents in our laboratory, we found it interesting to
Fig. 1 Structure of representative oxindole-based drugs.
study the alkylation of oxindoles. Recently, the C3-alkylation of
N-methyl oxindole with alcohols in the presence of metal catalysts
in a basic medium, has been reported.6
substitution of oxindole to generate new molecular entities is very
important. The present work focuses in this direction and reports
the first acid-catalyzed alkylation of oxindoles with alcohols.
Oxindole derivatives are one of the important classes of
heterocyclic compounds and known to possess a wide range of
biological activities including anti-inflammatory, anti-angiogenic,
anti-cancer, tyrosine kinase A inhibition and cyclooxygenase
inhibition.7 Many of these compounds have generated substantial
pharmaceutical interest.8 For instance, Sunitinib (SU11248) as
anti-cancer drug, Tenidap for the treatment of arthritis, Ziprasi-
done for Schizophrenia and Ropinirole, a dopamine agonist, for
Parkinson’s disease, are being used (Fig. 1). Several research
groups have aimed towards identification of more potent oxin-
dole derivatives with variation of the substitution on specified
positions.9 Therefore, the development of new methods for the
Results and discussion
As an initial experiment, oxindole (1a) was treated with 4-
methoxybenzyl alcohol (2a) under the influence of pTSA (5 mol%)
in nitromethane at room temperature. However, it was observed
that under these conditions the reaction does not take place. On
the◦other hand, when the reaction temperature is increased to
90 C, the starting material completely disappears on TLC after
7 h. The spectral data of the isolated product revealed that the
alkylation takes place on the benzene ring of oxindole, but not at
the C3-position (active methylene) as we anticipated (Scheme 1).
Extensive 1D and 2D NMR data (1H (DQFCOSY, TOCSY and
NOESY) and 13C NMR (DEPT)) have established the resonance
assignments.
aOrganic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad 500 607, India. E-mail: rajireddy@iict.res.in; Fax: +91-40-
27160512
bCenter for NMR, Indian Institute of Chemical Technology, Hyderabad 500
607, India
The results have suggested that the alkylation occurred at the
C5-position of oxindole to give compound 3aa in 74% yield along
with 17% of dialkylated product 3aa¢. The unambiguous NOE
† Electronic supplementary information (ESI) available: DEPT-135,
NOESY spectra for compound 3aa, 3ba and 1H and 13C NMR spectra
of all new compounds. See DOI: 10.1039/c0ob01144d
3940 | Org. Biomol. Chem., 2011, 9, 3940–3947
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
gives mono- and dialkylated products, N-methyl oxindole (1b) was
used as the substrate for more studies (Table 1). Accordingly, 1b
was subjected to alkylation using 4-methoxybenzyl alcohol (2a)
in nitromethane using pTSA (5 mol%) at 90 ◦C. The reaction
resulted in the formation of 5-alkylated product 3ba in 92% yield,
which was fully characterized. Next, we examined a variety of
alcohols, including benzylic, allylic and propargylic, under pTSA-
catalyzed conditions. From the results of Table 1, the protocol
has been proven to be useful for the alkylation of N-methyl
oxindole with secondary benzylic alcohols 2c and 2d to give the
corresponding 5-benzylated N-methyloxindole products 3bc and
3bd in good yields (entries 3 and 4, Table 1). Cinnamyl alcohol
2e and another allylic alcohol 2f also provided the 5-alkylated
products 3be and 3bf in 91% and 92% yields, respectively (entries
5 and 6, Table 1). Interestingly, benzylic propargyl alcohols 2b
and 2g and a non-benzylic propargyl alcohol 2h are also found to
be equally effective as agents for the C5-alkylation of 1b under
the depicted reaction conditions (entries 2, 7 and 8, Table 1).
Furthermore, heterocyclic based benzyl alcohols 2i and 2j have
also provided the corresponding 5-alkylated N-methyl oxindoles
3bi and 3bj in 96 and 95% yields, respectively (entries 9 and 10,
Table 1). However, the aliphatic alcohol 2k didn’t participate in
the alkylation reaction with 1b (entry 11, Table 1).
To include more diversity in the substrates, differently substi-
tuted oxindoles were next subjected to the alkylation reaction with
benzylic alcohol 2b under the described reaction conditions (5
mol% of pTSA, CH3NO2, 90 ◦C) and the results are summarized
in Table 2. To our realization, 6-chloro N-methyl oxindole (1c)
has undergone alkylation with 2b to afford the 5-propargylated
product 3cb in 92% yield (entry 1, Table 2). N-Benzylated
oxindoles 1d and 1e successfully provided the corresponding
products 3db and 3eb in 94% and 95% yields, respectively (entries
2 and 3, Table 2). Attractively, N-methyl 3-benzyloxindole (1f) has
also participated in C5-alkylation with 2b to give the product 3fb
in 93% yield (entry 4, Table 2).
Scheme 1 Reactions of oxindole with 2a.
pattern with Hb–Hc, Hc–Hf, Hd–He and He–Ha cross-peaks has
confirmed the conformation of 3aa and the alkylation at the C5-
position, as shown in Fig. 2. The present result is an interesting
distinction from the earlier known methods,6 where the basic
reaction medium in the presence of metal catalyst provided the C3-
alkylated product 3a from the same starting materials (Scheme 1).
The basis for this result is that under acid-catalyzed Friedal–
Crafts conditions alcohols are prone to generate carbocations
which participate in the C5-alkylation of oxindole. Whereas the
reaction sequence in basic medium in the presence of metal catalyst
is dehydrogenation of alcohol–Knoevenogel-type condensation–
hydrogenation to give the C3-alkylated product.6
Fig. 2 nOe correlations observed in compound 3aa.
To further confirm the C5-alkylation, a different benzylic
alcohol 2b was used as an alkylating agent for the alkylation of 1a,
which also successfully provided the 5-alkylated product 3ab in
75% yield, along with 15% N-alkylated product 3ab¢ (Scheme 2).
In light of the above findings, we became interested in testing the
reactivity of the C5-alkylated oxindoles with aldehydes to achieve
the corresponding 3-alkenyl derivatives, which are one of the
important classes of bio-active compounds among the oxindole
family. Thus, the reaction of 3ba with pyrrole-2-carboxaldehyde
4a has been examined using the known method, which resulted
in successful formation of condensed product 5a in 87% yield
(entry 1, Table 3). Compound 3ab also afforded the products 5b
and 5c from the reaction with pyrrole-2-carboxaldehyde (4a) and
benzaldehyde (4b) in high yields (entries 2 and 3, Table 3).
Finally, various readily available acid catalysts have been tested
for the C5-alkylation of 1b with 2b and the desired product 3bb was
observed in good yield regardless of the catalyst tried (Table 4).
Interestingly, BF3·Et2O, I2 and FeCl3 were found to catalyse the
reaction at room temperature (entries 1, 4 and 5, Table 4).
Scheme 2 C5-Alkylation of oxindole (1a) with 2b.
The above success of the reactions at room temperature12 led us
to verify the selective C5-alkylation of unprotected oxindole (1a).
Thus, the reaction of 1a with 2a was carried out in the presence
of BF3·Et2O (5 mol%) at room temperature and to our delight
exclusively C5-alkylated product 3aa was obtained in 91% yield
(entry 1, Table 5). A similar result was obtained in the case of I2
as well as FeCl3 (entry 2 and 3, Table 5). Further, selective C5-
alkylated product 3ab was also accomplished from the reaction of
1a with 2b at room temperature (entries 4 to 6, Table 5).
Although there are methods known for the C5-substituion of
oxindoles such as bromination, nitration and acylation etc.,10
no literature precedent is available for direct C5-alkylation of
oxindoles. Commonly, C5-alkylation has been accomplished in
a two-step sequence of acylation followed by reduction.11 Hence,
the above result of C5-alkylation in one step is a useful method and
we decided to further explore the C5-alkylation of oxindoles with
various alcohols under acid catalysis. However, as oxindole (1a)
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3940–3947 | 3941
©

View Article Online
Table 1 C5-Alkylation of N-methyl oxindole (1b) with various alcoholsa
Entry
1
Alcohol
Time/h
7
Productb
Yield (%)c
92
2
3
5
8
93
92
4
7
93
5
6
7
6
91
92
7
8
9
7
90
88
96
10
5
10
5
95
11
36
no reaction
—
a Reaction conditions: pTSA (5 mol%), CH3NO2, 90 ◦C. b All the products were characterized by 1H, 13C NMR and mass spectra. c Isolated yields after
column chromatography.
a greener and atom economic protocol. A variety of alcohols
such as benzylic, allylic and propargylic alcohols were successfully
Conclusions
In summary, we have demonstrated an unprecedented C5-
alkylation of oxindoles in the presence of an acid catalyst. The
striking feature that has been revealed from the present studies is
the use of alcohols as alkylating agents in this new method towards
utilized as alkylating agents. Furthermore, the synthesis of C3-
alkenyl derivatives using the products obtained from the present
method has also demonstrated. We believe that this selective C5-
alkylation method, leaving C3 untouched, may find applications.
3942 | Org. Biomol. Chem., 2011, 9, 3940–3947
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 2 C5-Alkylation of substituted oxindoles with 2ba
Entry
1
Substituted oxindole
Time/h
5
Productb
Yield (%)c
92
2
3
4
5
5
6
94
95
93
a Reaction conditions: pTSA (5 mol%), CH3NO2, 90 ◦C. b All the products were characterized by 1H, 13C NMR and mass spectra. c Isolated yields after
column chromatography.
Table 3 Synthesis of 3-alkenyl derivatives from 3ba and 3aba
Entry
1
C5-alkylated oxindole
Aldehyde
Time/h
5
Productb
Yield (%)c
87
3ba
2
3
3ab
3ab
4a
5
6
85
90
a Reaction conditions: piperidine (5 mol%), EtOH, reflux. b All the products were characterized by 1H, 13C NMR and mass spectra. c Isolated yields after
column chromatography.
◦
45 C. IR spectra were recorded on Perkin– Elmer 683, Nicolet
Experimental
Nexus 670 spectrometer. H NMR and 13C NMR spectra were
1
General
recorded in CDCl3 and DMSO-d6 solvent on Varian Gemini
200, Bruker AV-300 and Varian Innova 500 NMR spectrometers.
Chemical shifts were reported in parts per million (ppm) with
respect to internal TMS. Coupling constants (J) are quoted in
hertz (Hz). Mass spectra were obtained on Finnigan MAT1020B,
micromass VG 70–70H or Agilent technologies LC/MSD trapSL
spectrometer operating at 70 eV using direct inlet system. Starting
materials 1b, 1c, 1d, 1e and 1f.13
All the solvents and reagents were purified by standard techniques;
reactions were performed in oven-dried round bottom flasks;
crude products were purified by column chromatography on
silica gel (60–120 mesh). Thin layer chromatography plates were
visualized by exposure to ultraviolet light and/or by exposure to a
methanolic acidic solution of p-anisaldehyde, an aqueous solution
of potassium permanganate (KMnO4) or an ethanolic solution of
ninhydrin followed by heating (<1 min) on a hot plate (~250 ◦C).
Organic solutions were concentrated on a rotary evaporator at 40–
General experimental procedure for C5-Alkylation of oxindoles.
To a mixture of oxindole (1) (1.0 mmol) and alcohol (2) (1.0 mmol)
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3940–3947 | 3943
©

View Article Online
Table 4 C5-Alkylation of N-methyl oxindole (1b) with 2b to obtain 3bb
5-(1,3-Diphenylprop-2-ynyl)indolin-2-one (3ab). Brown solid;
Mp: 108–112 ◦C; Rf 0.50 (hexanes/EtOAc = 1 : 1); 1H NMR
(300 MHz, CDCl3): d 9.53 (s, 1H), 7.47–7.16 (m, 12H), 6.82 (d,
1H, J = 7.9 Hz), 5.11 (s, 1H), 3.46 (s, 2H); 13C NMR (75 MHz,
CDCl3): d 177.8, 141.7, 141.3, 136.1, 131.6, 131.6, 128.6, 128.6,
128.2, 128.2, 128.0, 127.7, 127.7, 127.4, 126.9, 125.7, 124.2, 123.3,
109.6, 90.0, 85.0, 36.2, 29.6; IR (KBr): nmax 3190, 2869, 1707, 1488,
1325, 756, 692 cm-1; MS (ESI): m/z 324.1 (M+H)+; HRMS-ESI
(m/z): calcd for C23H18 NO (M+H)+: 324.1383, found: 324.1383.
under various acid catalystsa
Entry
Acid catalystb
Temperature
r.t.
Time/h
Yield (%)c
1
2
3
4
5
6
BF3·Et2O
B(C6F5)3
ZnCl2
3.5
5
93
94
92
91
92
90
90 ◦
90 ◦
r.t.
C
C
5
4
I2
FeCl3
Amberlyst-15
r.t.
4
5
90 ◦
C
a Reactions were carried out in CH3NO2 on 0.1 mmol scale. b 5 mol% of
the catalyst used. c Isolated yields after column chromatography.
1, 5-Bis(1,3-diphenylprop-2-ynyl)indolin-2-one (3ab¢). Yellow
liquid; Rf 0.76 (hexanes/EtOAc = 1 : 1); H NMR (300 MHz,
1
CDCl3): d 7.58 (d, 1H, J = 7.3 Hz), 7.50–7.13 (m, 21H), 6.93–6.82
(m, 2H), 5.08 (s, 1H), 3.62 (s, 2H); 13C NMR (75 MHz, CDCl3):
d 174.3, 140.9, 136.1, 135.6, 131.8, 131.8, 131.6, 131.6, 128.6,
128.6, 128.6, 128.6, 128.6, 128.3, 128.3, 128.3, 128.1, 128.1, 128.1,
128.0, 127.7, 127.7, 127.7, 127.0, 126.9, 126.9, 124.8, 123.9, 111.2,
90.0, 86.9, 84.9, 83.4, 45.7, 43.3, 35.6, 29.6; IR (KBr): nmax 33417,
2921, 1715, 1446, 1029, 679 cm-1; MS (ESI): m/z 514.2 (M+H)+;
HRMS-ESI (m/z): calcd for C38H28NO (M+H)+: 514.2165, found:
514.2144.
Table 5 Selective C5-alkylation of unprotected oxindole (1a)a
Entry Alcohol
Acid catalystb
Time/h
Product
Yield (%)c
1
2
3
4
5
6
2a
2a
2a
2b
2b
2b
BF3·Et2O
I2
FeCl3
BF3·Et2O
I2
4
4
4
3.5
3.5
3.5
3aa
3aa
3aa
3ab
3ab
3ab
91
90
88
94
90
89
FeCl3
5-(4-Methoxybenzyl)-1-methylindolin-2-one
(3ba). Yellow
a Reactions were carried out in CH3NO2 on 0.1 mmol scale at room
temperature. b 5 mol% of the catalyst used. c Isolated yields after column
chromatography.
◦
1
solid; Mp: 88–92 C; Rf 0.22 (hexanes/EtOAc = 7 : 3); H NMR
(300 MHz, CDCl3): d 7.09–6.98 (m, 4H), 6.78 (d, 2H, J = 8.4 Hz),
6.68 (d, 1H, J = 7.9 Hz), 3.87 (s, 2H), 3.77 (s, 3H), 3.44 (s, 2H),
3.18 (s, 3H); 13C NMR (75 MHz, CDCl3): d 175.0, 157.9, 143.3,
135.8, 133.3, 129.6, 129.6, 129.6, 127.9, 124.8, 113.8, 113.8, 107.8,
55.1, 40.6, 35.7, 26.1; IR (KBr): nmax 3390, 2912, 1712, 1511, 1245,
1026, 811 cm-1; MS (ESI): m/z 290.8 (M+Na)+; HRMS-ESI
(m/z): calcd for C17H18 NO2 (M+H)+: 268.1332, found: 268.1332.
in nitromethane (20 mL), p-toluenesulfonic acid (5 mol %) was
added and the reaction mixture was stirred at 90 ◦C for the
given time (Table 1 and 2). After completion of the reaction
(monitored by TLC), the mixture was cooled to room temperature
and evaporated in vacuo. The crude compound was purified by
column chromatography on silica gel using ethyl acetate and
hexanes as eluent to give the corresponding alkylated products
(3).
5-(1,3-Diphenylprop-2-ynyl)-1-methylindolin-2-one (3bb). Yel-
low liquid; Rf 0.21 (hexanes/EtOAc = 7 : 3); 1H NMR (300 MHz,
CDCl3): d 7.45—7.11 (m, 12H), 6.67 (d, 1H, J = 7.9 Hz), 5.10 (s,
1H), 3.40 (s, 2H), 3.10 (s, 3H); 13C NMR (75 MHz, CDCl3): d
175.1, 144.0, 141.7, 136.2, 131.5, 131.5, 128.6, 128.6, 128.1, 128.1,
128.0, 127.6, 127.6, 127.2, 126.8, 124.9, 123.9, 123.2, 107.9, 90.0,
84.9, 43.3, 35.7, 26.1; IR (KBr): nmax 3453, 2923, 2363, 1715, 1611,
1496, 1280, 769 cm-1; MS (ESI): m/z 338.1 (M+H)+; HRMS-ESI
(m/z): calcd for C24H20 NO (M+H)+: 338.1539, found: 338.1528.
Spectral data for all new compounds
5-(4-Methoxybenzyl)indolin-2-one (3aa). Light brown solid;
Mp: 174–178 ◦C; Rf 0.42 (hexanes/EtOAc = 1 : 1); 1H NMR
(500 MHz, CDCl3): d 8.42 (br s, 1H), 7.03 (d, 2H, J = 8.4 Hz), 6.99–
6.95 (m, 2H), 6.77 (d, 2H, J = 8.4 Hz), 6.73 (d, 1H, J = 7.5 Hz), 3.81
(s, 2H), 3.72 (s, 3H), 3.41 (s, 2H); 13C NMR (75 MHz, CDCl3): d
177.6, 157.9, 140.4, 135.8, 133.3, 129.6, 129.6, 128.1, 125.5, 125.1,
113.9, 113.9, 109.4, 55.2, 40.6, 36.2; IR (KBr): nmax 3432, 2919,
1702, 1513, 1244, 1029 cm-1; MS (ESI): m/z 276.0 (M+Na)+;
HRMS-ESI (m/z): calcd for C16H16NO2 (M+H)+: 254.1176, found
254.1164.
1-Methyl-5-(1-phenylethyl)indolin-2-one (3bc). Light yellow
1
liquid; Rf 0.40 (hexanes/EtOAc = 7 : 3); H NMR (300 MHz,
CDCl3): d 7.28–7.01 (m, 7H), 6.68 (d, 1H, J = 8.1 Hz), 4.09 (q,
1H, J = 7.1 Hz), 3.42 (s, 2H), 3.17 (s, 3H), 1.61 (d, 3H, J = 7.1
Hz); 13C NMR (75 MHz, CDCl3): d 175.0, 146.3, 143.3, 140.8,
128.3, 128.3, 127.3, 127.3, 126.7, 126.0, 124.6, 123.7, 107.7, 44.3,
35.7, 26.1, 21.9; IR (KBr): nmax 3616, 2964, 1711, 1496, 1347, 1093,
772 cm-1; MS (ESI): m/z 252.1 (M+H)+; HRMS-ESI (m/z): calcd
for C17H18 NO (M+H)+: 252.1383, found: 252.1386.
1,5-Bis(4-methoxybenzyl)indolin-2-one (3aa¢). Light brown
solid; Mp: 129–133 ◦C; Rf 0.67 (hexanes/EtOAc = 1 : 1); 1H NMR
(300 MHz, CDCl3): d 7.20 (d, 2H, J = 8.6 Hz), 6.99 (d, 3H, J = 8.3
Hz), 6.92 (d, 1H, J = 7.9 Hz), 6.76 (t, 4H, J = 8.6 Hz), 6.58 (d, 1H,
5-Benzhydryl-1-methylindolin-2-one (3bd). Brown solid; Mp:
144–148 ◦C; Rf 0.40 (hexanes/EtOAc = 7 : 3); 1H NMR (300 MHz,
CDCl3): d 7.31–7.14 (m, 6H), 7.10–6.89 (m, 6H), 6.69 (d, 1H, J =
7.9 Hz), 5.49 (s, 1H), 3.45 (s, 2H), 3.18 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 175.0, 143.8, 138.3, 129.2, 129.2, 129.2, 129.2, 129.2,
128.7, 128.7, 128.3, 128.3, 128.3, 128.3, 128.3, 126.3, 126.3, 125.4,
107.7, 56.4, 35.7, 26.1; IR (KBr): nmax 3409, 1714, 1495, 1338,
803, 698 cm-1; MS (ESI): m/z 335.9 (M+Na)+; HRMS-ESI (m/z):
calcd for C22H20 NO (M+H)+: 314.1539, found: 314.1545.
J = 7.9 Hz), 4.78 (s, 2H), 3.81 (s, 2H), 3.75 (s, 6H), 3.50 (s, 2H); 13
C
NMR (75 MHz, CDCl3): d 175.0, 158.9, 157.9, 142.3, 135.8, 133.2,
129.6, 129.6, 128.7, 128.7, 127.8, 127.8, 124.8, 124.8, 114.0, 114.0,
113.8, 113.8, 108.8, 55.1, 55.1, 43.1, 40.5, 35.7; IR (KBr): nmax
3383, 2921, 1702, 1510, 1245, 1176, 1028, 809 cm-1; MS (ESI): m/z
396.3 (M+Na)+; HRMS-ESI (m/z): calcd for C24H24NO3 (M+H)+:
374.1751, found: 374.1735.
3944 | Org. Biomol. Chem., 2011, 9, 3940–3947
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
5-Cinnamyl-1-methylindolin-2-one (3be). Yellow liquid; Rf
0.23 (hexanes/EtOAc = 7 : 3); H NMR (300 MHz, CDCl3): d
(d, 2H, J = 7.7 Hz), 7.37–7.01 (m, 11H), 6.70 (d, 1H, J = 7.9
Hz), 5.25 (s, 1H), 3.45 (s, 2H), 3.19 (s, 3H), 2.06 (s. 3H); 13C
NMR (75 MHz, CDCl3): d 174.9, 148.8, 143.2, 139.9, 137.5, 129.1,
129.1, 129.1, 128.49, 128.4, 128.4, 128.4, 128.4, 128.0, 127.0, 127.0,
126.4, 125.5, 124.7, 118.2, 118.2, 107.8, 46.9, 35.7, 26.1, 12.3; IR
(KBr): nmax 2924, 1709, 1498, 1355, 755 cm-1; MS (ESI): m/z
394.0 (M+H)+; HRMS-ESI (m/z): calcd for C26H24 N3O (M+H)+:
394.1914, found: 394.1926.
1
7.35–7.06 (m, 7H), 6.80–6.66 (m, 1H), 6.46–6.21 (m, 2H), 3.54–
3.42 (m, 4H), 3.20 (s, 3H); 13C NMR (75 MHz, CDCl3): d 175.0,
143.3, 137.2, 134.2, 130.9, 129.1, 128.4, 128.4, 127.7, 127.0, 125.9,
124.7, 124.1, 122.2, 107.8, 38.8, 35.6, 26.1; IR (KBr): nmax 3454,
2924, 2097, 1705, 1497, 1098 cm-1; MS (ESI): m/z 264.1 (M+H)+;
HRMS-ESI (m/z): calcd for C18H18 NO (M+H)+: 264.1383, found:
264.1387.
6-Chloro-5-(1, 3-diphenylprop-2-ynyl)-1-methylindolin-2-one
5-(1,3-Diphenylallyl)-1◦-methylindolin-2-one (3bf). Light yel-
(3cb). Brown solid; Mp: 104–108 ◦C; Rf 0.37 (hexanes/EtOAc =
1
1
low solid; Mp: 119–123 C; Rf 0.23 (hexanes/EtOAc = 7 : 3); H
7 : 3); HNMR (300 MHz, CDCl3): d 7.47–7.38 (m, 5H), 7.33–
NMR (300 MHz, CDCl3): d 7.44–7.02 (m, 12H), 6.86–6.59 (m,
2H), 6.34 (d, 1H, J = 15.8 Hz), 4.87 (d, 1H, J = 7.3 Hz), 3.49 (s, 2H),
3.20 (s, 3H); 13C NMR (75 MHz, CDCl3): d 175.0, 143.6, 143.4,
137.8, 137.0, 128.4, 128.4, 128.4, 128.4, 128.4, 27.9, 127.8, 127.3,
126.4, 126.2, 126.2, 124.7, 124.6, 124.2, 122.2, 107.8, 53.7, 35.7,
26.1; IR (KBr): nmax 3022, 1718, 1495, 1094, 979, 747 cm-1; MS
(ESI): m/z 362.1 (M+Na)+; HRMS-ESI (m/z): calcd for C24H22
NO (M+H)+: 340.1696, found: 340.1690.
7.22 (m, 6H), 6.77 (s, 1H), 5.69 (s, 1H), 3.42(s, 2H), 3.14 (s,
3H); 13C NMR (75 MHz, CDCl3): d 174.8, 145.0, 140.4, 133.1,
132.2, 131.6, 131.6, 128.5, 128.5, 128.2, 128.2, 128.1, 127.6, 127.6,
126.9, 125.6, 125.6, 109.0, 109.0, 89.4, 84.5, 39.6, 35.3, 26.2; IR
(KBr): nmax 3066, 1708, 1490, 1366, 1100, 971, 758 cm-1; MS (ESI):
m/z 372.1 (M+H)+; HRMS-ESI (m/z): calcd for C24H19ClNO
(M+H)+: 372.1150, found: 372.1146.
1-Benzyl-5-(1, 3-diphenylprop-2-ynyl)indolin-2-one (3db).
◦
5-(1-(4-Methoxyphenyl)-3-phenylprop-2-ynyl)-1-methylindolin-
2-one (3bg). Yellow liquid; Rf 0.20 (hexanes/EtOAc = 7 : 3); 1H
NMR (300 MHz, CDCl3): d 7.47–7.40 (m, 2H), 7.33–7.20 (m,
7H), 6.81 (d, 2H, J = 8.6 Hz), 6.71 (d, 1H, J = 8.3 Hz), 5.08 (s,
1H), 3.78 (s, 3H), 3.46 (s, 2H), 3.18 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 175.0, 158.4, 143.9, 136.5, 133.8, 131.5, 131.5, 128.6,
128.6, 128.1, 128.1, 127.9, 127.9, 127.1, 123.8, 123.8, 113.9, 113.9,
107.8, 90.3, 84.8, 55.2, 42.4, 35.7, 26.1; IR (KBr): nmax 3621, 3054,
2830, 2223, 1700, 1500, 1345, 1247, 759 cm-1; MS (ESI): m/z
368.1 (M+H)+; HRMS-ESI (m/z): calcd for C25H22 NO2 (M+H)+:
368.1645, found: 368.1648.
Brown solid; Mp: 145–149 C; Rf 0.42 (hexanes/EtOAc = 7 : 3);
1H NMR (300 MHz, CDCl3): d 7.47–7.14 (m, 17H), 6.62 (d,
1H, J = 7.7 Hz), 5.09 (s, 1H), 4.85 (s, 2H), 3.56 (s, 2H); 13C
NMR (75 MHz, CDCl3): d 175.0, 143.1, 141.6, 136.1, 135.7,
131.6, 131.6, 128.6, 128.6, 128.6, 128.6, 128.1, 128.1, 128.0, 127.6,
127.6, 127.5, 127.3, 127.3, 127.2, 126.9, 124.9, 124.0, 123.2, 108.8,
90.0, 84.9, 43.7, 43.3, 35.7; IR (KBr): nmax 3419, 2923, 1700,
1489, 1343, 1177, 690 cm-1; MS (ESI): m/z 436.1 (M+Na)+;
HRMS-ESI (m/z): calcd for C30H23NONa (M+Na)+: 436.1672,
found: 436.1694.
5-(1, 3-Diphenylprop-2-ynyl)-1-(4-methoxybenzyl)indolin-2-one
1-Methyl-5-(1-phenylhex-1-yn-3-yl) indolin-2-one (3bh). Yel-
low liquid; Rf 0.29 (hexanes/EtOAc = 7 : 3); 1H NMR (300 MHz,
CDCl3): d 7.43–7.37 (m, 1H), 7.37–7.18 (m, 5H), 6.99 (t, 1H, J =
7.5 Hz), 6.80–6.70 (m, 1H), 3.78 (t, 1H, J = 7.5 Hz), 3.49 (s, 3H),
3.21 (s, 2H), 1.85–1.69 (m, 2H), 1.58–1.44 (m, 2H), 0.97 (t, 3H, J =
7.5 Hz); 13C NMR (75 MHz, CDCl3): d 175.1, 143.7, 136.6, 133.2,
131.5, 129.9, 128.1, 127.7, 126.7, 124.1, 123.5, 122.2, 107.8, 91.5,
83.1, 40.1, 37.7, 35.6, 26.0, 20.4, 13.7; IR (KBr): nmax 3059, 2959,
1716, 1612, 1369, 1085, 755 cm-1; MS (ESI): m/z 304.1 (M+H)+;
HRMS-ESI (m/z): calcd for C21H22 NO (M+H)+: 304.1696, found:
304.1698.
(3eb). Light brown solid; Mp: 149–153 ◦C; Rf 0.34 (hex-
1
anes/EtOAc = 7 : 3); H NMR (300 MHz, CDCl3): d 7.46–7.16
(m, 14H), 6.78 (d, 2H, J = 8.6 Hz), 6.64 (d, 1H, J = 8.3 Hz), 5.09
(s, 1H), 4.77 (s, 2H), 3.73 (s, 3H), 3.52 (s, 2H); 13C NMR (75 MHz,
CDCl3): d 175.0, 159.0, 143.2, 141.7, 136.1, 131.6, 131.6, 128.7,
128.7, 128.6, 128.6, 128.6, 128.2, 128.2, 128.0, 127.9, 127.7, 127.7,
127.1, 126.9, 124.9, 124.0, 114.0, 114.0, 108.8, 90.0, 84.9, 55.2, 43.3,
43.2, 35.8; IR (KBr): nmax 33382, 2930, 1698, 1489, 1249, 1178,
1027, 754, 693 cm-1; MS (ESI): m/z 444.1 (M+H)+; HRMS-ESI
(m/z): calcd for C31H26NO2 (M+H)+: 444.1958, found: 444.1949.
3-Benzyl-5-(1, 3-diphenylprop-2-ynyl)-1-methylindolin-2-one
(3fb). Yellow liquid; Rf 0.25 (hexanes/EtOAc = 7 : 3); 1H NMR
(500 MHz, CDCl3): d 7.47–7.38 (m, 2H), 7.34–7.18 (m, 9H), 7.13–
6.99 (m, 5H), 6.83–6.76 (m, 1H), 6.67–6.62 (m, 1H), 5.03 (d, 1H,
J = 5.0 Hz), 3.67–3.60 (m, 1H), 3.45–3.40 (m, 1H), 3.13 (d, 3H, J =
3.3 Hz), 2.90–2.82 (m, 1H); 13C NMR (75 MHz, CDCl3): d 177.0,
142.9, 141.7, 137.5, 135.7, 131.5, 131.5, 129.3, 128.5, 128.5, 128.1,
128.1, 128.1, 128.1, 128.1, 127.9, 127.5, 127.2, 127.1, 126.7, 126.4,
124.4, 124.2, 123.3, 107.7, 89.9, 84.9, 47.1, 43.2, 36.6, 26.1; IR
(KBr): nmax 3421, 2926, 1711, 1617, 1492, 1089, 756, 696 cm-1; MS
(ESI): m/z 428.1 (M+H)+; HRMS-ESI (m/z): calcd for C31H26NO
(M+H)+: 428.2009, found: 428.2006.
1-Methyl-5-(phenyl (1-tosyl-1H-indol-3-yl)methyl)indolin-2-one
(3bi). Light yellow solid; Mp: 135–139 ◦C; Rf 0.18 (hex-
anes/EtOAc = 7 : 3); H NMR (300 MHz, CDCl3): d 7.94 (d,
1
1H, J = 8.3 Hz), 7.66 (d, 2H, J = 8.3 Hz), 7.29–7.18 (m, 6H),
7.10–6.95 (m, 6H), 6.84 (s, 1H), 6.67 (d, 1H, J = 7.9 Hz), 5.43 (s,
1H), 3.41 (s, 2H), 3.18 (s, 3H), 2.37 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 174.9, 144.8, 143.9, 142.1, 136.3, 135.6, 135.0, 129.7,
129.7, 129.7, 128.6, 128.6, 128.6, 128.6, 128.1, 128.1, 126.7, 126.7,
126.7, 126.7, 125.6, 124.7, 124.7, 123.1, 120.4, 113.7, 107.9, 48.0,
35.7, 26.1, 21.5; IR (KBr): nmax 3407, 1711, 1497, 1369, 1174, 1093,
750, 679 cm-1; MS (ESI): m/z 528.8 (M+Na)+; HRMS-ESI (m/z):
calcd for C31H27 N2O3S (M+H)+: 507.1737, found: 507.1745.
Compounds 5a to 5c have been prepared using the known
procedure: ref. 14
1-Methyl-5-((4-methyl-1-phenyl-1H -pyrazol-3-yl)(phenyl)-
◦
methyl)indolin-2-one (3bj). Yellow solid; Mp: 83–87 C; Rf 0.14
(Z)-3-((1H -Pyrrol-2-yl)methylene)-5-(4-methoxybenzyl)-1-
methylindolin-2-one (5a). Yellow solid; Mp: 119–123 ◦C; Rf 0.53
1
(hexanes/EtOAc = 7 : 3); H NMR (300 MHz, CDCl3): d 7.55
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3940–3947 | 3945
©

View Article Online
1
(hexanes/EtOAc = 7 : 3); H NMR (300 MHz, CDCl3): d 13.44
Tetrahedron Lett., 2008, 49, 7413–7415; (f) U. Jana, S. Maiti and S.
Biswas, Tetrahedron Lett., 2007, 48, 7160–7163; (g) Z.-P. Zhan, J.-L.
Yu, H.-J. Liu, Y.-Y. Cui, R.-F. Yang, W.-Z. Yang and J.-P. Li, J. Org.
Chem., 2006, 71, 8298–8301; (h) C. Lofberg, R. Grigg, A. Keep, A.
Derrick, V. Sridhrana and C. Kilner, Chem. Commun., 2006, 5000–
5002; (i) J. J. Kennedy-Smith, L. A. Young and F. D. Toste, Org. Lett.,
2004, 6, 1325–1327; (j) Y. Nishibayashi, Y. Indada, M. Yoshikawa, M.
Hidai and S. Uemura, Angew. Chem., Int. Ed., 2003, 42, 1495–1498.
3 For representative examples, see: (a) M. Zhu, K-I. Fujita and R.
Yamaguchi, Org. Lett., 2010, 12, 1336–1339; (b) F. Shi, M. K. Tse, S.
Zhou, M.-M. Pohl, J. Radnik, S. Huebner, K. Jaehnisch, A. Brueckner
and M. Beller, J. Am. Chem. Soc., 2009, 131, 1775–1779; (c) B.
Anxionnat, A. Guerinot, S. Reymond and J. Cossy, Tetrahedron Lett.,
2009, 50, 3470–3473; (d) G.-W. Wang, Y.-B. Shen and X.-L. Wu,
Eur. J. Org. Chem., 2008, 4367–4371; (e) H. Qin, N. Yamagiwa, S.
Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2007, 46, 409–
413.
4 For representative examples, see: (a) H. F. Vischer, J. W. Hulshof, S.
Hulscher, S. A. Fratantoni, M. H. P. Verheij, J. Victorina, M. J. Smit,
I. J. P. De Esch and R. Leurs, Bioorg. Med. Chem., 2010, 18, 675–688;
(b) R. Mezaache, Y. A. Dembele, Y. Bikard, J.-M. Weibel, A. Blanc and
P. Pale, Tetrahedron Lett., 2009, 50, 7322–7326; (c) T. Thiemann, Lett.
Org. Chem., 2009, 6, 515–525.
5 (a) Ch. R. Reddy, J. Vijaykumar and R. Gree, Synthesis, 2010, 21, 3715–
3723; (b) Ch. R. Reddy and E. Jithender, Tetrahedron Lett., 2009, 50,
5633–5635; (c) Ch. R. Reddy, B. Srikanth, N. N. Rao and D.-S. Shin,
Tetrahedron, 2008, 64, 11666–11672; (d) Ch. R. Reddy, G. Rajesh, S. V.
Balaji and N. Chethan, Tetrahedron Lett., 2008, 49, 970–973; (e) Ch.
R. Reddy, P. P. Madhavi and A. S. Reddy, Tetrahedron Lett., 2007, 48,
7169–7172.
(brs, 1H), 7.35 (s, 1H), 7.28 (s, 1H), 7.16–7.10 (m, 3H), 7.04
(dd, 1H, J = 7.7, 0.9 Hz), 6.8 (d, 2H, J = 8.6 Hz), 6.80–6.70
(m, 2H), 6.39–6.33 (m, 1H), 3.94 (s, 2H), 3.78 (s, 3H), 3.32 (s,
3H); 13C NMR (75 MHz, CDCl3): d 168.1, 157.9, 135.3, 133.5,
129.9, 129.7, 129.7, 129.7, 127.3, 126.0, 124.9, 124.8, 120.0, 118.3,
116.4, 113.9, 113.9, 111.4, 107.8, 55.2, 40.8, 26.1; IR (KBr): nmax
3403, 2928, 1659, 1511, 1239, 1087, 1034, 743 cm-1; MS (ESI): m/z
345.2 (M+H)+; HRMS-ESI (m/z): calcd for C22H21N2O2 (M+H)+:
345.1598, found: 345.1602.
(Z)-3-((1H-Pyrrol-2-yl)methylene)-5-(1,3-diphenylprop-2-ynyl)-
indolin-2-one (5b). Yellow solid; Mp: 244–246 ◦C; Rf 0.57
(hexanes/EtOAc = 7 : 3); 1H NMR (300 MHz, DMSO-d6): d 13.30
(s, 1H), 10.89 (s, 1H), 7.71 (d, 2H, J = 13.5 Hz), 7.54–7.46 (m,
4H), 7.40–7.18 (m, 8H), 6.88–6.82 (m, 2H), 6.33 (brs, 1H), 5.39
(s, 1H); 13C NMR (50 MHz, DMSO-d6): d 169.2, 142.1, 137.7,
134.9, 131.3, 131.3, 129.4, 128.6, 128.6, 128.6, 128.6, 128.6, 127.3,
127.3, 126.7, 126.5, 126.1, 125.7, 125.5, 122.6, 120.6, 117.6, 116.4,
111.4, 109.5, 91.0, 84.0, 42.3; IR (KBr): nmax 3166, 1669, 1340,
1127, 754 cm-1; MS (ESI): m/z 401.2 (M+H)+; HRMS-ESI (m/z):
calcd for C28H21N2O (M+H)+: 401.1648, found: 401.1633.
(Z)-3-Benzylidene-5-(1, 3-diphenylprop-2-ynyl)indolin-2-one
(5c). Yellow solid; Mp: 100–103 ◦C; Rf 0.64 (hexanes/EtOAc =
7 : 3); 1H NMR (300 MHz, CDCl3): d 9.76 (br s, 1H), 7.79–
7.73 (m, 2H), 7.61–7.54 (m, 2H), 7.38–7.17 (m, 14H), 6.87 (d,
1H, J = 7.9 Hz), 5.02 (s, 1H); 13C NMR (75 MHz, CDCl3): d
170.8, 141.7, 140.3, 139.5, 138.0, 135.6, 134.4, 133.3, 131.9, 131.6,
131.6, 130.0, 129.7, 129.2, 129.2, 128.6, 128.6, 128.5, 128.5, 128.3,
128.1, 128.0, 127.7, 126.9, 125.3, 122.6, 110.2, 89.9, 84.9, 43.2; IR
(KBr): nmax 3028, 1702, 1610, 1476, 1264, 694 cm-1; MS (ESI): m/z
412.2 (M+H)+; HRMS-ESI (m/z): calcd for C30H22NO (M+H)+:
412.1696, found: 412.1711.
6 (a) T. Jensen and R. Madsen, J. Org. Chem., 2009, 74, 3990–3992; (b) R.
Grigg, S. Whitney, V. Sridharan, A. Keep and A. Derrick, Tetrahedron,
2009, 65, 4375–4383.
7 (a) S. Peddibhotla, Curr. Bioact. Compd., 2009, 5, 20–38; (b) A.
Millemaggi, A. Perry, A. C. Whitwood and R. J. K. Taylor, Eur. J. Org.
Chem., 2009, 2947–2952; (c) N. Kammasud, C. Boonyarat, K.
Sanphanya, M. Utsintong, S. Tsunoda, H. Sakurai, I. Saiki, I. Andre,
D. S. Grierson and O. Vajragupta, Bioorg. Med. Chem. Lett., 2009,
19, 745–750; (d) A. Andreani, S. Burnelli, M. Granaiola, A. Leoni,
A. Locatelli, R. Morigi, M. Rambaldi, L. Varoli, N. Calonghi, C.
Cappadone, M. Voltattorni, M. Zini, C. Stefanelli, L. Masotti and R. H.
Shoemaker, J. Med. Chem., 2008, 51, 7508–7513; (e) M. C. Michel, M.
Oelke and N. Zinner, Drug Discov. Today, 2005, 2, 1–6; (f) C. Marti
and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209–2219; (g) L. Sun, N.
Tran, C. Liang, S. Hubbard, F. Tang, K. Lipson, R. Schreck, Y. Zhou
and C. Tang, J. Med. Chem., 2000, 43, 2655–2663.
8 (a) A. Millemaggi and R. J. K. Taylor, Eur. J. Org. Chem., 2010, 4527–
4547; (b) G. S. Papaetis and K. N. Syrigos, BioDrugs, 2009, 23, 377–389;
(c) J. Lubkoll, A. Millemaggi, A. Perry and R. J. K. Taylor, Tetrahedron,
2010, 66, 6606–6612; (d) J. A. Jhonson, R. Loeser, D. M. Smith and
R. A. Turner, Agents Actions, 1990, 31, 102–109; (e) W. M. Greenberg
and L. Citrome, CNS Drug Rev., 2007, 13, 137–177; (f) H. R. Howard,
C. Prakash and T. F. Seeger, Drugs Future, 1994, 19, 560–563; (g) W. H.
Jost and D. Angersbach, CNS Drug Rev., 2005, 3, 253–272.
Acknowledgements
EJ, GK and GVR thank the Council of Scientific and Industrial
Research (CSIR), New Delhi for research fellowships. The authors
are thankful to the reviewers for their suggestions in improving the
quality of the manuscript.
Notes and references
9 (a) G. J. Roth, A. Heckel, F. Colbatzky, S. Handschuh, J. Kley, T.
Lehmann-Lintz, R. Lotz, U. Tontsch-Grunt, R. Walter and F. Hilberg,
J. Med. Chem., 2009, 52, 4466–4480; (b) W. Zhang and M. Go, Bioorg.
Med. Chem., 2009, 17, 2077–2090; (c) H. N. Bramson, J. Corona, S. T.
Davis, S. H. Dickerson, M. Edelstein, S. V. Frye, R. T. Gampe, P. A. Jr.
Harris, A. Hassell, W. D. Holmes, R. N. Hunter, K. E. Lackey, J. M.
Veal, D. H. Walker and L. F. Kuyper, J. Med. Chem., 2001, 44, 4339–
4358; (d) L. Maskell, E. A. Blanche, M. A. Colucci, J. L. Whatmore
and C. J. Moody, Bioorg. Med. Chem. Lett., 2007, 17, 1575–1578.
10 (a) W. Frohner, B. Monse, T. M. Braxmeier, L. Casiraghi, H. Sahagu
and P. Seneci, Org. Lett., 2005, 7, 4573–4576; (b) T. Kniess, M. Kuchar
and F. Wuest, Synth. Commun., 2008, 38, 3017–3022; (c) N. Kammasud,
C. Boonyarat, K. Sanphanya, M. Utsintong, S. Tsunoda, H. Sakuri,
I. Saiki, I. Andre, D. S. Grierson and O. Vajragupta, Bioorg. Med.
Chem. Lett., 2009, 19, 745–750; (d) H. Ogawa, S. Tamada, T. Fujioka,
S. Teramoto, K. Kondo, S. Yamashita, Y. Yabuuchi, M. Tominaga
and K. Nakagawa, Chem. Pharm. Bull., 1988, 36, 2253–2258; (e) J. S.
Yadav, B. V. S. Reddy, A. D. Krishna, Ch. S. Reddy and A. V. Narsaiah,
Synthesis, 2005, 6, 961–964; (f) S. Debarge, K. Kassou, H. Carreyre,
B. Violeau, M.-P. Jouannetaud and J.-C. Jacquesy, Tetrahedron Lett.,
2004, 45, 21–23.
1 For review, see: (a) G. Guillena, D. J. Ramon and M. Yus, Chem. Rev.,
2010, 110, 1611–1641; (b) G. Guillena, D. J. Ramon and M. Yus, Angew.
Chem., Int. Ed., 2007, 46, 2358–2364For recent representative examples
that use alcohols: (c) R. Kawahara, K. Fujita and R. Yamaguchi, J. Am.
Chem. Soc., 2010, 132, 15108–15111; (d) T. Ohshima, Y. Miyamoto, J.
Ipposhi, Y. Nakahara, M. Utsunomiya and K. Mashima, J. Am. Chem.
Soc., 2009, 131, 14317–14328; (e) P. G. Cozzi and L. Zoli, Angew. Chem.,
Int. Ed., 2008, 47, 4162–4166; (f) F. Alonso, P. Riente and M. Yus,
Eur. J. Org. Chem., 2008, 4908–4914; (g) K. Motokura, N. Nakagiri,
T. Mizugaki, K. Ebitani and K. Kaneda, J. Org. Chem., 2007, 72,
6006–6015; (h) J. Muzarat, Eur. J. Org. Chem., 2007, 3077–3089; (i) C.
Lofberg, R. Grigg, M. A. Whittaker, A. Keep and A. Derrick, J. Org.
Chem., 2006, 71, 8023–8027;(j) J. Muzarat, Tetrahedron, 2005, 61, 4179–
4212; (k) H. Kinoshita, H. Shinokubo and K. Oshima, Org. Lett., 2004,
6, 4085–4088.
2 For review, see: (a) M. Bandini and M. Tragni, Org. Biomol. Chem.,
2009, 7, 1501–1507for representative examples, see: (b) P. Thirupathi
and S. S. Kim, Tetrahedron, 2010, 66, 2995–3003; (c) Y.-M. Pan,
S.-Y. Zhao, W.-H. Ji and Z.-P. Zhan, J. Comb. Chem., 2009, 11, 103–
109; (d) C.-R. Liu, M.-B. Li, C.-F. Yang and S.-K. Tian, Chem.–
Eur. J., 2009, 15, 793–797; (e) S. J. Pridmore and J. M. J. Williams,
3946 | Org. Biomol. Chem., 2011, 9, 3940–3947
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
11 H. R. Howard, J. A. Lowe III, T. F. Seeger, P. A. Seymour, S. H. Zorn,
P. R. Maloney, F. E. Ewing, M. E. Newman, A. W. Schmidt, J. S.
Furman, G. L. Robinson, E. Jackson, C. Johnson and J. Morrone,
J. Med. Chem., 1996, 39, 143–148.
12 The experiments at room temperature for C5-alkylation of oxindoles
were carried out during the revision of the manuscript based on the
reviewer suggestion.
13 (a) F. G. Bordwell and H. E. Fried, J. Org. Chem., 1991, 56, 4218–4223;
(b) C. Marti and E. M. Carreira, J. Am. Chem. Soc., 2005, 9, 11505–
11515; (c) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti, B.
Giannichi, L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur. J.,
2009, 15, 7846–7849.
14 L. Sun, N. Tran, F. Tang, H. App, P. Hirth, G. Mcmahon and C. Tang,
J. Med. Chem., 2009, 41, 2588–2603.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3940–3947 | 3947
©