Highly regioselective and metal-free γ-addition of β-keto esters to isatins, catalyzed by DABCO: Direct access to novel class of diversely functionalized 3-hydroxy-2-oxindole scaffolds

Article abstract of DOI:10.1016/j.tet.2013.05.101

DABCO catalyzed, highly regioselective γ-addition of β-keto esters has been achieved in the aldol reaction with isatins to afford γ-(3-hydroxy-2-oxindole)-β-keto ester structural framework under metal-free condition. The generality of the method has been

Full text of DOI:10.1016/j.tet.2013.05.101

Tetrahedron 69 (2013) 6415e6423
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly regioselective and metal-free g-addition of b-keto esters to
isatins, catalyzed by DABCO: direct access to novel class of diversely
functionalized 3-hydroxy-2-oxindole scaffolds
Pramod Bhagwan Thakur a, Katukuri Sirisha b, Akella Venkata Subrahmanya Sarma b,
,
Jagadeesh Babu Nanubolu c, Harshadas Mitaram Meshram a
*
a Natural Product Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Center for NMR and SC, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
DABCO catalyzed, highly regioselective
action with isatins to afford g-(3-hydroxy-2-oxindole)-b
g
-addition of
b
-keto esters has been achieved in the aldol re-
-keto ester structural framework under metal-
free condition. The generality of the method has been demonstrated by screening series of isatin elec-
trophiles as well as linear and cyclic -keto esters. Compare to the dianion method, the present method is
very simple and handy, which provides straightforward access for the new diversely functionalized 3-
Received 23 October 2012
Received in revised form 20 May 2013
Accepted 22 May 2013
b
Available online 29 May 2013
b
-
keto ester substituted-3-hydroxy-2-oxindole structural scaffolds in very good yields from readily avail-
able starting materials.
Keywords:
Metal-free reaction
Regioselective aldol reaction
3-Hydroxy-2-oxindole
DABCO
Ó 2013 Elsevier Ltd. All rights reserved.
Green synthesis
1. Introduction
3-Substituted-3-hydroxy-2-oxindole framework is a privileged
structural motif persistently occurs in many biologically active
compounds and natural products.1 Selective representative exam-
ple includes donaxaridine, maremycin A, maremycin B, con-
volutamydine A, B, C, D, E, welwitindolinone C, SM-130686, and
dioxibrassinine (Fig. 1). As a result of this prevalence and promi-
nence of 3-substituted-3-hydroxy-2-oxindole moiety, enormous
research is promoted in the development of synthesis of such
structural framework. Among the different reported protocols, di-
rect addition of various nucleophiles to isatin is very general and
straightforward approach used for the synthesis of this structural
Fig. 1. Selected representative examples of natural products and pharmaceuticals
possessing 3-substituted-3-hydroxy-2-oxidole structural framework.
scaffold due to the fact that highly reactive b-carbonyl group of
isatin is much susceptible to nucleophilic attack.2 From the various
nucleophiles, enolizable ketones3 and aldehydes4 have been ex-
plored extensively with isatins. However, only a handful of reports
are available on direct nucleophilic addition of other enolizable
carbonyl components5e8 on isatin.
In the class of carbonyl compounds, b-keto esters are well rec-
ognized as simple, easily available, and versatile starting material in
the chemical synthesis for the construction of diversely functional-
ized complex molecular system.9 Additionally,
b-keto esters also
explored in the aldol reaction,10 which is one of the most important
CeC bonds forming reaction of carbonyl compound in organic syn-
thesis. In general, aldol reaction of
compounds in the presence of organic bases affords
products.11 The formation of
-addition product is logical because, a-
b
-keto esters with carbonyl
a-addition
* Corresponding author. Tel.: þ91 40 27191643; fax: þ91 40 27193275; e-mail
addresses: hmmeshram@yahoo.com, hmmeshram@gmail.com (H.M. Meshram).
a
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.101

6416
P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
proton of
b
-keto ester is more acidic than
g
-proton. Alternately,
-keto esters with
-additionreactionto give
with 5-bromo isatin in MeOH. As like previous results, reaction does
not proceed to afford the desired product even after longer reaction
time. From these results it is understandable that, -keto esters
-position, does not to undergo aldol
Huckin and Weiler developed aldol reaction of
aldehyde, whichundergoes regioselective
b
g
b
g-hydroxy
b
-keto ester structural motifs by using dianion method.12
having no enolizable proton at
reaction with isatin.
g
The dianion protocol was also applied on ketones,13 however the
scope of this method is not tested on other electrophilic systems.
O
O
A search of literature revealed that
able protons both at and position remains totally unexplored for
the aldol reaction with isatins. So far only one example of aldol
reaction of -keto
-keto ester14 with isatin is reported in which
ester having enolizable proton only at -position is employed. In
this context, as a part of our efforts in the synthesis of 3-substituted
3-hydroxy-2-oxindoles,15 we herein wish to report a DABCO cata-
lyzed, metal-free, highly efficient, and novel method for regiose-
b-keto ester having enoliz-
O
a
g
O2N
DABCO (30 mol %), THF, rt, 24 h
b
b
No Reaction
O
O
g
F
F
O
F
DABCO (30 mol %), THF, rt, 24 h
No Reaction
No Reaction
O
O
lective g-addition of b-keto esters to isatins for the synthesis of b-
keto esters substituted 3-hydroxy-2-oxindole frameworks by using
aldol reaction.
O
DABCO (30 mol %), THF, rt, 24 h
O
O
O
O
Br
2. Results and discussions
DABCO (30 mol %), THF, rt, 24 h
No Reaction
No Reaction
O
O
O
N
F
H
In continuation of our ongoing interest in the development of
1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed organic trans-
formation,15c,16 we planned to explore the potential of DABCO as
O
F
F
Imidazole (30 mol %), THF, rt, 24 h
O
O
a catalyst in the aldol reaction of
b-keto ester with isatin. As
O
a model reaction, we first attempted the reaction of ethyl acetoa-
cetate with 5-bromo isatin in tetrahydrofuran (THF) in the presence
of 10 mol % DABCO (Scheme 1). The reaction proceeded smoothly at
room temperature to afford the new product as a white solid. Both
crude and pure products were subjected for 1H NMR spectral
O2N
N
K2CO3 (30 mol %), CH3CN, rt, 24 h
No Reaction
No Reaction
O
O
O
MeONa (30 mol %), MeOH, rt, 24 h
analysis. To our surprise, we have not observed the formation of
addition product 3f0 even in trace amount. Indeed, the reaction
afforded
-addition product 3f as a sole product. The 1H NMR
spectra of the product showed signal for the characteristic qua-
ternary hydroxy at 6.1 ppm but, does not showed the anticipated
2.3 ppm for three hydrogen of acetyl group and
3.9 ppm for one -hydrogen of ethyl acetoa-
a-
Scheme 2. Reaction of 5-bromo isatin with those
protons at -position; Reaction conditions: 5-bromo isatin (1 mmol),
(1 mmol) in 5 mL solvent at room temperature.
b-keto esters having no enolizable
g
b-keto esters
g
d
In addition to these, the observed g-regioselectivity of the re-
singlet at approx.
d
action obtained with DABCO was also confirmed by spectral anal-
ysis of the product obtained under dianion method17 (Scheme 3).
The 1H NMR signal pattern observed for the crude reaction mixture
obtained by using DABCO was in good agreement with one that
observed for the crude reaction mixture obtained under dianion
method. All this above experiments validates the formation of
-(3-hydroxy-2-oxindole)-
of -(3-hydroxy-2-oxindole)-
DABCO. In dianion method, use of excess of base and combination
singlet at approx.
d
a
cetate group in expected product 3f0. Moreover, 1H NMR shows the
multiplet for four protons at
-protons and two -protons present in ethyl acetoacetate group of
product 3f. Thus, our observation showed that, the reaction of
keto ester with isatin in the presence of 10 mol % DABCO affords
single regioisomer, i.e., -(3-hydroxyoxindol)- -keto ester (3f) in-
-keto ester (3f0).
d 3.77e3.22 ppm consistent to the two
a
g
b
-
regioselective
g
b-keto ester (3f) instead
g
b
a
b
-keto ester (3f0) in the presence of
stead of
a-(3-hydroxyoxindol)-b
of metallic bases, sodium hydride, and n-butyllithium is mandatory
O
to get
literature search does not showed any report regarding the
regioselective addition of -keto ester on carbonyl component
g-hydroxy b-keto ester structural framework. Our extensive
O
O
O
O
O
O
O
O
O
HO
HO
g
-
O
Br
Br
O
O
Br
O
O
O
b
N
H
N
N
H
3f
DABCO (10 mol %)
THF, rt, 24 h
DABCO (10 mol %)
THF, rt, 24 h
H
under the metal-free condition. To the best of our knowledge, this is
the first study on metal-free, tertiary amine base (DABCO) catalyzed
3f'
Expected envisioned product
not formed
Unexpected regeoisomer
formed as a sole product
aldol reaction of
(3-hydroxy-2-oxindole)-
b
-keto ester with isatin to provide regioselective
-keto ester structural framework.
g-
Scheme 1. Synthesis of b-keto esters substituted 3-hydroxy-2-oxindole framework.
b
To authenticate theobserved
planned. In this regard, we performed the reaction of 5-bromo isatin
with those -keto esters having no enolizable proton at -position
under different conditions (Scheme 2). First we screened -keto es-
g-regioselectivity, furtherstudy was
b
g
b
ters like, ethyl 3-(4-nitrophenyl)-3-oxopropanoate, ethyl 4,4,4-
trifluoro-3-oxobutanoate, ethyl 4,4-dimethyl-3-oxopentanoate,
ethyl 3-oxo-3-phenylpropanoate with 5-bromo isatin in the pres-
ence of DABCO in THF. However we have not observed the formation
of new product under this reaction condition. Latter we carried out
reaction of 5-bromo isatin with ethyl 3-(4-nitrophenyl)-3-
oxopropanoate, ethyl 4,4,4-trifluoro-3-oxobutanoate in the pres-
ence of other catalyst like imidazole and K2CO3, which also failed to
form new product. Finally we tried to explore the catalytic activity of
MeONa in the reaction of ethyl 3-oxo-3-(pyridin-4-yl)propanoate
Scheme 3. Aldol reaction of 5-bromo isatin with ethyl acetoacetate under dianion
method.
With these cheering observations, next we studied the reaction
in detail to get optimized reaction condition. In this context, we
tested the scope of different organic catalyst for the aldol reaction
of 5-bromo isatin with ethyl acetoacetate and results are summa-
rized in Table 1 (entries 1e9). As a part of study, we have also
screened some other catalyst like K2CO3, Cs2CO3, MeONa, and

P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
6417
Table 1
only with linear
b
-keto esters but also with cyclic
b
-keto esters,
Optimization of reaction conditionsa
which reacted smoothly with isatins and afforded their respective
-regioselective aldol products as mixture of diastereomers (Table
2, products 3seu). Further to rule out any rearrangement, we
have also screened those -keto esters having no enolizable proton
at carbon atom. In that case, we observed that the reaction of
g
O
O
O
O
O
O
O
O
b
HO
HO
O
Br
O
Br
Br
a
O
O
O
ethyl 2,2-diethyl-3-oxobutanoate with isatin and 5-chloro isatin
under optimized reaction condition proceeds smoothly to afford
desired product in good yield (products 3v,w, respectively).
N
H
3f'
catalyst, solvent,
rt
N
N
H
3f
H
not formed
All the screened structurally varied
efficient -addition on different isatin electrophiles to provide
hydroxy-2-oxindole)- -keto ester structural scaffolds in mild re-
action condition. Results depicted in Table 2 also showed that, aldol
reaction of -keto esters with isatins does not hold the definite
b-keto esters underwent
Entry
Catalyst (mol %)
Solvent
Time (h)
Conversionb 3f/3f0
g
g
-(3-
1
2
3
4
5
6
7
8
DABCO (10)
DABCO (30)
TEA (30)
THF
THF
THF
24
8
8
8
8
8
8
8
8
8
8
8
8
94:0
95:0
71:0
76:0
68:0
65:0
63:0
72:0
61:0
74:0
67:0
82:0
81:0
0:0
b
b
DIPEA (30)
DBU (30)
THF
THF
correlation between the electronic nature of substituent on isatin
and efficiency of the reaction.
To understand the detailed mechanistic pathways of this
regioselective g-addition aldol reaction, we screened other active
methylene compound, such as malononitrile and 3-
oxopentanenitrile under optimized reaction condition. By the ob-
tained spectral data, we found that reaction of 5-chloro isatin with
malononitrile afforded Knoevenagel condensation product 3x as
a sole product in quantitative yield. Similarly the reaction of 5-
chloro isatin with 3-oxopentanenitrile afforded Knoevenagel con-
densation product 3y as a major product with trace amount of aldol
addition product (Scheme 4). This results encouraged us to un-
dertake the detailed NMR study for better understanding of re-
DBN (30)
THF
Piperidine (30)
Imidazole (30)
DMAP (30)
K2CO3 (30)
Cs2CO3 (30)
MeONa (30)
EtONa (30)
d
THF
THF
THF
CH3CN
CH3CN
MeOH
EtOH
THF
9
10
11
12
13
14
24
a
Reaction conditions: 5-bromo isatin (1 mmol), ethyl acetoacetate (1 mmol) in
5 mL of solvent.
b
By 1H NMR analysis. TEA¼triethylamine, DIPEA¼diisopropylethylamine,
DBU¼1,8-diazabicyclo[5.4.0]undec-7-ene, DBN¼1,5 diazabicyclo[4.3.0]non-5-ene,
DMAP¼4-dimethylaminopyridine.
action mechanism for
with isatins.
g-regioselective aldol reaction of b-keto ester
EtONa (entries 10e13). All the catalysts screened in this study
showed their potential to afford the desired products; however
they differ in the degrees of conversions as obtained by 1H NMR
analysis. It is notable from the above results that, both the organic
and inorganic catalysts have given only regioselective
product 3f and the formation of
observed. Control reaction without catalyst was also performed,
but the formation of product was not observed even after stretch-
ing reaction time up to 24 h (entry 14). After extensive screening of
various bases and solvents, 30 mol % DABCO in THF (entry 2, Table
1) was eventually preferred as set of optimized reaction condition
for the efficient aldol reaction of 5-bromo isatin with ethyl ace-
toacetate. In that case, the desired product 3f was obtained within
8 h with 95% conversion.
On the basis of NMR study, the reaction mechanism for
regioselective aldol reaction of -keto ester with isatins is shown in
Scheme 5 (see Supplementary data file for details). The formation
of -regioselective products can be rationalized on the basis of the
transition state between enolate of -keto ester and isatin. When
we recorded 1H NMR spectrum of ethyl acetoacetate in absence of
DABCO in CDCl3 with D2O, we found signal at 2.310 ppm (s, 3 -H),
3.490 (s, 2 -H) 4.237e4.213 (q, 2H), 1.336e1.302 (t, 3H) and not
g-
b
g
-addition
g
a
-addition product 3f0 was not
b
g
a
found any deuteration under this condition. However when we
recorded 1H NMR spectrum of ethyl acetoacetate in presence of
30 mol % DABCO in CDCl3 with D2O, we found the two active a-
proton get quickly deuterated due to which signal obtained at
3.490 ppm in previous experiment get disappeared. In this case we
With this established optimum condition, we were keen to
found signal at 2.310 ppm (s, 3g-H), 4.265e4.211 (q, 2H),
explore the scope of
to various other -keto esters and isatins and results are depicted in
Table 2. To our delight, we found that, array of -keto esters and
g
-regioselectivity of the reaction with respect
1.337e1.302 (t, 3H). Additionally and more importantly, we found
the extra signal at 2.822 ppm under this condition. Signal at
b
b
2.822 ppm corresponds to the partial deuteration on
g-H due to
isatins with diverse functional groups including halogens were
well-tolerated and afforded desired products with complete regio-
selectively in very good yields under optimized condition (Table 2).
Encouraged by these results, next we screened some N-alkylated
isatins, which also afforded the moderate to good yield of desired
acidic nature of 3 -H. Occurrence of partial deuteration on g
be rationalized only by formation of kinetic enolate. With this
study, we believe that the reaction get initiated by formation of
enolate of b-keto ester with the aid of DABCO. When b-keto ester
like ethyl acetoacetate is treated with DABCO, along with major
thermodynamic enolate, small amount of kinetic enolate also
g
-H can
product (Table 2, 3g,h,q). Moreover,
stituents at -&/ -carbon atom were also reacted smoothly with
isatins under standard reaction condition and given desired -ad-
b-keto esters having sub-
a
g
formed due to acidic nature of protons present on g-carbon atom.
g
Further we propose the formation of disfavored transition state due
to high steric interaction between thermodynamic enolate of ethyl
acetoacetate and isatin. This high steric interaction might have
reduced the nucleophilicity of thermodynamic enolate. As a result
of such high steric interaction and reduction in nucleophilicity,
dition products in good to excellent yield as a mixture of inseparable
diastereomers (Table 2, products 3leu). Similarly, the reaction of
ethyl 2-benzyl-3-oxobutanoate with isatin carried out in optimized
condition afforded corresponding
ester adduct 3k, with complete
g
-(3-hydroxy-2-oxindole)-
b-keto
g-regioselectivity. The desired
g-
thermodynamic enolate does not react with isatin to give a-addi-
regioselectivity of the reaction was also confirmed by X-ray crys-
tallographic structure18 obtained for product 3k (Fig. 2, also see
Supplementary data file for detail single crystal X-ray data).
tion product (Scheme 5, Path 1). However as depicted in Path 2, the
steric interaction with isatin is much avoided with kinetic enolate
of ethyl acetoacetate, which form favored transition state with
isatin. Consequence of this, nucleophilicity of kinetic enolate might
have increased and hence it reacts effectively with isatin to afford
It is worthy to mention that
ethyl 2-chloro-3-oxobutanoate was reacted in the same fashion
under optimized reaction condition to give -regioselective aldol
product (Table 2, products 3neq). The reaction was successful not
a-halogenated b-keto ester like
g
g-addition product 3f exclusively (Scheme 5, Path 2). Even the ki-
netic enolate present in minor amount, it shifts the equilibrium to

6418
P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
Table 2
Scope of aldol reaction of b
-keto esters with isatins under optimized reaction conditiona
R7
O
R6
R8
O
R2
O
O
R2
O
O
R3
HO
R3
H
R7
R5
O
30 mol % DABCO
THF, rt, 5-8 h
O
R8
+
R6
N
O
R5
N
R1
R4
R1
R4
3(a-w)
1(a-h)
R1 = H, Phenyl, Benzyl, CH2OH,
R2, R4 = H, Cl, R3 = H, Br, I, NO2
2(a-i)
R5, R6, R8 = H, Ethyl, Cl, Benzyl, Cyclic
R7 = Methyl, Ethyl, tButyl, Cyclic
O
O
I
O
O
O
O
O
O
O
O
Cl
HO
HO
O
HO
HO
O
O
O
HO
Br
O
O2N
O2N
O
O
O
O
O
O
N
H
N
H
N
H
N
H
N
H
Cl
3b, 6 h
92 %
3a, 5.2 h
94 %
3d, 6 h
90 %
3e, 6 h
95 %
3c, 6 h
93 %
O
O
O
O
O
O
O
O
O
HO
O
HO
O
HO
Br
HO
HO
O
Br
O
O
O2N
I
I
O
O
O
O
O
N
N
N
H
N
H
N
H
OH
3j, 5.2 h
93 %
3i, 5 h
97 %
3h, 7.5 h
82 %
3g, 6.5 h
89 %
3f, 5.8 h
91 %
Cl
Cl
O
O
O
O
O
O
O
O
O
O
HO
HO
O
O
HO
HO
O2N
O
O
I
Br
O2N
HO
O
O
O
O
O
N
H
N
H
O
N
H
N
H
N
H
3m, 6 h
94 %, dr, 52:48
3o, 6 h
93 %, dr, 52:48
3n, 5.2 h
94 %, dr, 57:43
3l, 5.8 h
95 %, dr, 54:46
3k, 8 h
92 %, dr, 52:48
Cl
Cl
O
O
O
O
O
O
O
O
HO
O
HO
O
HO
HO
O2N
O
O
I
I
Cl
O
O
O
N
O
N
H
N
N
H
H
3s, 7.2 h
81 %, dr, 52:48
3r, 8 h
82 %, dr, 58:42
3p, 6 h
89 %, dr, 55:45
3q, 7 h
90 %, dr, 53:47
O
O
O
O
O
O
O
O
O
O
HO
O
HO
HO
O
HO
Cl
I
O
O
O
O
N
H
N
N
H
N
H
H
3v, 8 h
81 %
3w, 8 h
87 %
3t, 7.8 h, 94 %,
dr, 53:17:17:9:4
3u, 7 h, 95 %
dr, 63:31:6
a
Reaction conditions: isatin 1(aeh) (1 mmol), b-keto esters 2(aei) (1 mmol) in 5 mL THF in the presence of 30 mol % DABCO and yields are given as isolated yields. All
products 3(aew) are characterized by NMR, Mass, and IR spectroscopic techniques. (See Supplementary data file for characterization data and copies of 1H and 13C NMR
spectrum).
forward direction by reacting with isatin and hence the reaction
proceeds to completion to form new product. We believe that this
NMR study has provided reasonable explanation for the formation
study for in-depth understanding of this reaction, which will also
throw a light on described mechanistic pathway is currently in
progress in our laboratory and results will be published in due
course.
of
g-addition product under our reaction condition. The further

P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
6419
hydroxy-2-oxindole framework with intact
b
-keto ester structural
motif provides an additional functional handle for further trans-
formations, which can be effectively utilize in natural products
synthesis and preparation of library of pharmaceutically important
compounds. The preliminary study on an asymmetric version of
this regioselective g-addition of b-keto esters on isatins is initiated
and results will be reported in due course.
4. Experimental section
Fig. 2. ORTEP diagram of product 3k.
4.1. General remarks
N
N
O
Cl
30 mol % DABCO
Cl
N
N
All materials used in this study were obtained from commercial
supplier and used without further purification as received. Reaction
involving moisture and/or air sensitive reagents were performed in
oven-dried glassware under a positive pressure of nitrogen using
freshly distilled solvents. Tetrahydrofuran (THF) was distilled over
Na/Ph2CO under nitrogen atmosphere. Commercial grade solvents
and reagents were used without further purification. All reactions
were monitored by E. Merck analytical thin layer chromatography
(TLC) plates (AL SIL G/UV, aluminum back) and one or more of the
following methods were used for visualization: 254 nm UV light
fluorescence quenching; iodine staining; anisaldehyde stain (eth-
anol (135 mL)/H2SO4 (5 mL)/AcOH (1.5 mL)/p-anisaldehyde 3.7 mL).
Evaporation of solvents was performed at reduced pressure on
a BUCHI rotary evaporator. Column chromatography was carried
out with acme’s silica gel grade 60e120 and 100e200 mesh. Col-
umns were typically packed as slurry and equilibrated with the
appropriate solvent system prior to use. Ethyl acetate and hexane
were the common eluents used. All 1H and 13C NMR spectra were
recorded in CDCl3/DMSO-d6/CDCl3þDMSO-d6 on Gemini 200,
O
O
N
N
H
H
THF, rt, 8 hr
3x, 98 %
Knoevenagel condensation product
5-Chloro-isatin
malononitrile
N
O
O
Cl
HO
N
O
Cl
N
O
Cl
O
O
N
H
O
30 mol % DABCO
THF, rt, 8 hr
N
H
N
H
5-Chloro-isatin
3-oxopentanenitrile
3y, 78 %
aldol addition
product (trace)
Knoevenagel condensation
product (major)
unconsumed reactants 5-Chloro-isatin
and 3-oxopentanenitrile(minor)
Scheme 4. Reaction of 5-chloro isatin with malononitrile and 3-oxopentanenitrile
under optimized reaction condition.
Avance 300 or Inova 500 spectrometers. Chemical shifts (
reported in parts per million (ppm) relative to either residual CHCl3
(1H: 7.26 ppm, 13C: 77.00 ppm) or DMSO-d6 (1H: 2.50 ppm, 13C:
39.43 ppm) as an internal reference. The number of protons (n) for
d) are
d
d
d
d
a given resonance is indicated by nH. Coupling constants (J) are
reported in Hertz (Hz). Peak multiplicity is indicated as follows:
sdsinglet, dddoublet, tdtriplet, qdquartet, brdbroad,
mdmultiplet, ddddoublet of doublet, and br sdbroad singlet.
Melting points were measured on a BUCHI melting point machine.
IR spectra were recorded on Thermo Nicolet FT/IR-5700 spec-
trometer. Mass spectra were recorded using Waters mass spec-
trometers. High resolution mass spectra (HRMS) were recorded
using Applied Bio-Sciences HRMS spectrometer at national center
for mass spectroscopy-IICT.
4.2. General procedure for DABCO catalyzed regioselective
addition of -keto esters to isatins
g-
b
To the stirred solution of b-keto ester 2(aei) (1.0 mmol) and
DABCO (30 mol %) in 5 mL THF was added isatin 1(aeh) (1 mmol).
The mixture was then stirred at room temperature for stipulated
time (5e8 h). After completion of reaction as indicated by TLC, the
solvent was removed at reduced pressure on a BUCHI rotary
evaporator. The residue was then purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate¼4:1 to 1:1) to afford the
desired product 3(aew).
Scheme 5. Plausible mechanism for the formation of
reaction of -keto esters with isatins.
g-addition product in the aldol
b
3. Conclusion
In summary, we have demonstrated DABCO catalyzed, novel,
regioselective -addition of -keto esters to isatins under metal-
g
b
free condition for the efficient synthesis of diversely functional-
ized 3-substituted 3-hydroxy-2-oxindoles framework. The discov-
ery and development of this method led to a general route for the
straightforward preparation of new class of 3-hydroxy-2-oxindole
structural scaffolds in very good yields under mild reaction condi-
tion from readily available starting materials. In addition to sim-
plicity, this method has one salient feature in its ability to tolerate
4.2.1. Methyl 4-(3-hydroxy-5-nitro-2-oxo-2,3-dihydro-1H-indol-3-
yl)-3-oxobutanoate (3a, Table 2). Yield: 94%; Time 5.2 h; Rf (50%
EtOAc/hexanes) 0.13; Pale yellow solid; mp 161e163 ꢀC; 1H NMR
(500 MHz, DMSO-d6)
J¼9.1 Hz, 1H), 6.41 (br s, 1H), 3.67 (s, 3H), 3.62e3.27 (m, 4H) ppm;
13C NMR (50 MHz, DMSO-d6)
: 199.39, 178.29, 166.74, 148.76,
142.28, 131.55, 126.12, 119.48, 109.63, 72.28, 51.83, 49.39,
48.80 ppm; IR (KBr):
¼3256, 1713, 1626, 1526, 1480, 1338, 1254,
d: 10.85 (br s, 1H), 8.23e8.11 (m, 2H), 6.98 (d,
d
a variety of functionalized isatins as well as
b
-keto esters. Such a 3-
n

6420
P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
1188, 1107, 1072, 908, 841, 747, 592 cmꢁ1; MS (ESI): m/z¼331
[MþNa]þ; HRMS (ESI): m/z calcd for C13H12N2O7Na
[MþNa]þ¼331.05367, found 331.05412.
(50% EtOAc/hexanes) 0.50; White solid; mp 105e108 ꢀC; 1H NMR
(500 MHz, CDCl3) : 7.56 (br s, 1H), 7.47e7.29 (m, 7H), 6.62 (d,
d
J¼8.4 Hz,1H), 5.00 (d, J¼15.1 Hz,1H), 4.88 (d, J¼15.1 Hz,1H), 4.22 (q,
J¼7.5 Hz, 2H), 3.67e3.62 (m, 4H), 1.33 (t, J¼7.4 Hz, 3H) ppm; 13C
4.2.2. Methyl 4-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-
yl)-3-oxobutanoate (3b, Table 2). Yield: 92%; Time 6 h; Rf (50%
EtOAc/hexanes) 0.13; White solid; mp 112e114 ꢀC; 1H NMR
NMR (50 MHz, CDCl3) d: 199.91, 176.22, 166.44, 141.92, 134.74,
132.57, 131.35, 128.76, 127.68, 127.05, 115.70, 111.19, 73.51, 61.56,
49.61, 49.06, 43.94, 13.95 ppm; IR (KBr):
n
¼3296, 2973, 2929, 1741,
(200 MHz, CDCl3þDMSO-d6)
d
: 10.27 (br s, 1H), 7.35 (d, J¼1.1 Hz,
1699, 1607, 1484, 1364, 1276, 1172, 1034, 951, 802, 698, 560,
475 cmꢁ1; MS (ESI): m/z¼468 [MþNa]þ; HRMS (ESI): m/z calcd for
C21H20BrNO5Na [MþNa]þ¼468.04171, found 468.04211.
1H), 7.26 (dd, J¼8.1, 1.1 Hz, 1H), 6.75 (d, J¼8.1 Hz, 1H), 6.11 (br s, 1H),
3.67 (s, 3H), 3.61e3.12 (m, 4H) ppm; 13C NMR (50 MHz,
CDCl3þDMSO-d6)
d: 200.31, 177.51, 167.25, 141.91, 133.68, 131.68,
130.05, 126.79, 111.50, 72.53, 51.80, 49.27, 48.98 ppm; IR (KBr):
4.2.8. Ethyl 4-[3-hydroxy-1-(hydroxymethyl)-5-iodo-2-oxo-2,3-
dihydro-1H-indol-3-yl]-3-oxobutanoate (3h, Table 2). Yield: 82%;
Time 7.5 h; Rf (50% EtOAc/hexanes) 0.22; White solid; mp
n
¼3235, 2960, 1698, 1618, 1446, 1349, 1258, 1184, 1062, 825, 729,
635 cmꢁ1; MS (ESI): m/z¼364 [MþNa]þ; HRMS (ESI): m/z calcd for
C13H12BrNO5Na [MþNa]þ¼363.97911, found 363.97952.
104e106 ꢀC; 1H NMR (200 MHz, CDCl3þDMSO-d6)
d: 7.65e7.48 (m,
2H), 6.67 (d, J¼8.3 Hz, 1H), 6.51 (br s, 1H), 6.11 (br s, 1H), 4.16 (q,
4.2.3. Methyl 4-(4,7-dichloro-3-hydroxy-2-oxo-2,3-dihydro-1H-in-
dol-3-yl)-3-oxobutanoate (3c, Table 2). Yield: 93%; Time 6 h; Rf (50%
EtOAc/hexanes) 0.30; White solid; mp 134e136 ꢀC; 1H NMR
J¼7.8 Hz, 2H), 3.66e3.14 (m, 6H), 1.26 (t, J¼7.8 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3þDMSO-d6)
d: 200.19, 176.71, 163.96, 141.89,
136.55, 132.78, 131.11, 111.19, 82.44, 71.81, 64.30, 60.13, 49.87, 48.91,
(500 MHz, CDCl3þDMSO-d6)
d
: 10.67 (br s, 1H), 7.17 (d, J¼9.0 Hz,
13.81 ppm; IR (KBr):
n
¼3248, 2981, 1443, 1698, 1616, 1477, 1347,
1H), 6.85 (d, J¼9.0 Hz,1H), 6.32 (br,1H), 3.83 (d, J¼18.0 Hz,1H), 3.64
1185, 1089, 1025, 826, 729, 530 cmꢁ1; MS (ESI): m/z¼456 [MþNa]þ;
HRMS (ESI): m/z calcd for C15H16INO6Na [MþNa]þ¼455.99145,
found 455.99179.
(s, 3H), 3.52e3.45 (m, 2H), 3.42e3.39 (d, J¼18.0 Hz, 1H) ppm; 13C
NMR (75 MHz, CDCl3þDMSO-d6)
d: 199.32, 177.05, 166.52, 142.05,
130.13, 128.52, 123.07, 113.19, 107.02, 73.98, 51.77, 48.61, 47.76 ppm;
IR (KBr):
n
¼3424, 2926, 1743, 1621, 1468, 1104, 801, 466 cmꢁ1; MS
4.2.9. tert-Butyl 4-(3-hydroxy-5-nitro-2-oxo-2,3-dihydro-1H-indol-
3-yl)-3-oxobutanoate (3i, Table 2). Yield: 97%; Time 5 h; Rf (50%
EtOAc/hexanes) 0.18; Pale yellow solid; mp 155e157 ꢀC; 1H NMR
(ESI): m/z¼354 [MþNa]þ; HRMS (ESI): m/z calcd for
C13H11Cl2NO5Na [MþNa]þ¼353.99065, found 353.99098.
(500 MHz, CDCl3þDMSO-d6)
d: 10.66 (br s, 1H), 8.09e7.98 (m, 2H),
4.2.4. Methyl 4-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-
yl)-3-oxobutanoate (3d, Table 2). Yield: 90%; Time 6 h; Rf (50%
EtOAc/hexanes) 0.28; White solid; mp 162e164 ꢀC; 1H NMR
6.86 (d, J¼9.0 Hz, 1H), 6.21 (br s, 1H), 3.41 (d, J¼17.0 Hz, 1H), 3.28
(d, J¼15.0 Hz, 1H), 3.24e3.17 (m, 2H), 1.30 (s, 9H) ppm; 13C NMR
(50 MHz, CDCl3þDMSO-d6)
d: 198.87, 177.62, 164.71, 148.25, 141.63,
(200 MHz, CDCl3þDMSO-d6)
d: 10.30 (br s, 1H), 7.57e7.43 (m, 2H),
131.06, 125.42, 118.80, 108.89, 80.88, 71.64, 49.80, 48.86,
6.65 (d, J¼8.1 Hz, 1H), 6.12 (br s, 1H), 3.67 (s, 3H), 3.57e3.21 (m,
26.91 ppm; IR (KBr):
n
¼3265, 2980, 1712, 1626, 1526, 1480, 1336,
4H) ppm; 13C NMR (75 MHz, CDCl3þDMSO-d6)
d: 198.29, 175.71,
1256, 1187, 1071, 841, 746, 589 cmꢁ1; MS (ESI): m/z¼373 [MþNa]þ;
HRMS (ESI): m/z calcd for C16H18N2O7Na [MþNa]þ¼373.10062,
found 373.10173.
165.44, 140.66, 135.71, 132.10, 130.36, 110.40, 82.07, 70.72, 50.18,
48.82, 47.40 ppm; IR (KBr):
n
¼3252, 1699, 1616, 1477, 1333, 1186,
1058, 827, 731, 531 cmꢁ1; MS (ESI): m/z¼412 [MþNa]þ; HRMS
(ESI): m/z calcd for C13H12NO5INa [MþNa]þ¼411.96524, found
411.96595.
4.2.10. tert-Butyl 4-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-
3-yl)-3-oxobutanoate (3j, Table 2). Yield: 93%; Time 5.2 h; Rf (50%
EtOAc/hexanes) 0.14; White solid; mp 159e161 ꢀC; 1H NMR
4.2.5. Ethyl 4-(3-hydroxy-5-nitro-2-oxo-2,3-dihydro-1H-indol-3-yl)-
3-oxobutanoate (3e, Table 2). Yield: 95%; Time 6 h; Rf (50% EtOAc/
hexanes) 0.22; Pale yellow solid; mp 142e144 ꢀC; 1H NMR
(500 MHz, CDCl3þDMSO-d6) : 10.19 (br s, 1H), 7.53 (d, J¼2.0 Hz,
d
1H), 7.49 (dd, J¼8.0, 2.0 Hz, 1H), 6.67 (d, J¼8.0 Hz, 1H), 6.10 (br s,
1H), 3.40 (d, J¼16.0 Hz, 1H), 3.36e3.30 (m, 2H), 3.16 (d, J¼17.0 Hz,
(200 MHz, DMSO-d6)
d: 10.89 (br s, 1H), 8.21e8.09 (m, 2H), 6.97 (d,
1H), 1.44 (s, 9H) ppm; 13C NMR (50 MHz, CDCl3þDMSO-d6)
d:
J¼9.2 Hz, 1H), 6.29 (br s, 1H), 4.09 (q, J¼7.2 Hz, 2H), 3.69e3.19 (m,
198.28, 175.87, 164.18, 140.86, 136.02, 132.28, 130.76, 110.58, 82.15,
4H), 1.21 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6)
d
:
79.64, 71.10, 49.21, 48.07, 26.27 ppm; IR (KBr):
n
¼3249, 2980, 1737,
199.80, 178.59, 166.55, 149.03, 142.43, 131.78, 126.37, 119.62, 109.91,
1697, 1616, 1552, 1477, 1346, 1186, 1085, 1050, 829, 730, 534 cmꢁ1
;
72.41, 61.03, 49.57, 49.19, 13.87 ppm; IR (KBr):
n
¼3260, 2927, 1749,
MS (ESI): m/z¼454 [MþNa]þ; HRMS (ESI): m/z calcd for
1712, 1626, 1526, 1479, 1337, 1255, 1188, 1107, 1072, 841, 747,
587 cmꢁ1; MS (ESI): m/z¼345 [MþNa]þ; HRMS (ESI): m/z calcd for
C14H14N2O7Na [MþNa]þ¼345.06932, found 345.07007.
C16H18INO5Na [MþNa]þ¼454.01219, found 454.01203.
4.2.11. Ethyl 2-benzyl-4-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-
yl)-3-oxobutanoate (3k, Table 2). Yield: 92%; Time 8 h; Rf (50%
EtOAc/hexanes) 0.40; White solid; mp 170e172 ꢀC; 1H NMR
(200 MHz, CDCl3þDMSO-d6) (inseparable diastereomeric ratio,
4.2.6. Ethyl 4-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-
yl)-3-oxobutanoate (3f, Table 2). Yield: 91%; Time 5.8 h; Rf (50%
EtOAc/hexanes) 0.24; White solid; mp 153e155 ꢀC; 1H NMR
major/minor, 52:48, * denotes minor diastereomer peaks) d: 10.09
(200 MHz, DMSO-d6)
d
: 10.28 (br s, 1H), 7.35 (d, J¼1.5 Hz, 1H), 7.27
(br s, 1H), 10.09* (br s, 1H), 7.27e6.96 (m, 7H), 7.27e6.96* (m, 7H),
6.93e6.76 (m, 2H), 6.93e6.76* (m, 2H), 5.90 (br s, 1H), 5.88* (br s,
1H), 4.04 (q, J¼7.0 Hz, 2H), 4.04* (q, J¼7.0 Hz, 2H), 3.87e3.82* (m,
1H), 3.80e3.76 (m, 1H), 3.39e3.22 (m, 2H), 2.97e2.91 (m, 2H),
2.97e2.91* (m, 2H),1.16 (t, J¼7.0 Hz, 3H),1.13* (t, J¼7.0 Hz, 3H) ppm;
13C NMR (50 MHz, CDCl3þDMSO-d6) (inseparable diastereomeric
(dd, J¼8.1, 1.5 Hz, 1H), 6.75 (d, J¼8.1 Hz, 1H), 6.10 (br s, 1H), 4.10 (q,
J¼7.0 Hz, 2H), 3.77e3.22 (m, 4H), 1.21 (t, J¼7.0 Hz, 3H) ppm; 13C
NMR (50 MHz, DMSO-d6) d: 199.58, 177.68, 166.45, 141.60, 133.29,
131.70, 126.87, 113.60, 111.65, 72.96, 60.73, 49.60, 49.43, 14.02 ppm;
IR (KBr):
n
¼3344, 2985, 1739, 1711, 1621, 1479, 1344, 1278, 1184,
1062, 813, 577 cmꢁ1; MS (ESI): m/z¼378 [MþNa]þ; HRMS (ESI): m/z
calcd for C14H14BrNO5Na [MþNa]þ¼377.99476, found 377.99470.
ratio, major/minor, 54:46, * denotes minor diastereomer peaks) d:
200.85*, 200.75, 177.95, 177.87*, 168.06*, 167.91, 142.45*, 142.31,
137.76*, 137.63, 130.66*, 130.51, 128.94*, 128.43, 128.09, 126.18*,
123.47*, 123.21, 121.26*, 121.20, 109.63, 72.65*, 72.51, 60.90*, 60.87,
4.2.7. Ethyl 4-(1-benzyl-5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-
indol-3-yl)-3-oxobutanoate (3g, Table 2). Yield: 89%; Time 6.5 h; Rf
60.12*, 59.90, 49.22, 49.08*, 33.05, 13.67 ppm; IR (KBr):
n
¼3068,

P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
6421
2937, 2876, 2717, 1703, 1636, 1591, 1508, 1457, 1333, 1112, 995, 833,
761, 632, cmꢁ1; MS (ESI): m/z¼390 [MþNa]þ; HRMS (ESI): m/z
calcd for C21H21NO5Na [MþNa]þ¼390.13119, found 390.13172.
MS (ESI): m/z¼379 [MþNa]þ; HRMS (ESI): m/z calcd for
C14H13ClN2O7Na [MþNa]þ¼379.03035, found 379.03147.
4.2.15. Ethyl 4-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-
yl)-2-chloro-3-oxobutanoate (3o, Table 2). Yield: 93%; Time 6 h; Rf
(50% EtOAc/hexanes) 0.27; White solid; mp 134e136 ꢀC; 1H NMR
(200 MHz, DMSO-d6) (inseparable diastereomeric ratio, major/mi-
4.2.12. Ethyl 2-benzyl-4-(3-hydroxy-5-nitro-2-oxo-2,3-dihydro-1H-
indol-3-yl)-3-oxobutanoate (3l, Table 2). Yield: 95%; Time 5.8 h; Rf
(50% EtOAc/hexanes) 0.34; White solid; mp 174e176 ꢀC; 1H NMR
(200 MHz, DMSO-d6) (inseparable diastereomeric ratio, major/mi-
nor, 52:48, * denotes minor diastereomer peaks) d: 10.36* (br s, 1H),
nor, 54:46, * denotes minor diastereomer peaks)
d
: 10.81* (br s, 1H),
10.34 (br s, 1H), 7.37 (d, J¼1.7 Hz, 1H), 7.37* (d, J¼1.7 Hz, 1H), 7.29
(dd, J¼8.1, 1.7 Hz, 1H), 7.29* (dd, J¼8.1, 1.7 Hz, 1H), 6.75 (d, J¼8.1 Hz,
1H), 6.75* (d, J¼8.1 Hz, 1H), 6.27* (br s, 1H), 6.20 (br s, 1H), 5.36 (s,
1H), 5.20* (s, 1H), 4.25 (q, J¼7.0 Hz, 2H) 4.21* (q, J¼7.0 Hz, 2H),
3.57e3.55 (m, 2H), 3.30e3.20* (m, 2H), 1.32* (t, J¼7.0 Hz, 3H), 1.28
(t, J¼7.0 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) (inseparable
diastereomeric ratio, major/minor, 52:48, * denotes minor di-
astereomer peaks) d: 195.73, 195.61*, 177.28, 164.66, 164.57*, 142.11,
142.05*, 133.18, 132.10, 131.96*, 126.89*, 126.84, 113.28, 113.25*,
111.80, 72.73*, 72.53, 63.01*, 62.95, 61.26*, 61.15, 46.89, 46.46*,
10.80 (br s, 1H), 8.18e8.08 (m, 1H), 8.18e8.08* (m, 1H), 8.03* (d,
J¼1.2 Hz, 1H), 7.87 (d, J¼1.2 Hz, 1H), 7.29e7.06 (m, 4H), 7.29e7.06*
(m, 4H), 7.03e6.93 (m, 2H), 7.03e6.93* (m, 2H), 6.21* (br s, 1H), 6.16
(br s, 1H), 4.08 (q, J¼7.2 Hz, 2H), 4.03* (q, J¼7.2 Hz, 2H), 3.90e3.84
(m, 1H), 3.82e3.76* (m, 1H), 3.57 (d, J¼18.1 Hz, 1H), 3.37* (d,
J¼18.1 Hz, 1H), 3.33* (d, J¼18.0 Hz, 1H), 3.18 (d, J¼18.0 Hz, 1H),
2.98e2.92 (m, 2H), 2.98e2.92* (m, 2H), 1.19(t, J¼7.2 Hz, 3H), 1.13*(t,
J¼7.2 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) (inseparable di-
astereomeric ratio, major/minor, 54:46,
* denotes minor di-
astereomer peaks) : 201.92, 201.84*,178.16,168.26*,168.12,149.53,
d
13.84 ppm; IR (KBr):
n
¼3251, 1697, 1619, 1480, 1447, 1348, 1260,
149.44*, 141.91*, 141.85, 137.86*, 137.78, 132.13, 132.10*, 128.67*,
128.58, 128.23*, 128.12, 126.63*, 126.55, 126.43*, 126.31, 119.36,
119.24*, 109.70*, 109.59, 71.91*, 71.85, 61.00, 59.31*, 59.03, 49.17,
1188, 1062, 1019, 827, 729, 539 cmꢁ1; MS (ESI): m/z¼412 [MþNa]þ;
HRMS (ESI): m/z calcd for C14H13BrClNO5Na [MþNa]þ¼411.95578,
found 411.95597.
48.99*, 32.90*, 32.81, 13.79, 13.70* ppm; IR (KBr):
n
¼3257, 1711,
1626, 1525, 1457, 1336, 1258, 1188, 1104, 844, 748, 698, 594 cmꢁ1
;
4.2.16. Ethyl 2-chloro-4-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-
indol-3-yl)-3-oxobutanoate (3p, Table 2). Yield: 89%; Time 6 h; Rf
(50% EtOAc/hexanes) 0.31; White solid; mp 154e156 ꢀC; 1H NMR
(500 MHz, CDCl3þDMSO-d6) (inseparable diastereomeric ratio,
MS (ESI): m/z¼435 [MþNa]þ; HRMS (ESI): m/z calcd for
C21H20N2O7Na [MþNa]þ¼435.11627, found 435.11667.
4.2.13. Ethyl 2-benzyl-4-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-
indol-3-yl)-3-oxobutanoate (3m, Table 2). Yield: 94%; Time 6 h; Rf
(50% EtOAc/hexanes) 0.36; White solid; mp 259e261 ꢀC; 1H NMR
(200 MHz, CDCl3þDMSO-d6) (inseparable diastereomeric ratio,
major/minor, 55:45, * denotes minor diastereomer peaks) d: 10.26*
(br s, 1H), 10.22 (br s, 1H), 7.50 (d, J¼2.0 Hz, 1H), 7.50* (d, J¼2.0 Hz,
1H), 7.47 (dd, J¼7.9, 2.0 Hz, 1H), 7.47* (dd, J¼7.9, 2.0 Hz, 1H), 6.67 (d,
J¼7.9 Hz, 1H), 6.67* (d, J¼7.9 Hz, 1H), 6.17* (br, s, 1H), 6.09 (br, s, 1H),
5.21 (s, 1H), 5.02* (s, 1H), 4.26* (q, J¼7.9 Hz, 2H), 4.22 (q, J¼7.9 Hz,
2H), 3.48* (d, J¼16.8 Hz, 1H), 3.44 (d, J¼16.8 Hz, 1H), 3.28* (d,
J¼16.8 Hz, 1H), 3.21 (d, J¼16.8 Hz, 1H), 1.31 (t, J¼7.9 Hz, 3H), 1.28* (t,
J¼7.9 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6) (inseparable di-
astereomeric ratio, major/minor, 55:44,* denotes minor di-
major/minor, 52:48, * denotes minor diastereomer peaks) d: 10.27
(br s, 1H), 10.27* (br s, 1H), 7.54e7.30 (m, 2H), 7.54e7.30* (m, 2H),
7.27e7.14 (m, 3H), 7.27e7.14* (m, 3H), 7.09e7.01 (m, 2H),
7.09e7.01* (m, 2H), 6.67 (d, J¼8.0 Hz, 1H), 6.65* (d, J¼8.0 Hz, 1H),
6.05 (br s, 1H), 6.01* (br s, 1H), 4.08 (q, J¼6.98 Hz, 2H), 4.08* (q,
J¼6.98 Hz, 2H), 3.91e3.84 (m, 1H), 3.82e3.75* (m, 1H), 3.52e3.28
(m, 2H), 2.98e2.94 (m, 2H), 2.98e2.94* (m, 2H), 1.18 (t, J¼7.0 Hz,
3H), 1.18* (t, J¼7.0 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3þDMSO-
d6) (inseparable diastereomeric ratio, major/minor, 52:48,* denotes
astereomer peaks) d: 194.13*, 194.04, 176.23, 163.49, 141.47*, 141.30,
136.87, 132.25, 131.99*, 131.52, 111.42, 82.79, 71.97, 71.88*, 61.82,
61.70*, 60.19, 60.01*, 45.84*, 45.35, 13.03, 12.97* ppm; IR (KBr):
n
¼3194, 1759, 1697, 1615, 1478, 1443, 1346, 1186, 1018, 827, 729, 637,
minor diastereomer peaks)
d: 200.73*, 200.61, 177.23, 177.17*,
532 cmꢁ1; MS (ESI): m/z¼460 [MþNa]þ; HRMS (ESI): m/z calcd for
166.77*, 167.62, 142.34*, 142.28, 137.66*, 137.40, 133.38*, 133.32,
131.93, 131.78*, 128.35, 128.15, 128.06*, 126.23, 126.17*, 112.09*,
112.03, 83.43*, 83.32, 72.46*, 72.38, 60.91, 60.86*, 60.04, 59.93*,
C14H13ClINO5Na [MþNa]þ¼459.94191, found 459.94235.
4.2.17. Ethyl
2-chloro-4-(3-hydroxy-2-oxo-1-phenyl-2,3-dihydro-
52.10, 52.01*, 33.25*, 33.05, 13.87*, 13.73 ppm; IR (KBr):
n
¼3241,
1H-indol-3-yl)-3-oxobutanoate (3q, Table 2). Yield: 90%; Time 7 h;
Rf (50% EtOAc/hexanes) 0.54; Yellow semi solid; mp 50 ꢀC; 1H NMR
(200 MHz, CDCl3) (inseparable diastereomeric ratio, major/minor,
1742, 1699, 1616, 1444, 1348, 1186, 827, 698, 582 cmꢁ1; MS (ESI): m/
z¼516 [MþNa]þ; HRMS (ESI): m/z calcd for C21H20INO5Na
[MþNa]þ¼516.02784, found 516.02797.
53:47, * denotes minor diastereomer peaks) d: 7.71e7.33 (m, 7H),
7.71e7.33* (m, 7H), 7.25e7.18 (m, 1H), 7.25e7.18* (m, 1H), 7.08e7.01
(m, 1H), 7.08e7.01* (m, 1H), 6.75 (br s, 1H), 6.72* (br s, 1H), 4.78* (s,
1H), 4.75 (s, 1H), 4.19 (q, J¼7.2 Hz, 2H), 4.14* (q, J¼7.2 Hz, 2H),
3.82e3.68* (m, 2H), 3.60e3.41 (m 2H),1.22 (t, J¼7.2 Hz, 3H),1.71* (t,
J¼7.2 Hz, 3H) ppm; 13C NMR (50 MHz, CDCl3) (inseparable di-
4.2.14. Ethyl 2-chloro-4-(3-hydroxy-5-nitro-2-oxo-2,3-dihydro-1H-
indol-3-yl)-3-oxobutanoate (3n, Table 2). Yield: 94%; Time 5.2 h; Rf
(50% EtOAc/hexanes) 0.22; Pale yellow solid; mp 122e124 ꢀC; 1H
NMR (500 MHz, DMSO-d6) (inseparable diastereomeric ratio, ma-
jor/minor, 57:43, * denotes minor diastereomer peaks)
d
: 10.84 (br s,
astereomeric ratio, major/minor, 53:47,
*
denotes minor di-
1H),10.83* (br s,1H), 8.18e8.09 (m, 2H), 8.18e8.09* (m, 2H), 6.97 (d,
J¼9.0 Hz, 1H), 6.97* (d, J¼9.0 Hz, 1H), 6.38 (br s, 1H), 6.33* (br s, 1H),
5.24e5.16 (m, 1H), 5.11e5.06* (m, 1H), 4.21 (q, J¼7.0 Hz, 2H), 4.24*
(q, J¼7.0 Hz, 2H), 3.67 (dd, J¼17.8, 1.97 Hz, 1H), 3.64* (d, J¼17.8 Hz,
1H), 3.43 (d, J¼17.8 Hz, 1H), 3.37* (dd, J¼17.8, 1.97 Hz, 1H), 1.30* (t,
J¼7.0 Hz, 3H), 1.26 (t, J¼7.0 Hz, 3H) ppm; 13C NMR (50 MHz, DMSO-
d6) (inseparable diastereomeric ratio, major/minor, 57:43, * denotes
astereomer peaks)
d: 195.69*, 195.32, 176.14*, 175.89, 169.09*,
168.72, 144.04, 143.99*, 133.85, 129.96*, 129.49, 128.20, 128.09*,
126.51, 126.22*, 123.83*, 123.79, 123.36, 109.79, 109.60*, 73.58,
63.19*, 63.16, 61.03*, 60.86, 46.55, 46.41*, 13.70*, 13.67 ppm; IR
(KBr):
n
¼3250, 1729, 1613, 1500, 1463, 1372, 1296, 1253, 1207, 1023,
757, 700, 578 cmꢁ1; MS (ESI): m/z¼410 [MþNa]þ; HRMS (ESI): m/z
calcd for C20H18ClNO5Na [MþNa]þ¼410.07657, found 410.07611.
minor diastereomer peaks)
d: 195.93, 195.65*, 177.97, 177.96*,
164.44, 164.41*, 149.38, 149.29*, 142.06, 132.13*, 131.70, 126.69,
126.53*,119.75*,119.66,109.85,109.73*, 72.18*, 72.05, 62.86*, 62.78,
4.2.18. Ethyl 4-chloro-4-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-
indol-3-yl)-3-oxobutanoate (3r, Table 2). Yield: 82%; Time 8 h; Rf
(50% EtOAc/hexanes) 0.40; Light orange solid; mp 102e104 ꢀC; 1H
NMR (200 MHz, DMSO-d6) (inseparable diastereomeric ratio,
61.12*, 60.89, 46.76*, 46.39, 13.67 ppm; IR (KBr):
n
¼3263, 1715,
1626, 1526, 1477, 1338, 1253, 1185, 1101, 1017, 843, 745, 588 cmꢁ1
;

6422
P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
major/minor, 58:42, * denotes minor diastereomer peaks)
d
: 10.57
MS (ESI): m/z¼452 [MþNa]þ; HRMS (ESI): m/z calcd for
C16H16INO5Na [MþNa]þ¼451.99654, found 451.99671.
(br s, 1H),10.50* (br s,1H), 7.77* (d, J¼1.5 Hz,1H), 7.58e7.55 (m,1H),
7.54e7.52* (m, 1H), 7.49 (d, J¼1.5 Hz, 1H), 7.13 (br s, 1H), 6.69* (br s,
1H), 6.69 (d, J¼8.1 Hz, 1H), 6.67* (d, J¼8.1 Hz, 1H), 5.04* (s, 1H), 4.96
(s, 1H), 4.22 (q, J¼7.2 Hz, 2H), 4.19* (q, J¼7.2 Hz, 2H), 4.16e4.09* (m,
2H), 4.06e3.92 (m, 2H), 1.31(t, J¼7.2 Hz, 3H), 1.25* (t, J¼7.2 Hz,
3H) ppm; 13C NMR (50 MHz, DMSO-d6) (inseparable diastereomeric
4.2.22. Ethyl 2,2-diethyl-4-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-
3-yl)-3-oxobutanoate (3v, Table 2). Yield: 81%; Time 8 h; Rf (50%
EtOAc/hexanes) 0.25; White solid; mp 105e107 ꢀC; 1H NMR
(300 MHz, DMSO-d6)
d: 9.98 (br s, 1H), 7.30e7.06 (m, 2H),
ratio, major/minor, 58:42,* denotes minor diastereomer peaks)
d
:
7.03e6.79 (m, 2H), 5.86 (br s, 1H), 4.31e4.05 (m, 2H), 3.30 (d,
J¼17.9 Hz, 1H), 3.26 (d, J¼17.9 Hz, 1H), 1.94e1.65 (m, 4H), 1.23 (t,
J¼7.2 Hz, 3H), 0.67 (t, J¼7.6 Hz, 3H), 0.48 (t, J¼7.6 Hz, 3H) ppm; 13C
195.62, 195.28*, 175.20, 175.02*, 166.28, 166.24*, 142.44, 142.25*,
138.52, 138.30*, 134.15, 133.16*, 131.01*, 129.13, 112.37*, 112.33,
84.07, 83.97*, 76.68, 75.58*, 67.04*, 62.80, 60.97, 60.90*, 49.12,
NMR (125 MHz, DMSO-d6) d: 203.46, 177.92, 171.41, 142.70, 131.11,
47.08*, 13.98, 13.87* ppm; IR (KBr):
n
¼3324, 1732, 1615, 1472, 1436,
128.93, 123.33, 120.99, 109.31, 72.21, 62.78, 60.87, 46.05, 22.70,
1324, 1181, 1132, 819, 625 cmꢁ1; MS (ESI): m/z¼460 [MþNa]þ;
HRMS (ESI): m/z calcd for C14H13ClINO5Na [MþNa]þ¼459.94191,
found 459.94243.
22.49, 13.82, 7.60, 7.47 ppm; IR (KBr):
n
¼3264, 2976, 1739, 1700,
1627, 1474, 1211, 1028, 756 cmꢁ1; MS (ESI): m/z¼356 [MþNa]þ;
HRMS (ESI): m/z calcd for C18H23NO5Na [MþNa]þ¼356.14739,
found 356.14746.
4.2.19. 3-Hydroxy-5-nitro-3-[2-oxo-2-(2-oxotetrahydro furan-3-yl)
ethyl]-1,3-dihydro-2H-indol-2-one (3s, Table 2). Yield: 81%; Time
7.2 h; Rf (50% EtOAc/hexanes) 0.33; White solid; mp 247e249 ꢀC; 1H
NMR (500 MHz, DMSO-d6) (inseparable diastereomeric ratio, major/
4.2.23. Ethyl 4-(5-chloro-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-
yl)-2,2-diethyl-3-oxobutanoate (3w, Table 2). Yield: 87%; Time 8 h;
Rf (50% EtOAc/hexanes) 0.26; White solid; mp 172e174 ꢀC; 1H NMR
minor, 52:48, * denotes minordiastereomer peaks)
d
: 10.79 (br s,1H),
(500 MHz, DMSO-d6)
d
: 10.36 (br s, 1H), 7.32 (d, J¼1.2 Hz, 1H), 7.22
10.79* (br s, 1H), 8.20e8.05 (m, 2H), 8.20e8.05* (m, 2H), 6.96 (d,
J¼7.0 Hz, 1H), 6.96* (d, J¼7.0 Hz, 1H), 6.31* (br s, 1H), 6.28 (br s, 1H),
4.30e4.19 (m, 2H), 4.30e4.19* (m, 2H), 3.99e3.94 (m, 1H),
3.99e3.94* (m, 1H), 3.89* (d, J¼17.8 Hz, 1H), 3.68 (d, J¼17.8 Hz, 1H),
3.55* (d, J¼17.8 Hz, 1H), 3.40 (d, J¼17.8 Hz, 1H), 2.42e2.29 (m, 2H),
2.26e2.12* (m, 2H) ppm; 13C NMR (50 MHz, DMSO-d6) (inseparable
diastereomeric ratio, major/minor, 52:48,* denotes minor di-
(dd, J¼8.2, 1.2 Hz, 1H), 6.79 (d, J¼1.2 Hz, 1H), 6.12 (br s, 1H),
4.18e4.08 (m, 2H), 3.43 (d, J¼18.2 Hz, 1H), 3.13 (d, J¼18.2 Hz, 1H),
1.81e1.60 (m, 4H), 1.17 (t, J¼7.1 Hz, 3H), 0.60 (t, J¼7.5 Hz, 3H), 0.45
(t, J¼7.5 Hz, 3H) ppm; 13C NMR (125 MHz, DMSO-d6)
d: 203.77,
177.61, 171.25, 148.84, 133.24, 128.66, 125.09, 123.74, 110.72, 72.34,
62.73, 60.89, 45.95, 22.72, 22.42, 13.79, 7.55, 7.40 ppm; IR (KBr):
n
¼3242, 2974, 1701, 1622, 1478, 1238, 1183, 1132, 833 cmꢁ1; MS
astereomer peaks)
d
: 200.06*, 200.05, 178.20*, 178.12, 172.44,
(ESI): m/z¼390 [MþNa]þ; HRMS (ESI): m/z calcd for C18H22ClNO5Na
[MþNa]þ¼390.10842, found 390.10851.
149.28*, 149.23, 141.98, 132.06*, 132.04, 126.16, 119.61*, 119.32,
109.42, 72.05*, 71.98, 66.73*, 66.61, 51.92*, 51.42, 48.74, 48.55*,
23.30*, 23.14 ppm; IR (KBr):
n
¼3246, 1763, 1713, 1628, 1526,
4.2.24. (5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)propane-
dinitrile (3x, Scheme 4). Yield: 98%; Time 8 h; Rf (50% EtOAc/hex-
anes) 0.34; Red solid; mp 224e226 ꢀC; 1H NMR (500 MHz, DMSO-
1459, 1336, 1148, 1109, 1017, 911, 749, 639 cmꢁ1; MS (ESI):
m/z¼343 [MþNa]þ; HRMS (ESI): m/z calcd for C14H12N2O7
[MþNa]þ¼343.05367, found 343.05393.
d6)
d
: 10.62 (br s, 1H), 7.48 (d, J¼1.1 Hz, 1H), 7.37 (dd, J¼8.3, 1.1 Hz,
1H), 6.61 (d, J¼1.1 Hz, 1H) ppm; 13C NMR (125 MHz, DMSO-d6)
d:
4.2.20. Ethyl 3-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-2-
oxocyclopentanecarboxylate (3t, Table 2). Yield: 94%; Time 7.8 h;
Rf (50% EtOAc/hexanes) 0.37; Yellow solid; mp 101e103 ꢀC; 1H NMR
(200 MHz, DMSO-d6) (complex inseparable diastereomeric ratio,
171.26, 170.01, 147.14, 134.54, 131.11, 126.01, 124.24, 113.8, 113.3,
109.94, 76.21 ppm; IR (KBr):
n
¼3258, 2230, 2169, 2109, 1716, 1619,
1587, 1465, 1340, 1185, 754 cmꢁ1; MS (ESI): m/z¼252 [MþNa]þ;
HRMS (ESI): m/z calcd for C11H4ClN3ONa [MþNa]þ¼251.99406,
found 251.99417.
53:17:17:9:4, spectral data given only for major isomer) d: 8.97 (br s,
1H), 7.34 (d, J¼7.4 Hz, 1H), 7.26 (t, J¼7.4 Hz, 1H), 7.06 (t, J¼7.4 Hz,
1H), 6.91 (d, J¼7.4 Hz,1H), 5.34 (br s,1H), 4.21 (q, J¼7.2 Hz, 2H), 3.34
(dd, J¼11.8, 8.5 Hz, 1H), 2.95 (dd, J¼11.1, 8.7 Hz, 1H), 2.29e2.08 (m,
4H), 1.28 (q, J¼7.2 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6)
(complex inseparable diastereomeric ratio, 53:17:17:9:4, spectral
4.2.25. 2-(5-Chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-
oxopentanenitrile (3y, Scheme 4). Yield: 78%; Time 8 h; Rf (50%
EtOAc/hexanes) 0.38; Orange red solid; mp 203e205 ꢀC; 1H NMR
(500 MHz, DMSO-d6)
d
: 10.61 (br s, 1H), 7.49 (d, J¼1.2 Hz, 1H), 7.36
data given only for major isomer)
d
: 209.85, 178.16, 168.67, 142.49,
(dd, J¼8.2, 1.2 Hz, 1H), 6.59 (d, J¼1.2 Hz, 1H), 3.16e3.05 (m, 2H), 1.51
129.37, 124.48, 121.78, 110.11, 75.84, 60.80, 55.87, 54.49, 24.49,
(t, J¼7.3 Hz, 3H) ppm; 13C NMR (125 MHz, DMSO-d6)
d: 203.78,
22.51, 14.02 ppm; IR (KBr):
n
¼3327, 2929, 1722, 1620, 1365, 1195,
171.23, 148.82, 140.11, 133.21, 128.65, 125.08, 123.73, 116.3, 115.8,
1099, 1026, 938, 752, 672 cmꢁ1; MS (ESI): m/z¼326 [MþNa]þ;
HRMS (ESI): m/z calcd for C16H17NO5Na [MþNa]þ¼326.09989,
found 326.09978.
110.71, 31.14, 8.10 ppm; IR (KBr):
n
¼3258, 2261, 1716, 1701, 1622,
1617, 1588, 1466, 1341, 1239, 1186, 833, 755 cmꢁ1; MS (ESI): m/
z¼283 [MþNa]þ; HRMS (ESI): m/z calcd for C13H9ClN2O2Na
[MþNa]þ¼283.02502, found 283.02511.
4.2.21. Ethyl 3-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-
yl)-2-oxocyclopentanecarboxylate (3u, Table 2). Yield: 95%; Time
7 h; Rf (50% EtOAc/hexanes) 0.41; White solid; mp 200e202 ꢀC; 1H
NMR (200 MHz, DMSO-d6) (complex inseparable diastereomeric
Acknowledgements
P.B.T. thanks CSIR New Delhi for the award of a fellowship and Dr.
Ahmed Kamal, Director IICT, for his support and encouragement.
ratio, 63:31:6, spectral data given only for major isomer) d: 10.31
(br s, 1H), 7.63 (d, J¼1.7 Hz, 1H), 7.51 (dd, J¼8.1, 1.70 Hz, 1H), 6.66 (d,
J¼8.1 Hz, 1H), 5.93 (br s, 1H), 4.15 (q, J¼7.2 Hz, 2H), 3.24e3.10 (m,
2H), 2.41e2.18 (m, 4H), 1.25 (t, J¼7.2 Hz, 3H) ppm; 13C NMR
(50 MHz, DMSO-d6) (complex inseparable diastereomeric ratio,
Supplementary data
63:31:6, spectral data given only for major isomer)
167.25, 141.05, 136.71, 131.79, 130.85, 111.04, 82.63, 74.31, 59.51,
54.52, 53.10, 23.20, 21.19, 12.74 ppm; IR (KBr):
¼3252, 2978, 1729,
1697, 1615, 1472, 1439, 1336, 1185, 1129, 1098, 947, 830, 688 cmꢁ1
d
: 208.12, 176.11,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.05.101.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
n
.

P.B. Thakur et al. / Tetrahedron 69 (2013) 6415e6423
6423
10. For reviews, see: (a) Mukaiyama, T. Org. React. 1982, 28, 203; (b) Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004.
References and notes
11. (a) Givaudan, S. USA Patent, WO2006/76821 A1, 2006. (b) Marvel, S. J. Org.
Chem. 1957, 22, 1451; (c) Huang, X.; Chen, X.; Chen, Y.; Zhang, A.; Li, X. Tetra-
hedron: Asymmetry 2008, 19, 2529.
12. (a) Huckin, S. N.; Weiler, L. J. Am. Chem. Soc. 1974, 96, 1082; (b) Xu, C. F.; Yuan, C.
Y. Tetrahedron 2005, 61, 2169.
1. For recent examples, see: (a) Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki,
K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Noguchi, M.; Nagata,
R. J. Med. Chem. 2001, 44, 4641; (b) Dounay, A. B.; Overman, L. E. Chem. Rev.
2003, 103, 2945; (c) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627; (d) Kagata, T.;
Saito, S.; Shigemori, H.; Ohsaki, A.; Kubota, H.; Kobayashi, J. J. Nat. Prod. 2006,
69, 1517; (e) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20; (f) Badillo, J. J.;
Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug Discovery Dev. 2010, 13, 758.
2. (a) Popp, F. D. Adv. Heterocycl. Chem. 1975, 18, 1; (b) da Silva, J. F. M.; Garden, S.
J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 12, 273.
3. For selected recent examples, see: (a) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2009, 11, 3854; (b) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381;
(c) Guan, X.-Y.; Wei, Y.; Shi, M. Chem.dEur. J. 2010, 16, 13617; (d) Liu, Y.-L.;
Wang, B.-L.; Cao, J.-J.; Chen, L.; Zhang, Y.-X.; Wang, C.; Zhou, J. J. Am. Chem. Soc.
2010, 132, 15176; (e) Zheng, K.; Yin, C.-K.; Liu, X.-H.; Lin, L.-L.; Feng, X.-M. An-
gew. Chem., Int. Ed. 2011, 50, 2573; (f) Guo, G. L.; Hua, Z.; Yu, B. L.; Bin, W.; Xiao,
F. H.; Jian, C.; Jing, C. T.; Xing, W. W. Tetrahedron 2012, 68, 3843.
4. (a) Xue, F.; Zhang, S.-L.; Liu, L.; Duan, W.-H.; Wang, W. Chem.dAsian J. 2009, 4,
1664; (b) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Chem.dEur. J. 2009, 15,
6790; (c) Chen, W.-B.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahe-
dron 2010, 66, 1441; (d) Qunsheng, G.; John, C.-G. Z. Tetrahedron Lett. 2012, 53,
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13. Freifeld, I.; Shojaei, H.; Langer, P. J. Org. Chem. 2006, 71, 4965.
14. Johnson, R. S.; Lovett, T. O.; Stevens, T. S. J. Chem. Soc. C 1970, 796.
15. (a) Meshram, H. M.; Ramesh, P.; Reddy, B. C.; Shreedhar, B.; Yadav, J. S. Tetra-
hedron 2011, 67, 3150; (b) Meshram, H. M.; Kumar, D. A.; Reddy, B. C.; Ramesh, P.
Synth. Commun. 2010, 40, 39; (c) Meshram, H. M.; Ramesh, P.; Kumar, A. S.;
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Reddy, B. C.; Kumar, G. S.; Thakur, P. B. Int. J. Org. Chem. 2012, 2, 159.
17. Reaction of 5-bromo isatin with ethyl acetoacetate under dianion method: to
a suspension of sodium hydride (80%, 54 mg, 1.8 mmol) in dry THF (2 mL) was
added ethyl acetoacetate (1.5 mmol) under nitrogen, after 30 min stirring at
room temperature, n-butyllithium (in hexane 1.6 M, 1.13 mL, 1.8 mmol) was
added at ꢁ15 to ꢁ10 ꢀC (ice-salt bath). The mixture was kept this temperature
for 30 min and then 5-bromo isatin (1.5 mmol) dissolved in 3 mL dry THF was
added at this temperature. Reaction was monitored by TLC and after 6 h, as
completion of reaction indicated by TLC, saturated NH4Cl (5 mL) was added to
the reaction mixture and the reaction mixture was extracted with ethyl acetate
(3ꢂ5 mL). The combined extract was dried and evaporated in vacuum and
crude reaction mixture was subjected for 1H NMR analysis.
5. Zrike, L. J. Am. Chem. Soc. 1936, 58, 49.
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8. (a) Marschalk, C. J. Prakt. Chem. (Leipzig) 1913, 2, 246; (b) Du Puis, L. J. Am. Chem.
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18. X-ray crystallographic data for compound 3k: crystal data for compound ethyl
2-benzyl-4-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-3-oxobutanoate (3k,
Table 2): C21H21NO5, M¼367.39, colorless block, 0.40ꢂ0.30ꢂ0.20 mm3, mono-
ꢀ
clinic, space group P21/c (No. 14), a¼13.0027(8), b¼9.9994(6), c¼18.3895(8) A,
3
3
ꢀ
ꢀ
b
¼128.820(3) , V¼1862.86(18) A , Z¼4, Dc¼1.310 g/cm , F000¼776, CCD area
ꢀ
detector, Mo Ka radiation, l
¼0.71073 A, T¼294(2) K, 2qmax¼50.0ꢀ, 17,355 re-
flections collected, 3273 unique (Rint¼0.0225). Final GoF¼1.020, R1¼0.0371,
wR2¼0.0999, R indices based on 2899 reflections with I>2
s(I) (refinement on
F2), 257 parameters,
m
¼0.094 mmꢁ1. CCDC 890261 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44(0) 1223 336 033; e-mail: deposit@ccdc.cam.ac.uk].
9. Simonetta, B.; Romeo, R.; Carmela, D. R.; Giampiero, S.; Vinicio, Z. Chem. Rev.
1995, 95, 1065.