DABCO promoted regioselective synthesis of new diversely functionalized 3-hydroxy-2-oxindole scaffolds

Article abstract of DOI:10.1071/CH13580

An efficient and highly regioselective γ-addition of β-keto sulfones on isatins has been achieved in the presence of a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) to afford a γ-(3-hydroxy-2-oxindole) -β-keto sulfone structural framework. The scope of the method is tested by screening a series of isatin electrophiles as well as β-keto sulfones. The described method was found to be very handy and provides straightforward access for the diversely functionalized 3-β-keto sulfone substituted-3-hydroxy-2- oxindole structural scaffolds in very good yields from readily available starting materials under metal-free reaction conditions. CSIRO 2014.

Full text of DOI:10.1071/CH13580

CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 768–776
Full Paper
http://dx.doi.org/10.1071/CH13580
DABCO Promoted Regioselective Synthesis of New
Diversely Functionalized 3-Hydroxy-2-Oxindole Scaffolds
A
B
Pramod B. Thakur, Jagdeesh B. Nanubolu,
A C
,
and Harshadas M. Meshram
A
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute
of Chemical Technology, Hyderabad, 500007, India.
B
Laboratory of X-Ray Crystallography, CSIR-Indian Institute
of Chemical Technology, Hyderabad, 500007, India.
C
Corresponding author. Email: hmmeshram@yahoo.com
An efficient and highly regioselective g-addition of b-keto sulfones on isatins has been achieved in the presence of
a catalytic amount of 1,4-diazabicyclo[2.2.2]octane (DABCO) to afford a g-(3-hydroxy-2-oxindole)-b-keto sulfone
structural framework. The scope of the method is tested by screening a series of isatin electrophiles as well as b-keto
sulfones. The described method was found to be very handy and provides straightforward access for the diversely
functionalized 3-b-keto sulfone substituted-3-hydroxy-2-oxindole structural scaffolds in very good yields from readily
available starting materials under metal-free reaction conditions.
Manuscript received: 27 October 2013.
Manuscript accepted: 19 December 2013.
Published online: 31 January 2014.
b-keto sulfones,[12–14] which have been explored in many
nucleophilic addition reactions[15] and affords a-addition
products. Alternately b-keto sulfones undergo regioselective
g-addition with aldehydes to give g-hydroxy-substituted b-keto
sulfone frameworks using a dianion method.[16]
Introduction
The alkaloid class of natural products and pharmaceuticals, in
particular the 3-substituted 3-hydroxy-2-oxindoles, possesses a
large array of biological activities.[1] As a result of the preva-
lence of the 3-substituted 3-hydroxy-2-oxindole framework, it
remains a highly investigated synthetic target for worldwide
chemists (Fig. 1). In addition to this, organosulfones show a
wide range of bioactivities such as antibacterial, antiparasitic,
DNA cleavage, anti-HIV, antiviral, and antiandrogen.[2–4]
A specific example is the well known drug Bicalutamide, an oral
non-steroidal antiandrogen that possesses a sulfonyl function-
ality (Fig. 1). Because of the prominence of 3-hydroxy-2-
oxindole and organosulfone structural motifs in the biological
arena, the synthesis of 3-hydroxy-2-oxindoles having an
organosulfone framework is highly desirable from a medicinal
chemistry point of view.
Recently we reported that 1,4-diazabicyclo[2.2.2]octane
(DABCO) catalyzed the highly regioselective g-addition
reaction of b-keto esters on isatin to afford g-(3-hydroxy-2-
oxindole)-b-keto ester structural frameworks.[17a] In this con-
text we intend to study DABCO as a catalyst for the g-addition
reaction of b-keto sulfones with isatin. Although one example of
a g-addition reaction of a b-keto sulfone on isatin has been
reported,[17b] no detailed study specially focussed on the reac-
tions of b-keto sulfones with isatin in the presence of DABCO
appears in the literature. In this regard, and as a part of our
effort towards the synthesis of new 3-substituted 3-hydroxy-2-
oxindoles,[18] we herein report the DABCO catalyzed highly
regioselective g-addition of b-keto sulfones to isatins for the
synthesis of b-keto sulfone substituted 3-hydroxy-2-oxindole
frameworks (entry 3, Scheme 1).
The direct addition of a nucleophile[5–10] to isatin is a very
common approach used for the synthesis of this framework as
the b-carbonyl group of isatin is highly susceptible to nucleo-
philic attack.[11] In this context, we focussed our attention on
(a)
(b)
Results and Discussion
F
O
S
HO
R
N
F
HO
C
F
As part of our persistent interest in 1,4-diazabicyclo[2.2.2]
octane (DABCO) catalyzed reactions,[18c,19] we intended to
investigate the potential of DABCO in the reaction of b-keto
sulfones with isatin. As a model reaction, initially we attempted
the reaction of 1-(phenylsulfonyl)propan-2-one with isatin in
THF in the presence of 10 mol-% DABCO (Scheme 2). The
reaction proceeded to afford the new product as a white solid.
O
O
N
O
N
H
F
H
Fig. 1. (a) Representation of the bioactive 3-substituted-3-hydroxy-2-
oxindole structural framework and (b) the drug Bicalutamide containing
the organosulfone structural framework.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

DABCO Catalyzed Regioselective Aldol Reaction
769
Both crude and pure products were subjected to 1H NMR anal-
ysis. By the extensive analysis of 1H NMR spectroscopic data,
we elucidated the formation of the g-addition product 3a as the
sole product and did not observe the formation of the a-addition
product 3a9 even in trace amounts. Thus, our results showed that
the reaction of the b-keto sulfone 1-(phenylsulfonyl)propan-2-
one with isatin in the presence of 10 mol-% DABCO affords a
single regioisomer, i.e. g-(3-hydroxy-2-oxindol)-b-keto sulfone
(3a) instead of a-(3-hydroxy-2-oxindol)-b-keto sulfone (3a9).
The observed g-regioselectivity was also validated by an
additional study (Scheme 3). When we performed the reaction of
isatin with 2-[(4-methylphenyl)sulfonyl]-1-phenylethanone
under different conditions, we did not observe the formation
of a new product. These results clearly indicate that b-keto
sulfones, having no enolizable proton at the g-position, do not
undergo an aldol reaction with isatin to give 3-b-keto sulfone
substituted 3-hydroxy-2-oxindoles.
All the above experiments validate the formation of regio-
selective g-(3-hydroxy-2-oxindole)-b-keto sulfone (3a). In the
light of these studies, next we tested the scope of different
catalysts for the aldol reaction of isatin with 1-(phenylsulfonyl)
propan-2-one and the results are summarized in Table 1. It is
worth noting that all screened catalysts have afforded only the
regioselective g-addition product 3a. Subsequently, 30 mol-%
DABCO (10 mol-%), THF, r.t., 48h
No reaction
O
O
S
CH3
DABCO (50 mol-%), THF, r.t., 48h
DABCO (100 mol-%), THF, r.t., 48h
Imidazole (50 mol-%), THF, r.t., 48h
No reaction
No reaction
O
ϩ
O
No reaction
No reaction
No reaction
No reaction
O
K2CO3 (50 mol-%), CH3CN, r.t., 48h
MeONa (50 mol-%), MeOH, r.t., 48h
NaH (50 mol-%), THF, r.t., 48h
N
H
It is important to note that the reaction does not afford even
a trace of the a-addition product under the screened reaction
conditions. The g-regioselectivity was also confirmed by inde-
pendent synthesis of compound 3a using the dianion method[16]
(Scheme 4).
Scheme 3. Reaction of isatin with 2-[(4-methylphenyl)sulfonyl]-1-
phenylethanone. Reaction conditions: isatin (1 mmol), b-keto sulfone
(1 mmol) in 5 mL of solvent at room temperature.
(a) Previous work: α-addition reaction of β-keto sulfone nucleophile to various electrophiles
O
O
S
O
O
Organic or inorganic catalyst
Ref. [15]
S
Electrophile (E)
ϩ
O
O
E
(b) Previous work: γ-selective addition under harsh dianion method
N,N,NЈ,NЈ,NЉ,NЉ-
hexamethylphosphoric
triamide
O
O
S
O
O
OH
O
S
Ar
ϩ
and lithium diisopropyl
amide
Ar
O
O
(c) This work: DABCO catalyzed regioselective γ-addition of β-keto sulfone to isatin electrophile
O
OH O
O
O
S
O
S
DABCO (30 mol-%)
THF, r.t.
ϩ
O
HN
O
O
N
H
O
Scheme 1. a, b) Selected reported reactions of b-keto sulfones with various electrophiles. c) Our present
work with 1,4-diazabicyclo[2.2.2]octane (DABCO) at room temperature (r.t.).
Expected singlet for 3H
at 2.1 ppm was not found
Expected singlet for
1H at 4.5 ppm was not found
O
O
O
S
d, 1H, 4.55 ppm (J 13.6)
O
S
Ha
Hb
Hd
Hc
O
H3C
O
O
S
H
O
d, 1H, 4.32 ppm (J 13.6)
d, 1H, 3.21 ppm (J 16.6)
O
HO
S
O
HO
O
O
O
O
d, 1H, 3.45 ppm (J 16.6)
O
N
H
O
N
DABCO (10 mol-%)
THF, r.t.,
N
H
3a
H
DABCO (10 mol-%)
THF, r.t.,
24 h
3aЈ
24 h
γ-addition product
formed as a sole
product
α-addition
product not
formed
Scheme 2. Synthesis of b-keto sulfone substituted 3-hydroxy-2-oxindole frameworks using 1,4-diazabicyclo[2.2.2]octane (DABCO) at room
temperature (r.t.).

770
P. B. Thakur, J. B. Nanubolu, and H. M. Meshram
DABCO in THF was ultimately favoured as the optimized
reaction condition (entry 3, Table 1).
products in good yield as a mixture of inseparable diastereomers
(Table 2, products 3k–p). All the screed structurally varied
b-keto sulfones underwent g-addition on different isatins to
provide g-(3-hydroxy-2-oxindole)-b-keto sulfone structural
scaffolds under mild reaction conditions.
With optimum conditions in hand, we demonstrated the
scope of the reaction with respect to various b-keto sulfones
and isatins. To be specific, halogen-containing substrates
such as 5-chloro isatin, 5-bromo isatin, and 5-iodo isatin as well
as 1-(4-chlorophenylsulfonyl)propan-2-one were well tolerated
and afforded desired products with complete regioselectivity in
very good yields under optimized conditions (Table 2). The
reaction of N-benzyl isatin with 1-(4-chlorophenylsulfonyl)
propan-2-one also afforded a good yield of the desired product
(Table 2, 3j). Di-substituted isatins such as 4,7-dichloro isatin
also reacted very smoothly to afford the desired product 3i with
complete g-regioselectivity. The obtained regioselectivity of
compound 3i was also confirmed by single crystal X-ray data
(Fig. 2; see also Supplementary Material for detailed single
crystal X-ray data).
The formation of g-regioselective products can be
explained on the basis of a previous study.[17a] When b-keto
sulfones like 1-(phenylsulfonyl)propan-2-one are treated with
DABCO, along with the major thermodynamic enolate prod-
uct, a trace amount of kinetic enolate also might form because
of the presence of an acidic proton at the g-carbon atom
(Scheme 5). Because of less steric interaction of the kinetic
enolate with isatin, the nucleophilicity of the kinetic enolate
might have increased and hence it reacts effectively with isatin
to afford the g-addition product 3a exclusively (Path 2). Even
though the kinetic enolate is present in trace amounts, its
formation equilibrium is shifted forwards by its reaction with
isatin and hence the reaction proceeds to completion to form a
product.
a-Substituted b-keto sulfones also reacted smoothly under
standard reaction conditions and afford the desired g-addition
O
O
O
ϩ
S
LDA
C, in
THF
Li
HO
Ϫ
O
O
S
O
Ϫ O
0
Њ
O
O
N
H
S
O
4h
O
in THF,
Ϫ78ЊC 2h
N
H
O
3a, 62 %
Scheme 4. Reaction of isatin with 1-(phenylsulfonyl)propan-2-one using the dianion method (LDA: lithium
diisopropylamine).
Table 1. Optimization of reaction conditionsA
O
O
S
O
O
S
O
O
O
HO
HO
S
O
O
O
2a
O
O
O
catalyst, solvent,
r.t.
N
H
N
H
N
H
1a
3a
3aЈ (not formed)
Entry
Solvent
CatalystB (mol-%)
Time [h]
YieldC [%] 3a/3a0
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
MeCN
MeCN
MeOH
EtOH
THF
THF
DABCO (10)
DABCO (10)
DABCO (30)
DABCO(100)
TEA (30)
24
8
91/00
31/00
90/00
91/00
73/00
78/00
61/00
63/00
69/00
71/00
64/00
76/00
71/00
78/00
71/00
58/00
00/00
2
3
8
4
8
5
8
6
DIPEA (30)
DBU (30)
8
7
8
8
DBN (30)
8
9
Piperidine (30)
Imidazole (30)
DMAP (30)
K2CO3 (30)
Cs2CO3 (30)
MeONa (30)
EtONa (30)
NaH (30)
8
10
11
12
13
14
15
16
17
8
8
8
8
8
8
8
–
24
AReaction conditions: isatin (1 mmol), 1-(phenylsulfonyl) propan-2-one (1 mmol) in 5 mL of solvent.
BDABCO: 1,4-diazabicyclo[2.2.2]octane, TEA: triethyamine, DIPEA: diisopropylethylamine, DBU: 1,8-
diazabicyclo[5.4.0]undec-7-ene, DBN: 1,5-diazabicyclo[4.3.0]non-5-ene, DMAP: 4-dimethylaminopyridine.
CDetermined by 1H NMR analysis.

DABCO Catalyzed Regioselective Aldol Reaction
771
Table 2. The scope of the aldol reaction of b-keto sulfones with isatins under optimized reaction condition
Reaction conditions: isatin 1a–h (1 mmol), b-keto sulfone 2a–c (1 mmol) in 5 mL THF in the presence of 30 mol-% (DABCO). Yields are given as an isolated
yield. * denotes an inseparable mixture of diasteromers, threo : erythro ratio written in parentheses
R5
O
O
R2
O
S
R2
HO
O
R3
O
O
S
R3
O
R6
30 mol-% DABCO
THF, rt, 8 h
O
ϩ
N
R6
O
N
R1
R5
R4
R1
R4
1a–h
2a–c
3a–p
R1 ϭ H, Bn; R2 ϭ H, Cl; R3 ϭ H, Cl, Br, I, NO2, Me; R4 ϭ H, Cl; R5 ϭ H, Me; R6 ϭ H, Cl, Me
O
O
O
O
O
O
O
O
S
S
S
S
HO
O
HO
HO
O
HO
O
O
Cl
I
O
O
O
O
Cl
N
H
N
H
N
H
N
H
3a, 88 %
3b, 94 %
3c, 84 %
3d, 91 %
O
O
O
O
O
O
O
O
S
S
S
S
HO
HO
HO
O
O
HO
O
O
O2N
I
Cl
H3C
O
O
O
O
Cl
Cl
Cl
N
H
Cl
N
H
N
H
N
H
3e, 92 %
3f, 88 %
3g, 81 %
3h, 94 %
CH3
CH3
O
O
O
O
S
S
O
O
S
Cl
Cl
O
O
HO
HO
O
O
S
HO
O
HO
O
Cl
O
O
Cl
O
Cl
N
O
N
O
CH3
N
H
CH3
H
N
H
3l, 91∗
dr, (56:44)
∗
3k, 89
dr, (57:43)
3i, 96 %
3j, 87 %
CH3
CH3
CH3
CH3
O
S
O
O
O
O
O
S
O
S
S
HO
HO
O
O
HO
HO
H3C
O
O
O2N
I
Br
O
O
O
O
CH3
CH3
N
H
CH3
CH3
N
H
N
H
N
H
∗
∗
∗
∗
3m, 88
dr, (55:45)
3n, 86
dr, (59:41)
3o, 83
dr, (59:41)
3p, 81
dr, (63:37)
Conclusions
attached b-keto sulfone framework on the 3-hydroxy-2-
oxindole molecule provides an additional functional handle for
further transformations which can be effectively utilized in
natural product synthesis and the preparation of a library of
pharmaceutically important compounds.
To conclude, we demonstrate the use of DABCO in the regio-
selective g-addition of b-keto sulfones to isatins to afford
diversely functionalized g-(3-hydroxy-2-oxindole)-b-keto sul-
fone structural scaffolds under metal-free reaction conditions.
The developed method provides straightforward access to a
novel class of 3-substituted 3-hydroxy-2-oxindole frameworks
in very good yields under mild reaction conditions from readily
available starting materials. The method is applicable to a
variety of functionalized isatins as well as b-keto sulfones. The
Experimental
Materials and Equipment
All 1H and 13C NMR spectra were recorded in d6-DMSO on an
Avance 300 MHz or Inova 500 MHz spectrometer, respectively.

772
P. B. Thakur, J. B. Nanubolu, and H. M. Meshram
O5
C9
C10
S1
O2
O
O1
C11
O4
O
S
O3
Cl2
C8
C5
Cl
Cl
C7
N1
C13
HO
O
C12
C14
C4
C6
C17
O
C3
C15
Cl
N
C16
C1
C2
H
Cl1
Cl3
3i
Fig. 2. Single crystal X-ray structure of compound 3i.
Kinetic
enolate (minor)
Thermodynamic
enolate (major)
O
S
N
N
O
O
S
O
O
O
S
H3C
Ϫ
Ϫ
O
O
O
Enolate formation
N
N
N
N
ϩ
ϩ
H
H
ϪO
H3C
O
S
O
O
S
O
O
ϩ
ϩ
O
O
Path 1
Path 2
O
O
N
N
H
H
O
OϪ
H3C
O
S
O
O
O
O
S
O
O
O
N
N
H
H
disfavoured
transition state due to high steric interaction
favoured
transition state due to less steric interaction
O
O
H3C
HO
O
S
O
HO
S
O
Br
Br
O
O
O
N
H
N
H
3aЈ
not formed
3a
formed as a sole
product
Scheme 5. Plausible mechanism for the formation of g-addition product in the aldol reaction of b-keto sulfone with isatins.
Chemical shifts (d) are reported in parts per million (ppm)
relative to either residual TMS (1H: 0.00 ppm, 13C: 00.00 ppm)
or d6-DMSO (1H: 2.50 ppm, 13C: 39.43 ppm) as an internal
reference. Melting points were measured on a BUCHI melting
point machine. IR spectra were recorded on Thermo Nicolet
FT/IR-5700 spectrometer. Mass spectra were recorded
using Waters mass spectrometers. High resolution mass
spectrometry (HRMS) was performed using an Applied Bio-
Sciences HRMS spectrometer.
Typical Experimental Procedure for the DABCO
Catalyzed g-Addition of b-Keto Sulfones to Isatins
To a stirred solution of b-keto sulfone (1.0 mmol) and DABCO
(30 mol-%) in 5 mL of THF was added isatin (1 mmol). The

DABCO Catalyzed Regioselective Aldol Reaction
773
mixture was then stirred at room temperature for a stipulated
time (Table 2). After completion of the reaction as indicated by
TLC, the solvent was removed at reduced pressure on a BUCHI
rotary evaporator. The residue was then purified by column
chromatography on silica gel (hexane/ethyl acetate, 4 : 1–1 : 1)
to afford the desired product. (See Supplementary Material for
spectroscopic data and copies of 1H and 13C NMR spectra for all
synthesized compounds 3a–p.)
129.4, 129.0, 128.7, 123.5, 121.6, 109.8, 72.9, 66.1, 50.1. nmax
(KBr)/cmꢀ1 3359, 3093, 2927, 1723, 1621, 1579, 1475, 1394,
1324, 1154, 1086, 1034, 761, 654, 559, 467. m/z (ESI) 402
[M þ Na]þ. m/z 402.01675. HRMS Anal. Calc. for C17H14O5N-
ClSNa [M þ Na]þ 402.01734.
5-Chloro-3-{3-[(4-chlorophenyl)sulfonyl]-2-oxopropyl}-
3-hydroxy-1,3-dihydro-2H-indol-2-one (3e, Table 2)
Yield 92 %, 0.380 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.22,
white solid, mp 161–1638C. dH (300 MHz, CDCl3 þ d6-DMSO)
10.24 (br s, 1H), 7.70 (d, J 9.1, 2H), 7.50 (d, J 8.3, 2H), 7.26–7.13
(m, 2H), 6.79 (d, J 8.30, 1H), 6.32 (br s, 1H), 4.56 (d, J 13.6, 1H),
4.39 (d, J 14.4, 1H), 3.48 (d, J 17.4, 1H), 3.26 (d, J 17.4, 1H). dC
(75 MHz, CDCl3 þ d6-DMSO) 193.9, 175.7, 139.6, 137.9,
135.6, 131.0, 128.1, 127.4, 127.1, 124.0, 122.4, 109.2, 71.0,
64.1, 48.9. nmax (KBr)/cmꢀ1 3429, 3236, 2898, 1714, 1621,
1475, 1393, 1328, 1153, 1089, 1037, 822, 767, 648, 553. m/z
(ESI) 436 [M þ Na]þ. m/z 435.97803. HRMS Anal. Calc. for
C17H13O5NCl2SNa [M þ Na]þ 435.97837.
Characterization Data
3-Hydroxy-3-[2-oxo-3-(phenylsulfonyl)propyl]-
1,3-dihydro-2H-indol-2-one (3a, Table 2)
Yield 88 %, 0.303 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.10,
pale yellow solid, mp 62–648C. dH (300 MHz, CDCl3 þ d6-
DMSO) 10.09 (br s, 1H), 7.80–7.61 (m, 3H), 7.57–7.46 (m, 2H),
7.25–7.17 (m, 2H), 6.95 (t, J 7.6, 1H), 6.83 (d, J 7.6, 1H), 6.2
(br s, 1H), 4.55 (d, J 13.6, 1H), 4.32 (d, J 13.6, 1H) 3.45
(d, J 16.6, 1H), 3.21 (d, J 16.6, 1H). dC (75 MHz, CDCl3 þ
d6-DMSO) 194.4, 177.2, 141.1, 137.42, 133.0, 129.5, 128.4,
128.1, 127.1, 123.0, 120.9, 109.2, 72.3, 65.7, 50.1. nmax (KBr)/
cmꢀ1 3329, 2927, 1723, 1622, 1473, 1317, 1153, 1081, 1032,
753, 687, 529. m/z (ESI) 368 [M þ Na]þ. m/z 368.05582. HRMS
Anal. Calc. for C17H15O5NSNa [M þ Na]þ 368.05631.
3-{3-[(4-Chlorophenyl)sulfonyl]-2-oxopropyl}-3-
hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one
(3f, Table 2)
Yield 88 %, 0.444 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.30,
brown solid, mp 67–698C. dH (200 MHz, CDCl3 þ d6-DMSO)
10.25 (br s, 1H), 7.69 (d, J 8.5, 2H), 7.61–7.42 (m, 4H), 6.65
(d, J 8.7, 1H), 6.29 (br s, 1H), 4.55 (d, J 14.0, 1H), 4.36 (d, J 14.0,
1H), 3.48 (d, J 17.18, 1H), 3.27 (d, J 17.2, 1H). dC (75 MHz,
CDCl3 þ d6-DMSO) 194.1, 175.9, 141.0, 138.8, 136.4, 135.6,
132.0, 131.2, 128.6, 127.9, 110.9, 82.5, 71.4, 65.0, 49.5. nmax
(KBr)/cmꢀ1 3376, 3272, 2929, 1755, 1716, 1612, 1472, 1319,
1154, 1083, 1021, 818, 761, 642, 529, 464. m/z (ESI) 506
[M þ H]þ. m/z 505.93336. HRMS Anal. Calc. for C17H14ClI-
NO5S [M þ H]þ 505.93259.
5-Chloro-3-hydroxy-3-[2-oxo-3-(phenylsulfonyl)
propyl]-1,3-dihydro-2H-indol-2-one (3b, Table 2)
Yield 94 %, 0.356 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.25,
white solid, mp 137–1398C. dH (200 MHz, CDCl3 þ d6-DMSO)
10.22 (br s, 1H), 7.73 (d, J 7.4, 2H), 7.66 (t, J 7.4, 1H), 7.52
(t, J 7.7, 2H) 7.21 (d, J 1.7, 1H), 7.17 (dd, J 8.1, 1.7, 1H), 6.77
(d, J 8.3, 1H), 6.29 (br s, 1H), 4.52 (d, J 13.6, 1H), 4.32 (d, J 13.6,
1H), 3.50 (d, J 17.2, 1H), 3.26 (d, J 17.2, 1H). dC (50 MHz,
CDCl3 þ d6-DMSO) 194.1, 176.8, 139.90, 137.3, 132.8, 131.3,
127.9, 127.8, 126.8, 125.1, 123.1, 109.9, 71.8, 65.3, 49.7. nmax
(KBr)/cmꢀ1 3378, 3274, 2994, 2898, 1761, 1712, 1621, 1482,
1317, 1160, 1025, 882, 745, 528. m/z (ESI) 380 [M þ H]þ. m/z
380.03611. HRMS Anal. Calc. for C17H15ClNO5S [M þ H]þ
380.03595.
3-{3-[(4-Chlorophenyl)sulfonyl]-2-oxopropyl}-3-
hydroxy-5-methyl-1,3-dihydro-2H-indol-2-one
(3g, Table 2)
Yield 81 %, 0.318 g, time 8 h, Rf (50 % EtOAc/hexanes)
0.26, light orange solid, mp 65–678C. dH (200 MHz, CDCl3 þ
d6-DMSO) 9.64 (br s, 1H), 7.65 (d, J 8.5, 2H) 7.44 (d, J 8.7, 2H),
7.07 (s, 1H), 7.03 (d, J 7.9, 1H), 6.74 (d, J 7.9, 1H), 5.90 (br s,
1H), 4.53 (d, J 13.8, 1H), 4.31 (d, J 13.8, 1H) 3.38 (d, J 16.1, 1H),
3.21 (d, J 16.1, 1H), 2.29 (s, 3H). dC (50 MHz, CDCl3 þ d6-
DMSO) 195.1, 177.9, 139.9, 138.7, 136.2, 131.1, 129.7, 129.4,
129.3, 128.8, 124.3, 109.6, 73.1, 66.1, 50.5, 20.4. nmax (KBr)/
cmꢀ1 3364, 2923, 1721, 1627, 1493, 1322, 1154, 1087, 1033,
821, 764, 559, 468. m/z (ESI) 416 [M þ Na]þ. m/z 416.03421.
HRMS Anal. Calc. for C18H16ClNO5SNa [M þ Na]þ
416.03354.
3-Hydroxy-5-iodo-3-[2-oxo-3-(phenylsulfonyl)propyl]-
1,3-dihydro-2H-indol-2-one (3c, Table 2)
Yield 84 %, 0.395 g, time 8 h, Rf (50 % EtOAc/hexanes)
0.13, yellow solid, mp 102–1048C. dH (200 MHz, CDCl3 þ
d6-DMSO) 9.98 (br s, 1H), 7.94–7.78 (m, 1H), 7.58–7.48
(m, 6H), 7.45 (br s, 1H), 6.62 (d, J 8.1, 1H), 4.43 (d, J 13.4,
1H), 4.20 (d, J 13.3, 1H), 3.47 (d, J 16. 8, 1H), 3.25 (d, J 16.8,
1H). dC (75 MHz, CDCl3 þ d6-DMSO) 194.7, 177.0, 141.5,
137.6, 132.6, 132.2, 128.7, 128.6, 127.7, 112.0, 82.7, 72.7, 66.5,
50.5. nmax (KBr)/cmꢀ1 3316, 2927, 2856, 1724, 1614, 1474,
1310, 1149, 1080, 731, 687, 527. m/z (ESI) 494 [M þ Na]þ. m/z
493.95346. HRMS Anal. Calc. for C17H14O5NISNa [M þ Na]þ
493.95296.
3-{3-[(4-Chlorophenyl)sulfonyl]-2-oxopropyl}-3-
hydroxy-5-nitro-1,3-dihydro-2H-indol-2-one
(3h, Table 2)
3-{3-[(4-Chlorophenyl)sulfonyl]-2-oxopropyl}-3-
hydroxy-1,3-dihydro-2H-indol-2-one (3d, Table 2)
Yield 94 %, 0.398 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.13,
white solid, mp 176–1788C. dH (500 MHz, d6-DMSO) 10.64
(br s, 1H), 8.20–8.12 (m, 2H), 7.71 (d, J 8.3, 2H), 7.48 (d, J 8.3,
2H), 6.95 (d, J 9.3, 1H), 6.36 (br s, 1H), 4.41 (d, J 13.5, 1H), 4.34
(d, J 14.5, 1H), 3.57 (d, J 17.6, 1H), 3.43 (d, J 17.6, 1H).
dC (75 MHz, d6-DMSO) 194.7, 177.7, 148.2, 142.1, 140.0,
136.2, 129.2, 128.8, 128.1, 125.9, 119.4, 109.4, 72.1, 65.9,
50.3. nmax (KBr)/cmꢀ1 3359, 3128, 2927, 1717, 1623, 1522,
Yield 91 %, 0.345 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.13,
pale yellow solid, mp 132–1348C. dH (500 MHz, CDCl3 þ d6-
DMSO) 9.78 (br s, 1H), 7.66 (d, J 8.5, 2H), 7.44 (d, J 8.5, 2H),
7.26 (d, J 7.4, 1H), 7.22 (t, J 7.4, 1H), 6.98 (t, J 7.4, 1H), 6.85
(d, J 7.4, 1H), 5.95 (br s, 1H), 4.53 (d, J 14.9, 1H), 4.31 (d, J 13.8,
1H) 3.41 (d, J 17.0, 1H), 3.22 (d, J 16.0, 1H). dC (75 MHz,
CDCl3 þ d6-DMSO) 195.0, 177.8, 141.3, 139.9, 136.2, 129.7,

774
P. B. Thakur, J. B. Nanubolu, and H. M. Meshram
1471, 1334, 1161, 1094, 835, 795, 744. m/z (ESI) 447 [M þ
Na]þ. m/z 447.00258. HRMS Anal. Calc. for C17H13ClN2O7SNa
[M þ Na]þ 447.00242.
(inseparable diastereomeric ratio, major : minor, 56 : 44, *
denotes minor diastereomer peaks) 9.91* (br s, 1H), 9.87 (br s,
1H), 7.60–7.53* (m, 3H), 7.42–7.36 (m, 3H), 7.30* (d, J 8.7,
2H), 7.25 (dd, J 8.7, 1.7, 1H), 7.22 (d, J 7.8, 2H), 7.17* (dd, J 8.7,
2.3, 1H), 6.82 (d, J 8.7, 1H), 6.79* (d, J 8.7, 1H), 6.00 (br s, 1H),
5.94* (br s, 1H), 4.45 (q, J 7.0, 1H), 4.35* (q, J 7.0, 1H), 3.70 (d,
J 17.4, 1H), 3.62* (d, J 16.5, 1H), 3.46 (d, J 17.4, 1H), 3.27* (d, J
16.5, 1H), 2.43* (s, 3H), 2.41 (s, 3H), 1.26* (d, J 6.9, 3H), 1.25
(d, J 6.9, 3H). dC (75 MHz, CDCl3 þ d6-DMSO) (inseparable
diastereomeric ratio, major : minor, 56 : 44, * denotes minor
diastereomer peaks) 197.9*, 197.7, 176.6*, 176.5, 143.9*,
143.9, 140.3, 139.9*, 131.7*, 131.5, 131.3*, 131.1, 129.8,
128.3*, 128.2, 128.0, 127.9*, 127.7*, 127.7, 127.4, 125.0,
123.3*, 123.1, 109.9, 72.2*, 71.8, 68.7*, 67.5, 50.3, 49.0*,
20.3*, 20.3, 10.3, 10.0*. nmax (KBr)/cmꢀ1 3327, 2925, 2859,
1727, 1622, 1477, 1311, 1143, 1077, 1010, 817, 722, 653, 580.
m/z (ESI) 408 [M þ H]þ. m/z 408.06650. HRMS Anal. Calc. for
C19H19O5NClS [M þ H]þ 408.06670.
4,7-Dichloro-3-{3-[(4-chlorophenyl)sulfonyl]-2-
oxopropyl}-3-hydroxy-1,3-dihydro-2H-indol-2-one
(3i, Table 2)
Yield 96 %, 0.429 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.33,
white solid, mp 180–1828C. dH (500 MHz, CDCl3 þ d6-DMSO)
10.35 (br s, 1H), 7.75 (d, J 7.2, 2H), 7.49 (d, J 7.2, 2H), 7.15
(d, J 9.6, 1H), 6.85 (d, J 7.2, 1H), 6.31 (br s, 1H), 4.46 (d, J 14.3,
1H), 4.35 (d, J 14.3, 1H), 3.74 (d, J 16.7, 1H), 3.58 (d, J 16.7,
1H). dC (75 MHz, CDCl3 þ d6-DMSO) 194.2, 175.8, 140.9,
138.9, 135.9, 129.2, 128.6, 128.0, 127.6, 127.0, 122.1, 112.3,
73.1, 64.8, 48.0. nmax (KBr)/cmꢀ1 3484, 3218, 3089, 2925, 1731,
1612, 1470, 1322, 1156, 1089, 1032, 943, 765, 621, 562. m/z
(ESI) 448 [M þ H]þ. m/z 447.95776. HRMS Anal. Calc. for
C17H13O5NCl3S [M þ H]þ 447.95745.
5-Bromo-3-hydroxy-3-{3-[(4-methylphenyl)sulfonyl]-2-
oxobutyl}-1,3-dihydro-2H-indol-2-one (3m, Table 2)
1-Benzyl-3-{3-[(4-chlorophenyl)sulfonyl]-2-oxopropyl}-
3-hydroxy-1,3-dihydro-2H-indol-2-one (3j, Table 2)
Yield 88 %, 0.417 g, time 8 h, Rf (50 % EtOAc/hexanes)
0.19, brown solid, mp 170–1728C. dH (500 MHz, CDCl3 þ d6-
DMSO) (inseparable diastereomeric ratio, major : minor,
55 : 45, * denotes minor diastereomer peaks) 10.92* (br s,
1H), 10.67 (br s, 1H), 7.72–7.66* (m, 3H), 7.43–7.37 (m, 3H),
7.29* (d, J 8.6, 2H), 7.26 (dd, J 8.6, 1.7, 1H), 7.24 (d, J 8.1, 2H),
7.18* (dd, J 8.6, 2.3, 1H), 6.73 (d, J 8.7, 1H), 6.69* (d, J,8.7, 1H),
6.01 (br s, 1H), 5.95* (br s, 1H), 4.46 (q, J 7.0, 1H), 4.34* (q, J 7,
1H), 3.71 (d, J 17.4, 1H), 3.63* (d, J 16.5, 1H), 3.47 (d, J 17.4,
1H), 3.27* (d, J 16.5, 1H), 2.43* (s, 3H), 2.41 (s, 3H), 1.27* (d, J
6.9, 3H), 1.25 (d, J 6.9, 3H). dC (75 MHz, CDCl3 þ d6-DMSO)
(inseparable diastereomeric ratio, major : minor, 55 : 45, *
denotes minor diastereomer peaks) 198.27, 198.05*, 176.81*,
176.88, 144.50*, 144.25, 140.81*, 140.44, 132.06*, 131.85,
131.05, 130.71*, 128.90*, 128.66, 128.47*, 128.38, 128.09,
128.01*, 126.32, 126.15*, 124.82*, 124.32, 123.13, 112.98*,
110.88, 72.54, 72.11*, 69.45, 68.90*, 50.48*, 49.19* 20.05,
19.96*, 10.53*, 10.24. nmax (KBr)/cmꢀ1 3383, 3245, 2925,
1748, 1619, 1480, 1304, 1142, 1068, 1009, 830, 720, 650,
581. m/z (ESI) 474 [M þ Na]þ. m/z 473.99929. HRMS Anal.
Calc. for C19H18BrNO5SNa [M þ Na]þ 473.99868.
Yield 87 %, 0.408 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.38,
orange viscous liquid. dH (500 MHz, CDCl3 þ d6-DMSO) 7.56
(d, J 7.1, 2H), 7.39–7.27 (m, 5H), 7.28–7.18 (m, 3H), 7.14
(t, J 7.1, 1H), 6.98 (t, J 7.1, 1H), 6.62 (d, J 7.1, 1H), 6.16 (br s,
1H), 4.70 (d, J 15.3, 1H), 4.76 (d, J 15.3, 1H), 4.44 (d, J 13.3,
1H), 4.27 (d, J 13.3, 1H), 3.58 (d, J 17.3, 1H), 3.42 (d, J 17.3,
1H). dC (75 MHz, CDCl3 þ d6-DMSO) 194.8, 176.0, 142.5,
139.9, 135.9, 135.0, 129.4, 129.3, 129.0, 128.7, 128.0, 126.9,
126.6, 123.3, 122.1, 108.9, 72.5, 66.1, 50.8, 43.1. nmax (KBr)/
cmꢀ1 3420, 2925, 2854, 1720, 1614, 1580, 1491, 1469, 1357,
1325, 1282, 1156, 1087, 1065, 761, 701, 564. m/z (ESI) 492
[M þ Na]þ. m/z 492.06387. HRMS Anal. Calc. for
C24H20O5NClSNa [M þ Na]þ 492.06429.
3-Hydroxy-3-{3-[(4-methylphenyl)sulfonyl]-2-
oxobutyl}-1,3-dihydro-2H-indol-2-one (3k, Table 2)
Yield 89 %, 0.332 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.13,
white solid, mp 171–1738C. dH (300 MHz, CDCl3 þ d6-DMSO)
(inseparable diastereomeric ratio, major : minor, 57 : 43,
* denotes minor diastereomer peaks) 9.85* (br s, 1H), 9.79 (br
s, 1H), 7.71–7.51* (m, 4H), 7.49–7.38* (m, 2H), 7.36–7.24
(m, 4H), 7.20–7.15 (m, 2H), 7.04 (t, J 7.6, 1H), 6.97* (t, J 7.6,
1H), 6.89 (d, J 7.7, 1H), 6.85* (d, J 7.7, 1H), 5.95 (br s, 1H),
5.92* (br s, 1H), 4.50 (q, J 6.8, 1H), 4.38* (q, J 6.8, 1H), 3.73
(d, J 17.4, 1H), 3.65* (d, J 15.5, 1H), 3.47 (d, J 17.5, 1H), 3.18*
(d, J 15.5, 1H), 2.43* (s, 3H), 2.40 (s, 3H), 1.27 (d, J 8.5, 3H),
1.23* (d, J 6.8, 3H). dC (75 MHz, d6-DMSO) (inseparable
diastereomeric ratio, major : minor, 57 : 43, * denotes minor
diastereomer peaks) 198.1*, 198.0, 177.2, 177.1*, 144.0*,
143.8, 141.4, 141.0*, 132.0, 131.1, 131.0*, 129.9*, 129.7,
129.3*, 128.4*, 128.2, 128.1, 127.9*, 127.4, 122.9*, 122.9,
120.6*, 120.5, 108.9*, 108.9, 72.5*, 72.0, 69.0*, 67.6, 50.5,
49.5* 20.3*, 20.3, 10.4, 10.0*. nmax (KBr)/cmꢀ1 3475, 3415,
3205, 2922, 1715, 1623, 1475, 1298, 1144, 1074, 749, 715, 656,
573. m/z (ESI) 396 [M þ Na]þ. m/z 396.08691. HRMS Anal.
Calc. for C19H19O5NSNa [M þ Na]þ 396.08761.
3-Hydroxy-5-iodo-3-{3-[(4-methylphenyl)sulfonyl]-2-
oxobutyl}-1,3-dihydro-2H-indol-2-one (3n, Table 2)
Yield 86 %, 0.429 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.31,
Yellow solid, mp 216–2188C. dH (200 MHz, d6-DMSO) (insep-
arable diastereomeric ratio, major : minor, 59 : 41, * denotes
minor diastereomer peaks) 10.06* (br s, 1H), 10.04 (br s, 1H),
7.68* (d, J 1.0, 2H), 7.59–7.50 (m, 4H), 7.39–7.28* (m, 4H),
7.23 (d, J 8.1, 2H), 6.68 (d, J 8.3, 1H), 6.65* (d, J 8.3, 1H), 6.15
(br s, 1H), 6.10* (br s, 1H), 4.50–4.43 (m, 1H), 4.37–4.30* (m,
1H), 3.73 (d, J 17.5, 1H), 3.63* (d, J 16.6, 1H), 3.44 (d, J 17.5,
1H), 3.27* (d, J 16.6, 1H), 2.44* (s, 3H), 2.42 (s, 3H), 1.34* (d, J
6.8, 3H), 1.24 (d, J 6.8, 3H). dC (50 MHz, d6-DMSO) (insepara-
ble diastereomeric ratio, major : minor, 59 : 41, * denotes minor
diastereomer peaks) 199.1*, 199.1, 177.0*, 176.9, 144.9, 142.5,
142.3*, 137.5, 133.7, 133.6*, 132.9, 132.2, 129.6*, 129.4,
128.9, 128.9*, 112.0, 119.9*, 83.9*, 83.8, 72.5*, 72.1, 68.8*,
67.9, 51.1, 50.1* 21.1, 11.2, 10.9*. nmax (KBr)/cmꢀ1 3382, 3236,
2988, 1740, 1615, 1477, 1387, 1305, 1212, 1140, 1066, 1005,
828, 716, 646, 578. m/z (ESI) 517 [M þ NH4]þ. m/z 517.02999.
HRMS Anal. Calc. for C19H22IN2O5S [M þ NH4]þ 517.02941.
5-Chloro-3-hydroxy-3-{3-[(4-methylphenyl)sulfonyl]-2-
oxobutyl}-1,3-dihydro-2H-indol-2-one (3l, Table 2)
Yield 91 %, 0.370 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.29,
white solid, mp 85–878C. dH (500 MHz, CDCl3 þ d6-DMSO)

DABCO Catalyzed Regioselective Aldol Reaction
775
3-Hydroxy-3-{3-[(4-methylphenyl)sulfonyl]-2-
oxobutyl}-5-nitro-1,3-dihydro-2H-indol-2-one
(3o, Table 2)
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre (CCDC), 12 Union
Road, Cambridge CB2 1EZ, UK; fax: þ44(0) 1223 336 033;
email: deposit@ccdc.cam.ac.uk)
Yield 83 %, 0.347 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.30,
pale yellow solid, mp 199–2018C. dH (500 MHz, CDCl3
þ
Supplementary Material
d6-DMSO) (inseparable diastereomeric ratio, major : minor,
59 : 41, * denotes minor diastereomer peaks) 10.65 (br s, 1H),
10.64* (br s, 1H), 8.29–8.21* (m 2H), 8.20–8.13 (m, 2H), 7.57*
(d, J 7.8, 2H), 7.4 (d, J 7.8, 2H), 7.30* (d, J 7.8, 2H), 7.21 (d, J
7.8, 2H), 6.99 (d, J 8.8, 1H), 6.97* (d, J 8.8, 1H), 6.34 (br s, 1H),
6.30* (br s, 1H), 4.49–4.39 (m, 1H), 4.38–4.31* (m, 1H), 3.80
(d, J 18.5, 1H), 3.73* (d, J 16.5, 1H), 3.54 (d, J 17.5, 1H), 3.52*
(d, J 17.5, 1H), 2.43* (s, 3H), 2.41 (s, 3H) 1.32* (d, J 6.8, 3H),
1.26 (d, J 6.8, 3H). dC (50 MHz, CDCl3 þ d6-DMSO) (insepa-
rable diastereomeric ratio, major : minor, 59 : 41, * denotes
minor diastereomer peaks) 197.9*, 197.8, 176.9*, 176.8,
147.9, 147.8*, 143.8, 143.8*, 140.9*, 140.9, 131.5*, 131.3,
130.5, 130.4*, 128.2*, 128.0, 127.6*, 127.5, 124.9, 118.5,
108.4, 108.4*, 71.2*, 71.0, 68.1*, 67.2, 49.9, 49.0*, 20.0*,
20.0, 10.0, 9.9*. nmax (KBr)/cmꢀ1 3289, 2931, 1715, 1624,
1520, 1456, 1327, 1141, 1006, 909, 715, 640. m/z (ESI) 441
[M þ Na]þ. m/z 441.07398. HRMS Anal. Calc. for
C19H18N2O7SNa [M þ Na]þ 441.07324.
Details of experimental procedures, characterisation data of
1
products and copies of H and 13C NMR spectra are available
on the Journal’s website.
Acknowledgements
PBT thanks CSIR New Delhi for the award of senior research fellowship and
Dr Ahmed Kamal (Outstanding Scientist), Head, Medicinal Chemistry and
Pharmacology Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad for his support and encouragement. The authors thank CSIR,
New Delhi for financial support as part of XII Five Year plan program under
title ACT (CSC-0301).
References
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Yield 81 %, 0.313 g, time 8 h, Rf (50 % EtOAc/hexanes) 0.19,
brown solid, mp 80–828C. dH (300 MHz, CDCl3 þ d6-DMSO)
(inseparable diastereomeric ratio, major : minor, 63 : 37, *
denotes minor diastereomer peaks) 9.72* (br s, 1H), 9.67 (br s,
1H), 7.53–7.41* (m, 3H), 7.27–7.18 (m, 3H), 7.15 (d, J 7.6, 1H),
7.10 (d, J 8.1, 2H), 6.98* (d, J 6.8, 2H), 6.92* (d, J 7.6, 1H), 6.68
(d, J 7.9, 1H), 6.64* (d, J 7.9, 1H), 5.90 (br s, 1H), 5.84* (br s,
1H), 4.45 (q, J 6.8 1H), 4.32* (q, J 6.8 1H), 3.58* (d, J 15.5, 1H),
3.53 (d, J 17.2, 1H), 3.37 (d, J 17.2, 1H), 3.05* (d, J 15.5, 1H),
2.08 (s, 3H), 2.08* (s, 3H), 2.08 (s, 3H), 2.08* (s, 3H) 1.19* (d, J
6.9, 3H), 1.14 (d, J 6.9, 3H). dC (75 MHz, CDCl3 þ d6-DMSO)
(inseparable diastereomeric ratio, major : minor, 63 : 37, *
denotes minor diastereomer peaks) 198.71*, 198.41, 177.84,
177.70*, 144.71*, 144.26, 139.03, 138.57*, 132.28*, 131.37,
130.46, 130.20*, 129.91, 129.57*, 128.97*, 128.82, 128.54,
128.33*, 124.01, 109.26, 73.22*, 72.70, 69.58*, 68.12, 50.87,
49.75*, 22.02*, 21.72*, 20.73, 20.19, 10.81, 10.42*. nmax (KBr)/
cmꢀ1 3331, 2924, 1721, 1628, 1494, 1318, 1146, 1082, 817,
718, 656. m/z (ESI) 410 [M þ Na]þ. m/z 410.10248. HRMS
Anal. Calc. for C20H21O5NSNa [M þ Na]þ 410.10326.
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X-Ray Crystallographic Data for Compound 4,7-
Dichloro-3-(3-(4-chlorophenylsulfonyl)-2-oxopropyl)-
3-hydroxyindolin-2-one (3i, Table 2)
Compound 3i, C17H12NO5Cl3S, M 448.69, crystallized as
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unique (Rint 0.0197). Final GoF 1.038, R1 0.0280, wR2 0.0766,
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