Zn(OTf)2-catalysed indolylation and pyrrolylation of isatins: Efficient synthesis and biochemical assay of 3,3-di(heteroaryl)oxindoles

Article abstract of DOI:10.1007/s12039-013-0510-y

An efficient and cheap synthetic approach to 3,3-di(indolyl)oxindoles and 3,3-di(pyrrolyl) oxindoles has been developed via Zn(OTf)2 catalysed indolylation and pyrrolylation of isatins. A preliminary biochemical assay of the synthesized molecules in roden

Full text of DOI:10.1007/s12039-013-0510-y

c
J. Chem. Sci. Vol. 125, No. 6, November 2013, pp. 1543–1553. ꢀ Indian Academy of Sciences.
Zn(OTf)2-catalysed indolylation and pyrrolylation of isatins: Efficient
synthesis and biochemical assay of 3,3-di(heteroaryl)oxindoles
C PRAVEENa, S NARENDIRANb, P DHEENKUMARa,c and P T PERUMALa,∗
aOrganic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600 020, India
bDepartment of Pharmaceutical Chemistry, Sri Venkateswara College of Pharmacy, Chitoor 517 127, India
cDepartment of Pharmaceutical Chemistry, EGS Pillay College of Pharmacy, Nagapattinam 611 002, India
e-mail: ptperumal@gmail.com
MS received 14 March 2013; revised 15 July 2013; accepted 12 August 2013
Abstract. An efficient and cheap synthetic approach to 3,3-di(indolyl)oxindoles and 3,3-di(pyrrolyl)
oxindoles has been developed via Zn(OTf)2 catalysed indolylation and pyrrolylation of isatins. A prelimi-
nary biochemical assay of the synthesized molecules in rodent models were performed to estimate the serum
glutamate oxaloacetate transaminase and malondialdehyde levels.
Keywords. Zn(OTf)2; 3,3-di(indolyl)oxindoles; 3,3-di(pyrrolyl)oxindoles; serum glutamate oxaloacetate
transaminase (SGOT); malondialdehyde (MDA).
1. Introduction
overtly toxic or are minor products. Of major toxico-
logical interest is malondialdehyde (MDA), formed as
a result of fission of cyclic endoperoxides (scheme 2).
MDA may also be formed in some tissues by enzy-
matic processes with prostaglandin precursors as sub-
strates. Thus, MDA and related aldehydes are the most
commonly estimated products of lipid peroxidation.3
Antioxidative enzyme activities and lipid peroxidation
levels were determined by measuring MDA levels in
biological systems. As part of our ongoing interest in
synthesis of bio-active heterocycles,4 we have previ-
ously communicated an efficient protocol for the 3,3-
diindolylation of isatins in the catalytic presence of
Cu(OTf)2.4a Since, we have already studied anticonvul-
sant potency of the resulting 3,3-di(indolyl)oxindoles,4a
we became interested in their biochemical assays. To
this end, we estimated SGOT and lipid peroxidation
for an extended series of di(heteroaryl)oxindoles syn-
thesized via Zn(OTf)2 catalysis, which was found to be
more effective than our previously reported Cu(OTf)2
protocol to include not only 3,3-di(indolyl)oxindoles
but also 3,3-di(pyrrollyl)oxindoles and all these results
are disclosed in this article.
Serum glutamate oxaloacetate transaminase (SGOT),
also known as aspartate transaminase (AST),1 is a
metabolic enzyme expressed mainly in heart muscle,
liver cells, skeletal muscle and kidneys. Injury to these
tissues results in the release of SGOT in blood. Ele-
vated levels are found in myocardial infarction, car-
diac operations, hepatitis, cirrhosis, acute pancreati-
tis, acute renal diseases and primary muscle diseases.
Decreased levels may be found in pregnancy, Beri-Beri
and diabetic ketoacidosis. SGOT catalyses the trans-
fer of an amino group between L-aspartate and keto-
glutarate to form oxaloacetate and L-glutamate. The
oxaloacetate thus formed reacts with nicotinamide ade-
nine dinucleotide hydrogen (NADH) in the presence
of malate dehydrogenase (MDH) to form nicotinamide
adenine dinucleotide (NAD+) (scheme 1). The rate of
oxidation of NADH to NAD+ is measured as a decrease
in absorbance which is proportional to the SGOT activ-
ity in the sample. Conversion of NADH chromophore to
NAD+ product, measured at 340 nm is proportional to
the level of SGOT enzyme in the sample. On the other
hand, lipid peroxidation is well-known to decrease
activities of enzymes associated with membranes. Lipid
peroxidation (LP) can be defined as the oxidative dete- 2. Experimental
rioration of lipids containing a large number of C=C
double bonds.2 Many of the products of LP are not
2.1 Materials, methods and instruments
All commercially available solvents and reagents were
used without further purification. Solutions in organic
∗For correspondence
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C Praveen et al.
SGOT
L-Aspartate + α-Ketoglutarate
Oxaloacetate + NADH + H+
Oxaloacetate + L-Glutamate
Malate + NAD+
MDH
Scheme 1. Bio-catalysis by SGOT and MDH.
H
LH + O2
O
O
O
O
O
oxidative
cleavage
O
H
LH = Unsaturated
lipid
Malondialdehyde
(MDA)
.
OOH
Scheme 2. Chemical representation of lipid peroxidation.
solvents were dried with anhydrous sodium sulphate. 2.2 Typical procedure for the synthesis of indolyl
Solvents were evaporated under reduced pressure. and pyrrolyl oxindoles
Melting points were obtained using open capillar-
To a homogeneous solution of indole or pyrrole deriva-
tive (1.0 mmol) in dichloromethane (2.0 mL) were
added isatin (0.5 mmol) and Zn(OTf)2 (1.0 mol%) in a
screw cap vial and stirred for 5 min. After completion
of the reaction as evidenced by TLC monitoring, the
reaction mixture concentrated under reduced pressure
and poured over crushed ice. The solid precipitated was
filtered, washed with ice-cold water (3 × 20 mL) and
dried to afford the pure product.
ies and are uncorrected. Infrared (IR) spectra were
recorded on a Perkin-Elmer Fourier Transform Infrared
(FTIR) spectrophotometer as KBr pellets for solid com-
1
pounds and neat sample for liquid compounds. H
and 13C Nuclear Magnetic Resonance (NMR) spec-
tra were obtained in CDCl3, DMSO-d6, acetone-d6 and
CD3CN on a JEOL spectrometer at 500 and 125 MHz,
respectively. Proton chemical shifts (δ) are relative to
tetramethylsilane tetramethylsilane (TMS, δ = 0.00) as
internal standard and expressed in parts per million.
The number of protons (n) for a given resonance was
indicated as nH. Spin multiplicities are given as s (sin-
glet), d (doublet), t (triplet), dd (doublet of doublet), dt
(doublet of triplet), ddd (doublet of doublet of doublet)
and m (multiplet). Coupling constants (J) are given in
hertz. Mass spectra were recorded on a Thermo Finnigan
LCQ Advantage MAX 6000 ESI mass spectrometer
using electrospray ionization method. Elemental analy-
ses were recorded using a Thermo Finnigan FLASH EA
1112CHN analyser. All the compounds gave C, H and
N analysis within 0.5% of the theoretical values. Col-
umn chromatography was performed using a mixture
of petroleum ether and ethyl acetate on silica gel (100–
200 mesh, SRL, India). Analytical thin layer chromato-
graphy (TLC) was performed on precoated plastic
2.2a 3,3-Bis(1-allyl-1H-indol-3-yl)-indolin-2-one (3a):
Yellow solid; Mp 269–271◦C; IR (KBr): 3431, 2511,
1
2331, 2028, 1700, 1365 cm−1. H NMR (500 MHz,
DMSO-d6): δH 4.72 (s, 4H); 4.92 (d, 2H, J = 16.8 Hz);
5.06 (d, 2H, J = 9.9 Hz); 5.85–5.94 (m, 2H); 6.79 (t,
2H, J = 7.6 Hz); 6.87 (s, 2H); 6.89–6.90 (m, 3H); 7.02
(t, 2H, J = 7.6 Hz); 7.22 (d, 3H, J = 8.4 Hz); 7.33 (d,
2H, J = 8.4 Hz); 10.64 (s, 1H). 13C NMR (125 MHz,
DMSO-d6): δC 48.3, 52.9, 103.6, 110.6, 111.6, 114.4,
117.0, 118.2, 119.0, 121.7, 126.7, 128.0, 134.8, 134.9,
137.2, 138.9, 151.2, 159.9, 179.0. MS (EI): m/z = 443
[M+]. Anal. Calcd for C30H25N3O: C, 81.24; H, 5.68;
N, 9.47%. Found: C, 80.98; H, 5.75; N, 9.55%.
sheets of silica gel G/UV-254 of 0.2 mm thickness 2.2b 3,3-Bis(1-allyl-1H-indol-3-yl)-5-nitroindolin-2-
(Macherey-Nagel, Germany) using analytical grade sol- one (3b): Yellow solid; Mp 249–251◦C; IR (KBr):
1
vents and visualized with iodine spray (10% w/w I2 2928, 1722, 1455, 1335, 911, 743 cm−1. H NMR
in silica gel), UV light (λ = 254 and 365 nm) and (500 MHz, DMSO-d6): δH 4.73 (s, 4H); 4.91 (d, 2H,
kagi solution. SGOT analysis was performed using AST J = 17.5 Hz); 5.06 (d, 2H, J = 9.9 Hz); 5.88–5.93 (m,
Enzymatic Assay kit (XpressBio Ltd., USA).
2H); 6.84 (t, 2H, J = 7.6 Hz); 7.01 (s, 2H); 7.05 (t, 2H,

Zn(OTf)2-catalysed indolylation of isatins
1545
J = 8.4 Hz); 7.18 (d, 1H, J = 8.4 Hz); 7.23 (d, 2H, 126.9, 127.4, 128.8, 132.6, 135.0, 137.1, 150.0, 153.3,
J = 7.6 Hz); 7.35 (d, 2H, J = 8.4 Hz); 8.00 (s, 1H); 159.5, 178.5. MS (EI): m/z = 580 [M+]; 582 [M+2].
8.21–8.23 (m, 1H); 11.38 (s, 1H). 13C NMR (125 MHz, Anal. Calcd for C32H28BrN3O3: C, 81.24; H, 5.68; N,
DMSO-d6): δC 48.4, 52.9, 110.6, 110.9, 112.8, 117.0, 9.47%. Found: C, 80.98; H, 5.75; N, 9.55%.
119.4, 120.6, 121.1, 121.9, 126.1, 126.4, 128.4, 134.9,
135.4, 137.3, 142.8, 148.2, 179.1. MS (EI): m/z = 488
[M+]. Anal. Calcd for C30H24N4O3: C, 73.76; H, 4.95;
N, 11.47%. Found: C, 74.02; H, 4.90; N, 11.38%.
2.2f Ethyl-2-(3,3-bis(1-allyl-5-methoxy-1H-indol-3-
yl)-2-oxoindolin-1-yl)acetate (3f): Brown paste; IR
1
(neat): 2924, 1722, 1464, 1212, 923 cm−1. H NMR
(500 MHz, CDCl3): δH 1.22 (t, 3H, J = 7.6 Hz);
2.2c 3,3-Bis(1-allyl-5-methoxy-1H-indol-3-yl)indolin- 3.61 (s, 6H); 4.10 (q, 2H, J = 6.9 Hz); 4.52 (s, 4H);
2-one (3c): Brown solid; Mp 247–249◦C; IR (KBr): 4.56 (s, 2H); 4.97 (d, 2H, J = 16.8 Hz); 5.07 (d,
3448, 1811, 1719, 1621, 1479, 1221, 1062, 871 cm−1. 2H, J = 10.7 Hz); 5.81–5.92 (m, 2H); 6.76 (d, 2H,
1H NMR (500 MHz, DMSO-d6): δH 3.98 (s, 6H); 4.67 J = 8.4 Hz); 6.87 (s, 2H); 6.94 (s, 2H); 7.00 (t, 2H,
(d, 4H, J = 5.3 Hz); 4.90 (d, 2H, J = 16.8 Hz); 5.04 J = 6.8 Hz); 7.10 (d, 2H, J = 9.1 Hz); 7.26 (t, 1H,
(d, 2H, J = 11.4 Hz); 5.86–5.89 (m, 2H); 6.68 (s, 2H); J = 7.6 Hz); 7.40 (d, 1H, J = 7.6 Hz). 13C NMR
6.87 (s, 2H); 6.92 (t, 2H, J = 6.8 Hz); 6.96 (d, 1H, (125 MHz, CDCl3): δC 14.2, 48.9, 52.7, 55.6, 60.4,
J = 7.6 Hz); 7.03 (t, 1H, J = 8.4 Hz); 7.21–7.24 (m, 61.7, 103.6, 108.4, 110.5, 112.1, 113.3, 116.9, 123.0,
4H); 10.68 (s, 1H). 13C NMR (125 MHz, DMSO-d6): 125.4, 127.1, 128.1, 128.6, 132.5, 133.7, 133.8, 141.8,
δC 48.4, 52.8, 55.5, 103.8, 111.3, 111.4, 112.7, 113.5, 153.6, 167.8, 177.8. MS (EI): m/z = 589 [M+]. Anal.
116.8, 123.3, 125.2, 127.1, 128.6, 132.5, 135.1, 151.2, Calcd for C36H35N3O5: C, 73.33; H, 5.98; N, 7.13%.
153.1, 159.9, 163.6, 179.0. MS (EI): m/z = 503 [M+]. Found: C, 73.47; H, 5.93; N, 7.07%.
Anal. Calcd for C32H29N3O3: C, 76.32; H, 5.80; N,
8.34%. Found: C, 76.59; H, 5.74; N, 8.25%.
2.2g 3,3-Bis(1-cinnamyl-1H-indol-3-yl)indolin-2-one
(3g): Brown solid; Mp 140–142◦C; IR (KBr):
2.2d 3,3-Bis(1-allyl-5-methoxy-1H-indol-3-yl)-5- 2928, 1720, 1611, 1460, 1175, 743 cm−1. H NMR
1
chloroindolin-2-one (3d): Brown solid; Mp 237– (500 MHz, DMSO-d6): δH 4.91 (d, 4H, J = 5.3 Hz);
239◦C; IR (KBr): 3432, 2919, 1712, 1476, 1218, 6.30–6.34 (m, 2H); 6.42 (d, 2H, J = 16.05 Hz); 6.88
1
920 cm−1. H NMR (500 MHz, DMSO-d6): δH 3.99 (s, 2H); 7.02 (t, 3H, J = 6.8 Hz); 7.16–7.26 (m, 4H);
(s, 6H); 4.69 (d, 4H, J = 3.8 Hz); 4.90 (d, 2H, 7.32 (d, 2H, J = 7.6 Hz); 7.46 (d, 2H, J = 7.6 Hz);
J = 16.8 Hz); 5.05 (d, 2H, J = 9.9 Hz); 5.87–5.90 7.54 (t, 1H, J = 6.9 Hz); 11.02 (s, 1H). 13C NMR
(m, 2H); 6.66 (s, 2H); 6.70 (d, 2H, J = 9.9 Hz); (125 MHz, DMSO-d6): δC 53.1, 59.6, 113.1, 119.2,
6.90 (s, 2H); 6.99 (d, 1H, J = 8.4 Hz); 7.15 (s, 1H); 120.1, 126.3, 126.9, 127.1, 127.3, 128.1, 128.7, 129.2,
7.24–7.28 (m, 3H); 10.79 (s, 1H). 13C NMR (125 MHz, 129.3, 130.1, 130.6, 131.2, 131.8, 133.7, 134.1, 135.0,
DMSO-d6): δC 48.5, 53.1, 55.6, 103.6, 111.4, 111.7, 141.0, 175.0. MS (EI): m/z = 595 [M+]. Anal. Calcd
112.7, 116.8, 125.1, 126.1, 126.9, 128.5, 128.8, 132.6, for C42H33N3O: C, 84.68; H, 5.58; N, 7.05%. Found:
135.1, 136.7, 140.8, 153.3, 178.6. MS (EI): m/z = 536 C, 84.79; H, 5.55; N, 7.00%.
[M+]; 538 [M+2]. Anal. Calcd for C32H28ClN3O3: C,
71.43; H, 5.25; N, 7.81%. Found: C, 70.99; H, 5.31; N,
7.92%.
2.2h 3,3-Bis(5-bromo-1-(3-methylbut-2-enyl)-1H-
indol-3-yl)indolin-2-one (3h): Brown solid; Mp 152–
154◦C; IR (KBr): 2919, 2360, 1701, 1166, 773 cm−1.
2.2e 3,3-Bis(1-allyl-5-methoxy-1H-indol-3-yl)-5- 1H NMR (500 MHz, DMSO-d6): δH 1.62 (s, 6H);
bromoindolin-2-one (3e): Brown solid; Mp 203– 1.68 (s, 6H); 4.68 (d, 4H, J = 6.1 Hz); 5.20 (t, 2H,
205◦C; IR (KBr): 2919, 1725, 1616, 1474, 1032, J = 6.9 Hz); 6.91 (s, 2H); 7.13–7.17 (m, 4H); 7.32–
1
911 cm−1. H NMR (500 MHz, DMSO-d6): δH 3.94 7.33 (m, 4H); 7.46 (d, 2H, J = 7.6 Hz); 7.54 (t, 2H,
(s, 6H); 4.68 (d, 4H, J = 4.5 Hz); 4.90 (d, 2H, J = 7.6 Hz); 10.75 (s, 1H). 13C NMR (125 MHz,
J = 16.8 Hz); 5.04 (d, 2H, J = 9.9 Hz); 5.86–5.91 DMSO-d6): δC 18.3, 25.8, 45.1, 52.5, 111.8, 112.7,
(m, 2H); 6.67 (s, 2H); 6.70 (d, 2H, J = 9.1 Hz); 112.8, 118.3, 120.5, 123.2, 123.5, 124.2, 125.2, 128.2,
6.91 (s, 2H); 6.95 (d, 1H, J = 8.4 Hz); 7.24 (d, 2H, 128.9, 129.3, 135.8, 136.3, 138.9, 151.2, 178.2. MS
J = 9.1 Hz); 7.29 (s, 1H); 7.39 (d, 1H, J = 8.4 Hz); (EI): m/z = 657 [M+]; 659 [M+2]; 661 [M+4]. Anal.
10.81 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δC48.5, Calcd for C34H31Br2N3O: C, 62.11; H, 4.75; N, 6.39%.
53.1, 55.6, 103.6, 111.5, 112.7, 113.3, 114.5, 116.8, Found: C, 61.99; H, 4.79; N, 6.44%.

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C Praveen et al.
2.2i 3,3-(Bis(5-bromo-1-(3-methylbut-2-enyl)-1H- NMR (125 MHz, DMSO-d6): δC 35.6, 52.6, 60.3, 75.1,
indol-3-yl)-1-(prop-2-ynyl)indolin-2-one (3i): Brown 76.1, 78.5, 79.7, 110.2, 110.8, 114.2, 119.6, 121.7,
solid; Mp 158–160◦C; IR (KBr): 2938, 2368, 1719, 122.1, 123.4, 125.3, 126.7, 127.9, 127.9, 128.7, 133.5,
1
1170, 752 cm−1. H NMR (500 MHz, DMSO-d6): δH 137.0, 141.2, 176.4. MS (EI): m/z = 477 [M+]. Anal.
1.62 (s, 6H); 1.68 (s, 6H); 3.30 (s, 1H); 4.62 (s, 2H); Calcd for C33H23N3O: C, 83.00; H, 4.85; N, 8.80%.
4.67 (d, 4H, J = 6.1 Hz); 5.19 (t, 2H, J = 7.6 Hz); Found: C, 82.67; H, 4.93; N, 8.92%.
6.89 (s, 2H); 7.08 (t, 1H, J = 7.6 Hz); 7.18 (td, 3H,
J = 8.4 Hz); 7.27 (d, 1H, J = 7.6 Hz); 7.32–7.40 (m,
5H). 13C NMR (125 MHz, DMSO-d6): δC 18.3, 25.8,
29.6, 44.1, 52.2, 75.3, 78.1, 110.3, 112.1, 112.9, 113.0,
120.5, 123.5, 124.4, 125.3, 128.0, 129.0, 129.5, 132.7,
135.8, 136.4, 141.2, 176.2. MS (EI): m/z = 695 [M+];
697 [M+2]; 699 [M+4]. Anal. Calcd for C37H33Br2N3O:
C, 63.90; H, 4.78; N, 6.04%. Found: C, 64.19; H, 4.74;
N, 5.97%.
2.2m 3,3-Bis(2-methyl-1-(prop-2-ynyl)-1H-indol-3-
yl)indolin-2-one (3m): Brown solid; Mp 210–212◦C;
IR (KBr): 2909, 1706, 1611, 1465, 1327, 1027,
745 cm−1. 1H NMR (500 MHz, DMSO-d6): δH 2.31 (s,
6H); 2.39 (s, 2H); 4.75 (s, 4H); 7.10–7.18 (m, 4H);
7.19 (t, 2H, J = 7.6 Hz); 7.30 (d, 4H, J = 7.6 Hz);
7.53 (d, 2H, J = 7.6 Hz); 10.59 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): δC 12.9, 38.1, 52.5, 71.1, 77.3,
109.1, 110.5, 119.4, 120.4, 121.9, 123.8, 125.1, 127.5,
2.2j 3,3-Bis(1-(prop-2-ynyl)-1H-indol◦-3-yl)indolin- 135.1, 135.3, 135.8, 136.1, 137.9, 141.0, 177.0. MS
2-one (3j): Brown solid; Mp 265–267 C; IR (KBr): (EI): m/z = 467 [M+]. Anal. Calcd for C32H25N3O: C,
1
3284, 1710, 1467, 1333, 745, 658 cm−1. H NMR 82.20; H, 5.39; N, 8.99%. Found: C, 81.99; H, 5.44; N,
(500 MHz, DMSO-d6): δH 3.34 (s, 2H); 5.02 (s, 4H); 9.07%.
6.84 (t, 2H, J = 7.6 Hz); 6.93 (t, 1H, J = 7.6 Hz), 6.98
(s, 2H); 6.99–7.00 (m, 1H); 7.09 (t, 2H, J = 7.6 Hz);
2.2n 3,3-Bis(2-phenyl-1H-indol-3-yl)indolin-2-one
7.22 (d, 4H, J = 7.6 Hz); 7.44 (d, 2H, J = 8.4 Hz);
(3n): Red solid; Mp 240–242◦C; IR (KBr): 3376,
10.61 (s, 1H). 13C NMR (125 MHz, DMSO-d6): δC
39.6, 52.9, 76.0, 79.8, 110.3, 110.7, 114.7, 119.5,
121.6, 122.0, 122.2, 125.4, 126.8, 127.7, 128.6, 134.6,
137.0, 141.7, 178.8. MS (EI): m/z = 439 [M+]. Anal.
Calcd for C30H21N3O: C, 81.98; H, 4.82; N, 9.56%.
Found: C, 82.25; H, 4.75; N, 9.44%.
1
1719, 1613, 1454, 1328, 746, 700 cm−1. H NMR
(500 MHz, Acetone-d6) δH 6.65 (t, 2H, J = 6.6 Hz,
Ar-H), 6.71 (t, 1H, J = 8.4 Hz, Ar-H), 6.85 (t, 1H,
J = 6.9 Hz, Ar-H), 6.92–6.98 (m, 4H, Ar-H), 7.00 (t,
2H, J = 7.6 Hz, Ar-H), 7.06 (t, 2H, J = 7.6 Hz, Ar-H),
7.16–7.21 (m, 6H, Ar-H), 7.25 (t, 4H, J = 8.4 Hz, Ar-
H), 9.36 (s, 1H, -NH-CO-), 9.78 (s, 1H, -NH), 10.11
2.2k 1-Benzyl-3,3-bis(1-(prop-2-ynyl)-1H-indol-3- (s, 1H, -NH). 13C NMR (75 MHz, Acetone-d6) δC
yl)indolin-2-one (3k): Brown paste; IR (neat): 3291, 54.2, 109.9, 111.2, 111.6, 112.3, 113.1, 113.4, 119.1,
1709, 1463, 1181, 907, 737 cm−1. 1H NMR (500 MHz, 119.4, 121.7, 122.3, 122.9, 123.8, 125.4, 126.7, 126.9,
CDCl3): δH 2.38 (s, 2H); 4.73 (s, 4H); 5.06 (s, 2H); 127.5, 127.9, 128.2, 128.6, 129.1, 129.9, 130.1, 134.8,
6.95–7.00 (m, 4H); 7.05 (s, 2H); 7.21–7.24 (m, 3H); 135.4, 135.9, 136.6, 138.8, 139.1, 141.9, 178.7.MS
7.33–7.42 (m, 9H); 7.49 (d, 1H, J = 7.4 Hz). 13C NMR (ESI): m/z = 1053 [dimer + Na+]. Anal. Calcd for
(125 MHz, CDCl3): δC 35.9, 44.2, 52.9, 73.8, 78.0, C36H25N3O: C, 83.86: H, 4.89; N, 8.15%. Found: C,
109.5, 109.8, 114.8, 119.8, 121.9, 122.2, 122.9, 125.5, 83.97; H, 4.85; N, 8.09%.
127.0, 127.5, 127.9, 128.3, 128.9, 129.1, 133.9, 136.2,
137.0, 142.1, 178.2. MS (EI): m/z = 529 [M+]. Anal.
2.2o 1-Methyl-3,3-bis(2-phenyl-1H-indol-3-yl)indolin-
Calcd for C37H27N3O: C, 83.91; H, 5.14; N, 7.93%.
2-one (3o): Brown solid; Mp 294–296◦C; IR (KBr):
Found: C, 84.05; H, 5.10; N, 7.88%.
3411, 3319, 1698, 1605, 1489, 1454, 1351, 741, 696
1
cm−1. H NMR (500 MHz, DMSO-d6) δH 2.83 (s,
2.2l 1-(Prop-2-ynyl)-3,3-bis(1-(prop-2-ynyl)-1H-indol- 3H, -NCH3), 6.58 (t, 1H, J = 6.8 Hz, Ar-H), 6.64
3-yl)indolin-2-one (3l): Brown solid; Mp 120–122◦C; (t, 2H, J = 6.8 Hz, Ar-H), 6.81 (t, 1H, J = 7.6 Hz,
1
IR (KBr): 3279, 1718, 1468, 1341, 1178 cm−1. H Ar-H), 6.89–7.09 (m, 11H, Ar-H), 7.23–7.33 (m, 7H,
NMR (500 MHz, DMSO-d6): δH 3.34 (s, 2H); 4.00 (q, Ar-H), 10.75 (s, 1H, -NH), 11.02 (s, 1H, -NH). 13C
1H, J = 6.8 Hz); 4.65 (s, 2H); 5.02 (s, 4H); 6.87 (t, 2H, NMR (75 MHz, DMSO-d6) δC 25.9, 52.2, 108.0, 110.2,
J = 7.6 Hz); 6.98 (s, 2H); 7.06 (t, 1H, J = 7.6 Hz); 110.9, 111.3, 117.8, 118.3, 119.6, 120.4, 121.5, 121.8,
7.12 (t, 2H, J = 7.6 Hz); 7.27 (d, 4H, J = 7.6 Hz); 124.8, 125.7, 126.6, 127.1 (2C), 127.4 (2C), 127.7,
7.37 (t, 1H, J = 7.6 Hz); 7.46 (d, 2H, J = 8.4 Hz). 13C 128.5 (2C), 128.6, 133.2, 134.0, 134.4, 134.5, 135.3,

Zn(OTf)2-catalysed indolylation of isatins
1547
1
135.4, 141.9, 175.5. MS (ESI): m/z = 552 [M+Na+]. 1713, 2925, 3385 cm−1. H NMR (500 MHz, DMSO-
Anal. Calcd for C37H27N3O: C, 83.91; H, 5.14; N, d6) δH 0.59 (t, 3H, J = 6.8 Hz, -CH3), 0.67 (t, 3H,
7.93%. Found: C, 84.01; H, 5.25; N, 7.85%.
J = 6.8 Hz, -CH3), 0.91–1.42 (m, 8H, -CH2-CH2-
CH3), 2.29–2.35 (m, 4H, Ar-CH2-), 6.39 (d, 1H, J =
7.6 Hz, Ar-H), 6.50 (t, 1H, J = 6.9 Hz, Ar-H), 6.58 (t,
1H, J = 7.6 Hz, Ar-H), 6.79–6.90 (m, 5H, Ar-H), 7.12–
7.18 (m, 4H, Ar-H), 10.47 (s, 1H, -NH-CO-), 10.70
(s, 1H, -NH), 10.75 (s, 1H, -NH). 13C NMR (75 MHz,
DMSO-d6) δC 13.4, 13.5, 22.0, 22.1, 26.4, 26.5, 30.8,
31.3, 52.6, 109.1, 110.1, 110.2, 110.5, 117.3, 117.4,
119.4, 119.7, 120.0, 120.4, 120.9, 125.1, 127.1, 127.5,
127.6, 135.1, 135.2, 135.3, 135.6, 135.8, 137.9, 141.0,
179.0. MS (ESI): m/z = 973 [dimer + Na+]. Anal.
Calcd for C32H33N3O: C, 80.81; H, 6.99; N, 8.83%.
Found: C, 80.97; H, 7.10; N, 8.72%.
2.2p 5-Methyl-3,3-bis(5-chloro-2-phenyl-1H-indol-3-
yl)indolin-2-one (3p): Pink solid; Mp 279–281◦C; IR
(KBr): 768, 1311, 1464, 1711, 2924, 3419 cm−1. H
1
NMR (500 MHz, DMSO-d6) δH 2.04 (s, 3H, -CH3),
6.89–7.10 (m, 19H, Ar-H), 10.49 (s, 1H, -NH-CO-),
11.14 (s, 1H, -NH), 11.21 (s, 1H, -NH). 13C NMR
(75 MHz, DMSO-d6) δC 31.5, 58.0, 114.2, 115.3,
116.2, 117.3, 125.1, 125.4, 125.8, 126.0, 128.1, 129.0,
131.6, 132.0, 132.3, 132.5, 133.5 (2C), 133.6 (2C),
133.7, 134.2, 135.2, 138.4, 138.5, 138.9, 139.0, 139.1,
142.6, 143.9, 183.0. MS (ESI): m/z = 1217 [dimer +
Na+], 1219 [dimer + M+2 + Na+], 1221 [dimer + M+4
+ Na+]. Anal. Calcd for C37H25ClN3O: C, 74.25; H,
4.21; N, 7.02%. Found: C, 74.11; H, 4.25; N, 7.15%.
2.2t
5-Fluoro-3,3-bis(5-nitro-1H-indol-3-yl)indolin-
2-one (3t): Yellow solid; Mp >250◦C; IR (KBr):
1342, 1479, 1519, 1677, 3324 cm−1. 1H NMR
(500 MHz, DMSO-d6): δH 7.00–7.20 (m, 3H), 7.20 (s,
2H), 7.58 (d, J = 8.9 Hz, 2H), 7.97 (d, J = 9.8 Hz,
2H), 8.23 (s, 2H), 11.0 (brs, 1H), 11.8 (brs, 2H). 13C
NMR (125 MHz, DMSO-d6): 52.5, 111.1, 112.4, 112.7,
115.1, 116.1, 116.9, 117.5, 124.4, 128.5, 134.6, 137.3,
140.2, 156.5, 159.8, 179.9. MS (ESI): m/z = 472
[M+1]+. Anal. Calcd for C24H14FN5O5: C, 61.15; H,
2.99; F, 4.03, N, 14.86%. Found: C, 59.97; H, 3.01; F,
3.97; N, 15.01%.
2.2q 3,3-Bis(5-methyl-2-phenyl-1H-indol-3-yl)indolin-
2-one (3q): Brown solid; Mp 270–272◦C; IR (KBr):
1105, 1250, 1601, 1706, 1712, 3377, 3409, 3473 cm−1.
1H NMR (500 MHz, DMSO-d6) δH 2.03 (s, 3H, -CH3),
2.13 (s, 3H, -CH3), 6.80–7.33 (m, 20H, Ar-H), 10.40
(s, 1H, -NH-CO-), 10.51 (s, 1H, -NH), 10.83 (s, 1H,
-NH). 13C NMR (75 MHz, DMSO-d6) δC 21.2, 22.0,
53.4, 109.4, 110.3, 110.5, 110.9, 111.6, 112.6, 120.6,
121.4, 121.7, 122.4, 123.2, 125.1, 125.9, 126.0, 126.4,
126.5, 126.7, 127.5, 127.6, 128.1 (2C), 128.7, 128.9,
129.3, 134.1, 134.4, 134.8, 135.3, 138.8, 141.4, 177.8.
MS (ESI): m/z = 1109 [dimer + Na+]. Anal. Calcd
for C38H29N3O: C, 83.95; H, 5.38; N, 7.73%. Found:
C, 84.05; H, 5.29; N, 7.81%.
2.2u 3,3-Bis(6-methoxy-1H-indol-3-yl)indolin-2-one
(3u): Colourless solid; Mp 242–244◦C; IR (KBr):
1
3382, 1686, 1481, 1211, 804, 754 cm−1. H NMR
(500 MHz, DMSO-d6): δH 3.52 (s, 6H), 6.64–6.74 (m,
4H), 6.84 (d, J = 3.0 Hz, 2H), 6.89–7.00 (m, 2H), 7.20
(d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.3 Hz, 3H), 10.5
(brs, 1H), 10.7 (brs, 2H). 13C NMR (125 MHz, DMSO-
d6): 52.6, 55.0, 103.5, 109.5, 110.3, 112.0, 113.5, 121.4,
125.0, 125.1, 126.4, 127.8, 132.2, 134.5, 141.2, 152.3,
178.2. MS (ESI) m/z = 424 [M+1]+. Anal. Calcd for
C26H21N3O3: C, 73.74; H, 5.00; N, 9.92%. Found: C,
73.97; H, 4.97; N, 10.01%.
2.2r 3,3-Bis(5-cyano-2-phenyl-1H-indol-3-yl)indolin-
2-one (3r): Colourless solid; Mp 320–322◦C; IR
(KBr): 1200, 1307, 1464, 1717, 2266, 3346, 3404,
1
3481 cm−1. H NMR (500 MHz, DMSO-d6) δH 6.63–
7.63 (m, 20H, Ar-H), 10.69 (s, 1H, -NH-CO-), 11.56
(s, 1H, -NH), 11.76 (s, 1H, -NH). 13C NMR (75 MHz,
DMSO-d6) δC 59.7, 100.5, 100.6, 109.5, 110.8, 111.7,
112.0, 112.3, 120.6, 120.8, 121.8, 123.4, 123.5, 123.6,
125.6, 125.8, 126.3, 126.4, 126.8, 127.2, 127.4, 127.9,
128.4, 128.5, 128.6, 132.1, 132.4, 133.9, 137.2, 138.0,
140.9, 177.4. MS (ESI): m/z = 1153 [dimer + Na+].
Anal. Calcd for C38H23N5O: C, 80.69; H, 4.10; N,
12.38%. Found: C, 80.55; H, 4.15; N, 12.25%.
2.2v 3,3-Di(1H-pyrrol-2-yl)indolin-2-one (3v):
Colourless solid; Mp 118–120◦C; IR (KBr): 3457,
2933, 1707, 1050, 775 cm−1. 1H NMR (500 MHz,
CDCl3) δH 5.79 (d, J = 3.4 Hz, 2H), 6.06 (dd,
J = 2.4; 3.4 Hz, 2H), 6.60 (d, J = 2.4 Hz, 2H),
6.89 (d, J = 8.1 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H),
7.19 (t, J = 8.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H),
2.2s 3,3-Bis(2-butyl-1H-indol-3-yl)indolin-2-one (3s): 9.70 (brs, 2H), 10.3 (brs, 1H). 13C NMR (125 MHz
Brown solid; Mp 199–201◦C; IR (KBr): 749, 1459, CDCl3): δC 27.5, 84.1, 110.0, 114.5, 119.5, 122.0,

1548
C Praveen et al.
123.3, 125.3, 127.4, 128.9, 132.7, 133.8, 135.1, 141.2, (500 MHz, CD3CN): δH 3.14 (s, 3H), 3.19 (s, 3H),
149.6, 177.6. MS (ESI) m/z = 263 [M]+. Anal. Calcd 5.79 (dd, J = 2.0, 3.6 Hz, 1H), 5.97 (dd, J = 2.9,
for C16H13N3O: C, 72.99; H, 4.98; N, 15.96%. Found: 3.5 Hz, 1H), 6.00–6.12 (m, 1H), 6.32–6.45 (m, 1H),
C, 73.20; H, 4.94; N, 15.88%.
6.60 (t, J = 2.5 Hz, 1H), 6.88–6.95 (m, 2H), 7.15 (d,
J = 2.2 Hz, 1H), 7.35–7.42 (m, 2H), 10.1 (brs, 1H).
13C NMR (125 MHz, CD3CN): δC 26.1, 57.1, 107.0,
108.1, 122.0, 122.2, 125.0, 127.8, 128.0, 129.9, 133.9,
169.9. MS (ESI) m/z = 291 [M]+. Anal. Calcd for
C18H17N3O: C, 74.20; H, 5.88; N, 14.42%. Found: C,
73.99; H, 5.92; N, 14.49%.
2.2w 5-Chloro-1-methyl-3,3-di(3,5-dimethyl-1H-pyrrol-
2-yl)-indolin-2-one (3w): Colourless solid; Mp 165–
167◦C; IR (KBr): 3451, 3001, 2930, 1705, 1093, 801,
1
640 cm−1. H NMR (500 MHz, CDCl3): δH 1.66 (s,
6H), 2.15 (s, 6H), 3.25 (d, J = 0.5 Hz, 3H), 5.67 (d,
J = 2.6 Hz, 2H), 6.80 (d, J = 8.2, 1H), 7.27 (ddd,
J = 0.5, 2.1, 8.2 Hz, 1H), 7.23–7.29 (m, 1H), 7.29 (s,
2H). 13C NMR (125 MHz CDCl3): δC 12.1, 13.1, 27.0,
53.9, 109.5, 110.5, 117.0, 120.5, 126.5, 126.9, 128.4,
128.5, 133.2, 141.9, 176.4. MS (ESI) m/z = 367 [M]+,
369 [M]+2. Anal. Calcd for C21H23ClN3O: C, 68.56; H,
6.03; N, 11.42%. Found: C, 68.75; H, 5.99; N, 11.35%.
2.3 Animals and drug dosage
2.3a Animals: The selection of animals, caring and
handling was done as per the guidelines set by the
Indian National Science Academy, New Delhi, India.
Inbred albino mice (Swiss strain) of both genders
weighing 25–30 g were used for the study. The mice
were housed individually in clean polypropylene cages
containing sterile paddy husk (procured locally) as bed-
ding throughout the experiment. All animals were fed
with sterile commercial pelleted rat chow supplied by
Hindustan Lever Ltd. (Mumbai, India) with free access
to water (ad libitum) under standardized housing condi-
tions (natural light–dark cycle, temperature 23◦ 1◦C,
relative humidity 55 5%). After 7 days of adaptation
to laboratory conditions, the animals were randomly
assigned to 25 experimental groups of five mice each.
Each mouse was used only once. All tests were per-
formed between 08:00 and 16:00 h. All efforts were
made to minimize animal suffering and to use only the
number of animals necessary to produce reliable scien-
tific data. Experimental protocols and procedures listed
here conformed to the Guide for the Care and Use of
Laboratory Animals and were approved by the Insti-
tutional Ethics Committee. The liver homogenate was
prepared and the clear supernatant was used for the
estimation of lipid peroxidation (MDA).5
2.2x 5-Chloro-1-methyl-3,3-di(5-ethyl-1H-pyrrol-2-
yl)-indolin-2-one (3x): Yellow solid; Mp 128–130◦C;
IR (KBr): 3535, 3360, 2925, 1680, 1352, 1048, 758,
1
672 cm−1. H NMR (500 MHz, CDCl3)δH 1.21 (dt,
J = 7.6, 15.1 Hz, 6H); 2.40–2.60 (m, 4H), 3.25 (d,
J = 20.1 Hz, 3H), 5.80 (t, J = 2.9 Hz, 2H), 5.81–
5.88 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 7.20–7.35
(m, 1H), 7.46 (d, J = 2.0 Hz, 1H), 8.36 (s, 2H). 13C
NMR (125 MHz, CDCl3)δC 13.1, 21.0, 26.7, 104.2,
106.9, 109.5, 125.5, 126.3, 128.3, 133.0, 135.4, 141.2,
175.9. MS (ESI) m/z = 367 [M]+, 369 [M]+2. Anal.
Calcd for C21H23ClN3O: C, 68.56; H, 6.03; N, 11.42%.
Found: C, 68.75; H, 5.99; N, 11.35%.
2.2y 5-Chloro-1-methyl-3,3-di(1-methyl-1H-pyrrol-
2-yl)-indolin-2-one (3y): Colourless solid; Mp 151–
153◦C; IR (KBr): 3394, 3108, 1702, 1475, 1081, 941,
861, 709 cm−1.1H NMR (500 MHz, CD3CN): δH 3.12
(s, 3H), 3.21 (s, 3H), 3.56 (s, 3H), 5.76 (dd, J = 2.0,
3.6 Hz, 1H), 5.92 (dd, J = 2.9, 3.5 Hz, 1H), 6.03–6.11
(m, 1H), 6.44 (t, J = 2.0 Hz, 1H), 6.50–6.55 (m, 1H),
6.60 (t, J = 2.5 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H),
7.17 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 2.2, 8.3 Hz,
1H). 13C NMR (125 MHz, CD3CN): δC 26.0, 34.0,
35.4, 105.9, 108.0, 110.0, 111.0, 120.4, 121.2, 122.1,
124.6, 124.7, 127.2, 127.9, 131.1, 134.9, 141.5, 176.6.
MS (ESI) m/z = 338 [M]+, 340 [M]+2. Anal. Calcd for
C19H19ClN3O: C, 67.15; H, 5.34; N, 12.37%. Found:
C, 66.99; H, 5.37; N, 12.44%.
2.3b Dose and administration of compounds: Mice
equivalent doses in mg/kg body weight of clinical
doses were calculated on the basis of the surface area
ratio as mg/kg body weight with the help of standard
tables (Karber’s method).6 The test compounds were
tested in mice after 14 days of administration for their
safety as per Organization for Economic Co-operation
and Development (OECD) guidelines.7 At the end of
this period, animals were kept fasting overnight and
killed. Group-I was treated with 0.5% aqueous solu-
2.2z 3,3-Bis(1-methyl-1H-pyrrol-2-yl)indolin-2-one tion of Tween 80 (polyoxyethylene sorbitan mononu-
(3z): Colourless solid; Mp 136–138◦C; IR (KBr): cleate) and served as control. Phenytoin was suspended
1
3389, 3102, 1707, 1479, 1080, 777 cm−1. H NMR in a 0.5% Tween 80 solution and administered

Zn(OTf)2-catalysed indolylation of isatins
1549
intraperitoneally (ip) to group-II (20 mg/kg) and served 0.5 mL of DNPH reagent, mixed well and allowed
as standard. All the test compounds were suspended in to stand at room temperature for 20 min and 0.1 mL
a 0.5% Tween 80 solution and administered intraperi- of distilled water added. Finally, 5.0 mL of NaOH
toneally (ip) to group-III (20 mg/kg).
solution was added and allowed to stand at room
temperature for 10 min. Absorbance of this blank
solution was measured at a wavelength of 505 nm
(Hg 546 nm/Green).
2.4 Statistical analysis
The obtained data were analysed using one-way anal-
ysis of variance (ANOVA) followed by Dunnet’s mul-
tiple comparison test using computerized Graph pad
Instat version 3.05 (Graphpad software, USA). The
results are presented as mean standard error of means
(SEM). Differences between data sets were considered
as significant when P < 0.001.
2.6 Procedure for the estimation of MDA
The measure of lipid peroxidation was determined as
described by Okhawa et al.,9 briefly the reaction mix-
ture consisted of 0.2 mL of 8.1% sodium lauryl sul-
phate, 1.5 mL of 20% HOAc (pH 3.5) and 1.5 mL of
0.8% aqueous solution of thiobarbituric acid was added
to 0.2 mL of processed liver homogenate. The mixture
was made up to 4.0 mL with distilled water and heated
at 95◦C for 60 min. After cooling with tap water, 5 mL
of n-butanol and pyridine (15:1 v/v) and 1 mL of dis-
tilled water was added and centrifuged. The organic
layer was separated out and its absorbance was mea-
sured at 532 nm using an UV-visible spectrophotometer
(THERMAL) and the MDA content was expressed as
nmol/mg protein and compared with an external stan-
dard, tetraethoxypropane. The % inhibition of lipid per-
oxidation by the test or standard drug was calculated by
using the formula; [(A−B)/B] × 100, where; A is the
control group and B is the test or standard group.
2.5 Procedure for the estimation of SGOT
SGOT assay was done by using AST enzymatic assay
kit by modified Reitman and Frankel method.8 In prin-
ciple, the amount of oxaloacetate or pyruvate produced
by transamination is reacted with 2,4-dinitrophenyl
hydrazine (DNPH) to form a brown coloured hydra-
zone, the colour of which in alkaline solution is read
at 505 to 520 nm. Blood samples were collected from
retro-orbital plexus under light ether anaesthesia in a
microfuge tube and the serum was used for the SGOT
assay. Into a clean dry test tube was pipetted 0.5 mL
of substrate reagent and incubated at 37◦C for 3 min
followed by addition of 0.1 mL of pyruvate standard.
To this solution was added 0.1 mL of sample mixed
well followed by incubation at 37◦C for 30 min. To this
mixture was added 0.5 mL of DNPH reagent, mixed
well and allowed to stand at room temperature for
20 min. Finally, 5.0 mL of NaOH solution was added
and allowed to stand at room temperature for 10 min.
Absorbance of this test solution was measured at a
wavelength of 505 nm (Hg 546 nm/Green). Similarly, a
blank analysis was performed. Into a clean dry test tube
was pipetted 0.5 mL of substrate reagent and incubated
at 37◦C for 3 min. To this solution was added 0.1 mL
of pyruvate standard, mixed well followed by incuba-
tion at 37◦C for 30 min. To this mixture was added
3. Results and discussion
3.1 Chemistry
It is pertinent to note that we have recently esta-
blished an efficient room temperature protocol for the
synthesis of 3,3-di(indolyl)oxindoles via 3-indolylation
of isatins in the presence of 5 mol% of Cu(OTf)2 in
acetonitrile (scheme 3).4a Despite the efficiency of this
R3
R3
N
N
O
R2
5 mol% Cu(OTf)2
MeCN/rt
R4
R
R
2
O
N
R1
R4
R
N
R1
O
R = H, Me
N
R1
R2
R2
R1 = allyl, prenyl, cinnamyl, propargyl
R
R
2 = H, OMe, Br
3 = H, propargyl, benzyl, CH2COOEt
R4 = H, Cl, Br, NO2
13 examples
Scheme 3. Copper-catalysed indolylation of isatin.

1550
C Praveen et al.
H
N
some other di(indolyl)oxindoles 3n-3u and observed
H
O
N
good to excellent yields. Structures of all the products
5 mol% Cu(OTf)2
MeCN / rt
H
O
1
were confirmed by spectral data (FTIR, H NMR, 13C
N
N
H
NMR and MS) and elemental analyses. For an illustra-
tive example, the IR spectrum of compound 3s showed
broad peaks at 1713 and 3385 cm−1, revealing the pres-
ence of lactam amide (-NH-CO-) and indole –NH func-
O
NH
Scheme 4. Attempted pyrrolylation under copper-catalysis.
1
tionalities, respectively. The H NMR spectrum of 4k
recorded in DMSO-d6, showed 33 protons. Broad sig-
nals at δH 10.47 ppm and δH 10.73 ppm were assigned
to –NH-CO- and –NH protons (D2O exchangeable),
respectively. In 13C NMR spectrum, a less intense peak
at δC 53.1 ppm indicates the presence of a spiro-carbon
and a peak at δC 179.6 ppm corresponds to an amide
carbonyl carbon. Moreover, no quaternary carbon sig-
nal at δC 53.1 ppm appeared in the 13C NMR 135 DEPT
spectra. MS data was acquired in the positive ioniza-
tion mode, exhibited peak at m/z = 973 [dimer +
Na+]. With a satisfactory procedure for the synthesis
of di(indolyl)oxindoles in hand, we next turned our
attention for the synthesis of few di(pyrrolyl)oxindoles
under our zinc-catalysed reaction conditions. To this
end, this new catalytic system was evaluated in the bis-
addition of substituted pyrroles. In all tested cases, bet-
ter results were obtained both in terms of reactivity and
isolated yield (figure 2). It is noteworthy to mention
that the results revealed the superiority of this methodo-
logy over the Cu(OTf)2-catalysed protocol that we pre-
viously described in terms of low catalytic loading and
short reaction time.
catalytic system for the indole derivatives,10 for rea-
sons which are not known, we encountered a more slug-
gish reactivity of the corresponding pyrrole counter-
parts,11 which led to their degradation in our initially
optimized Cu(OTf)2 conditions (scheme 4). Consider-
ing the high medicinal value of the 3,3-disubstituted
oxindole cores,12 its preparation still requires inves-
tigation to allow an efficient and cheap process for
the synthesis of a wide array of structurally diverse
3,3-di(heteroaryl)oxindoles. Based on the knowledge
gained from our previous study on Zn(OTf)2 cataly-
sis,4b we thought it will be catalytically effective for
the pyrrolylation of isatins. Firstly, the catalyst per-
formance was optimized separately in the reaction of
isatin with N-allylindole and pyrrole respectively, in
the presence of 1 mol% of Zn(OTf)2 at room tem-
perature in acetonitrile (scheme 5). Both reactions
proceeded spontaneously and was completed within
5 min.
In order to explore the scope, we first applied this
new condition for a range of isatins and indoles. Irre-
spective of nature of the substituent on the periph-
ery, all substrates underwent the reaction smoothly
affording the products in good to excellent yields
(figure 1). We did not observe any isomerization prod-
3.2 Biochemistry
uct, when (E)-1-cinnamyl indole was reacted with 3.2a SGOT and MDA estimation: AST levels are
isatin, the corresponding di(indolyl)oxindole (3g) was commonly used to monitor and attenuate the hepato-
provided in 85% yield with complete transfer of stereo- toxic effects of experimental drugs in rodents. All the
chemistry (as evidenced by the coupling constant value, compounds (3a–3z) were analysed for their hepatotoxic
J = 16.0 Hz). Also, substrates possessing alkynes side effects using liver function tests and compared
did not undergo isomerization to the corresponding with the standard anticonvulsant drug, phenytoin and
allenyl product.13 These two observations were in paral- control, Tween 80. The compounds were administered
lel agreement with our previously developed Cu(OTf)2 chronically to rats for 14 days at a dose of 20 mg/kg
catalysed protocol.4a Delighted with these results, we and SGOT levels were estimated (table 1). Results
extended our new methodology for the synthesis of revealed that all the compounds were safe at the tested
H
H
N
N
N
O
H
N
O
2.0 eq.
2.0 eq.
N
H
H
N
O
N
1 mol% Zn(OTf)2
MeCN/rt/5 min
94 %
1 mol% Zn(OTf)2
MeCN/rt/5 min
80 %
N
O
NH
3v
3a
Scheme 5. Zinc-catalyzed indolylation and pyrrolylation of isatin.

Zn(OTf)2-catalysed indolylation of isatins
1551
H
N
H
H
OMe
OMe
H
N
N
N
O
O
O
O
Cl
O2N
N
N
N
N
N
N
N
N
3d
3b
OMe
OMe
3c
90%
3a
94%
95%
97%
COOEt
H
N
H
H
N
Br
OMe
N
OMe
O
N
N
O
O
N
O
Br
N
N
N
N
N
N
Ph
Br
OMe
3g
OMe
3f
90%
Ph
3e
95%
3h
86%
90%
Bn
N
H
N
N
Br
N
O
O
N
O
O
N
N
N
N
N
N
N
3k
3j
3l
Br
3i
87%
91%
89%
90%
H
N
H
N
H
Me
N
N
O
Me
Me
Cl
O
Ph
NH
O
Ph
NH
O
Ph
N
NH
N
N
N
Me
N
H
Ph
Ph
Ph
H
H
3m
87%
Cl
3p
3n
85%
3o
84%
81%
H
N
H
H
N
N
O
H
H
N
N
MeO
O
O
O
Ph
Ph
O
Bu
F
Me
NC
NH
O2N
NH
NH
NH
NH
N
H
N
H
Me
3q
N
Ph
Ph
H
N
MeO
3u
92%
N
Bu
H
H
NC
O2N
3t
89%
3r
3s
82%
82%
80%
Figure 1. Synthesized 3,3-di(indolyl)oxindoles.
Et
Me
Me
Me
HN
Et
HN
HN
HN
HN
Cl
N
Cl
H
O
Me
3w
O
O
N
N
H
N
Me
3v
80%
3x
85%
Me
91%
MeN
MeN
N
N
Me
O
Cl
Me
O
N
Me
N
H
3y
87%
3z
82%
Figure 2. Synthesized 3,3-di(pyrrolyl)oxindoles.

1552
C Praveen et al.
Table 2. Estimation of MDA levels.
Table 1. SGOT estimation of compounds 3a–3z.
SGOT (units.mL−1
)
Entry
Treatment (20 mg/kg)
MDA level (nmol/mg)
Entry
Compound
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
3x
0.128 0.0068*
0.111 0.0044**
0.129 0.0071**
0.189 0.0071**
0.119 0.0071**
0.122 0.0066*
0.108 0.0054**
0.101 0.0061**
0.172 0.0021**
0.125 0.0011**
0.117 0.0055**
0.110 0.0002**
0.115 0.0007**
0.137 0.0045*
0.130 0.0018*
0.106 0.0009*
0.113 0.0072**
0.119 0.0008*
0.120 0.0006*
0.122 0.0001**
0.115 0.0032**
0.128 0.0013*
0.131 0.0047*
0.120 0.0009**
0.107 0.0012**
0.109 0.0047**
0.105 0.0071
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
0.399 0.010*
0.428 0.016**
0.385 0.006*
0.391 0.008*
0.388 0.012*
0.401 0.009*
0.381 0.003*
0.367 0.001**
0.359 0.003**
0.371 0.007**
0.377 0.005*
0.417 004*
0.420 0.014*
0.393 0.001*
0.369 0.001**
0.366 0.007**
0.399 0.002*
0.407 0.001*
0.358 0.001**
0.364 0.001**
0.385 0.005**
0.374 0.002*
0.369 0.008**
0.366 0.003**
0.388 0.005**
0.396 0.006*
0.365 0.002
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
3s
3t
3u
3v
3w
3x
3y
3y
3z
Control (No RS)
RS
3z
Phenytoin
Tween 80
0.213 0.0581*
0.412 0.004*
*P < 0.5; **P < 0.001, **more significant
RS - Restraint stress
Values are given as mean SEM, n = 5
*P < 0.02; **P < 0.01
One way ANOVA followed by Dunnet’s t-test
4. Conclusion
dose, since the serum level did not show any significant
variation compared to the standard drug.
In summary, we have developed an efficient and
The assay of MDA is based on the reaction of a chro- cheap zinc-catalytic system that allowed the bis-
mogenic reagent, N-methyl-2-phenylindole with MDA. addition of indoles or pyrroles onto isatins to
One molecule of MDA reacts with two molecules of form poly-substituted 3,3-di(heteroaryl)oxindoles. This
reagent to yield a stable chromophore with maximal study showed that the zinc-based catalytic sys-
absorbance at 586 nm (scheme 6). This principle was tem has a broad scope as it could be used
used for the measurement of MDA level, which is for the synthesis of both di(indolyl)oxindoles and
an index of tissue lipid peroxidation. Analysis of the di(pyrrolyl)oxindoles. This methodology allowed us to
results revealed that MDA level was found to be sig- synthesize highly substituted 3,3-di(indolyl)oxindoles
nificantly higher in the tested group than in the control and 3,3-di(pyrrolyl)oxindoles possesing halo, nitro,
group (table 2).
ester, alkyl, alkenyl, alkynyl and aryl groups. One-pot
NMe
O
O
+
2
Ph
Ph
Ph
N
Me
N
λmax
=
Me
586 nm
Scheme 6. Chemistry of isatin.

Zn(OTf)2-catalysed indolylation of isatins
1553
synthesis, short reaction time, excellent yield of prod-
ucts, low catalyst loading and simple purification are the
significant advantages from the perspective of synthetic
chemistry. The biochemical assays such as lipid per-
oxide and SGOT of all the compounds were evaluated
using rodent models.
5. (a) Lowry O H, Rosebrough N J, Farr A L and Randal
R J 1951 J. Biol. Chem. 193 265; (b) Naik R S,
Mujumdar A M and Ghaskadbi S 2004 J. Ethanophar-
macol. 95 31
6. (a) Ghosh M N 2005 Fundamentals of experimental
pharmacology, 3rd Edition (Kolkatta: Hilton and Co.)
p. 190; (b) Kale S R, Kale R R 1994 Practical phar-
macology and toxicology, 1st Edition (Pune: Nirali
Prakashan) pp. 56–57
Supplementary information
7. (a) Samudram P, Rajeshwari H, Vasuki R, Geetha A
and Sathiamoorthy P 2008 Afr. J. Biochem. Res. 2 61;
(b) OECD Guidelines for Testing Chemicals, No. 401,
Acute Oral Toxicity (Paris), 1987, 1
For supplementary information (figures S1–S7), see
www.ias.ac.in/chemsci website.
Acknowledgement
8. Reitman S and Frankel S 1957 Am. J. Clin. Pathol. 28 56
9. (a) Okhawa H, Ohishi N and Yagi K 1979 Anal.
Biochem. 95 351; (b) Lykkesfeldt J 2001 Clin. Chem. 47
1725
One of the authors, CP thanks the Council of Scien-
tific and Industrial Research (CSIR), New Delhi for pro-
viding research fellowship between January 2006 and
December 2010.
10. For the catalytic approach of indolylation of isatins, see:
(a) Rad-Moghadam K, Sharifi-Kiasaraie M and Taheri-
Amlashi H 2010 Tetrahedron 66 2316; (b) Klumpp D A,
Yeung K Y, Prakash G K S and Olah G A 1998 J. Org.
Chem. 63 4481; (c) Wang S and Ji S 2006 Tetrahedron
62 1527; (d) Azizian J, Mohammadi A A, Karimi, N,
Mohammadizadeh M R and Karimi A R 2006 Catal.
Commun. 7 752; (e) Paira P, Hazra A, Kumar S, Paira R,
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J A 2004 J. Med. Chem. 47 4979; (b) Joshi K C, Pathak
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