Indium(III) chloride/2-iodoxybenzoic acid: A novel reagent system for the conversion of indoles into isatins

Article abstract of DOI:10.1055/s-2007-965930

Indoles and azaindoles undergo smooth oxidation with 2-iodoxybenzoic acid (IBX) in the presence of indium(III) chloride at 80°C to afford the corresponding isatins in excellent yields. This method is very useful for the direct preparation of isatins from indoles. The reaction proceeds smoothly in aqueous media and the products are obtained in excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-965930

PAPER
693
Indium(III) Chloride/2-Iodoxybenzoic Acid: A Novel Reagent System for the
Conversion of Indoles into Isatins
I
ndium(III
.
)
C
hloride/2
S
-Iodoxybenz
o
.
A
cid: Con
Y
version of Indoles
atoIsatins dav,* B. V. Subba Reddy, Ch. Suresh Reddy, A. D. Krishna
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: yadav@iict.res.in
Received 19 October 2006; revised 29 November 2006
tive transformations.9 Furthermore, indium halides have
Abstract: Indoles and azaindoles undergo smooth oxidation with
2-iodoxybenzoic acid (IBX) in the presence of indium(III) chloride
at 80 °C to afford the corresponding isatins in excellent yields. This
method is very useful for the direct preparation of isatins from in-
emerged as versatile Lewis acid catalysts imparting high
regio-, chemo-, and diastereoselectivity in a variety of or-
ganic transformations. Compared to conventional Lewis
doles. The reaction proceeds smoothly in aqueous media and the acids, indium(III) chloride in particular has the advan-
products are obtained in excellent yields.
tages of low catalyst loading, moisture stability, and cata-
lyst recycling.10
Keywords: indole, indium(III) reagents, isatin, hypervalent iodine
As a part of our ongoing research program on the use of
indium(III) chloride for various transformations,11 herein
Isatins (1H-indole-2,3-diones) are versatile building
blocks for the synthesis of a large variety of heterocyclic
compounds1 such as indoles, isatoic anhydride, and quin-
olines, and as precursor for convolutamydines2 (Figure 1)
and proteasome inhibitors.3
we disclose a novel and efficient protocol for the conver-
sion of indoles into isatins. With the aim of preparing
isatins, indole was treated with 2-iodoxybenzoic acid in
the presence of indium(III) chloride in aqueous acetoni-
trile at 80 °C. The reaction went to completion within two
hours, and the product, isatin 2a was obtained as orange
needles in 85% yield (Table 1, entry 1). This result en-
couraged us to extend this methodology to various substi-
tuted indoles 1a–k. Interestingly, several indoles
underwent smooth oxidation to produce isatins 2a–k in
high yields (Scheme 1).
X
Br
HO
O
X = Cl or OH
N
H
Br
Figure 1
O
R1
R1
Isatins have also been found in mammalian tissue where
they act as a modulator of biochemical processes. The ver-
satility of isatins stems from their pharmacological and bi-
ological properties.1 Therefore, much attention has been
paid to the preparation of isatins. As a result, there have
been reports on the conversion of indoles into isatins.4,5
However, the conditions used may cause modification of
the substituents and yields are generally low, particularly
when the indole is unsubstituted at nitrogen.5 Hypervalent
iodine reagents have attracted increasing interest as oxi-
dants in organic synthesis due to their mild, selective, and
environmentally benign oxidizing properties.6 Among
various hypervalent iodine reagents, 2-iodoxybenzoic
acid (IBX) is a versatile oxidizing agent because of its
high efficiency, ready availability, mild reaction condi-
tions, and its stability to moisture and air.7 Wide function-
al group tolerance and high yielding reactions without
over oxidation, has made the use of 2-iodoxybenzoic acid
synthetically useful for the oxidation of alcohols, even in
the presence of alkenes, sulfides, and amino groups.8 In
recent reports, the use of 2-iodoxybenzoic acid as a mild
oxidant has been extended to many other elegant oxida-
InCl3/IBX
O
N
H
N
H
MeCN–H2O, 80 °C
R2
R2
1
2
Scheme 1
This method is compatible with various substituents such
as bromo, cyano, nitro, and ester groups on the indole
moiety (Table 1, entries 5–11). Acid labile ester and cy-
ano groups are unaffected under the reaction conditions
(Table 1, entries 5, 6, 11). The major advantage of this
method is that both and N-protected and N-unprotected
indoles underwent smooth oxidation by indium(III) chlo-
ride/2-iodoxybenzoic acid. 7-Azaindoles were also
oxidized smoothly with indium(III) chloride/2-iodoxy-
benzoic acid to furnish 7-azaisatins (Table 1, entries 12–
14). However, primary alcohols and amines are incompat-
ible with these reaction conditions. For example, the treat-
ment of indole-3-methanol with indium(III) chloride/2-
iodoxybenzoic acid gave the corresponding isatin in 70%
yield. The products thus obtained were characterized by
NMR, IR, and mass spectroscopy and also by comparing
their NMR spectrum with authentic samples.4 Attempted
oxidation of indole with 2-iodoxybenzoic acid in the ab-
SYNTHESIS 2007, No. 5, pp 0693–0696
x
x
.
x
x
.2
0
0
7
Advanced online publication: 13.02.2007
DOI: 10.1055/s-2007-965930; Art ID: Z21006SS
© Georg Thieme Verlag Stuttgart · New York

694
J. S. Yadav et al.
PAPER
sence of indium(III) chloride resulted in low yield of PhI(OAc)2, PhIO], 2-iodoxybenzoic acid was found to be
product (21%) even after a long reaction time (24 h). the best, giving good results. Of various indium reagents
However, no oxidation of indole was observed when the tested [i.e., In(OTf)3, In(ClO4)3], indium(III) chloride was
reaction was performed using 10 mol% of indium(III) shown to be the most effective Lewis acid for this conver-
chloride in the absence of 2-iodoxybenzoic acid. Both in- sion. The scope and generality of this process is illustrated
dium(III) chloride and 2-iodoxybenzoic acid are essential with respect to various indoles and the results are present-
for the success of the reaction. Among other hypervalent ed in the Table 1.
iodine reagents studied [i.e., Dess–Martin periodinane,
Table 1 Indium(III) chloride/2-Iodoxybenzoic Acid Promoted Oxidation of Indoles to Isatins
Entry
Indole
Producta
Time (h)
2.0
Yieldb (%)
O
1
1a
1b
2a
2b
85
O
N
H
N
H
O
CHO
2
3
2.5
1.5
79
90
O
O
N
H
N
H
O
1c
2c
N
N
Bn
Bn
O
4
5
1d
2d
2e
2f
1.5
2.0
1.5
2.0
1.5
2.0
1.5
93
82
91
85
83
86
82
O
N
N
Me
Me
O
NC
NC
NC
NC
1e
1f
1g
1h
1i
O
O
N
H
N
H
O
6
N
N
Bn
Bn
O
O2N
O2N
7
2g
2h
2i
O
N
H
N
H
O
O2N
O2N
8
O
N
N
Bn
Bn
O
Br
Br
Br
Br
9
O
N
H
N
H
O
10
2j
1j
O
N
N
Me
Me
Synthesis 2007, No. 5, 693–696 © Thieme Stuttgart · New York

PAPER
Indium(III) Chloride/2-Iodoxybenzoic Acid: Conversion of Indoles into Isatins
695
Table 1 Indium(III) chloride/2-Iodoxybenzoic Acid Promoted Oxidation of Indoles to Isatins (continued)
Entry
11
Indole
Producta
Time (h)
3.0
Yieldb (%)
O
MeO2C
MeO2C
1k
1l
2k
2l
85
87
O
N
H
N
H
O
12
13
14
3.5
4.0
3.5
O
O
O
N
N
N
N
N
N
Me
Me
O
2m
2n
80
85
1m
1n
N
N
N
N
Bn
Bn
O
N
N
Et
Et
a All products were characterized by 1H NMR, IR, and MS.
b Isolated and unoptimized yields.
IR (KBr): 3055, 2927, 1730, 1606, 1466, 1324, 1251, 1090, 1022,
951, 863, 758, 692 cm–1.
In conclusion, we have described a novel and efficient
protocol for the conversion of indoles into isatins using in-
dium(III) chloride/2-iodoxybenzoic acid as a novel re- 1H NMR (200 MHz, CDCl3): d = 7.55 (t, J = 7.4 Hz, 1 H), 7.49 (d,
J = 7.4 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 6.88 (d, J = 8.1 Hz, 1 H),
3.18 (s, 3 H).
agent system. The use of an inexpensive and water-
tolerant reagent system makes this procedure quite sim-
ple, more convenient, and environmentally friendly for
the preparation of synthetically and biologically potent
isatins in a one-pot operation.
MS (EI): m/z (%): = 161 (M+, 100), 146 (13), 132 (15), 104 (35), 78
(12).
1-Benzyl-5-nitro-1H-indole-2,3-dione (2h)
Orange needles; mp 166–167 °C.
All known compounds were characterized by 1H NMR, IR, and MS
IR (KBr): 3101, 2925, 1749, 1611, 1518, 1467 1331, 1168, 1123,
and their spectroscopic data was identical to that reported in the lit-
1074, 1020, 885, 826, 745, 700, 638, 596 cm–1.
erature.4 All new compounds were characterized by 1H NMR, 13
NMR, IR, and MS.
C
1H NMR (200 MHz, DMSO-d6): d = 8.36 (d, J = 8.6 Hz, 1 H), 8.3
(s, 1 H), 7.34–7.20 (m, 5 H), 6.98 (d, J = 8.6 Hz, 1 H), 4.95 (s, 2 H).
MS (EI): m/z (%) = 282 (M+, 50), 191 (30), 180 (4), 146 (4), 92
(100), 57 (10).
Indole-2,3-diones 2; General Procedure
Indole or azaindole 1 (1 mmol), IBX (2.5 mmol), and InCl3 (0.1
mmol) in MeCN–H2O (9:1) were stirred at 80 °C for the appropriate
time (Table 1). When the reaction was complete (TLC), the mixture
was filtered through Celite and washed with EtOAc (2 × 10 mL).
The combined organic extracts were washed with NaHCO3 soln and
then with brine and dried (anhyd Na2SO4). Removal of solvent fol-
lowed by purification on a short chromatography column (silica gel,
EtOAc–n-hexane, 2:8) afforded pure 2.
5-Bromo-1-methyl-1H-indole-2,3-dione (2j)
Orange needles; mp 152–154 °C.
IR (KBr): 3045, 2922, 1735, 1602, 1468, 1318, 1253, 1171, 1104,
904, 820, 709, 583 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.72 (d, J = 8.1 Hz, 1 H), 7.65 (s,
1 H), 6.91 (d, J = 8.1 Hz, 1 H), 3.22 (s, 3 H).
MS (EI): m/z (%) = 241 (M+ + 2, 98), 239 (98), 213 (85), 211 (88),
185 (88), 183 (100), 158 (24), 156 (26), 104 (24), 77 (50), 63 (50).
1-Benzyl-1H-indole-2,3-dione (2c)
Orange needles; mp 133–135 °C.
IR (KBr): 2923, 2855, 1732, 1608, 1462, 1343, 1171, 1081, 1002,
857, 750, 690 cm–1.
Methyl 2,3-Dioxo-2,3-dihydro-1H-indole-5-carboxylate (2k)
Orange needles; mp 258–259 °C.
1H NMR (200 MHz, CDCl3): d = 7.55 (d, J = 7.4 Hz, 1 H), 7.51 (t,
J = 7.4 Hz, 1 H), 7.09 (t, J = 7.4 Hz, 1 H), 7.37–7.24 (m, 5 H), 6.87
(d, J = 8.1 Hz, 1 H), 4.91 (s, 2 H).
IR (KBr): 2923, 2852, 1739, 1609, 1537, 1440, 1378, 1323, 1285,
1193, 1070, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 11.37 (br s, 1 H), 8.17 (d, J = 8.1
Hz, 1 H), 8.09 (s, 1 H), 6.99 (d, J = 8.1 Hz, 1 H), 3.89 (s, 3 H).
MS (EI): m/z (%) = 237 (M+, 70), 180 (40), 146 (100), 104 (12), 91
(85), 57 (10).
MS (EI): m/z (%) = 205 (M+, 30), 177 (100), 146 (60), 119 (25), 90
(20), 63 (25).
1-Methyl-1H-indole-2,3-dione (2d)
Orange needles; mp 130–132 °C.
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J. S. Yadav et al.
PAPER
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Synthesis 2007, No. 5, 693–696 © Thieme Stuttgart · New York