Use of pyridinium chlorochromate and reusable polyaniline salt catalyst combination for the oxidation of indoles

Article abstract of DOI:10.1055/s-2008-1077974

A novel method is described herein for the simple, convenient and efficient oxidation of indoles to isatins using pyridinium chlorochromate with the aid of polyaniline salt catalyst at room temperature or at reflux in dichloroethane. Interestingly, oxidation of 3-alkyl indoles by this procedure gave 3-hydroxy 3-alkyl oxindoles. On the other hand, indol-3-alkanols gave mixtures of isatins and 3-formyl indoles. This is the first example of use of polyaniline as a catalyst in oxidation reaction.

Full text of DOI:10.1055/s-2008-1077974

LETTER
2023
Use of Pyridinium Chlorochromate and Reusable Polyaniline Salt Catalyst
Combination for the Oxidation of Indoles
New
C
atalystCo
h
e
r
O
xidation
b
of Indoles olu Naga Sesha Sai Pavan Kumar,a Chebrolu Lavanya Devi,a Vaidya Jayathirtha Rao,a Srinivasan Palaniappan*b
a
Organic Chemistry Division II, Indian Institute of Chemical Technology, Hyderabad 500007, India
Organic Coatings & Polymers Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27193991; E-mail: palani74@rediffmail.com
b
Received 26 March 2008
using NBS in DMSO solvent.12 Recently Yadav et al.13
used 2-iodoxybenzoic acid (IBX)–InCl3 and subsequent-
ly, the preparation of 3-hydroxy oxindoles was also re-
ported with IBX–CeCl3 by the same group.14
Abstract: A novel method is described herein for the simple, con-
venient and efficient oxidation of indoles to isatins using pyridini-
um chlorochromate with the aid of polyaniline salt catalyst at room
temperature or at reflux in dichloroethane. Interestingly, oxidation
of 3-alkyl indoles by this procedure gave 3-hydroxy 3-alkyl oxin- Unfortunately, many of these methods suffer from limita-
doles. On the other hand, indol-3-alkanols gave mixtures of isatins
tions such as harsh reaction conditions, low to moderate
and 3-formyl indoles. This is the first example of use of polyaniline
as a catalyst in oxidation reaction.
yields, long reaction times, tedious workup procedures,
and co-occurrence of several side products. The main dis-
advantage of most of the existing methods is that the cat-
Key words: indoles, oxidation, PCC, isatin, polyaniline
alysts are destroyed in the workup procedure and cannot
be recovered and reused. Therefore, reinvestigation of the
Isatin and its derivatives display diverse biological activi- classical conditions seemed warranted for developing
ties, including anticancer,1 anticonvulsant,2 anti-inflam- conditions for suitable library synthesis.
matory,3 antimicrobial, antiviral,4 and antineoplastic5
Herein we report for the first time, use of pyridinium chlo-
activities. Isatins have also been found in mammalian tis-
rochromate (PCC) as oxidizing agent for the oxidation of
sue where they act as a modulator of biochemical process-
indoles to isatins. In order to enhance the yield, we have
es. The synthetic flexibility of isatin has led to the
catalyzed the reaction with polyaniline salt (PANI) as a
synthesis of a large variety of heterocyclic compounds
polymer-based solid acid catalyst. Pyridinium chloro-
such as indoles, oxindoles, quinolines, isatoic anhydrides,
chromate is well known for oxidation of alcohols to alde-
and it is a precursor of several pharmaceuticals such as
hydes or ketones with high efficiency.15 As part of an
melosatin A,6 SU5416 (VEGFR-2 inhibitor),7 and
ongoing development of efficient protocols for the prepa-
ration of organic compounds, we recently used polya-
donaxaridine8 (Figure 1).
The most common synthetic approach to this class of niline-sulfate salt catalyst as simple, mild, reusable
compounds is the Sandmeyer method9 starting from the polymer-based acid catalyst for the synthesis of quinoxa-
requisite aniline, chloral hydrate, hydroxylamine hydro- lines, benzimidazoles, and benzodiazepines.16,17
chloride and sulfuric acid, but the reaction suffers from
In a reference reaction, indole (1 mmol) was oxidized us-
harsh conditions and lack of generality. Very few reports
ing PCC (2.5 mmol) in 1,2-DCE solvent (5 mL) at room
are available for the direct synthesis of isatin from indole.
temperature for eight hours and isatin was obtained in
Synthesis of 6-nitroisatin (37% yield) from 6-nitro-3-in-
20% yield. In order to improve the yield, the reaction was
dole carboxaldehyde has been reported using CrO3–
carried out at reflux and the yield of the product was in-
AcOH;10 later Parrick et al. used NBS as oxidant in tert-
creased to 42%. In order to improve the yield further, we
butyl alcohol11 and Tatsugi et al. carried out the reaction
used polymer-based solid acid catalyst (PANI catalyst, 15
HN
HO
O
N
H
O
O
O
N
H
N
N
MeO
H
H
OMe
melosatin A
SU 5416
donaxaridine
Figure 1 Pharmaceutical isatin derivatives
SYNLETT 2008, No. 13, pp 2023–2027
x
x
.x
x
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077974; Art ID: D09708ST
© Georg Thieme Verlag Stuttgart · New York

2024
C. N. S. S. P. Kumar et al.
LETTER
wt% with respect to indole), obtaining isatin in 50% yield
at room temperature and 88% yield at reflux. This result
indicates that solid acid catalyst enhances the reaction
yield of isatin.
O
R2
R2
PANI, PCC
O
DCE
80 °C
N
N
H
H
R1
R1
Oxidation of indole was carried out with PCC in the pres-
ence of PANI catalyst using different solvents under re-
flux except for dichloromethane (r.t.) and the results are
reported in Table 1. Higher yield of the product was ob-
tained with the use of DCE as solvent although the reac-
tion also went smoothly in dichloromethane at room
temperature.
R1 = H, Me, NO2
R2 = H, Br, Cl, NO2, OMe
Scheme 1 Oxidation of indoles to isatins catalyzed by PANI and
PCC
O
R2
R2
PANI, PCC
O
To verify the recyclability of the PANI catalyst, we con-
ducted the oxidation reaction using indole as a model sub-
strate. The catalyst was filtered from the reaction mixture,
washed with EtOAc, methanol, dried and reused four
times. The reaction proceeded smoothly with a yield of
85–88% in each case.
DCE
80 °C
N
N
R3
X
X
R3
X = CH, N
R
2 = H, Cl, NO2
R3 = H, Me, Bu, i-Pr, n-C8H17, allyl
Scheme 2 Oxidation of N-substituted indoles and azaindoles cata-
lyzed by PANI and PCC
Table 1 Oxidation of Indole to Isatin with PANI and PCC in Vari-
ous Solvents
O
Entry
Solvent
1,2-DCE
CH2Cl2
benzene
MeCN
acetone
THF
Time (h) Temp (°C) Isolated yield (%)
PANI, PCC
O
DCE
N
N
X
1
2
3
4
5
6
7
8
2.5
8
80
25
88
80
45
30
20
trace
–
X
80 °C
H
O
X = CH, N
8
80
Scheme 3 Oxidation of N-acetyl indole and azaindole catalyzed by
8
80
PANI and PCC
8
56
O
OR'
H
O
8
66
PANI, PCC
O
hexane
H2O
12
12
69
DCE
r.t.
N
N
N
R'
100
–
R'
R'
R' = H, Me, Bn
In order to determine the versatility of the PANI and PCC
system, derivatives of indole (1 mmol) were subjected to
oxidation by PCC (2.5 mmol) with PANI (15 wt% with
respect to indole derivative) in DCE (5 mL) at 80 °C and
the reactions occurred smoothly in high yields without the
formation of any side products (Scheme 1).18,19 The re-
sults are reported in Table 2.
Scheme 4 Oxidation of indol-3-alkanols catalyzed by PANI and
PCC
R
R
HO
PANI, PCC
O
DCE
r.t.
N
R3
N
R3
Furthermore, the reaction was extended to the oxidation
of N-substituted indoles (Table 2, entries 8–11) and aza-
indoles (Scheme 2) to the corresponding isatins (Table 2,
entries 14 and 15).
R = Me
3 = H, Me
R
Scheme 5 Oxidation of 3-alkyl indoles to 3-hydroxy 3-alkyl oxin-
doles catalyzed by PANI and PCC
Oxidation of N-acetyl indole (Scheme 3) gave isatin in-
stead of N-acetyl isatin (entry 12). A similar product was
obtained in the case of N-acetyl azaindole (entry 13).
Acetyl cleavage was observed even when the reaction was
carried out at room temperature.
17). Oxidation of methyl and benzyl derivatives of the
carbinol also gave the corresponding 3-formyl indole and
isatin (entries 18 and 19).
The reaction was extended to the oxidation of 3-methylin-
dole (Scheme 5) to give 3-hydroxy 3-methyl oxindole in
high yield (80%) even at room temperature (entry 20).
Similarly, N-substituted 3-alkyl indole also underwent
smooth oxidation to the corresponding 3-hydroxy oxin-
dole (entry 21).
In order to evaluate the efficiency of the PANI–PCC sys-
tem, we also carried out the oxidation of 3-substituted in-
doles. 3-Formyl indole underwent oxidation to simple
isatin (entry 16). On the other hand, indole 3-carbinol on
oxidation at room temperature (Scheme 4) gave two prod-
ucts, i.e. 3-formyl indole and isatin in a 2:3 ratio (entry
Synlett 2008, No. 13, 2023–2027 © Thieme Stuttgart · New York

LETTER
New Catalyst Combination for Oxidation of Indoles
2025
Table 2 Oxidation of Indoles by PANI and PCC
Entry
Substrate
Product
Time (h)
2.5
Yield (%)a
O
1
88
87
85
81
83
O
N
N
H
H
O
Br
Br
2
3
4
5
2.5
2.5
2.5
3
O
N
N
H
H
O
O2N
MeO
O2N
MeO
O
N
N
H
H
O
O
N
N
H
H
O
O
N
N
H
H
O
6
7
3
82
84
O
O
N
N
H
NO2
H
NO2
Cl
Cl
2.5
O
O
N
N
H
H
O
Cl
Cl
8
9
3.0
2.5
85
83
N
N
Bu
Bu
O
O2N
O2N
O
N
N
O
10
11
2.5
85
84
O
N
N
O
O
3
N
N
Synlett 2008, No. 13, 2023–2027 © Thieme Stuttgart · New York

2026
C. N. S. S. P. Kumar et al.
LETTER
Table 2 Oxidation of Indoles by PANI and PCC (continued)
Entry
12
Substrate
Product
Time (h)
3
Yield (%)a
82
O
N
O
O
O
O
N
O
H
O
13
14
15
16
4.5
4
72
70
81
75
N
N
N
N
N
N
N
O
H
O
N
N
H
H
O
2
N
n-C8H17
O
4
O
N
H
O
CHO
17
18
8
80b
83b
80b
O
O
N
N
H
H
60%
40%
O
CHO
8
N
N
Me
Me
65%
35%
O
CHO
19
20
12
O
N
N
Bn
Bn
40%
60%
HO
8
8
80b
81b
O
O
N
H
HO
21
N
Me
a Isolated yield
b Reaction was carried out at r.t.
In summary, a new method has been reported for the prep- The advantages of the polyaniline salt catalyst are ease of
aration of isatins and oxindoles by the oxidation of indoles synthesis and handling, versatility, simple workup proce-
using PCC catalyzed by polyaniline salt for the first time. dure, mildness and recyclability.
Synlett 2008, No. 13, 2023–2027 © Thieme Stuttgart · New York

LETTER
New Catalyst Combination for Oxidation of Indoles
2027
(17) Palaniappan, S.; Lakshmi Devi, S. Polymer Degrad. Stabil.
2006, 91, 2415.
Acknowledgment
The authors thank Dr. J. S. Yadav, Director, Indian Institute of Che-
mical Technology, for facilities and encouragement. C.S.P. and
C.L.D thank the Council of Scientific and Industrial Research, New
Delhi for the research fellowship. The authors also thank Dr. S.
Raghavan, IICT for his helpful discussion.
(18) Representative Experimental Procedure: In a typical
experiment, PCC (2.5 mmol, 537 mg) was added to a
solution of indole (1 mmol, 117 mg) in 1,2-DCE (5 mL).
Polyaniline salt catalyst [15 wt% with respect to indole (17
mg)] was added and the reaction mixture was stirred at r.t. or
at reflux. Completion of the reaction was monitored by TLC.
After completion, the reaction mixture was filtered through
a Celite® pad and washed with EtOAc (2 × 5 mL). The
combined organic extracts were dried and evaporated under
vacuum. The crude product was purified by silica gel
column chromatography (n-hexane–EtOAc, 3:1) to furnish
isatin (129 mg, 88%). A similar procedure was adopted for
the preparation of other isatins, 3-hydroxy oxindoles and the
authenticity of the products was confirmed from their 1H
NMR and mass spectral data.
References and Notes
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(19) Spectral Data for New Compounds:
1-Butyl-5-chloroindoline-2,3-dione (Table 2, entry 8):
TLC: Rf 0.5 (30% EtOAc–hexanes); orange solid; mp 62–63
°C. IR (KBr): 3089, 2953, 1737, 1606, 1448, 1339, 1185,
1116, 844, 720 cm–1. 1H NMR (200 MHz, CDCl3): d = 7.49
(m, J = 8.1 Hz, 2 H), 6.80 (d, J = 8.1 Hz, 1 H), 3.70 (t, J =
7.3 Hz, 2 H), 1.67 (quint, J = 7.3 Hz, 2 H), 1.43 (m, J = 7.3
Hz, 2 H), 0.98 (t, J = 7.3 Hz, 3 H). 13C NMR (200 MHz,
CDCl3): d = 182.5, 157.6, 149.4, 137.5, 129.3, 125.1, 118.3,
111.8, 40.07, 29.08, 20.0, 13.5. MS (ESI): m/z = 238 [M +
H+]. HRMS (ESI): m/z [M + H+] calcd for C12H13NClO2:
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mp 203 °C. IR (KBr): 2924, 1743, 1610, 1465, 1331, 1289,
1109, 1074, 845, 747, 710, 600 cm–1. 1H NMR (200 MHz,
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J = 8.8 Hz, 1 H), 3.29 (s, 3 H). 13C NMR (200 MHz, CDCl3):
d = 182.1, 157.3, 150.3, 140.5, 128.0, 118.3, 116.7, 111.5,
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mp 74–76 °C. IR (KBr): 3063, 2925, 2855, 1737, 1592,
1456, 1353, 1263, 1085, 783, 738 cm–1. 1H NMR (200 MHz,
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(t, 2 H), 1.74 (t, 2 H), 1.25–1.35 (m, 10 H), 0.87 (t, 3 H). 13
C
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131.8, 118.1, 110.9, 38.9, 30.7, 28.6, 28.1, 26.5, 25.8, 21.6,
13.03. MS (ESI): m/z = 261 [M + H+]. HRMS (ESI): m/z [M
+ H+] calcd for C15H21N2O2: 261.1603; found: 261.1606.
Synlett 2008, No. 13, 2023–2027 © Thieme Stuttgart · New York