CeCl3·7H2O/IBX-promoted oxidation of 3-alkylindoles to 3-hydroxyoxindoles

Article abstract of DOI:10.1016/j.tetlet.2007.01.054

3-Alkylindoles undergo smooth oxidation with IBX in the presence of CeCl₃·7H₂O in aqueous acetonitrile at ambient temperature to afford the corresponding 3-hydroxyoxindoles in high yields. This method is very useful for the direct preparation of 3-hydroxyoxindoles from 3-alkylindoles. Operational simplicity, mild and neutral reaction conditions in aqueous solution are the key features of this protocol.

Full text of DOI:10.1016/j.tetlet.2007.01.054

Tetrahedron Letters 48 (2007) 2029–2032
CeCl3Æ7H2O/IBX-promoted oxidation of 3-alkylindoles
to 3-hydroxyoxindoles
J. S. Yadav,* B. V. Subba Reddy, Ch. Suresh Reddy and A. D. Krishna
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 September 2006; revised 29 December 2006; accepted 10 January 2007
Available online 14 January 2007
Abstract—3-Alkylindoles undergo smooth oxidation with IBX in the presence of CeCl3Æ7H2O in aqueous acetonitrile at ambient
temperature to afford the corresponding 3-hydroxyoxindoles in high yields. This method is very useful for the direct preparation
of 3-hydroxyoxindoles from 3-alkylindoles. Operational simplicity, mild and neutral reaction conditions in aqueous solution are
the key features of this protocol.
ꢀ 2007 Published by Elsevier Ltd.
The 3-hydroxyoxindole motif is a core structure in var-
ious biologically active molecules such as convolutamy-
dines.1 This framework exists in proteasome inhibitors
like TMC-95A/B (Fig. 1).2
have made IBX very popular for the oxidation of
alcohols even in the presence of olefins, thioethers and
amino groups.6 In recent reports, the use of IBX as a
mild oxidant has been extended to many other elegant
oxidative transformations.7 Lanthanide salts are unique
Lewis acids that are currently of great research interest.8
Of various lanthanide salts, cerium(III) chloride is a rel-
atively non-toxic, readily available at low cost, easy to
handle, neutral catalyst and is fairly stable to water.9
However, there have been no reports on the direct con-
version of 3-alkylindoles into 3-hydroxyoxindoles in a
single-step operation using IBX as an oxidant.
Furthermore, the 3-hydroxyindolin-2-one skeleton is
also found in various alkaloids such as donaxaridine,
dioxibrassinine, welwitindolinone C and 3-hydroxy-
glucoisatisin.3 Therefore, there is a need to develop a
simple and efficient protocol for the preparation of 3-
hydroxyindolin-2-ones.4 Iodoxybenzoic acid (IBX) is a
versatile oxidizing agent because of its high efficiency,
easy availability, mild reaction conditions and its stabil-
ity to moisture and air.5 A wide functional group toler-
ance and high-yielding reactions, without over oxidation
As a part of our ongoing research programme on the use
of rare earth metal salts for various transformations,10
herein we disclose a novel and efficient protocol for
the conversion of 3-alkylindoles into 3-hydroxyoxin-
doles. Accordingly, treatment of 3-methylindole with
IBX in the presence of CeCl3Æ7H2O at room temperature
gave the corresponding 3-hydroxyoxindole in 82% yield.
Likewise, several 3-alkylindoles underwent smooth oxi-
dation to produce 3-hydroxyindolin-2-ones in high
yields (Scheme 1).
O
HO
N
H
Me
HO
H
NH
O
O
N
H
CONH2
O
HO
NH
O
Me
Me
N
H
H
O
HO
R
Figure 1.
.
R
CeCl3 7H2O/IBX
O
N
H
CH3CN/H2O
N
H
Keywords: Hypervalent iodine; Oxidation; Indoles; Cerium reagents.
*
Corresponding author. Tel.: +91 40 27193030; fax: +91 40
27160512; e-mail addresses: yadav@iict.res.in; yadavpub@iict.res.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.054

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J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 2029–2032
Table 1. CeCl3Æ7H2O/IBX-promoted oxidation of 3-alkylindoles
Entry
a
Indole (1)
(CH2)3CO2Bn
Producta (2)
Time (h)
12.0
Yieldb (%)
80
HO
(CH2)3CO2Bn
O
N
H
N
H
HO
(CH2)3CO2Bn
(CH2)3CO2Bn
O
b
c
11.5
10.5
12.0
85
87
83
N
N
Bn
Bn
HO
(CH2)3CO2CH3
(CH2)3CO2CH3
O
N
Me
N
Me
HO
(CH2)3CH2OBn
(CH2)3CH2OBn
O
d
N
N
Bn
Bn
HO
(CH2)3CH2OBn
(CH2)3CH2OBn
O
e
f
12.0
11.5
80
85
N
H
N
H
HO
OBn
OBn
O
N
Me
N
Me
HO
OBn
OBn
O
g
h
i
11.0
11.5
12.0
82
80
82
N
N
Bn
Bn
HO
OBn
OBn
O
N
N
Bn
Bn
HO
Me
Me
O
N
H
N
H
HO
Me
Me
O
j
11.5
11.5
12.5
85
87
81
N
Me
N
Me
HO
Me
Me
O
k
N
N
Bn
Bn
HO
OBn
OAc
OBn
OAc
O
l
N
Me
N
Me

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 2029–2032
2031
Table 1 (continued )
Entry
Indole (1)
Producta (2)
Time (h)
3.5c
Yieldb (%)
O
m
n
86
85
87
N
H
O
N
H
CHO
O
3.0c
2.5c
O
N
H
N
H
SCN
O
o
O
N
H
N
H
a All products were characterised by 1H NMR, IR, mass spectroscopy and 13C NMR.
b Isolated and unoptimized yield.
c Reaction was carried at 80 ꢁC.
Acknowledgement
X
O
.
CeCl3 7H2O/IBX
O
C.H.S.R. and A.D.K. thank the CSIR for the award of
fellowships.
N
H
CH3CN/H2O, 80 oC
N
H
X = H, CHO, SCN
Scheme 2.
References and notes
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(b) Feldman, K. S.; Vidolova, D. B.; Karajjas, A. G. J.
Org. Chem. 2005, 70, 6429–6440.
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Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123–
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1997, 29, 409–458.
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Barn, P. S.; Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.;
Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124,
2233–2244.
Both free NH- and N-protected indoles such as N-alkyl
or N-benzyl derivatives were efficiently converted into
their corresponding 3-hydroxyindolin-2-ones. In all
cases, the reactions proceeded very well at ambient
temperature. Surprisingly, the oxidation of 3-formyl-
and 3-thiocyano-indoles gave exclusively isatin instead
of the desired 3-hydroxyoxindoles (Table 1, entries n
and o). Isatin was also formed during the oxidation of
indole with IBX/CeCl3Æ7H2O (Table 1, entry m; Scheme
2).
In the absence of CeCl3Æ7H2O, the oxidation was rather
slow affording the corresponding 3-hydroxyoxindoles in
lower yields (15–25%). However, no oxidation was ob-
served when the reaction was performed using
10 mol % of CeCl3Æ7H2O in the absence of IBX. Among
other hypervalent iodine reagents such as the Dess–
Martin periodinane, PhI(OAc)2 and PhIO, IBX was
found to be the best, giving good results. Of the various
cerium reagents such as Ce(OTf)3, and ceric ammonium
nitrate which were tested, cerium(III) chloride was
shown to be the most effective Lewis acid for this con-
version. The products thus obtained were characterized
by NMR, IR and mass spectroscopy. The scope and
generality of this process is illustrated with respect to
various 3-alkylindoles and the results are presented in
Table 1.11
8. Imamoto, T. Lanthanides in Organic Synthesis; Academic
Press: New York, 1994.
9. (a) Cappa, A.; Marcantoni, E.; Torregiani, E.; Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 1999,
64, 5696; (b) Marcantoni, E.; Nobili, F.; Bartoli, G.;
Bosco, M.; Sambri, L.; Torregiani, E. J. Org. Chem. 1997,
62, 4183; (c) Di Dea, M.; Marcantoni, E.; Torregiani, E.;
Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org.
Chem. 2000, 65, 2830.
10. (a) Yadav, J. S.; Reddy, B. V. S. Synlett 2000, 1275; (b)
Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Satyanara-
yana, M. Tetrahedron Lett. 2002, 43, 7009; (c) Yadav, J.
S.; Reddy, B. V. S.; Sathaiah, K.; Vishnumurthy, P.
Synlett 2005, 2811; (d) Yadav, J. S.; Reddy, B. V. S.;
Srinivas, M.; Padmavani, B. Tetrahedron 2004, 60, 3261.
In conclusion, we have described an efficient protocol
for the preparation of 3-hydroxyoxindoles from 3-alkyl
indoles using CeCl3Æ7H2O/IBX as a novel reagent sys-
tem. The use of an inexpensive and water-tolerant
reagent system makes this procedure simple, convenient
and environmentally friendly.
11. Experimental procedure:
A mixture of 3-alkylindole
(1 mmol), IBX (2.5 mmol) and CeCl3Æ7H2O (0.1 mmol)
in CH3CN/H2O (9:1) was stirred at room temperature for

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J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 2029–2032
the appropriate time (Table 1). After completion of the
J = 7.4 Hz), 5.06 (s, 2H), 4.95 (d, 1H, J = 15.6 Hz), 4.21
(d, 1H, J = 15.6 Hz), 3.06 (br s, 1H), 2.32 (t, 2H,
J = 7.4 Hz), 1.87–2.12 (m, 2H), 1.48–1.66 (m, 2H). 13C
NMR (75 MHz, CDCl3): d 178.1, 172.7, 142.5, 135.9,
135.4, 129.7, 129.6, 128.8, 128.5, 128.1, 127.6, 127.2, 124.0,
123.1, 109.5, 76.2, 66.1, 43.8, 37.8, 33.9, 18.7. FAB Mass:
m/z: 416 M+1, 398, 308, 290, 154, 136, 109, 95, 91, 81, 69,
55. HRMS calcd for C26H25NO4Na: 438.1679. Found:
438.1681. Compound 2g: Solid, mp 87–89 ꢁC. IR (KBr): m
3396, 2921, 2862, 1712, 1615, 1468, 1362, 1175, 1103, 748,
reaction, as indicated by TLC, the reaction mixture was
filtered through Celite and washed with ethyl acetate
(2 · 10 mL). The combined organic extracts were washed
with NaHCO3 followed by brine and dried over anhy-
drous Na2SO4. Removal of the solvent followed by
purification on a short silica gel column using a mixture
of ethyl acetate–n-hexane (2:8) afforded pure 3-hydroxy-
oxindole. Spectral data for selected products. Compound
2a: Viscous liquid, IR (KBr): m 3299, 1740, 1698, 1622,
1471, 1187, 752, 698 cmÀ1. 1H NMR (300 MHz, CDCl3): d
9.10 (br s, 1H), 7.18–7.30 (m, 6H), 7.10 (t, 1H, J = 7.4 Hz),
6.93 (t, 1H, J = 7.4 Hz), 6.77 (d, 1H, J = 8.1 Hz), 4.98 (s,
2H), 4.48 (br s, 1H), 2.22 (t, 2H, J = 7.4 Hz), 1.75–1.91 (m,
2H), 1.73–1.56 (m, 2H). 13C NMR (75 MHz, CDCl3): d
181.1, 173.4, 140.7, 135.9, 130.7, 129.5, 128.1, 128.5, 124.2,
123.0, 110.7, 76.8, 66.2, 37.4, 33.9, 18.6. EIMS: m/z: 325
M+, 155, 141, 91, 43. HRMS calcd for C19H19NO4Na:
348.1198. Found: 348.1211. Compound 2b: Mp 120–
122 ꢁC. IR (KBr): m 3280, 2910, 1720, 1680, 1616, 1180,
1
699 cmÀ1. H NMR (300 MHz, CDCl3): d 7.22–7.36 (m,
11H), 7.18 (t, 1H, J = 7.7 Hz), 7.02 (t, 1H, J = 7.7 Hz),
6.65 (d, 1H, J = 7.7 Hz), 4.85 (d, 1H, J = 15.8 Hz), 4.74
(d, 1H, J = 15.8 Hz), 4.56 (d, 1H, J = 12.0 Hz), 4.46 (d,
1H, J = 12.0 Hz), 4.41 (br s, 1H), 3.96 (td, 1H, J = 10.3,
3.8 Hz), 3.67 (q, 1H, J = 4.6 Hz), 2.37–2.53 (m, 1H), 2.08
(dt, 1H, J = 14.7, 4.6 Hz). 13C NMR (75 MHz, CDCl3): d
177.7, 142.3, 137.5, 135.6, 130.4, 129.3, 128.6, 127.7, 127.5,
127.1, 123.9, 122.8, 109.3, 75.7, 73.3, 66.0, 43.6, 37.3. FAB
Mass: m/z: 374 M+1, 326, 266, 250, 239, 105, 91, 83, 69, 55.
HRMS calcd for C24H23NO3Na: 396.1558. Found:
396.1575.
1
730, 690 cmÀ1. H NMR (300 MHz, CDCl3): d 7.13–7.38
(m, 12H), 7.02 (t, 1H, J = 7.4 Hz), 6.67 (d, 1H,