Synthesis of oxindoles via visible light photoredox catalysis

Article abstract of DOI:10.1039/c1ob06652h

2-Electron-withdrawing-group-substituted 2-bromoanilides can be converted to the corresponding 3,3-disubstituted oxindoles with high efficiency under visible light irradiation by using fac-Ir(ppy)₃ as the photoredox catalyst. This protocol is suitable for the synthesis of oxindoles with chloro and bromo atoms attached to the phenyl ring.

Full text of DOI:10.1039/c1ob06652h

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Synthesis of oxindoles via visible light photoredox catalysis†
Xuhui Ju,a Yan Liang,b Pingjing Jia,a Weifei Lia and Wei Yu*a
Received 29th September 2011, Accepted 1st November 2011
DOI: 10.1039/c1ob06652h
2-Electron-withdrawing-group-substituted 2-bromoanilides
can be converted to the corresponding 3,3-disubstituted oxin-
doles with high efficiency under visible light irradiation by
using fac-Ir(ppy)3 as the photoredox catalyst. This protocol is
suitable for the synthesis of oxindoles with chloro and bromo
atoms attached to the phenyl ring.
Scheme 2
Substituted oxindoles have long been of synthetic interest due
Table 1 Screening of the reaction conditionsa
to their existence in many biologically active molecules as well
as their usefulness as important synthetic building blocks.1 One
effective methodology to construct the substituted oxindole ring
structure involves the intramolecular homolytic aromatic substi-
tution of hydrogen on the phenyl ring by amidoalkyl radicals
(Scheme 1).2 The amidoalkyl radicals can be generated by (1)
halogen atom or phenylseleno group abstraction;3,4 (2) generation
of an aryl radical from o-halo-anilides followed by 1,5-hydrogen
atom translocation (1,5-HAT);5 or (3) single-electron oxidation
of anilides.6,7 These methods have been employed to prepare a
variety of 3,3-disubstituted oxindoles. Herein, we wish to report
a new protocol for the synthesis of substituted oxindoles based
on approach (1) in Scheme 1 and visible light photoredoxcatalysis
(Scheme 2).
Entry Catalyst
Additive (equiv.) Conversion (%) Yield (%)b
1
2
3
4
5
6
7
8
9
Ru(bpy)3Cl2
Et3N (2)
iPr2NEt (2)
Ph3N (2)
none
70
100
17
<1
80
35
60
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
14
N.D.c
71
Ir(ppy)2(dtbpy)PF6 Ph3N (2)
fac-(ppy)3Ir
fac-(ppy)3Ir
fac-(ppy)3Ir
none
2,6-lutidine (2) 100
95
none
none
none
100
<1d
<1
95
N.D.c
N.D.c
a A solution of 0.12 mmol of 1a and 2.4 ¥ 10-3 mmol of catalyst in DMF
(2.4 mL) was irradiated at room temperature under argon atmosphere
for 12 h. b Isolated yield. c Not determined. d Control experiment without
irradiation under the otherwise same conditions.
sustainable way.8 The recent employment of transitional metal
photocatalysts such as Ru(bpy)32+, Ir(ppy)2(dtbpy)+ and fac-
Ir(ppy)3 etc. enables the photo-induced electron transfer/energy
transfer process to take place at visible light wavelengths,
and hence significantly broadens the scope of photochemical
reactions.9 The studies by MacMillan et al.,10 Stephenson et al.,11
and Gagne´ et al.12 demonstrate that visible light photoredox
catalysis constitutes a mild and efficient means to generate free
radicals from activated carbon–halogen bonds. This method is
advantageous compared with the commonly used Bu3SnH-based
method in that the use of stoichiometric amounts of toxic reagents
can be avoided. As a continuation of our interest in the synthesis
of oxindoles,13 we envisaged that this strategy could be applied to
oxindole synthesis. As only the activated carbon–halogen bond
would be cleaved under the reaction conditions, we hoped that
substrates with a halogen atom attached to the phenyl ring could
be tolerated.
Scheme 1
Photocatalysis has long been of interest to organic chemists
due to its capacity to initiate organic reactions in a green and
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, P. R. China. E-mail: yuwei@lzu.edu.cn; Fax: +86-931-8912582;
Tel: +86-931-8912500
bSchool of Petrochemical Engineering, Lanzhou University of Technology,
Lanzhou, P. R. China
† Electronic supplementary information (ESI) available: General experi-
mental procedure, characterization data, 1H NMR and 13C NMR spectra
of compounds 1b–26b. See DOI: 10.1039/c1ob06652h
498 | Org. Biomol. Chem., 2012, 10, 498–501
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Table 2 Synthesis of 3,3-disubstituted oxindoles b from compounds aa
Entry
1
Substrate
Product(s)
Yield (%)b
95
Entry
15
Substrate
Product
Yield (%)b
81
2
3
88
95
16
17
80
93
81
4
5
6
7
94
93
80
98
18
19
20
Mixturec
—
28/70
8
9
85
96
21
27/64
10
11
12
13
14
98
95
98
96
92
22
23
24
25
26
86
87
98
89
92
a Reaction conditions: a mixture of 0.12 mmol of a and 2.4 ¥ 10-3 mmol of fac-Ir(ppy)3 dissolved in 2.4 mL DMF under argon atmosphere was irradiated
with a 40 W household fluorescent lamp at room temperature for 12–16 h. b Isolated yield. c Pure product not obtained.
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We commenced our study by subjecting compound 1a to various
irradiation conditions. Three commonly used transitional metal
photocatalysts, Ru(bpy)3Cl2, Ir(ppy)2(dtbpy)PF6 and fac-Ir(ppy)3,
were chosen to initiate the reaction, and a 40 W household
fluorescent lamp was used as the light source. The results are
summarized in Table 1. All these three complexes were capable of
effecting the reactions, but fac-Ir(ppy)3 was found to be the most
effective. With 2 mol% of fac-Ir(ppy)3 as the photocatalyst, the
reaction was complete in 12 h, giving rise to the desired product 1b
in excellent yield (Table 1, entries 6 and 7). It should be noted that
the fac-Ir(ppy)3-mediated reaction process does not need tertiary
amines as a sacrificial reductant, as fac-Ir(ppy)3* itself (E1/2
=
-1.73V, SCE in CH3CN)10c can fulfil the reducing task. In addition,
the reaction proceeded equally well in the presence or absence of
2,6-lutidine, indicating that the hydrogen bromide formed during
the reaction does not influence the catalytic process.
Scheme 4
at the same time. In the cases of 20a and 21a, the unusual
regioselectivity suggests that the electronic effect of the bromo
or methyl group plays a predominant role in directing the free
radical attack on the phenyl ring. Similar ortho selectivity has
been observed before in studies concerning the addition of aryl
radicals to arenes.14
In summary, an efficient protocol based on fac-Ir(ppy)3-
mediated visible light photoredox catalysis has been devel-
oped for the synthesis of 3,3-disubstituted oxindoles from 2-
electron-withdrawing-group-substituted 2-bromo-anilides. This
procedure is advantageous in terms of high yield, mild-
ness of reaction conditions and tolerance of functional
groups.
A variety of 3,3-disubstituted oxindoles was then prepared by
employing this photoredox protocol. The results are listed in Table
2. The yields were generally high for substrates incorporating
an electron-withdrawing group at the a-position, which is a
prerequisite for the reaction to take place. It is noteworthy
that 3-acetyl substituted oxindoles can be synthesized with high
efficiency. These compounds are relatively unstable compared with
their 3-ethylcarboxyl and cyano counterparts, and therefore the
copper-catalyzed direct oxidative coupling7 (approach (3), Scheme
1) is not suitable for their preparation. Although the oxidative
coupling can be achieved by using Ag2O as the oxidant, the yields
were not satisfactory, and a stoichiometric amount of Ag2O had
to be used.13a This obstacle can be overcome by using the mild
photochemical procedure. In addition, this protocol is tolerant
of substrates containing a bromo atom on the phenyl ring (Table
2, entries 15 and 20), which is liable to loss with conventional
free radical methods. However, when the substrate was 19a,
the reaction became complicated, and we failed to obtain the
expected oxindole product in pure form (Table 2, entry 19). It is
interesting to see that when compounds 20a and 21a were used
as the substrates, the sterically more hindered 20b¢ and 21b¢ were
obtained as the major products (Table 2, entries 20 and 21).
This protocol was also applied to effecting the reaction of
compound c. However, we failed to obtain the corresponding 3-
acetyl oxindole product from c (Scheme 3).
Acknowledgements
The authors thank the National Natural Science Foundation of
China (No. 20772053) for financial support.
Notes and references
1 For recent reviews on oxindole synthesis, see: (a) C. Marti and E. M.
Carreira, Eur. J. Org. Chem., 2003, 2209; (b) C. V. Galliford and K. A.
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and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381.
2 For reviews, see: (a) W. R. Bowman and J. M. D. Storey, Chem. Soc.
Rev., 2007, 36, 1803; (b) G. J. Rowlands, Tetrahedron, 2009, 65, 8603;
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Scheme 3
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A possible mechanism was proposed to rationalize the fac-
Ir(ppy)3-catalyzed photochemical synthesis of 3,3-disubstituted
oxindoles (Scheme 4). The reaction is initiated by the single
electron transfer between the visible light-excited fac-Ir(ppy)3 and
substrate a, which leads to the formation of the a-carbamoyl
+
radical d and the oxidation of fac-Ir(ppy)3* to fac-Ir(ppy)3 .
Cyclisation of d results in the formation of e. The latter is converted
+
to product b via single electron oxidation by fac-Ir(ppy)3 and
11 (a) J. W. Tucker, J. M. R. Narayanam, S. W. Krabbe and C. R. J.
subsequent deprotonation, with fac-Ir(ppy)3 being regenerated
Stephenson, Org. Lett., 2010, 12, 368; (b) L. Furst, B. S. Matsuura,
500 | Org. Biomol. Chem., 2012, 10, 498–501
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J. M. R. Narayanam, J. W. Tucker and C. R. J. Stephenson, Org. Lett.,
2010, 12, 3104; (c) J. W. Tucker, J. D. Nguyen, J. M. R. Narayanam,
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