Autoxidation/Aldol Tandem Reaction of 2-Oxindoles with Ketones: A Green Approach for the Synthesis of 3-Hydroxy-2-Oxindoles

Article abstract of DOI:10.1002/chem.201504282

In the presence of tetrabutylammonium fluoride and molecular sieves (MS) 4 ? in DMF, an efficient autoxidation reaction of 2-oxindoles with ketones under air at room temperature has been developed. This approach may provide a green, practical, and metal-free protocol for a wide range of biologically important 3-hydroxy-3-(2-oxo-alkyl)-2-oxindoles.

Full text of DOI:10.1002/chem.201504282

DOI: 10.1002/chem.201504282
Communication
&
Synthetic Methods
Autoxidation/Aldol Tandem Reaction of 2-Oxindoles with
Ketones: A Green Approach for the Synthesis of 3-Hydroxy-2-
Oxindoles
Qing-Bao Zhang,[a] Wen-Liang Jia,[a] Yong-Liang Ban,[a] Yong Zheng,[a] Qiang Liu,*[a] and
Li-Zhu Wu*[b]
been widely used in organic synthesis, in which various kinds
of chemical bonds could be constructed by the oxidation, hal-
ogenation and addition process through CÀH bond cleavage.[6]
For instance, 3-hydroxy-2-oxindoles, which are frequently ob-
served in bioactive natural products, can be produced directly
from the corresponding 3-subsituted 2-oxindoles by hydroxyl-
ation or amino-oxygenation reactions (Scheme 1).[7] Despite
the significance of these elegant methods, there have been no
reports in the literature concerning the auto-oxidative func-
tionalization of simple 2-oxindoles through CÀC bonds forma-
tion with other kinds of nucleophiles. Herein, we describe a tet-
rabutylammonium fluoride (TBAF)-promoted autoxidation reac-
tion of 2-oxindoles with ketones under air at room tempera-
ture. The reaction provides a sustainable approach to 3-substi-
tuted 3-hydroxy-2-oxindoles with simple and cheap reagents
and low levels of waste.
Abstract: In the presence of tetrabutylammonium fluoride
and molecular sieves (MS) 4 Š in DMF, an efficient autoxi-
dation reaction of 2-oxindoles with ketones under air at
room temperature has been developed. This approach
may provide a green, practical, and metal-free protocol for
a wide range of biologically important 3-hydroxy-3-(2-oxo-
alkyl)-2-oxindoles.
The use of molecular oxygen for the selective oxidation of or-
ganic substrates at room temperature is appealing because it
fits the current demands to develop highly atom-economical,
environmentally benign, and energy-saving chemical process-
es.[1] Although many organic compounds can undergo air oxi-
dation, certain types are particularly prone to autoxidation
under ambient O2 pressures at room temperature.[2] For in-
stance, the CÀH bonds adjacent to unsaturated moieties or
heteroatoms can be converted to hydroperoxides by autoxida-
tion. Further, the OÀO or CÀO bond cleavage of hydroperox-
ides and subsequent reactions provide useful transforma-
tions.[3] Recently, Klussmann et al. developed an auto-oxidative
CÀC bonds formation method for activated benzylic CH2
groups, like that in xanthene, with ketones and 1,3-dicarbonyl
compounds.[3c] Huo et al. developed the auto-oxidative cross-
coupling reaction of glycine derivatives with indoles, as well as
the auto-oxidative Povarov/aromatization tandem reaction of
glycine derivatives with olefins.[4] In these reactions, the prod-
ucts were formed by simply stirring the substrates under air or
oxygen in the presence of catalytic amounts of acid.
Scheme 1. Preparation of 3-hydroxy-2-oxindoles from 2-oxindoles.
Initially, we employed the autoxidation reaction of 1-methyl-
2-oxindole (1a) with acetophenone (2a) in air at room temper-
ature as a model for the investigation of optimized conditions.
As summarized in Table 1, no 3-hydroxy-3-(2-oxo-2-phenyleth-
yl)-2-oxindole (3a) was formed in acetonitrile in the absence of
additives. The addition of a catalytic amount of methane sul-
fonic acid, which has been successfully employed to promote
the aerobic cross-coupling of xanthenes and ketones, failed to
generate 3a (entry 2). Considering that base might promote
the enolization of oxindole, we tested a series of bases to ini-
tiate the reaction (entries 3–10). It was found that the desired
product 3a formed in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), K3PO4, or TBAF. After TBAF was
chosen as the ideal catalyst, several solvents, such as methanol,
1,4-dioxane, THF, DMSO, DCE, and DMF, were applied to this
reaction to replace CH3CN (entries 11–16); we were glad to see
2-Oxindoles are not only one of the promising drug candi-
dates but also useful starting materials for the synthesis of nat-
ural products.[5] The direct transformation of 2-oxindoles has
[a] Q.-B. Zhang, W.-L. Jia, Y.-L. Ban, Y. Zheng, Prof. Dr. Q. Liu
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou 730000 (P. R. China)
E-mail: liuqiang@lzu.edu.cn
[b] Prof. Dr. L.-Z. Wu
Key Laboratory of Photochemical Conversion and Optoelectronic Materials
Technical Institute of Physics and Chemistry
Chinese Academy of Sciences (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504282.
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Communication
Table 1. Optimization of the autoxidation reaction conditions[a]
Table 2. Scope of the autoxidation reaction of 2-oxindoles with aceto-
phenone[a,b]
Entry
Additives[b]
Solvent[c]
Yield [%][d]
1
none
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
1,4-dioxane
THF
0
0
0
0
23
0
trace
trace
40
48
0
18
32
34
43
86
80
0
2[e]
3
CH3SO3H
2,6-lutidine
DABCO
DBU
4
5
6
7
8
9
10
11
12
13
14
15
16
17[f]
18[g]
19[h]
CSF
K2CO3
K2HPO4
K3PO4
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
DMSO
DCE
DMF
DMF
DMF
TBAF
TBAF
TBAF, 4 Š MS
DMF
89
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.5 mmol), additives
(0.02 mmol), solvent (1 mL), stirred in air at rt for 18 h. [b] DABCO=1,4-di-
azabicyclo[2.2.2]octane;
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
[c] THF=tetrahydrofuran; DMSO=dimethyl sulphoxide; DCE=1,2di-
chloroethane; DMF=N,N- dimethylformamide. [d] Isolated yield.
[e] CH3SO3H (0.01 mmol) was used. [f] Pure O2 was used instead of air.
[g] Reaction was carried out under argon. [h] With addition of 20 mg MS
4 Š.
that the yield of 3a improved to 86% in DMF. Interestingly, the
use of pure oxygen instead of air decreased the yield of the
product (entry 17). As expected, the reaction did not occur
under argon atmosphere (entry 18). Finally, it was found that
the addition of molecular sieves (MS) 4 Š delivered 3a in 89%
yield (entry 19). Accordingly, we chose dry DMF (solvent),
20 mol% TBAF (additive), 20 mg MS 4 Š (co-additive), and
room temperature as the optimal reaction conditions.
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol), TBAF (0.02 mmol),
MS 4 Š (20 mg), DMF (1 mL), stirred in air at rt for 18 h. [b] Isolated yield.
With a set of optimized reaction conditions in hand, we first-
ly explored the scope of the reaction by using various 2-oxin-
doles 1a–1l and acetophenone (2a). The results are summar-
ized in Table 2. It was found that all the reactions proceeded
smoothly and afforded the desired 3-hydroxy-3-(2-oxo-2-phe-
nylethyl)-2-oxindoles 3a–3l under the optimized reaction con-
ditions. Initially, different N-protected 2-oxindoles were tested.
Oxindoles possessing N-protecting groups, such as ethyl, allyl,
and phenyl, resulted in satisfactory yields (3b, 3d, and 3e). A
lower yield was obtained with the benzyl protecting group
(3c). Furthermore, oxindoles bearing different substituents at
the arene moiety were used for the autoxidation. The reactions
of 2-oxindoles bearing electron-donating groups, such as 1,5-
dimethy-2-oxindole (1 f) and 5-methoxy-1-methyl-2-oxindole
(1g), proceeded well to give 3 f and 3g in 75% and 68%
yields, respectively. The process also appears to be general for
halo groups and their positions on the arene ring of oxindoles,
as demonstrated by the conversion of the halo-substituted 2-
oxindoles 1h–1l to the corresponding products 3h–3l.
Experiments exploring the generality of this methodology
with respect to different aliphatic and aromatic ketones are
summarized in Table 3. Acetophenone derivatives bearing elec-
tron-donating methoxyl group (2b) and electron-withdrawing
group (2c) on the phenyl ring could be employed in the au-
toxidation reaction with 1-methyl-2-oxindole (1a) and were
smoothly converted into the corresponding products (3m and
3n) in good yields. Similar good results were observed in the
cases of 1-acetonaphthone (2d) and 2-acetonaphthone (2e) as
substrates. Further exploration of the substrate scope was car-
ried out by reacting 1a with heteroaromatic ketones. As
shown in Table 3, 2-pyrrolyl (2 f), 2-furanyl (2g), 2-thienyl (2h),
and 3-pyridyl (2i) ketones were compatible with this auto-oxi-
dative approach (3q-3t, 55–95% yield). The cyclic ketone 3,4-
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To investigate the mechanism of this transformation, experi-
ments were carried out. It has been reported that ketones can
react with molecular oxygen to form 1,2-diketones in basic
Table 3. Scope of the autoxidation reaction of 2-oxindole (1a) with vari-
ous ketones.[a,b]
8]
media.[3a, Indeed, we found that isatin 4 was produced in
75% yield when oxindole 1a was stirred under the standard
reaction conditions without the addition of ketone 2a. On the
other hand, the aldol condensation of acetophenone (2a) with
isatin 4 under the same conditions provided 3-hydroxy-2-oxin-
dole (3a) in 95% yield (see the Supporting Information). The
overall yield of 3a by the stepwise reactions was 71%, which
is much lower than the yield obtained by one-pot process
(89%). Moreover, neither autoxidation of 1a nor aldol conden-
sation of 2a with 4 occurred in the absence of TBAF, indicating
the crucial role of TBAF in each step.[9]
On the basis of previous reports[10] and our experimental re-
sults, a plausible mechanism for the oxidation is postulated in
Scheme 2. First, an ammonium enolate is formed through a de-
protonation of 2-oxindole 1a in the presence of TBAF. The am-
monium enolate of 2-oxindole then reacts with the molecular
oxygen by a radical chain process[11] to generate 3-hydroper-
oxy-2-oxindole 5, which then undergoes an elimination reac-
tion in the presence of TBAF to form isatin 4. On the other
hand, acetophenone (2a) is also activated by the TBAF-cata-
lyzed enolation. The aldol condensation of 2a with 4 furnishes
the desired 3-hydroxy-3-(2-oxo-2-phenylethyl)-2-oxindole (3a).
In summary, we have developed an aerobic oxidative
method for the synthesis of 3-substituted 3-hydroxy-2-oxin-
doles by difunctionalization of the benzylic CH2 group of 2-ox-
indoles with molecular oxygen and ketones. The reaction pro-
ceeds smoothly in air at room temperature by using catalytic
amounts of TBAF. This approach may provide a green and
practical access to a wide range of 3-hydroxy-3-(2-oxo-alkyl)-2-
oxindoles. Further investigations of the autoxidation reaction
towards asymmetric synthesis are ongoing in our group.
Experimental Section
General procedure for the preparation of the products: A mix-
ture of 2-oxindoles (0.1 mmol), ketones (0.5 mmol), tetrabutylam-
monium fluoride (0.02 mmol), and molecular sieves (MS) 4 Š
[a] Reaction conditions: 1 (0.1 mmol), 2a (0.5 mmol), TBAF (0.02 mmol),
MS 4 Š (20 mg), DMF (1 mL), stirred in air at rt until 1a was no longer
consumed. [b] Isolated yield. [c] Acetone (5 mmol) was used.
dihydronaphthalen-1(2H)-one (2j) also worked well for the re-
action with 1a (3u, 93% yield). In addition, the present meth-
odology was successfully extended to aliphatic ketones under
the optimized reaction conditions. When butanone was used,
two regioisomers 3y and 3z were produced in 61% yield
(3y:3z=3.1:1). However, in the case of 3-methylbutan-2-one
(2m) as substrate, the reaction only gave the product 3x with
very high regioselectivity in 78% yield.
Scheme 2. Proposed mechanism
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Acknowledgements
We are grateful for financial support from the Ministry of Sci-
ence and Technology of China (2013CB834804), NSFC
(21572090 and 21172102), and the fundamental research funds
for the central universities (lzujbky-2015-49).
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Keywords: autoxidation
oxygen · tetrabutylammonium fluoride
·
CÀH activation
· oxindoles ·
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Received: October 25, 2015
Published online on January 21, 2016
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