A catalytic metal-free Ritter reaction to 3-substituted 3-aminooxindoles

Article abstract of DOI:10.1039/c2ob25319d

The first Ritter reaction of 3-substituted 3-hydroxyoxindoles with nitriles, catalyzed by HClO₄, is developed, which enables the synthesis of 3-substituted 3-aminooxindoles in good to excellent yield with rich diversity.

Full text of DOI:10.1039/c2ob25319d

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A catalytic metal-free Ritter reaction to 3-substituted 3-aminooxindoles†
Feng Zhou, Miao Ding and Jian Zhou*
Received 13th February 2012, Accepted 5th March 2012
DOI: 10.1039/c2ob25319d
achievements, the development of an efficient method for the
synthesis of aminooxindoles from easily available starting
materials with sufficient diversity is still highly desirable and of
significant value.
The first Ritter reaction of 3-substituted 3-hydroxyoxindoles
with nitriles, catalyzed by HClO4, is developed, which
enables the synthesis of 3-substituted 3-aminooxindoles in
good to excellent yield with rich diversity.
With our efforts in the synthesis of 3,3-disubstituted oxindoles
for biological evaluation,7 we have developed the amination of
unprotected 3-prochiral oxindoles using azodicarboxylates,7a,b
Hg(ClO4)2·3H2O catalyzed addition of allyltrimethylsilane to
isatin ketoimines,7c and the first catalytic asymmetric addition of
nucleophiles to isatin ketoimines using TMSCN.7d We are inter-
ested in preparing 3-substituted 3-aminooxindoles via the Ritter
reaction8 for three reasons: (1) the amide constitutes a very
important functional group in phamaceuticals,9 and much atten-
tion has been devoted to the synthesis of oxindoles with a C3
amido moiety to modulate the bioactivity;10 (2) the Ritter reac-
tion would be highly efficient to prepare quaternary aminooxin-
doles featuring a C3 amido group in rich structural diversity, as
many nitriles are commercially available and both 3-aryl and 3-
alkyl 3-hydroxyoxindoles 1 could be readily obtained in one step
from isatins; (3) it is an atom-economical method.11
The acid catalyzed Ritter reaction is an important C–N bond
forming reaction.8 Carbenium ions were invoked as intermedi-
ates in this SN1-type reaction, and substituents which can stabil-
ize the intermediates would facilitate this reaction. A variety of
catalytic Ritter reactions have been developed, but most of them
are limited to alcohols with α-electron-releasing groups. As far
as we knew, only one report was based on the employment of
alcohols with an α-electron-withdrawing group. In 2006, Hu
reported the use of a large excess of concentrated H2SO4 to
promote the Ritter reaction of α-CF2H alcohols, and only
CH3CN was used as the amidation reagent.8f
The 3,3′-disubstituted oxindoles are widely distributed in bio-
active natural products, drugs and pharmaceutically active com-
pounds.1 Among them, the 3-substituted-3-aminooxindoles are
very useful and are present in several pharmaceutical candi-
dates,2 including the vasopressin VIb receptor antagonist
SSR-1494152b and the potent gastrin/CCK-B receptor antagonist
AG-041R.2c In addition, several natural bioactive products could
be potentially accessed via 3-substituted 3-aminooxindoles, e.g.
psychotrimine2d and chartelline A2e which contains a spiro ring
system. Their biological activities are greatly affected by the
configuration and the substituents at the C3 position of the oxi-
ndole, as revealed by structure–activity relationship studies.1
Accordingly, the development of efficient methods for the syn-
thesis of 3-substituted 3-aminooxindoles in sufficient quantities
and diversity has received considerable attention, which would
accelerate the structure–activity relationship studies (Fig. 1).
A variety of synthetic methods have been developed during
the past decade, including the addition of nucleophiles to isatin
derived ketoimines,3 intramolecular cyclization reaction,4 direct
amination of 3-substituted oxindoles,5 alkylation of 3-aminoox-
indole6a and other reactions6b–e (Scheme 1). Despite these
Fig. 1 Representative bioactive compounds.
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal University, 3663
N. Zhongshan Road, Shanghai, 200062, P.R. China. E-mail: jzhou@
chem.ecnu.edu.cn
†Electronic supplementary information (ESI) available: Experimental
procedures and characterizations, copies of 1H NMR and 13C NMR of
new compounds. CCDC 859777. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ob25319d
Scheme 1 Methods for synthesis of 3-substituted-3-amino oxindoles.
3178 | Org. Biomol. Chem., 2012, 10, 3178–3181
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Table 1 Catalyst screening and conditions optimization
Conc.
(M)
Temp.
(°C)
Time
(h)
Conv.b
(%)
Entrya Cat.
1
2
3
4
5
6
7
8
Hg(ClO4)2·3H2O 0.2
In(ClO4)3·8H2O 0.2
Al(ClO4)3·9H2O 0.2
Fe(ClO4)3·xH2O 0.2
Cu(ClO4)2·6H2O 0.2
50
50
50
50
50
50
50
50
80
80
80
80
48
48
48
48
48
48
48
48
24
24
12
72
61
52
57
64
62
—
86
90
96
TFA
0.2
0.2
0.2
0.2
0.5
0.1
0.1
HOTf
HClO4
HClO4
HClO4
HClO4
HClO4
9
10
11
12d
94
97 (95)c
95
1
a On a 0.1 mmol scale. b Determined by H NMR analysis of the crude
mixture. c 0.3 mmol scale, isolated yield. d 5 mol% HClO4.
It was believed that the key point to develop a catalytic Ritter
reaction of 3-hydroxyoxindoles 1 was to overcome the difficulty
in the formation of the carbocationic intermediate, because of
the electron-withdrawing effect of the amide group. Based on
our recent finding that Hg(ClO4)2·3H2O could catalyze the
Friedel–Crafts arylation of 3-substituted-3-hydroxyoxindoles,7e
we first tried using Hg(ClO4)2·3H2O to catalyze the reaction of
hydroxyindole 1a and CH3CN, and 61% conversion was
observed after 48 hours at 50 °C by NMR analysis (entry 1,
Table 1). Encouraged by this result, other metal perchlorate
hydrates12 were also examined, and In(III), Al(III), Fe(III) and Cu
(II) derived perchlorate hydrates also worked, with similar reac-
tivity (entries 2–5). Typical Brønsted acids were then tried. Trifl-
uoroacetic acid was impotent for this reaction (entry 6). To our
delight, HOTf and HClO4 could catalyze this reaction much
more efficiently than Lewis acids we screened. The cheap and
easy to handle HClO4 was chosen as the optimal catalyst, which
also reduced the worry about heavy metal ion contamination of
products. Raising the temperature from 50 to 80 °C, 96% conver-
sion was obtained within 24 hours (entry 9). The influence of
the concentration of 1a was also checked, and lower concen-
tration resulted in better reactivity (entries 9–11). When the reac-
tion was carried out at 0.1 M of 1a, the reaction worked
efficiently to give product 3d in 95% yield (entry 11). Lowering
the catalyst loading to 5 mol% greatly slowed down the reaction
rate (entry 12).
Scheme 2 Scope of 3-hydroxyoxiondoles.
hydroxyoxindoles 1 in CH3CN, the yield of unprotected ami-
nooxindoles 3a–c was obviously lower than the corresponding
N-methyl products 3d–f. Both 3-aromatic and 3-aliphatic 3-
hydroxyoxindoles were viable substrates under these reaction
conditions, but 3-alkyl substituted ones were less reactive. The
3-allyl substituted 3-hydroxyoxindoles were the least reactive,
and products 3s–t were obtained in low yield, even using 50 mol
% of HClO4, but they were potentially useful synthon for the
synthesis of fused indoline ring system and polycyclic frame-
work present in many bioactive compounds.13
To demonstrate the generality of this method, we further
examined if other nitriles could work with 3-substituted 3-hydro-
xyoxindoles 1. After optimization, 1,2-dichloroethane (DCE)
turned out to be the best solvent, and the reaction was carried
out at 80 °C, using 20 mol% of HClO4 as the catalyst. A wide
array of nitriles, with aliphatic, vinyl or aromatic substituents,
could work with hydroxyoxindoles 1a to afford the desired pro-
ducts 4 in good to excellent yield (Table 2), except that 2,3,4-
trifluorobenzonitrile 2d and α-cyanoacetate 2j gave the corre-
sponding products 4c and 4i in moderate yields (entries 3 and
9). Accordingly, a variety of functional groups such as aldehyde,
vinyl, cyclopropyl and ester group could be introduced to the
amide moiety at the C3 position of oxindole.
Based on the above results, the optimum reaction conditions
to examine the scope of 3-substituted 3-hydroxyoxindoles 1 was
determined as: run the reaction in air at 80 °C in CH3CN, with
the concentration of hydroxyoxindole 1 at 0.1 M. The amount of
the catalyst HClO4 was dependent on the reactivity of the sub-
strates, as indicated in Scheme 2. We were pleased to find that a
variety of 3-hydroxyoxindoles, with electron-donating or elec-
tron-withdrawing substituents at different positions on the aro-
matic ring, could afford the desired products 3 in good to
excellent yield. Because of the poor solubility of unprotected
We further examined if this protocol could be applied for the
synthesis of 3-aminooxindoles with a spirolactam unit via an
intramolecular Ritter reaction. The substrates 5a–b were syn-
thesized using procedures shown in the ESI.† Unfortunately,
although we screened a lot of conditions, both 5a and 5b failed
to give the desired spirocyclic lactams, but were converted to
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Table 2 Scope of nitriles
Entrya
R3
Y
4
Time (h)
Yieldb (%)
1
2
3
Ph (2b)
p-CHOC4H4 (2c)
5.0
1.5
5.0
4a
4b
4c
24
12
36
82
66
35
(2d)
Vinyl (2e)
Bn (2f)
i-Pr (2g)
Cyclopropyl (2h)
n-Bu (2i)
4
5
6
7
8
9
10.0
5.0
5.0
5.0
5.0
5.0
4d
4e
4f
4g
4h
4i
12
24
36
24
20
20
94
70
90
92
81
41
nitriles. Our efforts in developing an intramolecular version
reveal that spirocyclic oxindole-lactones are obtained under
these conditions. The development of an intramolecular version
and the application of this protocol to the synthesis of natural
products and lead compounds for the medicinal chemistry is
currently under way in our lab and will be the subject of future
reports.
i-PrOOCCH2 (2j)
a On a 0.3 mmol scale. b Isolated yield.
Acknowledgements
The financial support from the NSFC (21172075), Shanghai
Pujiang Program (10PJ1403100), Specialized Research Fund for
the Doctoral Program of Higher Education (20090076120007),
Innovation Program of SMEC (12ZZ046), and the Fundamental
Research Funds for the Central Universities (East China Normal
University 11043) is highly appreciated.
Fig. 2 X-ray structure of compound 6a.
spirocyclic lactones 6 in moderate yield, possibly because the
cyano group of 5a or 5b was first hydrolyzed under the reaction
conditions to a carboxylic acid moiety which further reacted
with the hydroxyl group at C3 position to give the corresponding
spirocyclic oxindole-lactone 6a and 6b.14 Since the 3-hydroxy-
oxindoles 5a and 5b dissolved poorly in DCE, a mixed solvent
of DCE and CH3NO2 (1/1, v/v) was used. When 50 mol% of
HClO4 was used, 5a and 5b were converted to 6a and 6b in
37% and 61% yield, respectively. The structure of product 6a
was further confirmed by X-ray analysis (Fig. 2).15 This finding
also provided a new protocol for the synthesis of spirocyclic
oxindole-lactones, a structural motif of high synthetic interest.16
Since acrylonitrile worked well with hydroxyoxindoles, the
resulting Ritter adducts such as 4d could be easily modified to
increase the diversity of the amide substituents at C3 position.
For example, in the presence of 10 mol% NaOMe, product 4d
reacted with benzyl thiol at room temperature to give 7 in 83%
yield.
Notes and references
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