Catalytic and enantioselective α-functionalization of oxindoles through oxidative reactions with naphthoquinones

Article abstract of DOI:10.1002/chem.201200206

Strong as an oxindole: The enantioselective assembly of 3,3-disubstituted oxindoles is an attractive and valuable target because of the unique properties of the oxindole core. A new organocatalyzed and enantioselective aerobic oxidative strategy for the assembly of this core structure from oxindoles and simple naphthoquinones is reported (see scheme). Copyright

Full text of DOI:10.1002/chem.201200206

COMMUNICATION
DOI: 10.1002/chem.201200206
Catalytic and Enantioselective a-Functionalization of Oxindoles Through
Oxidative Reactions with Naphthoquinones
Woon-Yew Siau,[a] Wenjun Li,[a] Fei Xue,[a] Qiao Ren,[a] Minghu Xu,[b] Shaofa Sun,[b]
Haibing Guo,*[b] Xuefeng Jiang,*[c] and Jian Wang*[a]
The enantioselective assembly of 3,3-disubstituted oxin-
doles has emerged as one of the most attractive and valu-
able synthetic targets due to the unique properties of the ox-
indole core.[1,2] Their occurrence in a broad range of impor-
tant pharmaceutically active compounds, such as the exam-
ples outlined in Figure 1,[3] has garnered considerable atten-
tion in the synthetic chemistry community recently. The
synthesis of 3,3-disubstituted oxindoles is challenging due to
the molecular complexity induced by the quaternary stereo-
genic center.[4] To the best of our knowledge, only a few or-
ganocatalytic methods that use the readily available 3-sub-
stituted oxindoles have been reported. Examples include
asymmetric conjugate addition,[5] the Aldol reaction,[6] the
Morita–Baylis–Hillman (MBH) reaction,[7] and the direct al-
kylation reaction (Scheme 1).[8] In these cases, chiral tetraal-
kylphosphonium phase-transfer catalysts, primary amine-
Figure 1. Examples of 3,3-disubstituted oxindole-containing pharmaceuti-
cal compounds.
based thioureas, cinchona alkaloids, and 1,2,3-triazolium
salts were proven to be efficient catalysts. Unfortunately,
these synthetic methods limit the types of C3 substituents
that can be introduced onto the scaffold.
Although there have been several prominent examples
describing enantioselective strategies for preparing such
motifs, a direct method for introducing an aryl group at C3
to construct 3,3-disubstituted oxindoles has not been report-
ed. Herein, we describe a novel method for the organocata-
lytic, enantioselective, aerobic oxidative reaction of 3-substi-
tuted oxindoles under mild conditions in the presence of
[a] W.-Y. Siau, W. Li, F. Xue, Q. Ren, Prof. Dr. J. Wang
Department of Chemistry
National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
Fax : (+65)6516-1691
E-mail: chmwangj@nus.edu.sg
Scheme 1. Synthetic approaches for the organocatalytic enantioselective
synthesis of 3,3-disubstituted oxindole derivatives.
[b] Prof. M. Xu, Prof. S. Sun, Prof. H. Guo
College of Chemistry and Biology Sciences
Xianning University
Hubei Province, 437100 (P.R. China)
E-mail: haibingguojj@yahoo.com
a
bifunctional catalyst, an indane amine–thiourea III
[c] Prof. X. Jiang
Shanghai Key Laboratory of Green Chemistry and Chemical Process
East China Normal University
3663N Zhongshan Road, Shanghai, 200062 (P.R. China)
Fax : (+86)21-52133654
(Scheme 1), that was developed by our group.
Thiourea-based catalysts have been recognized as being
powerful and convenient tools for the synthesis of chiral
molecules.[9] Recently, we discovered a bifunctional thiourea
catalyst based on a chiral indane scaffold and applied it to
the promotion of several asymmetric transformations.[10] To
E-mail: xfjiang@chem.ecnu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200206.
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validate its unique performance and the scope of this
indane–thiourea catalytic system, we attempted the assem-
bly of sterically congested 3,3-disubstituted oxindoles. Ini-
tially, we examined the feasibility of this reaction by allow-
ing tert-butyl-2-oxo-3-phenylindoline-1-carboxylate (1a) to
react with 1,4-naphthoquinone (2a) in the presence of cata-
lysts I–IV (10 mol%) at room temperature (for reaction
conditions, see Table 1). The Takemoto catalyst I turned out
to be an active catalyst (Table 1, 83% yield), but exhibited
low enantioselectivity (Table 1, 27% ee). Catalyst II, a chiral
quinine–thiourea catalyst developed by the Soꢁs,[11] Connon,
and Dixon groups,[12] only gave À25% ee (Table 1). These
unsatisfactory results prompted us to develop a highly ste-
reocontrolled organocatalyst.
as required. We further investigated several other reaction
parameters, including the solvent and reaction temperature.
Our results showed that less polar solvents promoted rela-
tively higher enantioselectivity (Table 2, entries 1–3 and 8–
Table 2. Investigation of other reaction parameters.[a]
Entry
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
CH2Cl2
DCE
3
3
3
5
7
12
18
3
3
3
78
68
82
79
80
85
90
43
75
73
88
83
75
33
80
83
90
94
87
80
28
45
5
Table 1. Evaluation of bifunctional organocatalysts.[a]
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
xylenes
Et2O
4[d]
5[d,e]
6[d,f]
7[d,g]
8
9
10
11
12
DMF
DMSO
3
3
8
[a] Reaction conditions (unless otherwise specified): solvent (0.2 mL),
tert-butyl-2-oxo-3-phenylindoline-1-carboxylate 1a (0.12 mmol,
1.2 equiv), 1,4-naphthoquinone 2a (0.1 mmol, 1.0 equiv), catalyst III
(10 mol%), room temperature. [b] Yield of isolated product after column
chromatography. [c] Enantiomeric excess (ee) was determined by HPLC.
[d] Reaction concentration is 0.17 molLÀ1. [e] 08C. [f] À208C. [g] À408C.
10); CHCl3 and toluene both supported product formation
in 80% ee under standard conditions, but CHCl3 afforded
a higher reaction yield (Table 2, entries 3 (CHCl3) and 8
(toluene), 82 and 43% yield, respectively). Highly polar sol-
vents led to low enantioselectivities, which can be attributed
to the potential destruction of the H-bonding interaction be-
tween the catalyst and naphthoquinone (Table 2, entries 11
and 12, 5 and 8% ee, respectively). We concluded that
CHCl3 was an ideal solvent for this reaction. We then exam-
ined the effect of reaction temperature. Our results indicat-
ed that a temperature of À208C was able to assist in the
production of a 94% ee and 85% yield (Table 2, entry 6).
[a] Reaction conditions: 1a (0.12 mmol, 1.2 equiv), 2a (0.1 mmol,
1.0 equiv), catalyst III (10 mol%), CH2Cl2 (0.2 mL), À208C.
In this context, we sought to explore the new synthetic ap-
plications of the indane–amine–thiourea catalytic system
that our group has developed. Bifunctional indane amine–
thiourea organocatalysts have previously demonstrated sev-
eral unique aspects in asymmetric catalytic transformations,
such as high activity and excellent enantioselective control.
For the reaction of 1a with 2a, we examined a series of
indane–amine–thiourea catalysts that were designed by our
group (for full catalyst screening, see the Supporting Infor-
mation). Catalyst III was found to be very effective and pro-
vided a much improved enantioselectivity (Table 1, 75% ee).
Another indane catalyst IV was also found to be efficient
and provided an enantioselectivity of 66% ee, but with the
opposite optical rotation (Table 1), thus non-enantiomeric
indane–amine–thiourea catalysts III and IV could function
as enantiomeric catalysts to offer the opposite enantiomers
On the contrary,
a further reduction in temperature
(À408C) caused a reduction in enantioselectivity (87% ee;
Table 2, entry 7).
With the optimized reaction conditions in hand, we inves-
tigated the generality of the indane–amine–thiourea III-cat-
alyzed aerobic oxidative reaction for different substrates.
The representative results are summarized in Table 3. In the
reaction of 1,4-naphthoquinone (2a) with a 3-substituted ox-
indole 1, various 3-substituted oxindoles with electron-do-
nating, neutral, and electron-withdrawing substituents on
both the oxindole core (phenyl ring) and the C3-substituent
were accommodated with good to excellent enantioselectivi-
ties observed (3e–j and 3l–p; Table 3). In most cases, the
products were obtained in good to high yields within reason-
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a-Functionalization of Oxindoles
COMMUNICATION
Table 3. Substrate scope.[a]
cess and afforded excellent re-
sults (3k, 84% ee and 92%
yield; Table 3).
Finally, we investigated the
effect of various substituents on
different
1,4-naphthoquinone
derivatives. The results are indi-
cated in Equations (1) and (2).
For example, the symmetric 5,8-
bis(acetyloxy)-1,4-naphthalene-
dione (2q) afforded the desired
compound 3q in 77% yield and
86% ee [Eq. (1)]. Additionally,
an asymmetric 1,4-naphthoqui-
none 2r was applied in the re-
action with oxindole 1a in the
presence of indane catalyst III,
but only afforded a moderate
level of enantioselectivity (73
and 59% ee for the two re-
gioisomers, respectively) and
a low regiospecificity [Eq. (2);
regioisomer ratio=1.4:1]. After
catalyst screening, we found the
indane amine–thiourea catalyst
IV was effective and improved
the regioisomer ratio to >20:1
at room temperature. In addi-
tion, enantioselectivity was
slightly increased to 78% ee.
However, catalysts I and II
both demonstrated a low level
of stereocontrol (regioisomer
ratioꢀ2:1, see the Supporting
Information). Further enantio-
selective and regioselective im-
provements for asymmetrical
naphthoquinone substrates and
other types of quinones are cur-
rently under way and will be
presented in due course. The
absolute configuration of the
oxindole 3s (99% ee after re-
crystallization) was determined
by using single-crystal X-ray
diffraction analysis.[13,14]
[a] Reaction conditions: 1a (0.12 mmol, 1.2 equiv), 2a (0.1 mmol, 1.0 equiv), catalyst III (10 mol%), CH2Cl2
(0.6 mL), À208C.
able reaction times (3e–j and 3l–p; 75–94% yield, 7–36 h;
Table 3). More importantly, the C3-pyridine oxindole can
also be applied to this reaction and afforded a synthetically
useful product (3j; Table 3). Meanwhile, the N1 position of
oxindoles 1 tolerated a diverse range of functional groups,
such as tert-butyloxycarbonyl (Boc), carboxybenzyl (Cbz) or
acyl groups (3a–d, 80–94% ee, 75–87% yield, 12–36 h;
Table 3). Note that the present catalytic system will also ac-
commodate less active 3-alkyl oxindole substrates. For ex-
ample, the 3-methyl oxindole 2k was tolerated in this pro-
We proposed a plausible catalytic cycle to explain the re-
action pathway as shown in Scheme 2. Although the reac-
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H. Guo, X. Jiang, J Wang et al.
termediate C could be oxidized to the desired compound
3a, presumably by molecular oxygen or with 1,4-naphtho-
quinone. If the reaction was performed under N2 (1 atm),
low reaction yields were obtained (17% yield after a flash
column purification); however, if the reaction was carried
out under O2 (1 atm) at À208C, it was accelerated, but
yields and enantioselectivities were not affected (87% yield,
93% ee, 8 h). Hence, we surmised that molecular oxygen
was crucial for the oxidation step, allowing the completion
of this reaction cycle.
In summary, we report a novel organocatalytic approach
for the enantioselective synthesis of 3,3-disubstituted oxin-
doles to naphthoquinones by using aerobic oxidative reac-
tions of oxindole derivatives. Our methodology provides
a straightforward way to generate valuable chiral scaffolds
tion mechanism is still unclear at this stage, we believe that
the pathway is triggered by the generation of intermediate
B through the conjugate addition of 3-phenyl N-Boc-pro-
with the creation of a quaterna-
3
À
ry carbon center by a Csp
Csp2 bond formation. An array
of complex oxindoles contain-
ing a quaternary carbon stereo-
center at the C3 position were
efficiently prepared in moder-
ate to high yields (63–94%)
with good to excellent enantio-
selectivities (73–97% ee), and
may have biological significance
in the field of medicinal
chemistry,. Studies towards ex-
panding the applicability of bi-
functional indane–thiourea cat-
alysis and the synthetic utility
of this strategy are currently
underway in our laboratory.
Experimental Section
General procedure: 1,4-naphthoqui-
none (2a; 16 mg, 0.10 mmol) was dis-
solved in chloroform (0.1 mL) and
cooled at 08C for 10 min. This solution
was added to a stirred mixture of tert-
butyl-2-oxo-3-phenylindoline-1-carbox-
ylate (1a, 37 mg, 0.12 mmol) and the
catalyst (4.6 mg, 0.01 mmol) in chloro-
form (0.5 mL) at À208C. After stirring
at À208C for 12 h, the crude product
Scheme 2. Proposed reaction mechanism.
was purified by column chromatogra-
phy on silica gel (ethyl acetate/
hexane=1:15) to afford the desired
product 3a as a yellow solid (39.5 mg,
tected oxindole 1a to 1,4-naphthoquinone (2a) catalyzed by
indane–amine–thiourea catalyst III. This step was character-
ized by the formation of the chiral ion-pair intermediate A
through the interaction of the indane–amine–thiourea III
and 3-phenyl N-Boc-protected oxindole 1a. The enantiose-
lective conjugate addition of the ion-pair A to 1,4-naphtho-
quinone (2a) generated the corresponding chiral intermedi-
ate B, and the hydroquinone intermediate C was formed by
the rearrangement of intermediate B. This hydroquinone in-
85%). [a]2D5 =À113.7 (c=2.0 in CH2Cl2); 1H NMR (500 MHz, CDCl3):
d=8.04 (dd, J=1.5, 7.5 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.96 (dd, J=
1.5, 7.5 Hz, 1H), 7.74–7.67 (m, 2H), 7.43–7.36 (m, 6H), 7.19–7.13 (m,
1H), 7.13 (dd, J=1.0, 7.5 Hz, 1H), 6.65 (s, 1H), 1.64 ppm (s, 9H);
13C NMR (125 MHz, CDCl3): d 184.8, 183.1, 174.7, 153.0, 149.3, 140.2,
138.6, 135.3, 134.1, 134.0, 131.7, 129.4, 129.1, 128.9, 128.7, 127.3, 126.2,
124.9, 124.0, 116.0, 84.5, 59.7, 28.1 ppm; HPLC (Chiralpak IC, isopropa-
nol/hexane=20:80, flow rate 1.0 mLminÀ1
minor =10.72 min, ee=93%; HRMS (ESI): m/z calcd for C29H23NNaO5:
488.1468 [M+Na+]; found: 488.1477.
, l=254 nm): tmajor =8.07,
t
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a-Functionalization of Oxindoles
COMMUNICATION
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Acknowledgements
The authors acknowledge the National University of Singapore for finan-
cial support (Academic Research Grants: R143000408133,
R143000408733, R143000443112, R143000480112, and NRF-CRP7–2010–
03).
Keywords: asymmetric catalysis · indane · organocatalysis ·
oxindole · thiourea
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Received: January 19, 2012
Revised: May 22, 2012
Published online: && &&, 0000
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H. Guo, X. Jiang, J Wang et al.
Enantioselective synthesis
W.-Y. Siau, W. Li, F. Xue, Q. Ren,
M. Xu, S. Sun, H. Guo,* X. Jiang,*
J. Wang* ....................... &&&& — &&&&
Catalytic and Enantioselective a-Func-
tionalization of Oxindoles Through
Oxidative Reactions with Naphthoqui-
nones
Strong as an oxindole: The enantiose-
lective assembly of 3,3-disubstituted
oxindoles is an attractive and valuable
target because of the unique properties
of the oxindole core. A new organoca-
talyzed and enantioselective aerobic
oxidative strategy for the assembly of
this core structure from oxindoles and
simple naphthoquinones is reported
(see scheme).
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!