Highly enantioselective synthesis of 3-amino-2-oxindole derivatives: Catalytic asymmetric α-amlnation of 3-substituted 2-oxindoles with a chiral scandium complex

Article abstract of DOI:10.1002/chem.201000126

A highly enantioselective α-amination of 3-substituted oxindoles with azodicarboxylates catalyzed by a chiral Sc(OTf)₃/N,/N′-dioxide complex (Tf: triflate) has been developed and affords the corresponding 3-amino-2-oxindole derivatives in high yields (up to 98%) with excellent enantioselectivities (up to 99% ee). The procedure is capable of tolerating a relatively wide range of substrates, and excellent results (92-96 % ee) can also be obtained, even in the presence of 0.5 mol % of catalyst loading under mild conditions. These results showed the potential value of the catalytic approach. Moreover, with high synthetic versatility, the product could be easily transformed into optically active 3-amino-3-methyloxindole bearing a chiral quaternary stereogenic center.

Full text of DOI:10.1002/chem.201000126

DOI: 10.1002/chem.201000126
Highly Enantioselective Synthesis of 3-Amino-2-oxindole Derivatives:
Catalytic Asymmetric a-Amination of 3-Substituted 2-Oxindoles with a
Chiral Scandium Complex
Zhigang Yang, Zhen Wang, Sha Bai, Ke Shen, Donghui Chen, Xiaohua Liu, Lili Lin, and
Xiaoming Feng*[a]
Abstract: A highly enantioselective a-
amination of 3-substituted oxindoles
with azodicarboxylates catalyzed by a
capable of tolerating a relatively wide
range of substrates, and excellent re-
sults (92–96% ee) can also be obtained,
even in the presence of 0.5 mol% of
catalyst loading under mild conditions.
These results showed the potential
value of the catalytic approach. More-
over, with high synthetic versatility, the
product could be easily transformed
into optically active 3-amino-3-methyl-
oxindole bearing a chiral quaternary
stereogenic center.
chiral ScACHTUNGTRENNUNG(OTf)3/N,N’-dioxide complex
(Tf: triflate) has been developed and
affords the corresponding 3-amino-2-
oxindole derivatives in high yields (up
to 98%) with excellent enantioselectiv-
ities (up to 99% ee). The procedure is
Keywords: amination · asymmetric
catalysis · dioxides · oxindoles ·
scandium
Introduction
synthesis of optically active 3-amino-2-oxindole derivatives
with a chiral quaternary center, and studies in this field have
received special attention because oxindoles bearing C3-
quaternary structures are widely distributed in a number of
natural products and pharmaceutical molecules.[10] Several
catalytic asymmetric reactions of 3-substituted oxindoles, in-
cluding the aldol reaction,[11] conjugate addition reaction,[12]
Mannich reaction,[13] fluorination,[14] and other types of reac-
tion,[15] have been successively reported. However, relatively
fewer examples have been documented for catalytic asym-
metric a-amination of oxindoles, which is very useful for the
generation of quaternary 3-amino-2-oxindole alkaloid com-
pounds. Only during the course of our study, Chen, Zhou,
Barbas, and their respective co-workers independently de-
scribed such a process with cinchona alkaloid analogues as
promoters.[16] Moreover, Shibasaki, Matsunaga, and co-
workers very recently developed a highly enantioselective
version of this reaction by using Schiff base–nickel com-
plexes as catalysts.[17] Despite these impressive contributions,
the development of new and more efficient approaches for
the enantioselective a-amination of 3-substituted oxindoles
with azodicarboxylates is still challenging and in high
demand.
The asymmetric a-amination between carbonyl compounds
and azodicarboxylates constitutes one of the most versatile
synthetic methodologies for the construction of optically
active a-amino carbonyl units, which are important building
blocks for the conversion of many biologically active and
therapeutic compounds.[1] Since the catalytic enantioselec-
tive electrophilic a-amination of carbonyl compounds with
azodicarboxylates pioneered by Evans and Nelson,[2] a great
effort has been devoted to the development of more selec-
tive and efficient catalytic systems for this kind of syntheti-
cally useful transformation,[3] such as chiral metal com-
plexes,[4] chiral phase-transfer catalysts,[5] cinchona alkaloid
derivatives,[6] chiral amine catalysts,[7] chiral thiourea cata-
lysts,[8] and chiral guanidine catalysts.[9] Furthermore, the ap-
plication of prochiral 3-substituted oxindoles as nucleophiles
provides a very simple and straightforward approach for the
[a] Z. Yang, Z. Wang, S. Bai, K. Shen, D. Chen, Dr. X. Liu, Dr. L. Lin,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-8249
As excellent chiral scaffolds, chiral N,N’-dioxide–metal
complexes have exhibited excellent abilities for the activa-
tion of various substrates and have shown strong asymme-
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000126.
try-inducing capability for many reactions.[18,19] Sc
ACHTUNGTRENNUNG(OTf)3
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FULL PAPER
(Tf: triflate), which features advantages in stability, recov-
ery, and reusability, has shown high catalytic activity in
many transformations.[20] Herein, we would like to report
our work on the efficient a-amination reaction of 3-substi-
tuted oxindoles and azodicarboxylates catalyzed by chiral
was then complexed with various metal salts to catalyze the
asymmetric a-amination. A significant effect of the central
metal ion on the enantioselectivity was observed, as shown
in Table 1. Products of low enantiomeric excess were ob-
tained with Y
(OTf)3, or In(OTf)3 as the Lewis acid (Table 1, entries 2–5,
7, and 8). Fortunately, the L1–Sc(OTf)3 complex could cata-
ACHTNUGTENRN(UGN OTf)3, YbACHUTGTNREN(NUG OTf)3, CuACHTUNGETRG(NNUN OTf)2, ZnACHTNUGRTEN(NUGN OTf)2, La-
N,N’-dioxide–scandium
N
A
ACHTUNGTRENNUNG
and excellent enantioselectivity were obtained for a wide
range of substrates in this reaction.
ACHTUNGTRENNUNG
lyze the reaction to give adduct 3a in 55% ee (Table 1,
entry 6).
Further optimization of the reaction conditions was aimed
Results and Discussion
at exploring the effectiveness of ScACTHNGUTERNNU(G OTf)3 with other N,N’-
dioxide ligands (Table 2). After examining the steric and
In the preliminary study, l-proline-based N,N’-dioxide L1
(Scheme 1) was employed as an organocatalyst for the enan-
tioselective a-amination of 3-methyloxindole (1a) and diiso-
Table 2. Ligand screening in the asymmetric a-amination of 3-methylox-
indole (1a) and DIAD (2a).[a]
Entry
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
<5
<5
21
<5
17
43
61
<5
<5
<5
46
55
23
61
56
59
90
85
33
55
15
75
9
10
11
Scheme 1. Ligands employed for the a-amination reaction.
[a] Unless otherwise noted, reactions were carried out with 1a
(0.1 mmol) and 2a (0.1 mmol) in CH2Cl2 (1.0 mL) with a catalyst loading
of 10 mol% (metal/ligand=1:1) under nitrogen at À208C for 3 d.
[b] Yield of isolated product. [c] Determined by chiral HPLC analysis.
propylazodicarboxylate (DIAD; 2a) in CH2Cl2 at À208C.
Unfortunately, the reaction gave the desired product 3a in
less than 5% yield with only 4% ee (Table 1, entry 1). L1
electronic effects of N,N’-dioxides, we found that the reac-
tivity and enantioselectivities were closely dependent on the
R substituents of the amide moiety and that bulkier groups
provided better results (Table 2, entries 1–6 and 9–11). The
results also showed that, with regard to the chiral backbone
moiety, (S)-pipecolic acid derived N,N’-dioxides were found
to give superior ee values to l-proline and l-ramipril acid
derived ones (Table 2, entries 4 vs. 1 and 9, 5 vs. 2 and 10,
and 6 vs. 3 and 11). With the bulkier 2,6-diisopropylphenyl-
derived N,N’-dioxide L6, 90% ee and 43% yield could be
afforded (Table 2, entry 6). However, no better result was
obtained by using the 2-tert-butylphenylamine-based N,N’-
dioxide L7 (Table 2, entry 7). When the R group of the
amide moiety was the bulkier 1-adamantyl group, the reac-
tion had unexpectedly low enantioselectivity and reactivity
(Table 2, entry 8). Accordingly, L6 was chosen as the best
ligand for the next investigation.
Table 1. Screening of central metal ions in the asymmetric a-amination
of 3-methyloxindole (1a) and diisopropylazodicarboxylate (DIAD; 2a).[a]
Entry
Metal
none
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
<5
5
<5
trace
6
<5
<5
trace
4
9[d]
0
YACHTUNGTRENNUNG
G
A
N.D.[e]
6
ACHTUNGTRENNUNG
E
55
E
16[d]
N.D.[e]
ACHTUNGTRENNUNG
[a] Unless otherwise noted, reactions were carried out with 1a
(0.1 mmol) and 2a (0.1 mmol) in CH2Cl2 (1.0 mL) with a catalyst loading
of 10 mol% (metal/ligand=1:1) under nitrogen at À208C for 3 d.
[b] Yield of isolated product. [c] Determined by chiral HPLC analysis.
[d] An opposite configuration of product was obtained as determined by
HPLC. [e] N.D.: not determined.
Subsequently, we examined the effect of solvents in the
presence of 10 mol% L6–ScACTHNUTRGNE(UNG OTf)3 (1:1) complex. As shown
in Table 3, both the enantioselectivity and the yield were
very dependent on the solvent. If the reaction was carried
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X. Feng et al.
Table 3. Effect of solvent in the a-amination of 3-methyloxindole (1a)
and DIAD (2a).[a]
able for the reactivity (Table 4, entries 1–3). When the ratio
of ligand L6 to ScACHTNUTRGNE(NUG OTf)3 was changed from 1:1 to 1.2:1, a
better yield was obtained and the enantioselectivity was
maintained. (Table 4, entry 2 vs. 3). To our delight, when the
molar ratio of ligand L6 to ScACHTNUTRGNENG(U OTf)3 was increased to 1.5:1,
the product was obtained in excellent yield (96%) and the
enantioselectivity (92% ee) was not changed (Table 4,
entry 1). In contrast, no products were obtained with the use
of an excess amount of metal in the catalytic system
(Table 4, entry 4). Furthermore, the reaction could not occur
Entry
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CH2Cl2
tetrahydrofuran (THF)
toluene
EtOH
N,N-dimethylformamide (DMF)
CHCl3
ClCH2CH2Cl
EtOAc
43
5
16
25
5
24
68
21
90
47
57
65[d]
8
73
87
9[d]
with only ScACTHUNRGTNEUNG(OTf)3 as the catalyst (Table 4, entry 5).
When the catalyst loading was only 5 mol% with a pro-
longed reaction time at À208C, high yield and enantioselec-
tivity were achieved (Table 4, entry 6). To improve the reac-
tivity of the reaction, 4 ꢁ molecular sieves (5 mg) were em-
ployed. In this instance, the reaction was completed within
2.5 d to give product 3a with the enantioselectivity slightly
increased from 91 to 92% ee (Table 4, entry 7). The role of
the 4 ꢁ molecular sieves (extraction of water) might be
helpful for the promotion of an equilibrium for the forma-
tion of an enolate intermediate and to accelerate the reac-
tion rate.[6d] Hence, we found that treatment of 3-methylox-
indole (1a) and DIAD in the presence of N,N’-dioxide L6
[a] Unless otherwise noted, reactions were carried out with 1a
(0.1 mmol) and 2a (0.1 mmol) in the indicated solvent (1.0 mL) with Sc-
(OTf)3/L6 (10 mol%; 1:1) under nitrogen at À208C for 3 d. [b] Yield of
isolated product. [c] Determined by chiral HPLC analysis. [d] An oppo-
site configuration of product was obtained as determined by HPLC.
out in THF, toluene, or EtOH, it only afforded the desired
product 3a with up to 65% ee (Table 3, entries 2–4). A sig-
nificant drop in both the reactivity and enantioselectivity
was found for many other solvents, such as DMF and
EtOAc (Table 1, entries 5 and 8). As CH2Cl2 was a better
solvent for this reaction, other chlorinated alkanes such as
CHCl3 and ClCH2CH2Cl were investigated, but no superior
result was obtained (Table 3, entry 1 vs. 6 and 7). Therefore,
CH2Cl2 was chosen as the best solvent for this reaction
(Table 3, entry 1).
Next, we turned our attention toward investigating the in-
fluence of the molar ratio of the central metal ion to the
ligand on the a-amination of 3-methyloxindole (1a) and
DIAD (2a; Table 4, entries 1–5). This ratio was found to be
another important factor for the reactivity. The results indi-
cated that an increase in the amount of ligand L6 was favor-
(7.5 mol%), ScACTHNUTRGNEUNG(OTf)3 (5 mol%), and 4 ꢁ molecular sieves
(5 mg) gave the desired product 3a in 93% yield with 92%
ee.
Under the optimal reaction conditions (Table 4, entry 7),
a variety of oxindoles 1 and azodicarboxylates 2 were inves-
tigated. First, the ester-group effect of the azodicarboxylate
was tested for the asymmetric a-amination of 3-methyloxin-
dole. The ester groups apparently had little or no effect on
the enantioselectivity of the reaction (Table 5, entries 1–3).
Diethylazodicarboxylate (DEAD) turned out to be an out-
standing electrophile and the reaction was accomplished in
2 d in 98% yield with 92% ee (Table 5, entry 2). With
DEAD as the electrophilic substrate, various substituted ox-
indoles were then examined (Table 5, entries 4–23). In gen-
eral, the reactions took place efficiently with good yields
(70–95%) and excellent levels of enantioselectivity (83–
99% ee). This catalyst system was efficient when the R1
group was an aliphatic nonbranched alkyl group (Table 5,
entries 4 and 6), a branched alkyl group (Table 5, entry 5),
or a cyclohexylmethyl group (Table 5, entry 7), with the re-
spective reactions leading to the corresponding adducts 3d–
g in good yields with 97–98% ee values. It is interesting that
either the electronic nature or the position of the substitu-
ents on the aromatic ring of the R1 group had a limited in-
fluence on the enantioselectivity of the a-amination
(Table 5, entries 8–16). Remarkably, substrates bearing con-
densed-ring or heteroaromatic-ring in R1 substituents were
also suitable substrates for the reaction and afforded the
corresponding products 3q–s with excellent enantioselectivi-
ties (Table 5, entries 17–19). When 3-phenyloxindole, which
bears a bulky phenyl group as the R1 group, was used, 93%
ee and 85% yield could be obtained (Table 5, entry 20). For-
tunately, high enantioselectivity (91% ee) was also observed
for the 5-bromo-3-methyloxindole substrate (Table 5,
Table 4. Screening of the ratio of ligand/metal and the catalyst loading in
the a-amination of 3-methyloxindole (1a) and DIAD (2a).[a]
Entry Catalyst loading [mol%] T [8C] t [d] Yield [%][b] ee [%][c]
L6
Sc
ACHTUNGTRENNUNG(OTf)3
1
2
3
4
15
12
10
10
0
10
10
10
15
10
5
À20
À20
À20
À20
À20
À20
À20
3
3
3
3
3
4
96
79
43
trace
trace
95
92
91
90
N.D.[d]
N.D.[d]
91
5
6
7.5
7.5
7[e]
5
2.5 93
92
[a] Unless otherwise noted, reactions were carried out with 1a
(0.1 mmol) and 2a (0.1 mmol) in CH2Cl2 (1.0 mL). [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis. [d] N.D.: not deter-
mined. [e] In the presence of 4 ꢁ molecular sieves (MS; 5 mg).
6634
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Chem. Eur. J. 2010, 16, 6632 – 6637

Asymmetric a-Amination of 3-Substituted 2-Oxindoles
FULL PAPER
Table 5. Catalytic asymmetric a-amination of 3-substituted oxindoles 1
with azodicarboxylates 2 under the optimal conditions.[a]
Table 6. Substrate scope of the asymmetric a-amination of 3-substituted
oxindoles and diethylazodicarboxylate with 0.5 mol% catalyst loading.[a]
Entry
R1
R2
R3
R4
Yield [%][b]
ee [%][c]
92 (R)[d]
92
90 (R)
98
97
98
98
98
98
Entry
R1
t [d]
Yield [%][b]
ee [%][c]
1
Me
Me
Me
n-propyl
i-propyl
n-butyl
cyclohexylmethyl
Bn
2-MePhCH2
3-MePhCH2
4-MePhCH2
4-MeOPhCH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
iPr
Et
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
93 (3a)
98 (3b)
92 (3c)
78 (3d)
70 (3e)
77 (3 f)
71 (3g)
91 (3h)
81 (3i)
80 (3j)
95 (3k)
85 (3l)
2[e]
3[f]
4
1
2
3
4
5
6
7
cyclohexylmethyl
Bn
2
2.5
2
2
2
2
2
4
4
95 (3g)
92 (3h)
88 (3i)
85 (3j)
92 (3l)
90 (3n)
91 (3p)
85 (3h)
80 (3h)
92
94
94
96
95
94
94
80
74
2-MePhCH2
3-MePhCH2
4-MeOPhCH2
2-ClPhCH2
2,4-Cl2PhCH2
Bn
5
6
7
8
8[d]
9[e]
9
Bn
10
11
12
98
98
98
[a] Unless otherwise noted, the reactions were carried out with
(1.0 mmol) and 2b (1.0 mmol) in CH2Cl2 (3.0 mL) with 0.5 mol%
scandium(III) triflate, 0.75 mol% L6, and 4 ꢁ MS (20 mg) under nitro-
gen at 308C. [b] Yield of isolated product. [c] Determined by chiral
HPLC analysis. [d] Catalyst loading was 0.1 mol%. [e] Catalyst loading
was 0.01 mol%.
1
AHCTUNGTRENNUNG
13
H
H
Et
72 (3m)
98
14
15
16
17
18
19
20
21
22
23
2-ClPhCH2
4-ClPhCH2
2,4-Cl2PhCH2
1-naphthylmethyl
2-naphthylmethyl
2-thienylmethyl
Ph
Me
Bn
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
86 (3n)
94 (3o)
95 (3p)
80 (3q)
80 (3r)
83 (3 s)
85 (3t)
93 (3u)
85 (3v)
80 (3w)
98
97
99
98
98
98
93
91
95
83
tically active quarternary 3-amino-3-methyloxindole, which
is a useful medicinal chemistry intermediate.[21] As shown in
Scheme 2, catalytic asymmetric a-amination of 3-methylox-
indole (1a) and dibenzylazodicarboxylate (2c) was accom-
plished with good results (80% yield, 85% ee) by using only
Me
Bn
[a] Unless otherwise noted, the reactions were carried out with
1
(0.1 mmol) and 2 (0.1 mmol) in CH2Cl2 (1.0 mL) with 5 mol% scandium-
AHCTUNGTRENNUNG
(III) triflate, 7.5 mol% L6, and 4 ꢁ MS (5 mg) under nitrogen at À208C
for 2–3 d. Bn: benzyl. [b] Yield of isolated product. [c] Determined by
chiral HPLC analysis. [d] The absolute configuration was determined by
comparison with literature data.[16a] [e] Reaction time was 2 d. [f] The re-
action was carried out at À308C for 2.5 d, and dibenzylazodicarboxylate
(0.2 mmol) was used.
entry 21). Notably, N-protected groups apparently had little
effect on the results of the reaction (Table 5, entries 22 and
23).
Synthetic application with a low catalyst loading is clearly
desirable for a catalytic asymmetric reaction. Although the
asymmetric a-amination of carbonyl compounds with azodi-
carboxylates had been reported, most of these processes re-
quired 5 mol% or more of catalyst loading for sufficient for-
mation of the product and maintenance of the enantioselec-
tivity.[1–9,16] The reaction reported herein could be performed
without notable loss of reactivity (85–95% yield) and enan-
tioselectivity (92–96% ee) even with a catalyst loading of
0.5 mol%, although the reaction temperature was increased
from À208C to 308C (Table 6, entries 1–7). Further attempts
to decrease the catalyst loading (0.1 mol% and 0.01 mol%)
led to a decrease in the yield and enantiomeric excess of the
product, and the reaction time was prolonged (Table 6, en-
tries 8 and 9).
Scheme 2. Elaboration of adduct 3c after the a-amination of 3-methylox-
indole (1a) and dibenzylazodicarboxylate (2b).
2 mol% of L6–ScACTHNUTRGNE(UNG OTf)3 at 08C. Compound 3c was treated
with Pd/C hydrogenation to remove the Cbz group with
À
90% yield; this was followed by N N bond cleavage with
Raney nickel to afford 3-amino-3-methyloxindole (5a) in
60% yield, without loss of enantioselectivity (85% ee).
To gain a preliminary insight into the mechanism, a C2-
symmetric amide, compound 6 (Figure 1a), which is the pre-
cursor of chiral N,N’-dioxide L6, was synthesized and ex-
plored in the asymmetric a-amination of 3-methyloxindole
(1a) and DIAD (2a). No product was obtained under the
same reaction conditions. The results suggested that only
The benzyloxycarbonyl (Cbz) groups of product 3c can be
easily removed so it is conveniently transformed into an op-
the L6–ScACTHNUTRGENUG(N III) complex could form the active catalyst due to
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6635

X. Feng et al.
solvent resonance used as the internal standard. 13C NMR data were col-
lected at 100 or 150 MHz with complete proton decoupling. Enantiomer-
ic excess (ee) values were determined by chiral HPLC analysis on Daicel
Chiralcel AD-H, IA, and IB columns by comparison with the authentic
racemates. ESI-HRMS spectra were recorded on a commercial apparatus,
and methanol or acetonitrile was used to dissolve the sample. All reac-
tions were performed in sealed oven-dried glass tubes under an atmos-
phere of nitrogen unless otherwise noted. THF and toluene were distilled
from sodium benzophenone ketyl. CH2Cl2 was distilled over CaH2.
Unless noted, commercial reagents were used without further purifica-
tion. 3-Methyloxindole is commercially available and was used without
further purification. The other oxindoles were prepared according to the
literature and references therein.[11–16] The N,N’-dioxide ligands were pre-
pared according to the literature.[19]
Figure 1. a) Precursor of the chiral N,N’-dioxide L6. b) Chiral amplifica-
tion in the amination of 1a with 2a catalyzed by the L6–ScACHTNUTRGNEUNG(OTf)3 com-
plex. c) Proposed transition-state model.
General procedure for the enantioselective a-amination of 3-substituted
oxindoles with azodicarboxylates: N,N’-dioxide L6 (4.9 mg, 0.0075 mmol),
scandium triflate (2.5 mg, 0.005 mmol), 3-methyloxindole (1a; 14.7 mg,
0.10 mmol), and 4 ꢁ molecular sieves (5 mg) were stirred in a dry reac-
tion tube in CH2Cl2 (1.0 mL) under nitrogen at 308C for 0.5 h and then
cooled to À208C, at which point diisopropylazodicarboxylate (2a; 20 mL,
0.1 mmol) was added. The reaction mixture was stirred at À208C for
2.5 d. Purification by silica gel column chromatography (eluent: petrole-
um ether/ethyl acetate, 2:1) afforded the desired product 3a in 93%
yield with 92% ee: [a]2D0 =À7.0 (c=0.65 in CHCl3) (ref. [16a]: [a]2D0 =+6.0
(c=0.5 in CHCl3, 78% ee)); 1H NMR (400 MHz, CDCl3): d=7.84 (s,
1H), 7.77 (d, J=7.6 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 7.05 (t, J=7.2 Hz,
1H), 6.94 (d, J=4.4 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 5.05 (dt, J=12.8,
6.4 Hz, 1H), 4.73 (dt, J=12.4, 6.0 Hz, 1H), 1.54 (s, 3H), 1.33 (dd, J=6.4,
2.0 Hz, 6H), 1.08 (d, J=6.4 Hz, 3H), 0.93 ppm (brs, 3H); HPLC (chiral
the double N-oxide moieties. Next, the relationship between
the ee values of ligand L6 and product 3a was investigated
under the optimal conditions shown in Table 5. A positive
nonlinear effect was observed (Figure 1b), which suggests
that oligomeric aggregates of L6–Sc
reaction system. On the basis of the experimental results ob-
tained and the X-ray structure of the N,N’-dioxide–Sc(OTf)3
complex recently reported by us, as well as our previous re-
ports of using N,N’-dioxide–Sc(OTf)3 complexes as cata-
ACHTUNGRTEN(NUGN OTf)3 might exist in the
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AD-H column; iPrOH/hexane (10:90), 1.0 mLminÀ1
(major)=12.8 min, tR (minor)=16.7 min, 92% ee.
, 254 nm): tR
lysts,[19m,t] we propose that the carbonyl group of the oxin-
dole would coordinate to the active Ln–Sc complex to form
an enolate (Figure 1c). The azodicarboxylate also can coor-
dinate to the central metal ion through an ester carbonyl
group. Subsequently, diisopropylazodicarboxylate electro-
philic attack on the enolate would afford the corresponding
product 3a with excellent enantioselectivity (Figure 1c).
Acknowledgements
We appreciate the National Natural Science Foundation of China (grant
nos. 20732003 and 20872097), PCSIRT (grant no. IRT0846), and the Na-
tional Basic Research Program of China (973 Program; grant no.
2010CB833300) for financial support. We also thank Sichuan University
Analytical & Testing Center for NMR analysis.
Conclusion
We have developed a highly enantioselective a-amination of
3-substituted oxindoles with azodicarboxylates by using a
chiral N,N’-dioxide–ScIII complex as the catalyst. This simple
experimental protocol affords various optically active 3-
amino-2-oxindole derivatives in high yields (up to 98%)
with excellent enantioselectivities (up to 99% ee). More-
over, a relatively wide range of substrates can be tolerated
and excellent results can still be obtained with 0.5 mol%
catalyst loading; these results show the potential value of
this catalyst system. The product with enantiomeric excess
can be conveniently transformed into an optically active
quarternary 3-amino-3-methyloxindole in two steps. Further
efforts will be devoted to the investigation of the a-amina-
tion reaction with other kinds of carbonyl compounds and
to the application of this reaction to the synthesis of biologi-
cally interesting molecules.
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Chem. Eur. J. 2010, 16, 6632 – 6637

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Received: January 18, 2010
Published online: April 20, 2010
Chem. Eur. J. 2010, 16, 6632 – 6637
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