Asymmetric organocatalytic N-nitroso-aldol reaction of oxindoles

Article abstract of DOI:10.1016/j.tetasy.2010.11.002

An organocatalytic enantioselective N-nitroso-aldol reaction of 2-oxindoles promoted by a cinchona alkaloid catalyst has been developed. The reaction shows exclusively N-selectivity, affording corresponding products with good to excellent yields (up to 10

Full text of DOI:10.1016/j.tetasy.2010.11.002

Tetrahedron: Asymmetry 21 (2010) 2800–2806
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric organocatalytic N-nitroso-aldol reaction of oxindoles
⇑
⇑
Tao Zhang, Liang Cheng, Li Liu , Dong Wang, Yong-Jun Chen
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An organocatalytic enantioselective N-nitroso-aldol reaction of 2-oxindoles promoted by a cinchona alka-
loid catalyst has been developed. The reaction shows exclusively N-selectivity, affording corresponding
products with good to excellent yields (up to 100%) and moderate enantioselectivity. The regioselectivity
of nitroso-aldol reaction being controlled by different cinchona catalysts was also observed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 28 September 2010
Accepted 2 November 2010
Available online 20 December 2010
1. Introduction
recently Barbas et al.2y reported dimeric quinidine-catalyzed
enantioselective aminoxylations of 2-oxindoles with nitrosoben-
During the last several years, great progress has been made for
asymmetric nitroso-aldol reactions1 between carbonyl nucleophiles
and nitrosoarenes to accomplish aminoxylation (nucleophile at-
tacks the oxygen atom of the nitrosoarene) or hydroxyamination
(nucleophile attacks the nitrogen atom of the nitrosoarene) by
employing organometallic catalysts or organocatalysts, leading to
two regioisomers (Scheme 1, type A and type B). For organocatalytic
nitroso-aldol reactions, the nucleophiles used could be aldehydes,
zene to give aminoxylation products in high enantioselectivities
B, while only a few hydroxyamination products A (yield <15%) have
been observed occasionally. Herein, we report a new enantiomeric
process of exclusively regioselective N-nitroso-aldol reaction of
2-oxindoles with nitrosobenzene to produce hydroxyamination
products in good to excellent yields.
2. Results and discussion
ketones, b-dicarbonyl compounds, or
a-cyanoacetates. In most
cases, the aminoxylation product B was obtained,2 which was
mainly catalyzed by proline and its derivatives. Only a few examples
have been reported on the direct stereoselective version of the N-ni-
troso-aldol reaction, which affords chiral hydroxyamination prod-
ucts A.3 So far organocatalytic enantioselective N-nitroso-aldol
reactions include enamines, aldehydes, and ketones as nucleophiles
to provide moderate to high enantioselectivities via the catalysis of a
TADDOL derivative3e or chiral secondary amines.3a,c,d Jørgensen re-
ported the quinine-catalyzed enantioselective N-nitroso-aldol reac-
Initially, the reaction between 2-oxindole 1a and nitrosoben-
zene 2 was carried out in dichloromethane catalyzed by cinchona
alkaloids at 0 °C.
The reaction showed exclusive N-selectivity to afford the
hydroxyamination product 4a. For natural quinine 3a, although
the highest enantioselectivities were exhibited in the N-nitroso-
aldol reaction of
a
-cyanoacetates,3b product 4a was obtained in
63% yield with very poor enantioselectivity (9% ee) (Table 1, entry
1). To improve the enantioselectivity, a series of cinchona alkaloid
derivatives 3b–h were tested in the reaction of 1a with 2 (Fig. 1).
Cinchonidine 3b, which has no methoxyl at the C60-position, also
showed lower enantioselectivity (ee 14%) (entry 2). If the hydroxyl
group at C9 was blocked by phenanthryl group, the resulting cata-
lyst 3c did not increase the enantioselectivity effectively (entry 3).
When catalyst 3d bearing a free –OH both at the C60- and C9-
positions was used, an acceptable result was obtained (entry 4, ee
54%). However, a large decrease in enantioselectivity was observed
with the increase of steric hindrance at C9, for example, 3e and b-ICD
3f (entries 5 and 6). Next, 2-naphthol was used as an additive to pro-
vide a free phenolic hydroxyl instead of 3d; high yield but only 5% ee
was observed in the 3b-catalyzed system (entry 7). These results
showed that a free hydroxyl group at the C60-position and a small
hindrance at the C9-position in the same catalyst structure were
of importance. The use of dimeric cinchona alkaloid catalysts 3g
and 3h also gave lower enantioselectivities (entries 8 and 9).
tion of
a
-cyanoacetates.3b It is noteworthy that changing the
catalyst system could result in different regioselectivities of the ni-
troso-aldol reaction to afford aminoxylation or hydroxyamination
products respectively.2,3 To the best of our knowledge, there have
been no reports of N-nitroso-aldol reactions involving amides such
as 2-oxindoles.
Oxindoles4 bearing a quaternary carbon stereocenter at the
3-position of the indole ring constitute a ubiquitous structural
motif in a variety of natural products and biologically active drug
candidates.5 Among them, therapeutic agents such as SSR-149415
and AG-041R with a chiral 3-amino-2-oxindole unit have notewor-
thy pharmaceutical properties.6 Therefore, many procedures have
been developed for the synthesis of 3-amino-2-oxindoles.7 Very
⇑
Corresponding authors. Tel.: +86 010 62554614; fax: +86 010 62554449 (L.L.).
E-mail address: lliu@iccas.ac.cn (L. Liu).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.002

T. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 2800–2806
2801
O
O
O
OH
N
O
N-nitroso aldol
O-nitroso aldol
R2
O
Ar
R2
N
H
R2
Ar
N
A
R1
B
Ar
R1
R1
Hydroxyamination
Aminoxylation
Scheme 1. Nitroso-aldol reaction between carbonyl compounds with nitrosoarene.
To examine the solvent effect, various solvents, either apolar or
polar solvents, were used (Table 2). Although good to excellent
yields were obtained for the N-nitroso-aldol reaction in a wide
range of solvents, a significant variation of enantioselectivity was
displayed. The reaction of 1a with 2 in acetone and ethyl acetate
gave low ee (entries 5 and 6). THF gave 4a in 41% ee but with a
low yield (entry 3). DCM and toluene could increase the enantiose-
lectivity up to 62% and 55% ee, respectively (entries 1 and 2). When
the reaction was carried out in a co-ordinating solvent i-propanol
(entry 4), an inversion of stereointroduction was observed.3b
DCM was found to be the best solvent for this reaction, and the re-
sult was further improved upon by running the reaction in a dilute
concentration (entry 7). Lowering the reaction temperature did not
increase the enantioselectivity (entry 9). The optimum tempera-
ture ranged from 0 °C to 20 °C without any loss of enantioselectiv-
ity (entry 8).
Product 4a (68% ee) could be readily transformed to the corre-
sponding amine 5a in 94% yield with 65% ee by using zinc and ace-
tic acid as the reducing agent (Scheme 2). This transformation
further validated the formation of the N-selective product. More-
over, the asymmetric N-nitroso-aldol reaction could combine with
the cleavage of the N–O bond in one process to give 5a directly
(overall yield, 85%) from 1a and 2.
the reaction of 1a0 with 2 under either the Barbas’ (Scheme 3, C)
or our (Scheme 3, B) reaction conditions, N-selectivity was ob-
served, which was confirmed by the formation of 5a0 through
dehydroxylation. It seems that different types of cinchona alkaloid
catalysts control the O- and N-regioselectivity.
Under the optimum conditions, various 2-oxindoles 1a–d with
3-alkyl substituents including methyl, allyl, (E)-cinnamyl and ben-
zyl were applied to the asymmetric N-nitroso-aldol reaction of
oxindoles, affording N-selective products 4a–d in good to excellent
yields with moderate enantioselectivities (62–72% ee) (Scheme 4).
For 3-benzyl-2-oxindoles 1e–i, the substrates with functional
groups, either electron-withdrawing (CN, Cl) or donating-electron
(OMe, Me, OCH2O), at the meta- or para-position in the aromatic
ring of the benzyl group gave N-selective products 4e–i in up to
quantitative yield with 59–67% ee.
The absolute configuration of the main enantiomer was estab-
lished as (S) by X-ray single-crystal analysis of 4h with 86% ee after
recrystallization (Fig. 2). The results of the X-ray single-crystal
analysis also demonstrated the N-selectivity of the direct nitroso-
aldol reaction of 2-oxindoles with nitrosobenzene catalyzed by
demethylquinine 3d.
Based on aforementioned results, a possible model of dual acti-
vation of the nucleophile and the electrophile was proposed. Cata-
lyst 3d serves as the bifunctional chiral organocatalyst: the
phenolic hydroxyl activates nitrosobenzene by hydrogen bonding,
while the quinuclidine moiety deprotonates the C3 methine proton
leading to the generation of the enol intermediate of the 2-oxin-
dole.9 The attack of the enol intermediate to an activated nitroso-
benzene resulted in the formation of N-selective products (Fig. 3).
To further explore the factors controlling the regioselectivity of
nitroso-aldol reaction of 2-oxindoles, a contrast test was then
performed. It was reported that the dimeric cinchona alkaloid cat-
alyst developed by Barbas et al.2y could promote the formation of
O-selective products when N-benzyl protected 2-oxindoles were
used (Scheme 3, A). However, when catalyst 3d was employed in
Table 1
Catalyst screening for the asymmetric hydroxyamination reactiona
Ph
OH
O
N
N
Catalyst 3 (10 mol%)
O
O
N
H
DCM (1mol/L) 0ºC
N
H
1a
4a
2
Entry
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
3a
3b
3c
3d
3e
3f
3b
3g
3h
63
79
73
90
66
89
91
87
88
9
14
17
54
23
34
5
5
6d
7e
8
6
20
9d
a
b
c
Reaction performed at a 0.2 mmol scale 1a with 1 equiv of 2, using 10 mol % of catalyst 3 in 0.2 mL CH2Cl2 at 0 °C.
Isolated yield.
Determined by HPLC analysis.
The opposite enantiomer was obtained.
2-Naphthol (10 mol %) was added as an additive.
d
e

2802
T. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 2800–2806
H
R
HO
N
H
MeO
O
N
N
3a R= OMe (QN)
3b R= H (CD)
N
3c
H
RO
OH
HO
H
O
N
N
N
N
3d R=H
3e
R=phenanthryl
3f
β-ICD
N
N
N
N
N
N
O
O
H
O
O
H
H
H
H
H
H
O
N
N
O
O
O
N
N
N
N
3g (DHQ)2PHAL
3h
(DHQD)2PYR
Figure 1. Cinchona alkaloid catalysts for the N-nitroso-aldol reaction.
3. Conclusion
Table 2
Optimization of conditions for asymmetric hydroxyamination reaction of 1a with 2a
In conclusion, we have developed a novel organocatalytic enan-
tioselective N-nitroso-aldol reaction of 2-oxindoles in the presence
of the cinchona alkaloid catalyst, which showed exclusive N-selec-
tivity in good to excellent yields with moderate enantioselectivi-
ties. The application of the developed protocol and investigation
of the N-nitroso-aldol reaction in other asymmetric processes are
currently underway in our lab.
Entry
Solvent
Concd (mol/L)
Yieldb (%)
eec (%)
1
2
CH2Cl2
Toluene
THF
i-Propanol
Acetone
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
90
95
53
90
85
92
90
90
90
62
55
41
13
30
36
67
67
62
3
4d
5
6
7
8e
9f
4. Experimental
Unless otherwise noted, all reagents were obtained from com-
mercial suppliers and used without further purification. Natural cin-
chona alkaloids 3a,b, as well as 3g,h, were commercially available.
Cinchona alkaloid based catalysts 3c,f and all the substrates7d,10
except for 1c11 were prepared according to literature procedures.
All reactions were carried out directly in an air atmosphere, unless
otherwise noted. Chemical shifts are reported in ppm from tetra-
methylsilane with the solvent resonance as the internal standard.
The following abbreviations were used to designate chemical shift
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, h =
heptet, m = multiplet, br = broad. All first-order splitting patterns
were assigned on the basis of the appearance of the multiplet.
Splitting patterns that could not be easily interpreted are designated
as multiplet (m) or broad (br). IR spectra were recorded on a
Bruker tensor 27 infrared spectrometer. Melting points were mea-
sured on Beijing Tech X-4 apparatus and are uncorrected. Mass
spectra were obtained using electrospray ionization (ESI) mass
spectrometer. Optical rotations were measured using a 1 mL cell
a
Reaction performed at a 0.2 mmol scale 1a with 1 equiv of 2, using 10 mol % of
catalyst 3d in the indicated solvent at 0 °C.
b
Isolated yield.
Determined by HPLC analysis.
The opposite enantiomer was obtained.
At 20 °C.
c
d
e
f
At ꢁ40 °C.
Ph
Ph
OH
O
NH
N
Zn
O
CH3COOH
N
H
N
H
5a, 65% ee, yield 94%
4a, 68% ee
with a 1 dm path length and are reported as follows: ½a Drt
ꢀ
(c in g
Scheme 2. Cleavage of the N–O bond.

T. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 2800–2806
2803
NHPh
O
O
Barbas' cat. (10 mol%)
(A)
THF, -20 ºC, 48 h
85%, ref.2y
N
Bn
6
HO
cat. 3d (10 mol%)
2
Ph
O
O
(B)
(C)
N
DCM, 0ºC, overnight
80%
N
Bn
1a'
N
Bn
cat. 3d (10 mol%)
4a'
THF,-20 ºC, 48 h
91%
Zn
AcOH
N
H
N
Ph
O
N
HO
OH
H
H
H
H
O
O
N
N
N
Bn
Barbas' catalyst
5a'
Scheme 3. Catalyst-dependent aminoxylation and hydroxyamination.
per 100 mL of solvent). HPLC analysis was performed using com-
mercial ChiralPak columns. Column chromatography was per-
formed using silica gel (200–300 mesh). TLC was performed on
glass-backed silica plates.
6 h at 0–20 °C. After the reaction was complete (monitored by TLC),
the reaction mixture was purified by flash chromatography (DCM/
EtOAc, 10-5:1) to afford the target product.
4.2.1. (S)-3-(Hydroxy(phenyl)amino)-3-methylindolin-2-one 4a
and 1-benzyl-3-(hydroxy(phenyl)amino)-3-methylindolin-2-
one 4a0
4.1. Synthesis of oxindole 1c
To a solution of oxindole (1.33 g, 10 mmol) in THF (30 mL) at
ꢁ78 °C was added n-BuLi (8 mL, 2.5 M in hexanes) and TMEDA
(3.0 mL, 20 mmol) and the resulting solution was stirred for 2 h.
Cinnamyl bromide (2.0 g, 10 mmol) was then added dropwise
and the solution was slowly warmed up to ꢁ20 °C and stirred for
1 h at that temperature before it was brought to rt. The reaction
was then quenched with aq NH4Cl (70 mL) and extracted with
ethyl acetate. The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Purification
by flash chromatography (petroleum ether/EtOAc = 4:1–2:1) gave
1c. White solid. Mp 120–121 °C. 1H NMR (300 MHz, CDCl3): d
9.15 (s, 1H), d 7.32–7.20 (m, 7H), d 7.06–7.01 (t, J = 7.5 Hz, 1H), d
6.96–6.93 (d, J = 7.8 Hz, 1H), d 6.53–6.48 (d, J = 15.9 Hz, 1H), d
6.26–6.16 (m, 1H), d 3.64–3.60 (dd, J = 4.8 Hz, J = 7.5 Hz, 1H), d
3.09–3.00 (m, 1H), d 2.79–2.68 (m, 1H). 13C NMR (75.0 MHz,
CDCl3): d 180.5, 141.9, 137.2, 133.2, 129.4, 128.6, 128.1, 127.4,
126.3, 125.8, 124.5, 122.3, 110.1, 46.3, 34.3. IR mmax (KBr, film,
cmꢁ1): 3134, 1703, 1620, 1470, 1341, 1313, 1233. HRMS (ESI):
calcd for C17H15NaNO [M+Na]+ 272.1046; found: 272.1047.
Compound 4a yellowish solid, yield 90%, ee 67%, ½a D20
¼ þ43:4
ꢀ
(c 0.5, THF). Mp 137–138 °C. 1H NMR (300 MHz, DMSO): d 10.26
(s, 1H), d 8.92 (s, 1H), d 7.15–6.69 (m, 9H), d 1.49 (s, 3H). 13C
NMR (75.0 MHz, DMSO): d 177.7, 150.4, 141.9 131.0, 128.8,
127.9, 126.7, 126.5, 124.9, 123.5, 121.2, 109.3, 76.5, 42.2. IR mmax
(KBr, film, cmꢁ1): 3199, 3086, 1715, 1332, 1210. HRMS (ESI): calcd
for C15H14NaN2O2 [M+Na]+ 277.0948; found: 277.0949. HPLC anal-
ysis [Chiralcel AD-H, n-hexane/i-propanol (90:10), 15 °C,
1 mL minꢁ1, tR = 22.7 min (minor), 27.0 min (major)].
Compound 4a0 yellowish solid, yield 80%, ee 38%. ½a 2D0
¼ þ6:6 (c
ꢀ
0.5, THF). Mp 132–133 °C. 1H NMR (300 MHz, DMSO): d 9.06 (s,
1H), d 7.33–6.94 (m, 13H), d 6.70–6.67 (d, J = 7.8 Hz, 1H), d 4.96–
4.91 (d, J = 15.9 Hz, 1H), d 4.73–4.67 (d, J = 15.9 Hz, 1H), d 1.58 (s,
1H). 13C NMR (75.0 MHz, DMSO): d 176.0, 150.2, 142.4, 136.5,
130.4, 128.9, 128.1, 127.6, 127.4, 125.2, 125.0, 123.2, 122.3,
109.4, 70.6, 42.9, 23.9. IR mmax (KBr, film, cmꢁ1): 3241, 1706,
1609, 1415, 1384, 1188. HRMS (ESI): calcd for C22H20NaN2O2
[M+Na]+ 367.1417; found: 367.1424. HPLC analysis [Chiralcel
AD-H,
n-hexane/i-propanol
(90:10),
20 °C,
1 mL minꢁ1
,
tR = 22.5 min (major), 25.7 min (minor)].
4.2. General procedure for the asymmetric hydroxyamination
reaction of 2-oxindoles with nitrosobenzene
4.2.2. (S)-3-Allyl-3-(hydroxy(phenyl)amino)indolin-2-one 4b
Yellowish solid, yield 84%, ee 67%, ½a D20
¼ þ41:4 (c 5, THF). Mp
ꢀ
To the mixture of 2-oxindole (0.2 mmol) and catalyst 3d
(0.02 mmol, 6.2 mg) in 2 mL of DCM, nitrosobenzene (0.2 mmol,
22 mg) was added. Then, the reaction system was stirred for about
115–117 °C. 1H NMR (300 MHz, DMSO): d 10.23 (s, 1H), d 8.98 (s,
1H), d 7.21–6.88 (m, 8H), d 6.64–6.62 (d, J = 7.5, 1H), d 5.31–5.22
(dd, J = 16.5 Hz, J = 6.0 Hz, 1H), d 4.96–4.84 (m, 2H), d 2.86 (s,

2804
T. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 2800–2806
Ph
O
R
R
N
OH
O
N
Catalyst 3d (10%)
O
DCM,0-20 ºC
N
N
H
H
1a-i
2
4a-i
1a
1d
1f
1b
1c
R= allyl,
R= CH3,
R= (E)-cinnamyl
R= CH2-C6H4-4-OMe
1g
1e
R= benzyl,
R= CH2-C6H4-4-Me,
1h R= CH2-C6H4-3-Cl, 1i R= CH2-C6H4-3,4-OCH2O
R= CH2-C6H4-4-CN
HO
Ph
Ph
HO
HO
N
N
N
Ph
Ph
O
O
O
N
H
N
H
N
H
4a, yield 90%, ee 67%
4b, yield 84%, ee 67%
4c, yield 72%, ee 62%
HO
MeO
Ph
N
Ph
N
Bn
N
Ph
O
OH
OH
O
O
N
H
N
H
N
H
4e, yield 80%, ee 64%
4f, yield 100%, ee 67%
4d, yield 85%, ee 72%
Cl
O
NC
Ph
Ph
Ph
O
HO
O
N
N
N
OH
O
OH
O
HN
N
H
N
H
4g, yield 95%, ee 59%
4h, yield 71%, ee 66%
4i, yield 90%, ee 63%
Scheme 4. Catalytic asymmetric N-nitroso-aldol reaction of various oxindoles.
N
OH
N
H
H
O
H
O
NH
H
R
O
N
Figure 2. X-Ray single-crystal analysis of 4h with thermal ellipsoids at 30%
Figure 3. Proposed transition state for the N-nitroso-aldol reaction of 2-oxindoles
promoted by catalyst 3d.
probability levels.8
2H). 13C NMR (75.0 MHz, DMSO): d 177.7, 150.4, 141.9, 131.0,
128.8, 127.9, 126.7, 126.5, 124.9, 123.5, 121.2, 109.3, 76.5, 42.2.
IR mmax (KBr, film, cmꢁ1): 3258, 3058, 2924, 1712, 1641, 1346.
HRMS (ESI): calcd for C17H16NaN2O2 [M+Na]+ 303.1104; found:

T. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 2800–2806
2805
303.1106. HPLC analysis [Chiralcel AD-H, n-hexane/i-propanol
142.2, 141.6, 131.8, 129.4, 128.0, 127.4, 126.7, 125.1, 123.5,
121.5, 119.2, 109.7, 109.4, 76.3, 42.1. IR mmax (KBr, film, cmꢁ1):
3258, 2228, 1712, 1620, 1470, 1351, 1215. HRMS (ESI): calcd for
(90:10), 15 °C, 1 mL minꢁ1
,
tR = 26.1 min (major), 30.2 min
(minor)].
C
22H17NaN3O2 [M+Na]+ 378.1213; found: 378.1216. HPLC analysis
4.2.3. (S)-3-Cinnamyl-3-(hydroxy(phenyl)amino)indolin-2-one
[Chiralcel AD-H, n-hexane/i-propanol (90:10), 15 °C, 1 mL minꢁ1
tR = 45.3 min (minor), 62.1 min (major)].
,
4c
Yellowish solid, yield 72%, ee 62%, ½a D20
¼ þ33:8 (c 0.4, THF). Mp
ꢀ
119–122 °C. 1H NMR (300 MHz, DMSO): d 10.23 (s, 1H), d 9.05 (s,
1H), d 7.29–7.09 (m, 11H), d 7.29–7.09 (m, 11H), d 7.01–6.90 (m,
2H), d 6.30–6.60 (d, J = 7.8 Hz, 1H), d 6.34–6.29 (d, J = 15.9 Hz,
1H), d 3.08–2.95 (m, 2H). 13C NMR (75.0 MHz, DMSO): d 176.3,
150.5, 142.4, 137.3, 133.8, 129.1, 129.0, 128.7, 128.0, 127.7,
126.2, 126.0, 124.8, 123.9, 123.1, 121.5, 109.5, 79.6, 74.9. IR mmax
(KBr, film, cmꢁ1): 3249, 1706, 1620, 1599, 1488, 1470, 1335. HRMS
calcd: C23H20NaN2O2 [M+Na]+ 379.1417; found: 379.1419. HPLC
analysis [Chiralcel AD-H, n-hexane/i-propanol (90:10), 15 °C,
1 mL minꢁ1, tR = 27.8 min (minor), 45.0 min (major)].
4.2.8. (S)-3-(3-Chlorobenzyl)-3-(hydroxy(phenyl)amino)indo-
lin-2-one 4h
Yellowish solid, yield 71%, ee 66%, ½a D20
¼ þ57:6 (c 0.5, THF). Mp
ꢀ
140–141 °C. 1H NMR (300 MHz, DMSO): d 10.03 (s, 1H), d 9.13 (s,
1H), d 7.46–7.44 (d, J = 7.2 Hz, 1H), d 7.16–6.92 (m, 9H), d 6.85 (s,
1H), d 6.77–6.74 (d, J = 7.2 Hz, 1H), d 6.39–6.37 (d, J = 7.5 Hz, 1H),
d 3.53–3.49 (d, J = 12.3 Hz, 1H), d 3.43–3.39 (d, J = 12.3 Hz, 1H).
13C NMR (75.0 MHz, DMSO): d 175.3, 149.9, 141.8, 137.5, 132.0,
129.9, 129.2, 129.0, 128.7, 127.5, 127.2, 126.3, 126.1, 124.5,
122.9, 120.9, 108.9, 75.9, 41.2. IR mmax (KBr, film, cmꢁ1): 3219,
1704, 1619, 1470, 1352, 1210. HRMS (ESI): calcd for C21H17ClNa-
N2O2 [M+Na]+ 387.0871; found: 387.0872. HPLC analysis [Chiralcel
4.2.4. (S)-3-Benzyl-3-(hydroxy(phenyl)amino)indolin-2-one 4d
Yellowish solid, yield 85%, ee 72%, ½a D20
ꢀ
¼ þ62:0 (c 0.5, THF). Mp
AD-H,
n-hexane/i-propanol
(90:10),
15 °C,
1 mL minꢁ1
,
138–140 °C. 1H NMR (300 MHz, DMSO): d 9.95 (s, 1H), d 9.11 (s,
1H), d 7.41–7.43 (d, J = 6.9 Hz, 1H), d 7.13–6.82 (m, 12H), d 6.36–
6.34 (d, J = 7.2 Hz, 1H), d 3.51–3.40 (m, 2H). 13C NMR (75.0 MHz,
DMSO): d 176.0, 150.5, 142.4, 135.4, 130.7, 129.0, 128.0, 127.9,
122.7, 121.5, 109.7, 70.7, 23.7. IR mmax (KBr, film, cmꢁ1): 3254,
1709, 1468, 1354, 1204, 1173. HRMS (ESI): calcd for C21H18NaN2O2
[M+Na]+ 353.1261; found: 353.1261. HPLC analysis [Chiralcel AD-
H, n-hexane/i-propanol (90:10), 15 °C, 1 mL minꢁ1, tR = 25.8 min
(minor), 29.5 min (major)].
tR = 19.1 min (minor), 26.0 min (major)]. CCDC number 776869.
4.2.9. (S)-3-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(hydroxy-
(phenyl)amino)indolin-2-one 4i
Yellowish solid, yield 90%, ee 63%, ½a D20
¼ þ55:0 (c 1.0, THF). Mp
ꢀ
124–125 °C. 1H NMR (300 MHz, DMSO): d 9.97 (s, 1H), d 9.05 (s,
1H), d 7.41–7.39 (d, J = 7.2 Hz, 1H), d 7.15–6.89 (m, 7H), d 6.57–
6.54 (d, J = 7.8 Hz, 1H), d 6.41–6.38 (d, J = 7.5 Hz, 1H), d 6.31–6.27
(d, J = 10.2 Hz, 2H), d 5.84 (s, 2H), d 3.43–3.32 (m, 2H). 13C NMR
(75.0 MHz, DMSO): d 176.1, 150.5, 146.7, 146.0, 142.5, 129.1,
129.0, 128.1, 127.9, 126.5, 124.9, 124.0, 123.4, 121.2, 110.8,
109.3, 107.8, 101.0, 76.5, 41.8. IR mmax (KBr, film, cmꢁ1): 3250,
1705, 1620, 1488, 1251, 1039. HRMS (ESI): calcd for C22H18ClNa-
N2O4 [M+Na]+ 397.1159; found: 397.1161. HPLC analysis [Chiralcel
4.2.5. (S)-3-(Hydroxy(phenyl)amino)-3-(4-methoxybenzyl)indo-
lin-2-one 4e
Yellowish solid, yield 80%, ee 64%, ½a D20
¼ þ78:4 (c 0.5, THF). Mp
ꢀ
117–119 °C. 1H NMR (300 MHz, DMSO): d 9.91 (s, 1H), d9.06 (s,
1H), d 7.40–7.38 (d, J = 7.2 Hz, 1H), d 7.11–6.89 (m, 7H), d 6.72–
6.69 (d, J = 8.1 Hz, 2H), d 6.57–6.55 (d, J = 8.1 Hz, 1H), d 6.38–6.35
(d, J = 7.5 Hz, 1H), d 3.60 (s, 3H), d 3.43–3.33 (m, 2H). 13C NMR
(75.0 MHz, DMSO): d 176.0, 150.5, 142.4, 135.4, 130.7, 129.0,
128.0, 127.9, 122.7, 121.5, 109.7, 70.7, 23.7. IR mmax (KBr, film,
cmꢁ1): 3251, 1706, 1618, 1512, 1469, 1250, 1178. HRMS (ESI):
calcd for C22H20NaN2O3 [M+Na]+ 383.1366; found: 383.1367. HPLC
analysis [Chiralcel AD-H, n-hexane/i-propanol (90:10), 15 °C,
1 mL minꢁ1, tR = 37.1 min (minor), 46.0 min (major)].
OD-H, n-hexane/i-propanol (90:10), 15 °C, 0.5 mL minꢁ1
tR = 45.5 min (minor), 52.4 min (major)].
,
4.3. Cleavage of the N–O bond of 4a
To 4a or 4a0 (0.2 mmol), 80 mg of Zn and 1 mL of HOAc were
added. At room temperature, the reaction system was stirred for
about 8 h. Next, it was filtered and washed with DCM, the organic
phase collected was evaporated and purified by flash chromatogra-
phy (5a: petroleum ether/ethyl acetate, 10:4; 5a0: DCM/EA, 100:1).
4.2.6. (S)-3-(Hydroxy(phenyl)amino)-3-(4-methylbenzyl)indo-
lin-2-one 4f
4.3.1. (S)-3-Methyl-3-(phenylamino)indolin-2-one 5a
Yellowish solid, yield 100%, ee 67%, ½a D20
ꢀ
¼ þ68:8 (c 0.5, THF).
White solid, overall yield 94%, ee 65%, ½a D20
¼ ꢁ13:6 (c 1.0,
ꢀ
Mp 137–138 °C. 1H NMR (300 MHz, DMSO): d 9.91 (s, 1H), d 9.08
(s, 1H), d 7.41–7.38 (d, J = 6.9 Hz, 1H), d 7.12–6.89 (m, 7H), d
6.81–6.79 (d, J = 7.5 Hz, 2H), d 6.70–6.67 (d, J = 7.5 Hz, 2H), d
6.37–6.34 (d, J = 7.5 Hz, 1H), d 3.45–3.35 (m, 2H), d 2.11 (s, 3H).
13C NMR (75.0 MHz, DMSO): d 176.0, 150.5, 142.5, 135.6, 132.3,
130.6, 129.0, 128.6, 128.1, 127.9, 126.5, 124.9, 123.5, 121.2,
109.3, 76.5, 41.8, 21.0. IR mmax (KBr, film, cmꢁ1): 3255, 1710,
1620, 1469, 1213. HRMS (ESI): calcd for C22H20NaN2O2 [M+Na]+
367.1417; found: 367.1418. HPLC analysis [Chiralcel AD-H, n-hex-
ane/i-propanol (90:10), 15 °C, 1 mL minꢁ1, tR = 26.6 min (minor),
31.6 min (major)].
DCM). Mp 206–207 °C. 1H NMR (300 MHz, CDCl3): d 9.14 (s, 1H),
d
7.31–7.23 (m, 2H), d 7.08–6.92 (m, 4H), d 6.69–6.65 (t,
J = 7.5 Hz, 1H), d 6.30–6.28 (d, J = 7.8 Hz, 2H), d 4.59 (s, 1H), d
1.68 (s, 3H). 13C NMR (75.0 MHz, CDCl3): d 181.4, 145.3, 139.3,
132.0, 129.1, 128.9, 123.3, 123.2, 118.9, 114.4, 110.9, 61.6, 27.7.
IR mmax (KBr, film, cmꢁ1): 3313, 1711, 1604, 1500, 1214. HRMS
(ESI): calcd for C15H15N2O [M+H]+ 239.1179; found: 239.1183.
HPLC analysis [Chiralcel AD-H, n-hexane/i-propanol (90:10),
20 °C, 1 mL minꢁ1, tR = 16.3 min (minor), 22.0 min (major)].
4.3.2. 1-Benzyl-3-methyl-3-(phenylamino)indolin-2-one 5a0
White solid, yield 89%, Mp 147–148 °C. 1H NMR (300 MHz,
CDCl3): d 7.22–7.18 (m, 7H), d 7.06–7.01 (t, J = 7.5 Hz, 1H), d
6.96–6.91 (t, J = 7.5 Hz, 2H), d 6.80–6.77 (d, J = 7.8 Hz, 1H), d
6.71–6.66 (t, J = 7.5 Hz, 1H), d 6.24–6.21 (d, J = 7.8 Hz, 2H), d
5.12–5.07 (d, J = 15.6 Hz, 1H), d 4.79–4.74 (d, J = 15.3 Hz, 1H), d
4.36 (s, 1H), d 1.67 (s, 1H). 13C NMR (75.0 MHz, CDCl3): d 178.5,
145.4, 141.4, 135.7, 131.6, 129.0, 128.8, 128.7, 127.7, 127.6,
123.3, 123.2, 119.5, 115.6, 109.8, 61.5, 44.1, 27.7. IR mmax (KBr,
4.2.7. (S)-4-((3-(Hydroxy(phenyl)amino)-2-oxoindolin-3-yl)-
methyl)benzonitrile 4g
Yellowish solid, yield 95%, ee 59%, ½a D20
¼ þ88:2 (c 0.5, THF). Mp
ꢀ
132–133 °C. 1H NMR (300 MHz, DMSO): d 10.01 (s, 1H), d 9.17 (s,
1H), d 7.53–7.46 (m, 3H), d 7.16–6.92 (m, 9H), d 6.38–6.36 (d,
J = 7.5 Hz, 2H), d 3.62–3.58 (d, J = 12.0 Hz, 1H), d 3.51–3.47 (d,
J = 12.3 Hz, 1H). 13C NMR (75.0 MHz, DMSO): d 175.6, 150.3,

2806
T. Zhang et al. / Tetrahedron: Asymmetry 21 (2010) 2800–2806
film, cmꢁ1): 3364, 1712, 1607, 1530, 1355, 1326, 1181. HRMS (ESI):
calcd for C22H20NaN2O [M+Na]+ 351.1468; found: 351.1469.
Yamamoto, H. Synlett 2009, 2685–2687; (u) Kano, T.; Yamamoto, A.; Shirozu,
F.; Maruoka, K. Synthesis 2009, 9, 1557–1563; (v) Tong, S. T.; Brimble, M. A.;
Barker, D. Tetrahedron 2009, 65, 4801–4807; (w) Mielgo, A.; Velilla, I.; Gómez-
Bengoa, E.; Palomo, C. Chem. Eur. J. 2010, 16, 7496–7502; (x) Ding, X.; Tang, W.;
Zhu, C.; Cheng, Y. Adv. Synth. Catal. 2010, 352, 108–112; For the example
catalyzed by the cinchona alkaloid, see: (y) Bui, T.; Candeias, N. R.; Barbas, C. F.
J. Am. Chem. Soc. 2010, 132, 5574–5575; For the example catalyzed by the chiral
phosphoric acid, see: (z) Zhong, G. F.; Lu, M.; Zhu, D.; Lu, Y. P.; Zeng, X. F.; Tan,
B.; Xu, Z. J. J. Am. Chem. Soc. 2009, 131, 4562–4563.
Acknowledgments
We thank the National Natural Science Foundation of China,
Ministry of Science and Technology (nos. 2009ZX09501-006 and
2010CB833305) and the Chinese Academy of Sciences for the
financial support.
3. (a) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 6046–
6047; (b) Lopez-Cantarero, J.; Cid, M. B.; Poulsen, T. B.; Bella, M.; Ruano, J. L. G.;
Jorgensen, K. A. J. Org. Chem. 2007, 72, 7062–7065; (c) Guo, H. M.; Cheng, L.;
Cun, L. F.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. Chem. Commun. 2006, 429–431; (d)
Palomo, C.; Vera, S.; Velilla, I.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int.
Ed. 2007, 46, 8054–8056; (e) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc.
2005, 127, 1080–1081.
References
1. For reviews, see: (a) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292–4300; (b)
Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514–3525; (c)Guillena, G.;
Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465–1492; (d) Yamamoto, H.;
Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595–607; (e) Da Machado, F. L. S.
Synlett 2008, 3075–3076; (f) Yamamoto, H.; Saito, S.; Momiyama, N. J. Synth. Org.
Chem. Jpn. 2008, 66, 774–784; (g) Yanagisawa, A.; Arai, T. Chem. Commun. 2008,
1165–1172; (h) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15, 917–958.
2. For examples, catalyzed by amino acid and its derivatives, see: (a) Brown, S. P.;
Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808–
10809; (b) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett.
2003, 44, 8293–8296; (c) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 6038–6039; (d) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250; (e)
Bøgevig, A.; Sundén, H.; Córdova, A. Angew. Chem., Int. Ed. 2004, 43, 1109–1112;
(f) Cordova, A.; Sunden, H.; Bogevig, A.; Johansson, M.; Himo, F. Chem. Eur. J.
2004, 10, 3673–3684; (g) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.;
Shoji, M. J. Org. Chem. 2004, 69, 5966–5973; (h) Hayashi, Y.; Yamaguchi, J.;
Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112–1115; (i) Merino, P.;
Tejero, T. Angew. Chem., Int. Ed. 2004, 43, 2995–2997; (j) Wang, W.; Wang, J.; Li,
H.; Liao, L. X. Tetrahedron Lett. 2004, 45, 7235–7238; (k) Yamamoto, Y.;
Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963; (l)
Ramachary, D. B.; Barbas, C. F. Org. Lett. 2005, 7, 1577–1580; (m) Sunden, H.;
Dahlin, N.; Ibrahem, I.; Adolfsson, H.; Cordova, A. Tetrahedron Lett. 2005, 46,
3385–3389; (n) Guo, H. M.; Niu, H. Y.; Xue, M. X.; Guo, Q. X.; Cun, L. F.; Mi, A.
Q.; Jiang, Y. Z.; Wang, J. J. Green Chem. 2006, 8, 682–684; (o) Kim, S. G.; Park, T.
H. Tetrahedron Lett. 2006, 47, 9067–9071; (p) Kim, S. G.; Ahm, E. J.; Park, T. H.
Bull. Korean Chem. Soc. 2007, 28, 1665–1669; (q) Kano, T.; Yamamoto, A.;
Maruoka, K. Tetrahedron Lett. 2008, 49, 5369–5371; (r) Kano, T.; Yamamoto, A.;
Mii, H.; Takai, J.; Shirakawa, S.; Maruoka, K. Chem. Lett. 2008, 37, 250–251; (s)
Chua, P. J.; Tan, B.; Zhong, G. F. Green Chem. 2009, 11, 543–547; (t) Jiao, P.;
4. For the latest review of 2-oxindoles, see: Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381–1407.
5. For selected examples, see: (a) Smith, P. A. S. J. Am. Chem. Soc. 1984, 106, 4069–
4070; (b) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2001, 18, 66–87; (c) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 12, 2209–2219.
6. (a) Ochi, M.; Kawasaki, K.; Kataoka, H.; Uchio, Y.; Nishi, H. Biochem. Biophys. Res.
Commun. 2001, 283, 1118–1123; (b) Claudine, S. L. G.; Sylvain, D.; Gabrielle, B.;
Maurice, M.; Jacques, S.; Rolf, G.; Guy, G.; Gilles, G. Stress 2003, 6, 199–206; (c)
Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Pharmacol. 2005, 144, 1037–1050.
7. For selected examples, see: (a) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org.
Chem. 2005, 70, 3324–3327; (b) Watson, E. L.; Marsden, S. P.; Raw, S. A.
Tetrahedron Lett. 2009, 50, 3318–3320; (c) Bella, A. F.; Slawin, A. M. Z.; Walton,
J. C. J. Org. Chem. 2004, 69, 5926–5933; (d) Cheng, L.; Liu, L.; Wang, D.; Chen, Y. J.
Org. Lett. 2009, 11, 3874–3877.
8. Full crystallographic data for the structure of 4h have been deposited with the
Cambridge Crystallographic Data Centre, as supplementary publication
number CCDC 776869.
9. For selected examples catalyzed by 3d, see: (a) Xuan, Y.-n.; Nie, S.-z.; Dong, L.-
t.; Zhang, J.-m.; Yan, M. Org. Lett. 2009, 11, 1583–1586; (b) Gogoi, S.; Zhao, C.-G.
Tetrahedron Lett. 2009, 50, 2252–2255; (c) Dodda, R.; Goldman, J. J.; Mandal, T.;
Zhao, C.-G.; Broker, G. A.; Tiekink, E. R. T. Adv. Synth. Catal. 2008, 350, 537–541;
(d) Mandal, T.; Samanta, S.; Zhao, C.-G. Org. Lett. 2007, 9, 943–945; (e) Li, H.;
Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem.,
Int. Ed. 2005, 44, 105–108; (f) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906–9907; (g) Deng, J.; Zhang, S. L.; Ding, P.; Jiang, H. L.; Wang, W.;
Li, J. Adv. Synth. Catal. 2010, 352, 833–838.
10. Elliott, I. W.; Rivers, P. J. Org. Chem. 1964, 29, 2438–2440.
11. Trost, B. M.; Zhang, Y.; Zhang, T. J. Org. Chem. 2009, 74, 5115–5117.