Enantioselective organocatalytic oxyamination of unprotected 3-substituted oxindoles

Article abstract of DOI:10.1039/c1ob06503c

An enantioselective α-oxyamination of unprotected 3-substituted oxindoles with nitrosobenzene catalyzed by tertiary amine-thiourea bifunctional organocatalysts has been developed and affords the corresponding 3-amino-2-oxindole derivatives in good yields

Full text of DOI:10.1039/c1ob06503c

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PAPER
Enantioselective organocatalytic oxyamination of unprotected 3-substituted
oxindoles†‡
Xavier Companyo´,a Guillem Valero,a Oriol Pineda,a Teresa Calvet,b Merce` Font-Bard´ıa,b,c Albert Moyano*a
and Ramon Rios*a,d
Received 1st September 2011, Accepted 6th October 2011
DOI: 10.1039/c1ob06503c
An enantioselective a-oxyamination of unprotected 3-substituted oxindoles with nitrosobenzene
catalyzed by tertiary amine–thiourea bifunctional organocatalysts has been developed and affords the
corresponding 3-amino-2-oxindole derivatives in good yields and with moderate to excellent
enantioselectivities (up to > 99.9 : 0.1 er when the product is isolated by direct filtration from the
reaction mixture). The absolute configuration of the major enantiomers of the products has been
established both by chemical correlation and by comparison between the theoretically calculated and
the experimental ECD.
Introduction
The 3-amino-2-oxindole moiety is present in drug candidates
such as the gastrin/CCK-B receptor antagonist AG-041R,1 the
vasopressin VIb receptor antagonist SSR-14945,2 the antimalarial
NITD609,3 and some HIV protease inhibitors;4 on the other hand,
marine alkaloids such as the chartellines A–C5 and psychotrimine,
a terrestrial alkaloid isolated from the leaves of the Malaysian
plant Psychotria rostrata,6 contain 3-aminoindole substructures
that can be accessed from quaternary 3-aminooxindoles (Fig. 1).7,8
Although several different procedures are known for the synthe-
sis of tetrasubstituted 3-amino-2-oxindoles in racemic form,9 few
methodologies are presently available for the efficient asymmetric
preparation of these compounds, especially in a catalytic fashion.10
In 2008, Ku¨ndig and co-workers11 reported that the palladium-
catalysed intramolecular a-arylation of a-nitrogenated amide
enolates gave chiral 3-aminooxindoles in high yield and with
variable enantioselectivities (87 : 13–95 : 5 er) when a chiral N-
heterocyclic carbene ligand was used. Shortly afterwards, the
direct, highly efficient asymmetric organocatalytic amination
Fig. 1 Representative natural products and bioactive compounds with
3-aminoindole or 3-aminooxindole framework.
of 3-substituted oxindoles with azodicarboxylates was almost
simultaneously achieved by Liu and Chen,12 Zhou,13 and Barbas
III,14 using dimeric Cinchona-alkaloid derivatives as catalysts.
aDepartament de Qu´ımica Orga`nica, Universitat de Barcelona. Facultat
The nickel-catalyzed enantioselective amination of 3-substituted
oxindoles with azodicarboxylates was concurrently disclosed by
Matsunaga, Shibasaki et al.15 Very recently, an organocatalytic
asymmetric Strecker reaction of ketimine isatin derivatives with
trimethylsilyl cyanide, taking place with moderate yields and
enantioselectivities (70 : 30–87 : 13 er), has been reported by Zhou
et al.16
de Qu´ımica, C. Mart´ı i Franque`s 1-11, 08028, Barcelona, Spain. E-mail:
amoyano@ub.edu, rios.ramon@icrea; Fax: +34 93 3397878
bDepartament de Cristalografia, Mineralogia i Dipo`sits Minerals, Univer-
sitat de Barcelona. Facultat de Geologia, C. Mart´ı i Franque`s s/n, 08028,
Barcelona, Spain
cUnitat de Difraccio´ de RX. Centre Cient´ıfic i Tecnolo`gic de la Universitat
de Barcelona (CCiTUB). C. Sole´ i Sabar´ıs 1-3, 08028, Barcelona, Spain
dICREA, Pg. Llu´ıs Companys 23, 08019, Barcelona, Spain
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra and HPLC traces of compounds 3a–3i. CCDC reference numbers
831712 and 831713. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06503c
The catalytic asymmetric nitroso-aldol reaction17 has emerged
as an efficient tool for the enantioselective formation of carbon–
oxygen bonds (a-aminoxylation)18 and, in a few instances, of
carbon–nitrogen bonds (a-oxyamination)19 at the a-position of
‡ Dedicated to Prof. Miquel A. Perica`s on the occasion of his 60th birthday.
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enolizable carbonyl compounds. The regioselectivity of the reac-
tion appears to be controlled by the nature of the catalyst (Scheme
1). Thus, Yamamoto showed that the uncatalyzed reaction of
alkali-metal and tin enolates with nitrosobenzene took place
with almost exclusive N-selectivity,20 while the use of Lewis-acid
catalysis with silyl enol ethers resulted in high O-selectivities.18a,20,21
In a similar way, organocatalysts having Brønsted-acid sites give a-
aminoxylation products,18b–h and chiral secondary amine catalysts
afford a-oxyamination adducts.19
amine-catalyzed enantioselective reactions of N-unprotected, 3-
substituted oxindoles with nitrosobenzene.26 We present herein a
full account of our results in this topic.
Results and discussion
As a benchmark process, we selected the reaction between 3-
methyloxindole (1a) and nitrosobenzene (2). This reaction took
readily place in diethyl ether in the presence of 20 mol% of
triethylamine, affording exclusively the a-oxyamination product
3a in quantitative yield after only 2 h at room temperature.
The structure of 3a was unambiguously established by X-ray
diffraction analysis of a monocrystal (see later), and its spectral
data were moreover found to be coincident with those reported by
Liu et al.23 We decided then to examine the same reaction using
several chiral tertiary amine catalysts (Table 1).
Several interesting conclusions can be drawn from inspection of
the data gathered in Table 1. On the first place, and irrespective
Table 1 Catalyst screening in the reaction between 3-methyl-2-oxindole
(1a) and nitrosobenzene (2)a
Scheme 1 Possible products from the nitroso-aldol reaction.
The first application of the nitroso-aldol reaction for the
asymmetric heterofunctionalization of 3-substituted oxindoles has
been recently reported by the Barbas III group.22 After testing
several chiral tertiary amine catalysts, these authors found that a
newly designed quinidine dimer (A) promoted the enantioselective
addition of nitrosobenzene to a series of 3-substituted N-benzyl
oxindoles with good yields (65–85% yield) and stereoselectivities
(87 : 13–98 : 2 er). In most cases, the reaction was O-selective (less
than 15% of oxyamination products were formed), a fact that was
accounted for by invoking hydrogen-bonding between an hydroxyl
group of the catalyst and the nitrogen atom of nitrosobenzene.
Subsequently, Liu, Chen and co-workers23 have disclosed that
other Cinchona-alkaloid catalysts such as demethylquinine (B)
give preferentially rise to the oxyamination of N-benzyl 3-methyl
oxindole, although with low enantioselectivity (Scheme 2). Since
demethylquinine also led to the oxyamination of N-unprotected
oxindoles (enantioselectivities ranging from 79.5 : 20.5 to 86 : 14
er), these authors concluded that the regioselectivity of the nitroso-
aldol reaction largely depended on the structure of the catalyst.
Entry
Catalyst
Conversionb (%)
Erc (R : S)
1
2
3
4
5
6
7
8
9
NEt3
I
100d
100
100
100
100
100
100
100
100
100d
—
70 : 30
40 : 60
66 : 34
61 : 39
66 : 34
14 : 86
78 : 22
50 : 50
15 : 85
II
III
IV
V
VI
VII
VIII
(S,S)-IX
10
Scheme 2 Catalyst-dependent regioselectivity in the nitroso-aldol reac-
tion of 3-methyl-N-benzyloxindole.
a Experimental conditions: A mixture of 1a (0.10 mmol), nitrosobenzene 2
(0.12 mmol) and catalyst (0.02 mmol) in diethyl ether (1 mL) was stirred
1
at room temperature during 14 h. b Determined by H NMR analysis of
In the light of these precedents, and given our inter-
est on the development of new methodology for asymmetric
organocatalysis,24,25 we undertook a re-examination of the chiral
the reaction mixture. c Determined by HPLC analysis. d Conversion was
already complete after 2 h at rt.
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Table 2 Solvent screening in the reaction between 3-methyl-2-oxindole
(1a) and nitrosobenzene (2) catalyzed by (S,S)-IXa
Table 3 Solvent and temperature screening in the reaction between 3-
methyl-2-oxindole (1a) and nitrosobenzene (2) catalyzed by VI and by
(S,S)-IXa
Entry
Solvent
Conversionb (%)
Erc (R : S)
Entry
Catalyst
Solvent
T/◦C
Erb (R : S)
1
2
3
4
5
6
7
8
9
Et2O
100
< 5 (62d)
100
15 : 85
50 : 50
19 : 81
18 : 82
50 : 50
20 : 80
14 : 86
15 : 85
25 : 75
MeOH
Cl(CH2)2Cl
CH2Cl2
THF
1
2
3
4
5
6
7
8
VI
Et2O
Et2O
TBME
TBME
Et2O
TBME
Et2O
rt
-20
rt
50
rt
rt
4
-20
14 : 86
25 : 75
12.5 : 87.5
13.5 : 86.5
15 : 85
14 : 86
16.5 : 83.5
20 : 80
VI
100
100
100
100
100
100
VI
VI
(S,S)-IX
(S,S)-IX
(S,S)-IX
(S,S)-IX
DME
TBME
nBu2O
nPent2O
Et2O
a Experimental conditions: A mixture of 1a (0.10 mmol), 2 (0.12 mmol)
and catalyst (S,S)-IX (0.02 mmol) in the solvent specified (1 mL) was
a Experimental conditions: A mixture of 1a (0.10 mmol), nitrosobenzene 2
(0.12 mmol) and catalyst VI or (S,S)-IX (0.02 mmol) in diethyl ether or
in tert-butyl methyl ether (1 mL) was stirred at the temperature indicated
for 14 h. Full conversion was observed in all instances. b Determined by
HPLC analysis of the reaction mixture.
1
stirred at room temperature for 2 h. b Determined by H NMR analysis
of the reaction mixture. c Determined by HPLC. d Conversion after 24 h
reaction.
of the nature of the catalyst, complete and exclusive conversion
of 1a to the oxyamination product 3a was observed. Among the
chiral amine catalysts examined, only 9-amino-9-epiquinine VIII
gave a racemic product (entry 9 in Table 1). As it was logical to
expect, quinidine-derived catalysts (entries 2, 4, 5, 6 and 8) showed
opposite enantioselectivities to quinine (or cinchonidine) derived
catalysts (entries 3 and 7). The presence of a hydrogen-bond
donor thiourea moiety greatly increases the enantioselectivity of
the process. Thus, the highest enantiomeric ratios were obtained
with the 9-amino-9-epiquinine thiourea catalyst VI (entry 7) and
with Takemoto’s thiourea catalyst IX (entry 10). We decided next
to examine the effect of the solvent in the Takemoto’s thiourea-
catalyzed oxyamination of 3-methyloxindole 1a (Table 2).
When the reaction was run in methanol (entry 2 in Table 2),
it became very slow (62% conversion was achieved after 14 h),
and only racemic product 3a was obtained. Good conversions
were again recovered with the use of chlorinated solvents (entries
3 and 4), but the enantioselectivity of the process was eroded.
These results seem to indicate that the hydrogen bonding provided
by the catalyst plays a key role in the stereochemical outcome of
the oxyamination. Other ethereal solvents were then investigated
(entries 5–9 in Table 2). Complete conversion was achieved in
all instances after 2 h at r. t., but the enantiomeric excess of 3a
was strongly dependent on the structure of the solvent. Thus,
tetrahydrofuran (entry 5) unexpectedly led to the formation of
racemic product, and only with tert-butyl methyl ether (TBME,
entry 7) the enantiomeric ratio previously achieved with diethyl
ether (entry 1) could be slightly improved. In a further effort
to improve the performance of the reaction, and having selected
diethyl ether and TBME as the most suitable solvents, we examined
the effect of the temperature in oxyaminations catalyzed by VI or
IX (Table 3).
not lead to any improvement (entry 4). The optimal conditions
for the asymmetric oxyamination of 1a involve therefore the use
of either VI or IX as the catalyst, in tert-butyl methyl ether
at room temperature. In view of the commercial availability of
IX in both enantiomeric forms,27 and taking also into account
that the pseudo-enantiomeric form of VI (i.e., the quinidine–
thiourea derivative VII) gave substantially lower enantioselectivity
(compare entries 7 and 8 in Table 1), the scope of the oxyamination
of a set of 3-substituted, N-unprotected 2-oxindoles 1a–i was
examined with Takemoto’s thiourea IX (Table 4).
The N-nitroso-aldol adducts 3a–i were isolated, after chro-
matographic purification, in good yields (up to 96%) and with
moderate enantioselectivities. The highest enantiomeric purities
(up to 86 : 14 er) were achieved when the 3-substituent was methyl
(entries 1–3 in Table 4) or ethyl (entry 4). When bulkier substituents
were placed in the 3-position, the enantioselectivity decreased
considerably; for example 3-isobutyloxindole 1e afforded the
oxyamination adduct compound 3e in excellent yield (93%) but
with poor enantioselectivity (entry 5 in Table 4). In summary,
catalyst IX exhibits enantioselectivities similar to those reported
by Chen and co-workers with demethylquinine.23
On the other hand, in some of the reactions summarized in
Table 4 we observed the gradual precipitation of the product.
We collected this solid by simple filtration when the reaction was
complete, and we were delighted to find that in all instances the
enantiomeric purity of the precipitated product was much higher
than that resulting from the work up of the complete reaction
crude (Table 5).
Thus, enantiomerically pure (>99.7 : 0.3 er) compounds 3a and
3b can be obtained in practical yields and in both enantiomeric
forms (see entries 1–3 in Table 5). A substantial improvement in
the enantiomeric purity of the 3-isobutyloxyndole N-nitroso-aldol
adduct 3e (from 31.5 : 68.5 to 11.5 : 89.5 er) was also achieved in
this way (compare entry 5 in Table 4 with entry 4 in Table 5).28
In order to find some explanation for this crystallization effect
in the enantiomeric purity of the product, we performed X-ray
Both in diethyl ether and in tert-butyl methyl ether the enan-
tioselectivity of the process decreased when performed at reduced
temperatures, both with catalyst VI (entries 1–3) and with catalyst
IX (entries 5–8). Increasing the temperature in TBME to 50◦C did
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Table 4 Scope of the reaction between 3-substituted-2-oxindoles (1a–i) and nitrosobenzene (2) catalyzed by IXa
Entry
Oxindole
R1
R2
R3
Catalyst
Product
Yieldb (%)
Erc (R : S)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Me
Me
Me
Et
H
Br
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
(S,S)-IX
(S,S)-IX
(S,S)-IX
(R,R)-IX
(S,S)-IX
(S,S)-IX
(S,S)-IX
(S,S)-IX
3a
3b
3c
3d
3e
3f
82
92
96
93
93
75
68
54
14 : 86
15 : 85
19 : 81
85 : 15
31.5 : 68.5
28.5 : 71.5
23 : 77
CH2CHMe2
(CH2)2CHMe2
(CH2)3Ph
1g
1h
3g
3h
38.5 : 61.5
9
1i
H
H
(R,R)-IX
3i
87
82 : 18
a Experimental conditions: A mixture of 3-substituted oxindole 1a–i (0.10 mmol), nitrosobenzene 2 (0.12 mmol) and catalyst IX (0.02 mmol) in tert-butyl
methyl ether (1 mL) was stirred at room temperature until complete conversion (TLC). b Yield of isolated product after chromatographic purification.
c Determined by HPLC analysis. See text for the assignment of absolute configurations.
Table 5 Oxyamination of 3-substituted-2-oxindoles with filtration of the
product precipitatea
Entry
Catalyst
Product
Yieldb (%)
Erc (R : S)
< 0.1 : 99.9
> 99.7 : 0.3
> 99.9 : 0.1
11.5 : 89.5
1
2
3
4
5
6
(S,S)-IX
(R,R)-IX
(R,R)-IX
(S,S)-IX
(S,S)-IX
(R,R)-IX
3a
3a
3b
3e
3h
3i
58
60
42
68
78
72
31 : 69
88 : 12
a Experimental conditions: A mixture of 3-substituted oxindole 1a, 1b,
1e or 1e (0.10 mmol), nitrosobenzene 2 (0.12 mmol) and catalyst IX
(0.020 mmol) in tert-butyl methyl ether (1 mL) was stirred at rt during
14–24 h (conversion complete by TLC analysis). b Yield of isolated product
after filtration of the reaction mixture. c Determined by HPLC analysis.
diffraction analyses of both the racemic and of the enantiopure
crystals of 3a.29 The presence of an amide functional group and
a N-hydroxy group in adduct 3a makes it a potential building
block for the assembly of hydrogen-bonded supramolecular
aggregates. The single-crystal X-ray diffraction analysis of the
racemic compound 3a confirmed the existence of this hydrogen
bond network (Fig. 2). Racemic 3a crystallizes in the achiral
Fig. 2 Solid-state structure of racemic 3a.
In contrast, the crystal of enantiopure compound 3a shows
a different hydrogen-bond network. In the enantiopure crystal
(belonging to the P212121 space group) there is only one type
of hydrogen bond interaction, involving the hydroxylamine and
the carboxamide moieties of two adjacent homochiral molecules,
and as a result the monomer forms a chain even more stable
and structured than the racemic one (Fig. 3). This could explain
the high enhancement in the enantiomeric purity observed in the
¯
space group P1. In the solid state, the (R)-enantiomer selectively
recognizes the (S)-enantiomer by two types of hydrogen bond-
pairs: a pair involves the two carboxamide moieties of two
enantiomeric molecules, while another pair is formed between
the N-hydroxy amine moieties. As a result, the centrosymmetric
dimers are further linked to form an infinite chain-like structure.
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Fig. 4 Comparison of the calculated ECD spectrum of (S)-3a with the
experimental ECD spectrum of (+)-3a.
tetrahydrofuran (Scheme 3). This transformation further validated
our stereochemical assignment, since (R)-(+)-4a has been corre-
lated with (R)-3-amino-3-methyl-2-oxindole.26
Fig. 3 Solid-state structure of enantiomerically pure 3a.
precipitate. Coherent with this explanation is the fact that the
enantiomeric purity of precipitated 3a depends on the concentra-
tion of the reaction. When the oxyamination of 1a is performed
either at 0.1 M (standard conditions) or at 0.2 M concentration of
the substrate, enantiomerically pure 3a is obtained upon filtration.
When the concentration is increased to 0.5 M, the enantiomeric
ratio of the solid 3a goes down to 70 : 30, indicating that in this
case the more soluble racemic crystal begins to precipitate from
the reaction mixture.
Scheme 3 Reductive cleavage of the N–O bond in 3a.
The fact that the reaction of N-unprotected 3-substituted oxin-
doles with nitrosobenzene gives exclusively rise to a-oxyamination
products, irrespectively of the amine organocatalyst used, is
at variance with the commonly accepted hypothesis that the
regioselectivity of this process is controlled by the nature of the
catalyst.17,22,23 We decided therefore to test the reaction of N-
benzyl 3-methyl-2-oxindole 532 with 2 in the presence of a 20%
molar amount of (S,S)-IX in tetrahydrofuran at room temperature
(Scheme 4).
In the course of their study on the oxyamination of 3-substituted
oxindoles with demethylquinine,23 Liu, Chen and co-workers were
able to determine the absolute configuration of the N-nitroso-
aldol adduct derived from 3-(3-chlorobenzyl)-2-oxindole by X-ray
diffraction analysis; the stereochemistry of the remaining adducts
(including that of 3a) was assigned by analogy. In order to have an
alternative proof, we undertook a combined experimental and the-
oretical study (using a time-dependent density functional theory
approach, TDDFT) of the electronic circular dichroism (ECD) of
3a. This technique has been shown to predict circular dichroism
spectra with high accuracy and has been used successfully to
ascertain the absolute configuration of chiral organic molecules.30
The minimum energy conformers of 3a were located by using
DFT methods (see ESI† for details). The most stable conformation
of (S)-3a (accounting for 96% of the total conformer population)
was then used in a time-dependent DFT calculation, at the
B3LYP/6-311++G(d,p) level, to simulate the ECD and it was
compared with the experimental spectrum of enantiomerically
pure (+)-3a in methanol (c = 10-4 M). As it can be seen from
Fig. 4, the agreement in the 220–320 nm range is excellent, and we
concluded that the oxyamination of 1a, by using both Takemoto’s
thiourea (S,S)-IX and the quinine-derived thiourea VI as catalysts,
preferentially leads to the formation of the (S)-enantiomer of 3a.
This configurational assignment agrees with that made by Liu and
Chen for the same compound.23
Scheme 4 Reaction of N-benzyl-3-methyl-2-oxindole 5 with nitrosoben-
zene 2 catalyzed by (S,S)-IX.
The nitroso-aldol reaction of the N-protected derivative 5 was
very sluggish under these conditions, and after five days we were
able to isolate in low yield and after careful chromatographic
purification, the a-aminoxylation product 6 (identified by com-
parison of its spectral data with those reported by Barbas and
co-workers)22 and the known33 N-benzyl-3-hydroxy-3-methyl-2-
oxindole 7. As depicted in Scheme 4, compound 7 probably arises
from reaction of 6 with nitrosobenzene 2, followed by loss of
azobenzene from the intermediate adduct.18h,34 We can conclude
therefore that the regiochemical outcome of the reaction between
On the other hand, enantiomerically pure (+)-3a was conve-
niently reduced to (-)-3-methyl-3-(phenylamino)-2-oxindole 4a
by treatment with indium,31 acetic acid and acetic anhydride in
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in a Perkin-Elmer 241 MC polarimeter, using a sodium lamp (l =
589 nm) and a 1 dm-long 1 mL cell. NMR spectra were recorded
in DMSO-d6 solution at room temperature. 1H NMR (300 MHz)
and 13C NMR (75.5 MHz) were obtained on a Varian Unity 300 or
on a Unity-Innova 300 spectrometer; 1H NMR (400 MHz) and 13
C
NMR (100.6 MHz) were obtained on a Mercury 400 spectrometer.
Chemical shifts (d) are quoted in ppm and referenced to internal
TMS for 1H NMR and to DMSO-d6 (d 39.4) for 13C NMR;
data are reported as follows: s, singlet; d, doublet; t, triplet;
m, multiplet; br, broad; coupling constants (J) are quoted in
hertz. High-resolution mass spectra (HRMS) were obtained with
the ESI (+ or -) technique at the ‘Unitat d’ Espectrometria
de Masses’ of Barcelona University in a Bruker MirOTOF
spectrometer. Enantiomeric purities were determined by HPLC
R
using Daicel Chiralpakꢀ IA or IB columns in a Shimadzu LC-
Fig. 5 Proposed transition states for the nitroso-aldol reaction of
N-unprotected (left) and N-protected (right) 3-substituted-2-oxindoles.
20AD instrument with UV detection. Reactions were generally
run with magnetic stirring in loosely stoppered glass vials under
air. Commercially available reagents, catalysts and solvents were
used as received. 3-Substituted oxindoles 1b–i were prepared
according to a literature procedure.35 Catalysts VI, VII and VIII
were obtained from quinine or from quinidine as described by
So´os and co-workers.36 Silica gel (0.040–0.063 mm) was used
for chromatographic purifications. For thin-layer chromatography
(TLC), silica gel plates Merck 60 F254 were used and compounds
were visualized by UV irradiation.
nitrosobenzene and 3-substituted-2-oxindoles under catalysis by
amino-thiourea bifunctional catalysts such as IX also depends on
the structure of the starting oxindole. We hypothesize that this
change of regioselectivity is driven by intermolecular-hydrogen
bonding of the enolate oxygen in unprotected 3-substituted
oxindoles (Fig. 5).
Conclusions
In summary, we have found that the tertiary amine-catalyzed
nitroso-aldol reaction between N-unprotected 3-substituted-2-
oxindoles and nitrosobenzene takes place with N-selectivity,
and the corresponding a-oxyamination adducts are obtained
with good yields and enantioselectivities, especially so when
bifunctional amino-thioureas such as IX are used as the catalysts
(up to 86 : 14 er) in ethereal solvents such as tert-butyl methyl
ether. From a practical point of view, it is worth noting that
in some of these reactions gradual precipitation of the product
takes place, and isolation of this solid by simple filtration gives
rise in all instances to products with increased enantiomeric
purity. Thus, essentially enantiopure (er > 99.7 : 0.3) compounds
3a and 3b can be easily obtained in this way. When using the
(S,S)-enantiomer of Takemoto’s thiourea IX as the catalyst,
(S)-configured a-oxyamination products are primarily obtained.
In the same conditions, N-benzyl-3-methyl-2-oxindole 5 mainly
affords a-aminoxylation products. Work aiming at the elucidation
of this dependence of the regioselectivity of the nitroso-aldol
reaction on the presence of a nitrogen-protecting group in the
starting 3-substituted oxindole is currently being pursued in our
laboratory.
General experimental procedure for the oxyamination of
3-substituted indoles
To a stirred solution of the 3-substituted oxindole 1a–i (0.10 mmol)
and of the catalyst (S,S)- or (R,R)-IX (0.02 mmol) in tert-butyl
methyl ether (1 mL), nitrosobenzene 2 (0.12 mmol) was added in
one portion. The reaction mixture was stirred at room temperature
1
until the starting oxindole was not detected by H-NMR or by
TLC.
A. Standard work-up. Dichloromethane was added dropwise
until a clear solution was obtained (1–2 mL), and the reaction
crude was directly purified by column chromatography on silica
gel (hexane–ethyl acetate mixtures) to afford the a-oxyaminated
product 3a–i.
B. Filtration work-up. The crude reaction mixture was filtered
with suction through a Bu¨chner funnel. The precipitate was
washed twice with cold hexane, collected, and dried under
vacuum. Racemic products were obtained from the corresponding
substrates by catalysis with triethylamine.
(S)-3-(Hydroxy(phenyl)amino)-3-methylindolin-2-one (3a)
Note added in proof
Colorless solid. Er > 99.9 : 0.1. Mp 138–140 ◦C (lit.:9 137–138 ◦C).
20
20
[a]D = +52.4 (c 0.5, THF) [lit.:9 [a]D = +43.4 (c 0.5, THF)]. 1H
NMR (300 MHz) d 1.48 (s, 3H), 6.69 (d, J = 7.6 Hz, 1H), 6.87 (t,
J = 7.2 Hz, 1H), 6.98 (t, J = 7.2 Hz, 1H), 7.04–7.19 (m, 6H), 8.91
(s, 1H). 13C NMR (100.6 MHz) d 22.4, 70.3, 109.1, 120.7, 122.4,
124.1, 124.6, 126.9, 127.8, 129.7, 140.7, 149.2, 177.8. HRMS (ESI)
calc. from C30H29N4O4 (2M + H)+: 509.2183; found: 509.2186.
After the submission of this manuscript, a report on the asymmet-
ric oxyamination of N-benzyl-3-(arylmethyl)oxindole derivatives
by chiral bifunctional tertiary amine thiourea catalysts was
published online.37
Experimental section
R
HPLC conditions: Daicel Chiralpakꢀ IA column, i-PrOH–hexane
Melting points were taken on a Gallenkamp apparatus and are un-
corrected. Specific rotations were measured at room temperature
10 : 90, flow rate 1 mL min-1, UV detection at 254 nm, tmajor = 19.3
min, tminor = 16.4 min.
436 | Org. Biomol. Chem., 2012, 10, 431–439
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(S)-5-Bromo-3-(hydroxy(phenyl)amino)-3-methylindolin-2-one
(3b)
23.1, 28.4, 32.7, 34.5, 75.3, 109.7, 121.7, 123.5, 125.0, 128.1, 129.1,
129.3, 142.8, 150.8, 177.1. HRMS (ESI) calc. from C19H22NaN2O2
(M + Na)+: 333.1573; found: 333.1579. HPLC conditions: Daicel
20
1
Yellowish solid. Er = 85 : 15. [a]D = +14.2 (c 0.25, DMSO). H
NMR (300 MHz) d 1.46 (s, 3H), 6.67 (d, J = 7.3 Hz, 1H), 7.03
(t, J = 7.3 Hz, 1H), 7.08–7.13 (m, 2H), 7.15–7.25 (m, 3H), 7.32
R
Chiralpakꢀ IA column, i-PrOH–hexane 10 : 90, flow rate 1 mL
min-1, UV detection at 254 nm, tmajor = 19.9 min, tminor = 13.7 min.
(dd, J1 = 8.3 Hz, J2 = 2.0 Hz, 1H), 9.02 (s, 1H), 10.43 (s, 1H). 13
C
(S)-3-(Hydroxy(phenyl)amino)-3-(3-phenylpropyl)indolin-2-one
(3g)
NMR (100.6 MHz) d 22.7, 70.3, 111.2, 112.6, 122.3, 124.3, 127.4,
127.5, 130.9, 132.9, 140.7, 149.4, 176.6. HRMS (ESI) calc. from
C30H27Br2N4O4 (2M + H)+: 665.0394; found: 665.0392. HPLC
Colorless oil. Er = 77 : 23. [a]D = +8.6 (c 0.25, DMSO). 1H NMR
20
R
conditions: Daicel Chiralpakꢀ IA column, i-PrOH–hexane 10 : 90,
(300 MHz) d 0.95–1.11 (m, 1H), 1.25–1.44 (m, 1H), 1.97–2.19 (m,
2H), 2.39–2.54 (m, 2H), 6.62 (d, J = 7.7 Hz, 1H), 6.89 (t, J = 7.4 Hz,
1H), 6.96 (t, J = 7.1 Hz, 1H), 7.00–7.15 (m, 9H), 7.17–7.25 (m, 2H),
8.81 (s, 1H), 10.21 (s, 1H). 13C NMR (100.6 MHz) d 27.6, 37.4,
37.7, 76.7, 111.3, 123.2, 124.9, 126.5, 127.3, 127.9, 129.6, 130.3,
130.4, 130.7, 130.8, 143.9, 144.3, 152.2, 178.5. HRMS (ESI) calc.
from C46H45N4O4 (2M + H)+: 717.3435; found: 717.3430. HPLC
flow rate 1 mL min-1, UV detection at 254 nm, tmajor = 24.3 min,
tminor = 16.1 min.
(S)-6-Chloro-3-(hydroxy(phenyl)amino)-3-methylindolin-2-one
(3c)
20
1
Colorless oil. Er = 81.5 : 19.5. [a]D = +13.8 (c 0.5, DMSO). H
NMR (300 MHz) d 1.47 (s, 3H), 6.71 (d, J = 1.95 Hz, 1H), 6.93
(dd, J1 = 8.1 Hz, J2 = 1.95 Hz, 1H), 7.06–7.11 (m, 2H), 7.15–7.21
(m, 2H), 8.98 (s, 1H), 10.42 (s, 1H). 13C NMR (100.6 MHz) d 22.7,
69.9, 109.2, 120.6, 122.3, 124.3, 126.1, 127.5, 129.2, 132.5, 142.9,
149.5, 177.0. HRMS (ESI) calc. from C30H27Cl2N4O4 (2M + H)+:
R
conditions: Daicel Chiralpakꢀ IA column, i-PrOH–hexane 10 : 90,
flow rate 1 mL min-1, UV detection at 254 nm, tmajor = 28.1 min,
tminor = 17.9 min.
(S)-3-(4-Bromobenzyl)-3-(hydroxy(phenyl)amino)indolin-2-one
(3h)
R
577.1404; found: 577.1399. HPLC conditions: Daicel Chiralpakꢀ
IB column, i-PrOH–hexane 10 : 90, flow rate 1 mL min-1, UV
detection at 254 nm, tmajor = 14.5 min, tminor = 8.0 min.
20
Yellowish waxy solid. Er = 61.5 : 38.5. [a]D = +37.1 (c 0.4,
DMSO). 1H NMR (300 MHz) d 3.37 (d, J = 12.5 Hz, 1H), 3.45 (d,
J = 12.5 Hz, 1H), 6.37 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H),
6.92 (t, J = 7.5 Hz, 1H), 6.95–7.00 (m, 1H), 7.04 (t, J = 7.6 Hz, 1H),
7.07–7.16 (m, 4H), 7.21 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 7.5 Hz,
1H), 9.13 (s, 1H), 9.97 (s, 1H). 13C NMR (100.6 MHz) d 40.9,
75.8, 108.8, 119.6, 120.8, 122.8, 124.4, 125.9, 127.2, 127.4, 128.6,
130.2, 130.3, 132.3, 132.4, 134.3, 141.7, 149.8, 175.2. HRMS (ESI)
calc. from C21H18BrN2O2 (M + H)+: 409.0546; found: 409.0548.
(R)-3-Ethyl-3-(hydroxy(phenyl)amino)indolin-2-one (3d)
Colorless oil. Er = 85 : 15. [a]D = -22.3 (c 0.75, DMSO). 1H NMR
20
(300 MHz) d 0.53 (t, J = 7.5 Hz, 3H), 1.97–2.15 (m, 2H), 6.65 (d, J =
7.7 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.1 Hz, 1H), 7.03–
7.15 (m, 6H), 8.87 (s, 1H), 10.23 (s, 1H). 13C NMR (100.6 MHz)
d 7.8, 28.7, 75.1, 108.9, 120.9, 122.6, 124.2, 124.9, 127.3, 128.2,
128.3, 142.3, 150.1, 176.2. HRMS (ESI) calc. from C16H17N2O2
(M + H)+: 269.1285; found: 269.1283. HPLC conditions: Daicel
R
HPLC conditions: Daicel Chiralpakꢀ IA column, i-PrOH–hexane
10 : 90, flow rate 1 mL min-1, UV detection at 254 nm, tmajor = 22.7
min, tminor = 21.1 min.
R
Chiralpakꢀ IB column, i-PrOH–hexane 10 : 90, flow rate 1 mL
min-1, UV detection at 254 nm, tmajor = 7.8 min, tminor = 9.5 min.
(S)-3-(Hydroxy(phenyl)amino)-3-isobutylindolin-2-one (3e)
(R)-3-(2,6-Dichlorobenzyl)-3-(hydroxy(phenyl)amino)indolin-2-
one (3i)
20
20
Yellowish waxy solid. Er = 88 : 12. [a]D = -60.7 (c 0.25, DMSO).
Yellowish waxy solid. Er = 89.5 : 10.5. [a]D = +27.0 (c 0.1,
1H NMR (300 MHz) d 3.83 (d, J = 13.9 Hz, 1H), 4.18 (d, J =
13.9 Hz, 1H), 6.41 (d, J = 7.7 Hz, 1H), 6.69 (t, J = 7.5 Hz, 1H), 6.73–
6.85 (m, 1H), 6.91–7.27 (m, 6H), 7.23 (d, J = 8.3 Hz, 2H), 7.33 (d,
J = 7.3 Hz, 1H), 9.21 (s, 1H), 10.05 (s, 1H). 13C NMR (100.6 MHz)
d 36.5, 74.8, 108.6, 114.3, 120.1, 124.1, 124.9, 126.8, 127.1, 128.1,
128.2, 128.8, 134.1, 135.8, 142.0, 149.4, 176.1. HRMS (ESI) calc.
from C21H17Cl2N2O2 (M + H)+: 399.0662; found: 399.0664. HPLC
DMSO). 1H NMR (300 MHz) d 0.48 (d, J = 6.4 Hz, 3H), 0.75 (d,
J = 6.4 Hz, 3H), 1.19 (hept, J = 6.4 Hz, 1H), 2.07 (d, J = 6.2 Hz,
2H), 6.63 (d, J = 7.4 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 6.95–7.04
(m, 3H), 7.06–7.18 (m, 4H), 8.84 (s, 1H), 10.20 (s, 1H). 13C NMR
(100.6 MHz) d 25.9, 26.2, 26.3, 46.1, 76.5, 111.2, 116.7, 122.9,
125.6, 126.7, 128.0, 129.4, 130.7, 144.5, 152.0, 178.8. HRMS (ESI)
calc. from C18H20NaN2O2 (M + Na)+: 319.1413; found: 319.1413.
R
conditions: Daicel Chiralpakꢀ IA column, i-PrOH–hexane 10 : 90,
R
HPLC conditions: Daicel Chiralpakꢀ IB column, i-PrOH–hexane
flow rate 1 mL min-1, UV detection at 254 nm, tmajor = 27.4 min,
tminor = 17.0 min.
10 : 90, flow rate 1 mL min-1, UV detection at 254 nm, tmajor = 9.0
min, tminor = 7.3 min.
(S)-3-(Hydroxy(phenyl)amino)-3-isopentylindolin-2-one (3f)
(S)-3-Methyl-3-(phenylamino)indolin-2-one (4a)23
20
Yellowish waxy solid. Er = 71.5 : 28.5. [a]D = +16.3 (c 0.25,
To a stirred solution of enantiomerically pure (S)-3a (0.27 mmol,
1 equiv.) in dry THF (2 mL), Ac2O (0.15 mL, 6 equiv.),
AcOH (0.06 mL, 4 equiv) and indium (62 mg, 2 equiv.) were
added sequentially. The mixture was heated at reflux until total
consumption of the starting material (monitored by TLC analyses,
about 12 h). The reaction was cooled to 0◦C and water (2 ml) and
DMSO). 1H NMR (300 MHz) d 0.48–0.64 (m, 1H), 0.71 (d, J =
6.2 Hz, 3H), 0.76 (d, J = 6.2 Hz, 3H), 0.82–0.97 (m, 1H), 1.38
(hept, J = 6.2 Hz, 1H), 1.94–2.15 (m, 2H), 6.63 (d, J = 7.4 Hz,
1H), 6.89 (t, J = 7.4 Hz, 1H), 6.97 (t, J = 7.1 Hz, 1H), 7.01–7.17
(m, 6H), 8.86 (s, 1H), 10.19 (s, 1H). 13C NMR (100.6 MHz) d 23.0,
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aqueous saturated K2CO3 (2 ml) were added. The organic layer
was separated and the aqueous layer was extracted three times with
AcOEt (10 mL). The combined organic phases were dried over
anhydrous MgSO4, filtered and evaporated to dryness to afford
the crude product, that was purified by flash chromatography on
silica gel (hexane–AcOEt 1 : 1) to give 4a as a waxy solid (41 mg,
66% yield). [a]D = -20 (c 0.5, DMSO). H NMR (300 MHz) d
1.46 (s, 3H), 6.15 (d, J = 7.7 Hz, 2H), 6.38 (s, 1H), 6.45 (t, J =
7.3 Hz, 1H), 6.84–6.97 (m, 4H), 7.15 (d, J = 7.1 Hz, 1H), 7.21 (td,
J1 = 7.7 Hz, J2 = 1.5 Hz, 1H), 10.6 (s, 1H). HRMS (ESI) calc. from
C15H15N2O (M + H)+: 239.1179; found: 239.1176.
2008, 10, 125–128; (d) N. Takahashi, T. Ito, Y. Matsuda, N. Kogure, M.
Kitajima and H. Takayama, Chem. Commun., 2010, 46, 2501–2503.
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Shenvi, J. Am. Chem. Soc., 2006, 128, 14028–14029; (b) P. S. Baran and
T. Newhouse, J. Am. Chem. Soc., 2008, 130, 10886–10887.
9 See, inter alia: (a) H. Zhao, A. Thurkauf, J. Braun, R. Brodbeck and
A. Kieltyka, Bioorg. Med. Chem. Lett., 2000, 10, 2119–2122; (b) J. J.
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2010, 8, 3847–3850; (f) B. Alcaide, P. Almendros and C. Aragoncillo,
Eur. J. Org. Chem., 2010, 2845–2848, and references cited therein.
10 For a recent review on the catalytic asymmetric synthesis of oxindoles
bearing a tetrasubstituted stereocenter at the 3-position, see: F. Zhou,
Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381–1407.
11 Y.-X. Jia, M. Hillgren, E. L. Watson, S. P. Marsden and E. P. Ku¨ndig,
Chem. Commun., 2008, 4040–4042.
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3877.
13 Z.-Q. Qian, F. Zhou, T.-P. Du, B.-L. Wang, M. Ding, X.-L. Zhao and
J. Zhou, Chem. Commun., 2009, 6753–6755.
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20
1
N-Benzyl-3-methyl-3-(phenylaminoxy)indolin-2-one (6)22
1
Colorless oil. H NMR (300 MHz) d 1.72 (s, 3H), 4.63 (part A
of AB system, J = 15.3 Hz, 1H), 5.01 (part B of AB system, J =
15.3 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 6.96–7.02 (m, 3H), 7.08–
7.24 (m, 10H). HRMS (ESI) calc. from C22H21N2O2 (M + H)+:
345.1598; found: 345.1604.
N-Benzyl-3-hydroxy-3-methylindolin-2-one (7)36
Colorless oil. 1H NMR (300 MHz) d 1.70 (s, 3H), 3.47 (br s, 1H),
4.81 (part A of AB system, J = 15.5 Hz, 1H), 4.96 (part B of AB
system, J = 15.5 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 7.06 (td, J1 =
7.5 Hz, J2 = 1.0 Hz, 1H), 7.19 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H),
7.23–7.33 (m, 5H), 7.41 (d, J = 7.5 Hz, 1H). 13C NMR (100.6 MHz)
d 25.0, 43.7, 73.7, 109.5, 123.2, 123.4, 127.1, 127.6, 128.8, 129.4,
131.4, 135.4, 141.8, 178.7. HRMS (ESI) calc. from C16H16NO2
(M + H)+: 245.1176; found: 245.1173.
16 Y.-L. Liu, F. Zhou, J.-L. Cao, C.-B. Ji, M. Ding and J. Zhou, Org.
Biomol. Chem., 2010, 8, 3847–3850.
17 For a review, see: P. Merino and T. Tejero, Angew. Chem., Int. Ed., 2004,
43, 2995–2997.
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Acknowledgements
We thank the Spanish Ministry of Science and Innovation
(MICINN) for financial support (Project AYA2009-13920-C02-
02). We are also grateful to Dr. Z. El-Hachemi for his assistance
in the recording of the ECD of 3a, and to Prof. J. Vilarrasa for his
interest in this work.
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Alba, X. Companyo´, N. Bravo, A. Moyano and R. Rios, Synlett, 2010,
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26 During the preparation of this manuscript, a highly efficient oxyami-
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27 T. Okino, Y. Hoashi and K. Takemoto, J. Am. Chem. Soc., 2003, 125,
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31 S. Cicchi, M. Bonanni, F. Cardona, J. Revuelta and A. Gotti, Org. Lett.,
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