Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

Article abstract of DOI:10.3762/bjoc.12.72

A highly enantioselective α-amination of 3-substituted oxindoles with azodicarboxylates catalyzed by amino acids-derived chiral phosphine catalysts is reported. The corresponding products containing a tetrasubstituted carbon center attached to a nitrogen

Full text of DOI:10.3762/bjoc.12.72

Asymmetric α-amination of 3-substituted oxindoles using
chiral bifunctional phosphine catalysts
Qiao-Wen Jin1, Zhuo Chai2, You-Ming Huang2, Gang Zou*1,§ and Gang Zhao*2,¶
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 725–731.
1Laboratory of Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, People’s Republic of China and 2Key Laboratory of
Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, People’s Republic of China
doi:10.3762/bjoc.12.72
Received: 29 November 2015
Accepted: 05 April 2016
Published: 15 April 2016
This article is part of the Thematic Series "Bifunctional catalysis".
Guest Editor: D. J. Dixon
Email:
Gang Zou* - zougang@ecust.edu.cn; Gang Zhao* -
zhaog@mail.sioc.ac.cn
© 2016 Jin et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Fax: (+86)-21-6425-3881
¶ Fax: (+86)-21-6416-6128
Keywords:
3-aminooxindoles; asymmetric catalysis; phosphine catalyst;
tetrasubstituted stereogenic carbon centers
Abstract
A highly enantioselective α-amination of 3-substituted oxindoles with azodicarboxylates catalyzed by amino acids-derived chiral
phosphine catalysts is reported. The corresponding products containing a tetrasubstituted carbon center attached to a nitrogen atom
at the C-3 position of the oxindole were obtained in high yields and with up to 98% ee.
Introduction
Recently, chiral 3-substituted oxindoles have been attractive type of structures. For example, Chen et al. reported the first
targets in asymmetric synthesis due to their abundance in the organocatalytic enantioselective amination reaction of 2-oxin-
structures of numerous natural products and pharmaceutically doles catalyzed by biscinchona alkaloid catalysts [8]. Zhou
active compounds [1]. In particular, the chiral 3-aminooxin- [9,10] and Barbas [11,12], have independently reported similar
doles containing a tetrasubstituted carbon center have been organocatalytic processes. In the field of metal catalysis,
recognized as core building blocks for the preparation of many Shibasaki et al. reported the reaction between C3-substituted
biologically active and therapeutic compounds [2-7]. As a type oxindole and azodicarboxylates, using homodinuclear or
of commercially available electrophilic amination reagents, azo- monometallic Ni-Schiff base complexes as catalysts [13]; Feng
dicarboxylates have been extensively used in both asymmetric et al. also developed a similar procedure with chiral N,N’-
organocatalysis and metal catalysis for the construction of this dioxide-Sc(III) complexes as catalysts [14]. Despite these
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Beilstein J. Org. Chem. 2016, 12, 725–731.
impressive advances, current catalytic systems still more or less the zwitterion in situ generated from the chiral phosphine and
suffer from limitations such as long reaction times, relatively methyl acrylate acted as an efficient catalyst for the asymmetric
large catalyst loading in most organocatalytic systems and in Mannich-type reaction. As an extension of this work, we then
some cases unsatisfactory yields and/or enantioselectivities. wondered if other electrophilic partners instead of methyl acry-
Therefore, the development of more efficient catalytic systems late could be used to generate similar catalytically active species
for the asymmetric α-amination of 3-substituted oxindoles with in situ. Also inspired by the Mitsunobu reaction [43], we re-
azodicarboxylates is still desirable.
ported herein the reaction of azodicarboxylates with 3-substi-
tuted oxindole catalyzed by chiral amino acid-derived organo-
Chiral organophosphine catalysis [15-18] has captured consid- phosphine catalysts, in which the zwitterions in situ generated
erable attention over the past decades owing to its high from the phosphine and azodicarboxylates serve as highly effi-
catalytic efficiency in a variety of reactions such as aza- cient catalysts [44] (Scheme 1).
Morita–Baylis–Hillman reactions [19-21], Rauhut–Currier reac-
tions [22-27], Michael addition reactions [28-35], and various Results and Discussion
cycloadditions [36-39]. In recent years, our group has focused Initially, the reaction between 3-phenyloxindole 1a and DEAD
on the development of novel amino acid-derived chiral bifunc- (diethyl azodicarboxylate, 2a) was selected as the model reac-
tional organophosphine catalysts, which have successfully tion for the evaluation of chiral phosphine catalysts (Table 1).
applied to catalyze various asymmetric reactions [40,41]. As a Using bifunctional thiourea catalysts 4a and 4b, the reaction
general concept, a tertiary phosphine adds to an electrophilic proceeded smoothly at room temperature to afford the product
reactant to form a zwitterion which serves as either a nucleo- 3a in good yields, albeit with low enantiomeric excesses (ee)
phile or a Bronsted base to participate in the catalytic cycle. In (Table 1, entries 1 and 2). When the thiourea moiety in the cata-
2015, we reported a novel asymmetric dual-reagent catalysis lysts were replaced by amides, the enantioselectivities were
strategy based on these chiral phosphine catalysts [42], in which greatly improved (Table 1, entries 3–6). The examination of
Scheme 1: The mimetic activation mode of Mitsunobu reaction.
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Beilstein J. Org. Chem. 2016, 12, 725–731.
Table 1: Catalyst screening.
Entrya
PG
Catalyst
t (min)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
Boc (1a)
H (1b)
4a
4b
4c
4d
4e
4f
5
72
79
89
85
88
70
66
50
17
39
61
83
60
64
17
0
5
5
5
5
5
4d
4d
40
60
Bn (1c)
a0.1 mmol scale in 1.0 mL of DCM. bIsolated yield. cDetermined by chiral HPLC analysis.
catalysts 4c–f with further fine-tuning on the acyl group fied as optimal for di-tert-butyl azodicarboxylate (2d, DBAD,
revealed 4d as the optimal catalyst for this transformation 93% ee, Table 2, entry 20). It’s worth mentioning that the reac-
(Table 1, entry 4). Different from N-Boc-oxindole, using tion could still proceed to completion within 5 minutes under
N-unprotected oxindole and N-benzyl-substituted oxindole as such low reaction temperatures.
the substrates, accomplished the reaction with every low enan-
tioselectivity (Table 1, entries 7 and 8), incidated the N-Boc With the optimized reaction conditions in hand, a variety of
protecting group is crucial for this system.
oxindoles 1 and azodicarboxylates 2 were then examined to
probe the scope of the reaction (Table 3). In general, the catalyt-
Next, the influence of solvents and reaction temperature on the ic system showed excellent efficiency for all the substrates ex-
reaction were investigated with the best catalyst (Table 2). The amined to provide good to excellent yields and enantioselectivi-
use of both polar solvents (ethyl ether, tetrahydrofuran, acetone, ties within a very short reaction time (5 min). The use of the
acetonitrile or ethyl alcohol) including other chlorinated sol- sterically more hindered DBAD is much more favored than
vents such as chloroform, 1,2-dichloroethane and 1,1,2- DEAD in terms of enantioselectivity. The substitution type in-
trichloroethane or the less polar solvent toluene gave no cluding different electronic nature and/or positions of the sub-
improvement in enantioselectivity in comparison to the origi- stituents on the benzene ring of the oxoindole skeleton or 3-aryl
nally used DCM (Table 2, entries 1–9). To our delight, lowering group showed no pronounced influence on the reaction in terms
the reaction temperature increased the reaction yield significant- of both yield and enantioselectivity. It is noteworthy that prod-
ly (Table 2, entries 10–16), while the highest ee value (90%) ucts 3i, 3q, 3r and 3s, which contain a fluorine atom, were ob-
with DEAD was obtained at −30 °C (Table 2, entry 13). Inter- tained in good yield with good to execellent ee (Table 3, entries
estingly, the use of other azodicarboxylates with larger R group 6 and 14–16). Enantiomerically enriched fluorine-containing
as amination reagent revealed different optimum reaction tem- 2-oxoindoles are of great significance in drug discovery and de-
peratures for the best enantioselectivity, and −78 °C was identi- velopment [45]. Unfortunately, there was no ee observed when
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Beilstein J. Org. Chem. 2016, 12, 725–731.
Table 2: Optimization of conditions.
Entrya
R
Solvent
T (°C)
Yield (%)b
ee (%)c
1
Et
Et2O
rt
64 (3a)
62 (3a)
62 (3a)
41 (3a)
78 (3a)
70 (3a)
66 (3a)
66 (3a)
74 (3a)
81 (3a)
93 (3a)
86 (3a)
87 (3a)
87 (3a)
93 (3a)
85 (3a)
95 (3b)
93 (3b)
87 (3d)
80 (3d)
65
39
35
5
2
Et
THF
rt
3
Et
acetone
acetonitrile
EtOH
rt
4
Et
rt
5
Et
rt
0
6
Et
toluene
CHCl3
rt
79
79
77
53
83
84
85
90
84
81
68
82
89
64
93
7
Et
rt
8
Et
1,2-dichloroethane
1,1,2-trichloroethane
DCM
rt
9
Et
rt
10
11
12
13
14
15
16
17
18
19
20
Et
0
Et
DCM
−10
−20
−30
−40
−50
−78
−30
−78
−30
−78
Et
DCM
Et
DCM
Et
DCM
Et
DCM
Et
DCM
iPr
iPr
t-Bu
t-Bu
DCM
DCM
DCM
DCM
a0.1 mmol scale in 1.0 mL of solvent. bIsolated yield. cDetermined by chiral HPLC analysis.
Table 3: Substrate scope.
Entrya
X
R1
R2
Yield(%)b
ee(%)c
1
2
3
4
5
6
7
8
9
10
H
Ph
t-Bu
t-Bu
t-Bu
Et
87 (3d)
85 (3e)
88 (3f)
88 (3g)
84 (3h)
84 (3i)
85 (3j)
87 (3k)
89 (3l)
85 (3m)
93
96
96
86
88
87
90
87
81
95
5-Me
5-OMe
5-Me
5-OMe
5-F
Ph
Ph
Ph
Ph
Et
Ph
Et
5-Cl
6-Cl
H
Ph
Et
Ph
Et
4-MeC6H4
4-OMeC6H4
t-Bu
t-Bu
H
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Beilstein J. Org. Chem. 2016, 12, 725–731.
Table 3: Substrate scope. (continued)
11
12
13
14
15
16
17
18
H
4-MeC6H4
4-t-BuC6H4
3-OMeC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-MeC6H4
Me
Et
90 (3n)
81
87
87
95
85
98
96
0
H
Et
82 (3o)
86 (3p)
87 (3q)
89 (3r)
85 (3s)
86 (3t)
72 (3u)
H
Et
H
t-Bu
Et
H
5-Me
5-Me
H
t-Bu
t-Bu
Et
a0.1 mmol scale in 1.0 mL of DCM. At −78 °C when R = t-Bu, at −30 °C when R = Et. bIsolated yield. cDetermined by chiral HPLC analysis.
the 3-substituent was changed to an alkyl group (Table 3, entry tuted benzene ring may block the Re face of the enolate, driving
18).
the electrophile to attack from the Si face.
Subsequently, a scale-up experiment on 1.0 mmol scale of the
reaction was examined, and the corresponding product could be
obtained smoothly with a slightly reduced yield (70%) and ee
(85%). The ee value of the product could be raised to 96% after
a single recrystallization step (Scheme 2). The product could be
deprotected to provide the known compound 5 with no deterio-
ration in enantioselectivity. The absolute configuration of 3a
was deduced to be S by comparison the specific optical rotation
data of 5 with literature data [10,12], and the absolute configu-
rations of other adducts 3b–t were assigned by analogy.
To get some insight into this reaction, 31P NMR of the mixture
of 4d (0.5 mol %) and 2a (0.12 mmol) in CD2Cl2 was moni-
tored, followed by the addition of 1a (0.1 mmol) in to the mix-
Scheme 3: Proposed transition-state model.
ture (Figure 1). The formation of zwitterion intermediate A in Conclusion
Scheme 1, observed as a new 31P NMR chemical shift, was In summary, we have realized enantioselective α-aminations of
generated at δ = 30 ppm, and did not disappear until the reac- 3-substitued oxindoles with azodicarboxylates by using amino
tion was finished. On the basis of the experimental results and acid-derived bifunctional phosphine catalysts. These reactions
previous related studies, a plausible transition state was pro- afford a variety of chiral 2-oxindoles with a tetrasubstituted car-
posed to explain the stereochemistry of the product (Scheme 3). bon center attached to a nirogen atom at the C-3 position in high
We propose that after deprotonation by the basic in situ gener- yields and excellent enantioselectivities. Further studies
ated zwitterion, the resultant enolate form of 3-aryloxindoles regarding the mechanism as well as the development of related
might interact with the catalyst by both hydrogen bonding as reactions using this catalytic mode are currently under investi-
well as static interaction. The presence of the 3,5-CF3-substi- gation.
Scheme 2: Scale-up of the reaction and deprotection of the product.
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Beilstein J. Org. Chem. 2016, 12, 725–731.
Figure 1: The 31P NMR spectra research in CD2Cl2.
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