Enantioselective Synthesis of 3-Substituted 3-Amino-2-oxindoles by Amination with Anilines

Article abstract of DOI:10.1002/chem.202100829

A chiral N,N′-dioxide-nickel(II) complex-catalyzed asymmetric amination of 3-bromo-3-substituted oxindoles with anilines has been developed. A series of alkyl or aryl 3-amino-indolinones with quaternary stereocenters were obtained in high yields with excellent ee values in one step (up to 99 % yield, up to 96 % ee). The method provided a ready route to optically active intermediates of 3-amino-2-oxindole-based bioactive compounds. Moreover, a possible transition-state model is proposed so as to elucidate the origin of the chirality based on the X-ray crystal structure of the catalyst and the adduct.

Full text of DOI:10.1002/chem.202100829

Accepted Article
Accepted Article
Title: Enantioselective synthesis of 3-substituted 3-amino-2-oxindoles
via amination with anilines
Authors: Wenkun Yang, Pei Dong, Jian Xu, Jian Yang, Xiaohua Liu,
and Xiaoming Feng
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202100829
Link to VoR: https://doi.org/10.1002/chem.202100829
01/2020

10.1002/chem.202100829
Chemistry - A European Journal
COMMUNICATION
Enantioselective synthesis of 3-substituted 3-amino-2-oxindoles
via amination with anilines
Wenkun Yang,[a] Pei Dong, [a] Jian Xu,[a] Jian Yang,[a] Xiaohua Liu,*[a] and Xiaoming Feng*[a]
[a]
W. K. Yang, P. Dong, J. Xu, J. Yang, Prof. Dr. X. H. Liu, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry &Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064 (P. R. China)
E-mail: liuxh@scu.edu.cn; xmfeng@scu.edu.cn
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
chiral N,N′-dioxide-nickel(II) complex-catalyzed
asymmetric amination reaction of 3-bromo-3-substituted oxindoles
with anilines was developed. A series of alkyl or aryl 3-amino-
indolinones with quaternary stereocenters were obtained in high
yields with excellent ee values in one step (up to 99ꢀ% yield, up to
96% ee). The method provided a readily route to optically active
intermediates of 3-amino-2-oxindole-based bioactive compounds.
Besides, a possible transition state model was proposed to elucidate
the origin of the chirality induction based on the X-ray crystal structure
of the catalyst and the adduct.
(a) Some representative examples of bioactive compounds containing 3-amino-2-oxindole unit
H
O
OH
N
O
O
N
Tol
N
Ar
NH
Ar
N
NH
H
N
R2
*
*
O
X
O
N
X
O
N
N
H
O
N
H
OEt
AG-041R
gastrin/CCK-B receptor agonist
OEt
SSR-149415
GHSR antagonists
(b) Asymmetric catalytic routes to 3-substituted 3-aminooxindole derivatives
R2
= Ar
RO2C
N
N
: R1
(i)
N
CO2R
[ArBO]3
R1
N
Pg
R2HN
(ii)
= alkyl,
N
NuH: R1
O
O
Ph
R2 OH
allyl, alknyl
Oxindole skeleton bearing a stereogenic center at C3-position,[1]
such as 3-substituted 3-aminooxindole units and the related
represents a type of privileged structure, which presents in large
amount of alkaloid natural products, pharmaceutical or
agrochemical relevant compounds as well as synthetic
biologically active molecules [2, 3] (Scheme 1a). Due to their great
importance, much attention has been devoted to the efficient
synthesis of optically active 3-substituted 3-aminooxindole
derivatives by the use of chiral organocatalysts or chiral metal
complex catalysts from various precursors (Scheme 1b), and
several reviews have collected the advances in this area.[3]
In general, addition of isatin ketimines with various carbon-
nucleophiles provided a straightforward route to different 3-
substituted 3-aminooxindoles (path i).[4] Alternatively, amination of
3-substituted oxindoles with azodicarboxylates,[5] nitrosoarenes [6]
or N-electrophiles [7] (path ii) enabled the introduction of nitrogen-
containing functional group into C3-position. The transformations
O
N
Pg
N
H
R1
N
NHR2
O
O
,
N2
Cl3CCN
(iv)
(v)
(iii)
(vi)
ArNH2
H
COR
EWG
O
R
O
N
Pg
Pg(H)
N
Pg
R2
R
(OTf)
Br
R1
HN
Br
(cat* = L*-Pd)
R1
O
R1
= aryl, alkyl, allyl or alknyl
O
N
= H, Boc, Cbz, alkyl, aryl, CO
N
R2
2Et etc.
Pg NR2
H
Pg = Boc, alkyl, allyl, aryl
Scheme 1. Representative bioactive compounds and catalytic asymmetric
synthesis of 3-substituted 3-amino oxindoles
.
had potential to be an efficient catalyst for the enantioselective
addition of anilines to 3-bromo-3-substituted oxindoles,
overwhelming base-initiated racemic background reaction. Herein,
we report our effort in developing a N,N′-dioxide/Ni(II) catalytic
system[15] to promote asymmetric amination of 3-bromo-3-
substituted oxindoles with various anilines, providing 3-alkyl or 3-
aryl 3-aminooxindoles in good yields with high enantioselectivities.
It enabled the easily accessible to the optically active key
intermediates of AG-041R and others (Scheme 1a).
At the beginning of this study, 3-bromo-3-methylindolin-2-one
(1a) and 4-methoxyaniline (2a) were selected as the model
substrates to optimize the reaction conditions (Table 1). The
reaction occurred well in the presence of one equivalent of iPr2NEt
which was used to generate indol-2-one intermediate from 1a
(entry 1), indicating strong background reaction. Under this
condition, a primary screening of chiral N,N'-dioxide ligands
coordinated with Ni(OTf)2 was carried out. Several frequently-
used chiral N,N'-dioxide ligands were evaluated (See ESI for
details), and the desired product 3aa was obtained in high yield
with more or less enantioselectivity (entries 2-4). The effect of
base was investigated with the use of L2-PiiPr2 as the ligand in
THF at 35 °C, and the results showed that iPr2NEt was better than
of 3-aminooxindoles (path iii),[8] 3-diazooxindoles (path iv),[9] and
[10]
others
expanded the diversity of 3-substitution of 3-
aminooxindoles. Also, Pd-catalyzed asymmetric intramolecular α-
arylation of amide enolates [11] (path v) could directly construct the
functionalized oxindoles. Last but not least, the amination of 3-
substituted 3-bromooxindoles is a useful strategy to obtain this
fascinating skeleton (path vi) with advantages as 3-substitution
compatibility, N1-H free without protecting group, and readily
modification to the target derivatives. Using indolines as the
nucleophiles and chiral Box-Ni(II) complex catalyst, the Wang
group realized asymmetric synthesis of N-tryptamine-related 3-
alkyloxindole,
a precursor for the total synthesis of (+)-
psychotrimine.[12] However, the amination of 3-bromo-3-benzyl
oxindole with anilines rendered the desired products with high
yield but moderate enantioselectivity,[13] which might be due to the
background reaction and amine-poisoning of the metal catalysts.
Inspired by our previous works on catalytic asymmetric
reactions with 3-bromo-3-substituted oxindoles,[14] we envisioned
that chiral N,N’-dioxide-metal complex [15] developed by our group
1
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10.1002/chem.202100829
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COMMUNICATION
stronger organic base DMAP and inorganic base in terms of
enantioselectivity (entries 4-6). Since the 2,6-substitutions on the
amide units of the ligand had dramatic influence on the
enantioselection, careful modification of the substituents showed
that the N,N'-dioxide ligands containing 2,6-dialkoxy motifs[16]
afforded a better enantioselectivity than the 2,6-dialkyl based
ones (entries 7 and 8). Delightfully, the desired adduct 3aa was
obtained in 99% yield and 85% ee after switching the solvent to
ethyl acetate and lowing the reaction temperature to 0 oC (entries
9 and 10). Reinvestigating the substructure of the chiral ligands
confirmed that L2-Pi(OiBu)2 with two-carbon linker was superior
to the related L3-Pi(OiBu)2 bearing three-carbon (entry 11). It was
found that Ni(BF4)2•6H2O yielded comparable outcomes as
Ni(OTf)2 (entry 12), and the use of L2-Pi(OnBu)2/Ni(BF4)2 complex
chiral control of the reaction. Para-substituted anilines (2n, 2q, 2t,
2v, 2x and 2z) gave slightly higher enantioselectivity than meta-
and ortho-substituted ones (2l-2m, 2o-2p, 2r-2s, 2u, 2w and 2y).
Table 2. Substrate scope of anilines.
(10 mol%)
L2-Pi(OnBu)2
H
Br
N
Ar
•6H2O (10 mol%)
Ni(BF4)2
iPr2NEt (1.0 equiv)
NH2
Ar
O
O
N
N
H
EtOAc, 0 °C, 24 h
H
-
3at
(Ar = 4-BrC6
-
(R)-
1a
2b 2z
3ab 3az
H4
)
entry[a]
1
Ar
Ph
yield (%)[b]
ee (%)[c]
97 (3ab)
90 (3ac)
98 (3ad)
99 (3ae)
99 (3af)
90 (3ag)
97 (3ah)
99 (3ai)
92 (3aj)
99 (3ak)
99 (3al)
85 (3am)
99 (3an)
99 (3ao)
85 (3ap)
92 (3aq)
85 (3ar)
89 (3as)
99 (3at)
76 (3au)
99 (3av)
86 (3aw)
99 (3ax)
97 (3ay)
99 (3az)
93
86
88
88
90
92
86
92
92
88
92
92
94
88
92
95
86
92
94 (R)
90
94
92
96
92
94
i
in the presence of Pr2NEt enabled the generation of the adduct
3aa in 99% yield and 88% ee (entry 13).
2[d]
3
3-MeC6H4
4-MeC6H4
4-EtC6H4
4-iPrC6H4
2-MeOC6H4
4-EtOC6H4
4-CNC6H4
3-NO2C6H4
4-NO2C6H4
2-FC6H4
Table 1. Optimization of the reaction conditions.
4[d]
5
(10 mol%)
Ni(OTf)2
Br
HN
*
OMe
H2N
Ligand (10 mol%)
+
O
O
base (1.0 equiv)
solvent, 35 °C
N
N
OMe
H
H
6
3aa
1a
2a
L2-PiPh
: R = C
6H5
7
O
R
: R = 2,6-Et
O
R
L2-PiEt2
L2-PiiPr2
2C6H3
O
O
N
N
O
N
: R = 2,6-i
N
Pr2C6H3
8
N
N
O
N
N
O
O
: R = 2,6-(EtO)
L
2C6H3
H
2-Pi(OEt)2
H
R
R
H
H
L3-Pi(OiBu)2
R = 2,6-(iBuO)2C6H3
L2-Pi(OiBu)2
L2-Pi(OnBu)2
: R = 2,6-(i
: R = 2,6-(n
9
BuO)2C6H3
BuO)2C6H3
10
11
12[d]
13
14
15
16
17
18
19
20[d]
21
22
23
24
25
entry[a]
ligand
base
yield (%)[b]
ee (%)[c]
1
Without Ni(II)/ligand
L2-PiPh
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
DMAP
Na2CO3
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
67
96
89
99
52
92
92
90
97
99
74
99
99
0
3-FC6H4
2
11
40
48
4
4-FC6H4
3
L2-PiEt2
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-IC6H4
4
L2-PiiPr2
5
L2-PiiPr2
6
L2-PiiPr2
29
58
58
82
85
44
86
88
7
L2-Pi(OEt)2
L2-Pi(OiBu)2
L2-Pi(OiBu)2
L2-Pi(OiBu)2
L3-Pi(OiBu)2
L2-Pi(OiBu)2
L2-Pi(OnBu)2
8
9[d]
10[d,e]
11[d,e]
12[d-f]
13[d-f]
4-IC6H4
2-CF3OC6H4
4-CF3OC6H4
3-CF3C6H4
4-CF3C6H4
[a] Unless otherwise noted, the reactions were carried out with Ni(OTf)2/Ligand
(10 mol%, 1:1), 1a (0.1 mmol), 4-methoxyaniline 2a (1.5 equiv), and base (1.0
equiv) in THF (0.1 M) at 35 °C for 16 hours. [b] Isolated yield. [c] Determined by
HPLC. [d] In EtOAc. [e] At 0 °C for 24 hours. [f] Ni(BF4)2•6H2O was used.
[a] Unless otherwise noted, the reactions were carried out with 1 (0.10 mmol),
i
2 (1.5 equiv), Pr2NEt (1.0 equiv), Ni(BF4)2•6H2O/L2-Pi(OnBu)2 (1:1, 10 mol%)
With the optimized reaction conditions in hand, the substrate
scope with anilines was then explored. As demonstrated in Table
2, various substituted anilines 2b-2z performed the reaction with
3-bromo-3-methylindolinone 1a smoothly to give the amination
products 3ab–3az in good yield (76-99%) with high
enantioselectivity (86-96% ee). Generally, the position and
electronic nature of substituents exhibited a little effect on the
in EtOAc (0.1 M) at 0 °C for 24 hours. [b] Isolated yield of 3. [c] The ee value of
3 was determined by HPLC analysis. [d] 48 hours.
Furthermore, electron-poor anilines (2i-2z) obtained better results
than electron-rich anilines (2b-2h), which might be due to the
decreased background reaction. In addition, the absolute
configuration of the product 3at was determined to be R by X–ray
crystallography.[17] The absolute configurations of other products
2
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3 were assigned as the same by comparison with the Cotton
effect in the CD spectra with 3at (see ESI for details). In
comparison, alkylamine resulted in low enantioselectivity but
secondary amines obtained moderate enantioselectivity (see ESI
for details).
enantioselectivity (3tq, 86% yield, 82% ee and 3uq, 90% yield,
80% ee). Unfortunately, C7-substituted oxindoles exhibited poor
reactivity, yielding racemic product(see ESI for details).
H
NH2
L2-Pi(OnBu)2
a)
N
Br
(10 mol%)
•6H2O (10 mol%)
Ni(BF4)2
iPr2NEt (1.0 equiv)
O
O
R
Table 3. Substrate scope of oxindoles.
N
N
H
H
EtOAc, 0 °C
R
1a
: 1.26g; 99% yield; 95%ee
(10 mol%)
R = Br,
R = OMe,
2t
2a
3at
NH2
L2-Pi(OnBu)2
(6.0 mmol)
(4.4 mmol)
R2
H
N
R2
(4.0 mmol)
R1
R1
Br
: 0.97g; 91% yield; 88%ee
3aa
•6H2O (10 mol%)
iPr2NEt (1.0 equiv)
Ni(BF4)2
H
N
b)
O
O
NH2
O
Ar
Cl
N
H
N
H
CAN
EtOAc, 0 °C, 48 h
4
(R)-
O
Cl
2q
-
-
CN
aq. CH3
0 °C, 10 min
73% yield; 88%ee
1b 1v
3bq 3vq
N
N
H
H
3aa
entry[a]
1[d]
2[d]
3[d]
4
R1
R2
yield (%)[b]
98 (3bq)
99 (3cq)
96 (3dq)
99 (3eq)
90 (3fq)
82 (3gq)
84 (3hq)
83 (3iq)
99 (3jq)
99 (3kq)
96 (3lq)
95 (3mq)
99 (3nq)
99 (3oq)
92 (3pq)
96 (3qq)
99 (3rq)
95 (3sq)
86 (3tq)
90 (3uq)
97 (3vq)
99 (3wq)
97 (3wa)
ee (%)[c]
O
CO2Me
NH2
MeO2C
H
HN
N
Ar
2 steps
known
H
allyl
Bn
94
90
90
86
88
88
90
86
94
92
88
86
94
92
96
93
92
92
82
80
94
96
88
CAN
O
O
O
CN, 0 °C
aq. CH3
N
N
N
H
H
H
H
6
3wa
5
(R)-
chartellines core
42% yield; 88%ee
H
4-MeC6H4CH2
4 steps
CAN = ammonium cerium nitrate
c)
(+)-AG-041R
known
H
3,4-(MeO)2C6H3CH2
H
N
Ar
5
H
4-FC6H4CH2
O
N
6
H
4-ClC6H4CH2
H
1a
iPr2NEt
-3at
(R)
7
H
4-BrC6H4CH2
iPr2NHEt
Br
H
8
H
4-CNC6H4CH2
N
Ar
OH
9
H
furan-2-ylmethyl
N
C
NiL*
O
L2-Pi(OnBu)
2/Ni2+/L'
10
H
thiophen-2-ylmethyl
proton
transfer
CCDC 2063772
N
A
11
4-Cl
4-Br
5-Me
5-MeO
5-F
5-Cl
5-Br
5-I
6-Cl
6-Br
H
Me
H2N Ar
NiL*
O
O
12
Me
O
HN
N
Ar
X
B
NH2
13[d]
14[d]
15[d]
16[d]
17
Me
O
N
O
2
NH2
Ni
Me
OO
N
Re-face
O
N
O
Me
O
Re-face favored
Me
B
Me
Scheme 2. (a) Gram-scale synthesis; (b) further transformations; (c) Proposed
catalytic cycle and favorable transition state.
18[d]
19
Me
Me
To demonstrate the practicality of this transformation, two scale-
up experiments of oxindole 1a were performed with 2t (6.0 mmol)
or 2a (4.4 mmol) under the optimized reaction conditions,
providing the desired product 3at in 99% yield with 95% ee, and
20[d]
21
Me
C6H5
22[d]
23[d,e]
H
CH2CO2Me
CH2CO2Me
the product 3aa in 91% yield with 88% ee (Scheme 2a). Moreover,
[6b,18]
removal of the p-methoxyphenyl (PMP) group
was carried
H
out under conventional conditions to give 3-amino-3-
methyloxindole (R)-4 and 2-(3-amino-2-oxoindolin-3-yl)acetate
(R)-5 in good yield without loss of enantioselectivity (Scheme 2b).
The compound 5 could be converted into (+)-AG-041R and spiro-
β-lactam 6 by following the reported literature procedure.[4n, 5d]
The enantiocontrol of this amination reaction was considered
based on the X-ray crystal structure of the the catalyst [17] and the
outcome of this reaction process (Scheme 2c). The indol-2-one
[a-c] See the condition in entry 20, Table 2. [d] 24 hours.[e] 2a instead of 2q.
Subsequently, we turned attention to the scope of oxindoles 1
(Table 3). A variety of 3-allyl, 3-alkyl, and 3-aryl oxindoles reacted
with 2q smoothly to generate the products (3bq-3kq, 3vq-3wq)
with good yields (82-99%) and enantioselectivity (86-96% ee).
Then substrates with substituents on the oxindole ring at C4, C5,
and C6 positions were examined. Almost all of them could give
satisfactory results (3lq-3sq, 92-99% yields, 86-96% ee) except
the C6-substituted oxindoles 1t-1u exhibited slightly reduced
i
generated in situ in the assistant of Pr2NEt, could be activated
after coordinating to the N,N′- dioxide/NiII complex to form A. As
shown in B where the aniline conducts nucleophilic addition, the
3
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Si-face of the indol-2-one is shielded by downward amide unit of
the ligand, and the addition of aniline occurs preferentially from
the Re-facial, yielding the (R)-product as the major isomer.
In summary, a direct and efficient enantioselective synthesis of
3-substituted 3-amino oxindoles was realized by developing a
chiral nickel complex catalytic system for addition reaction of 3-
bromo-3-substituted oxindoles with anilines. A wide range of 3-
aminooxindoles with 3-alkyl or 3-aryl substitution was readily
available in excellent yield and enantioselectivity, including key
intermediates of the bioactive molecules. Further application of
the chiral catalysts to other enantioselective synthesis are
ongoing in our laboratory.
[5]
Acknowledgements
We appreciate the National Natural Science Foundation of China
(Nos.U19A2014 and 21921002) for financial support.
Keywords: oxindoles • amination • asymmetric catalysis • N,N’-
dioxides • nickel
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2045082
(product
3at);
CCDC
2063772
(L2-
5
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10.1002/chem.202100829
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
R2
H
L2-Pi(On
Bu)2
R1
N
R2
R1
(10 mol%)
O
O
Ar
O
Br
N
N
•6H2O (10 mol%)
Ni(BF4)2
(1.5 equiv)
N
N
O
N
H
O
O
Ar-NH2
iPr NEt
R
R
H
2C6
H
N
R = 2,6-(OnBu)
H3
49 examples
H
(1.0 equiv)
EtOAc, 0 °C, 24-48 h
2
L2-Pi(OnBu)2
up to 99% yield, 96% ee
Lewis acid catalyzed asymmetric synthesis of phenylamino-3-indolin-2-ones via amination reaction of 3-bromo-3-substituted
oxindoles with anilines.
6
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