Nickel(II)-Catalyzed Asymmetric Propargyl [2,3] Wittig Rearrangement of Oxindole Derivatives: A Chiral Amplification Effect

Article abstract of DOI:10.1002/anie.201804080

A highly enantioselective [2,3] Wittig rearrangement of oxindole derivatives was realized by using a chiral N,N′-dioxide/Ni^II complex as the catalyst under mild reaction conditions. A strong chiral amplification effect was observed, and allowed access to chiral 3-hydroxy 3-substituted oxindoles bearing allenyl groups in high yields and enantioselectivities (up to 92 % ee) by using a ligand with only 15 % ee. A reasonable explanation was given based on the experimental investigations and X-ray crystal structures of enantiomerically pure and racemic catalysts. Moreover, the first catalytic kinetic resolution of racemic oxindole derivatives by a [2,3] Wittig rearrangement was realized with high efficiency and stereoselectivity.

Full text of DOI:10.1002/anie.201804080

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Accepted Article
Title: Nickel(II)-Catalyzed Asymmetric Propargyl [2,3]-Wittig
Rearrangement of Oxindole Derivatives: A Remarkable Chiral
Amplification Effect
Authors: Xi Xu, Jianlin Zhang, Shunxi Dong, Lili Lin, Xiaobin Lin,
Xiaohua Liu, and Xiaoming Feng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804080
Angew. Chem. 10.1002/ange.201804080
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10.1002/anie.201804080
Angewandte Chemie International Edition
COMMUNICATION
Nickel(II)-Catalyzed
Asymmetric
Propargyl
[2,3]-Wittig
Rearrangement of Oxindole Derivatives: A Remarkable Chiral
Amplification Effect
Xi Xu,[a] Jianlin Zhang,[a] Shunxi Dong,[a] Lili Lin,[a] Xiaobin Lin,[a] Xiaohua Liu[a] and Xiaoming Feng*[a,b]
Abstract: A highly enantioselective [2,3]-Wittig rearrangement of
oxindole derivatives was realized by using a chiral N,N′-dioxide/NiII
complex as catalyst under mild reaction conditions. A strong chiral
amplification effect was observed, which allowed to access chiral 3-
hydroxy 3-substituted oxindoles bearing allenyl groups in high yields
and enantioselectivities (up to 92% ee) by using a ligand with only
15% ee. A reasonable explanation was given based on the
experimental investigations and X-ray crystal structures of
enantiomerically pure and racemic catalysts. Moreover, the first
catalytic kinetic resolution of racemic oxindole derivatives via [2,3]-
Wittig rearrangement was realized in high resolution efficiency and
stereoselectivity.
above, There is still greater room for promotion in this area in
term of several limitations, such as high catalyst loading, low
diastereoselectivities and limited substrates. In consequence,
the discovery of other new efficient catalyst systems and new
substrates for this reaction is a challenge but highly desirable.
[2,3]-Wittig rearrangement of propargylic ethers provides a
direct route to synthetically valuable functionalized allenes.
However, to date, there is no report on such kind of [2,3]-Wittig
rearrangement, probably due to challenges encountered. Firstly,
the proparagylic ethers show low reactivity in that the alkyne sp
centers distort the transition-state geometries. Secondly,
nucleophilic attack to alkyne may compete against direct [2,3]-
Wittig rearrangement. Based on Lewis acid catalyzed [2,3]-Wittig
rearrangement[13] and our previous works[14], we envisioned that
N,N′-dioxide/Lewis acid complex could engage the anionic
proparagyloxyoxindole substrate by coordination and induce
stereoselective rearrangement. Herein, we describe the first
process of such type using chiral N,N′-dioxide/NiII as catalysts
leading to various 3-hydroxy 3-substituted oxindoles bearing
allenyl groups with excellent yields and ee values (up to 99%
yield and 99% ee).
[2,3]-Sigmatropic rearrangement has received considerable
attention due to its utility in complex molecule synthesis.[1-3] Over
recent years, significant advances have been made towards
enantioselective catalysis of rearrangement with related ylides.[4]
In comparison, anionic [2,3]-Wittig rearrangement has lagged,
probably because strong bases are usually required to generate
the carbanion as the promoter of the rearrangement. Methods
based on chiral auxiliaries[5] or chiral substrates[6] have been
developed for achieving chiral homoallyl alcohols. In addition,
the enantioselective strategies involving stoichiometric amounts
of chiral boron reagent[7], chiral bases or complexation of chiral
ligands[8] with organolithium intermediate could afford
enantioenriched rearrangement products. However, catalytic
asymmetric [2,3]-Wittig rearrangements are rare. Inspired by
Gaunt's work,[9] several organocatalytic examples have been
reported so far. In 2015, Denmark′s group[10] presented the
stereoselective rearrangements of 3-(allyloxy)-2-oxindoles and
2-(allyloxy)-1-tetralone, but moderate ee values (up to 54% ee)
were obtained after investigation of various phase-transfer
catalysts. In 2016, improved outcomes (up to 2.7:1 d.r., 94%
ee/97% ee) were reported by Kanger′s group[11] by using
squaramide (20 mol%) (Scheme 1a). Meanwhile, Jacobsen and
coworkers described their unique strategy for the rearrangement
of allyloxy-1,3-dicarbonyl compounds and high yields with good
enantioselectivities (up to 99% yield, 92% ee, Scheme 1b) could
be afforded under synergistic ion-binding catalysis.[12] Although
great endeavors have been paid in this area as mentioned
We commenced our work with the N-benzyl protected 3-
phenylproparagyloxyoxindole 1a as the model substrate to
optimize the reaction conditions, and the representative results
were summarized in Table 1. Firstly, different metal salts
complexing with N,N′-dioxide L-PiPr2 were examined in the
presence of Na2CO3 in EtOAc at 35 C (Table 1, entries 1-4).
The complexes of Cu(OTf)2 or Yb(OTf)3 did not show any activity
towards compound 1a (entries 1 and 2). Pleasantly, the use of
[a]
[b]
X. Xu, J. L. Zhang, Prof. Dr. S. X. Dong, Prof. Dr. L. L. Lin, X. B. Lin,
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 (China)
E-mail: xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Asymmetric [2,3]-sigmatropic rearrangement.
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10.1002/anie.201804080
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COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope for substituents on the oxindoles.[a]
Entry
1
R1, R2
2
Yield [%][b]
98
ee [%][c]
99
H, Bn (1a)
2a
2b
2c
2d
2e
2f
2
5-F, Bn (1b)
5-Cl, Bn (1c)
6-Cl, Bn (1d)
4-Br, Bn (1e)
5-Br, Bn (1f)
6-Br, Bn (1g)
7-Br, Bn (1h)
5-I, Bn (1i)
68
87
3
84
92
4
84
96
5
90
97
6
99
93
Entry
L
Metal salts
Base
Yield [%][b]
ee [%][c]
7
2g
2h
2i
91
96
1
L-PiPr2
Yb(OTf)3
Cu(OTf)2
Sc(OTf)3
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Et3N
trace
n.r.
26
−
8[d]
9
96
90
2
L-PiPr2
−
99
94
3
L-PiPr2
56
64
91
97
67
93
99
−
10
11
12
13
14
15
16
17[e]
5-Me, Bn (1j)
5-MeO, Bn (1k)
5,7-Me2, Bn (1l)
5-F3CO, Bn (1m)
H, H (1n)
2j
94
>99
>99
99
4
L-PiPr2
36
2k
2l
97
5
L-PisEPh
L-PiCHPh2
L-RaCHPh2
L-PrCHPh2
L-PiCHPh2
−
80
85
6
99
2m
2n
2o
2p
90
92
7
15
51
99
8
22
H, Me (1o)
63
99
9
97
H, iPr (1p)
83
99
10[d]
11[e]
12[f]
13[g]
Et3N
18
2q
98
99/97
(3.3/1
d.r.)
L-PiCHPh2
L-PiCHPh2
L-PiCHPh2
Et3N
98
99
96
96
(1q)
Et3N
84
Et3N
55
[a] Unless otherwise noted, all reactions were carried out with L-
PiCHPh2/Ni(OTf)2 (1:1, 5 mol%), 1a (0.10 mmol) and Et3N (0.12 mmol) in
EtOAc (0.50 mL) at 35 C for 36 h. [b] Yield of isolated product. [c] Determined
by chiral HPLC analysis. [d] 10 mol% catalyst. [e] The reaction was carried out
with L-PicH/Ni(BF4)2•6H2O (1:1, 10 mol%) in EtOAc (1.0 mL).
[a] Unless otherwise noted, all reactions were carried out with L/metal (1:1, 10
mol%), 1a (0.10 mmol) and base (0.12 mmol) in EtOAc (1.0 mL) at 35 C for 36
h. [b] Yield of isolated product. [c] Determined by chiral HPLC analysis. [d]
without ligands. [e] 5 mol% catalyst, 0.50 mL EtOAc. [f] 2.5 mol% catalyst, 0.50
mL EtOAc. [g] 1 mol% catalyst, 0.50 mL EtOAc. Tf = trifluoromethanesulfonyl.
entry 9). When the reaction was conducted in the absence of
chiral ligand, low yield (18%) was obtained, indicating that strong
ligand-accelerated catalysis (LAC)[15] exists in the current system
(entry 10). Notably, there is no effect on the results when
reducing the loading to 5 mol% (entry 11). Further decreasing
the catalyst loading to 1 mol% resulted in much lower activity (55%
yield) but with maintained ee value (96% ee, entry 13). In
contrast, the rearrangement reaction showed poor reactivity and
stereoselective control using oxazolines as the ligands, instead
of L-PiCHPh2 (see SI for details). Therefore, the optimized
conditions involved the use of 5 mol% L-PiCHPh2/Ni(OTf)2 as
catalyst and Et3N as an additive in EtOAc at 35 C for 36 h.
Sc(OTf)3 and Ni(OTf)2 as the central metals could promote the
rearrangement, providing the desired product 2a in moderate
yields and enantioselectivities (26% yield, 56% ee and 36% yield,
64% ee, entries 3 and 4). Subsequently, various ligands were
investigated. It was found that switching aromatic amide group in
the ligand to aliphatic one, the outcomes increased dramatically.
The use of L-PisEPh with (S)-2-phenylethyl group led to the
formation of product 2a in 80% yield and 91% ee (entry 5).
Furtherly, 99% yield and 97% ee could be afforded using L-
PiCHPh2 with diphenylmethyl group as the ligand (entry 6). As
for the backbones of ligands, L-pipecolic acid-derived L-
PiCHPh2 was superior to L-proline-derived L-PrCHPh2 and L-
ramipril-derived L-RaCHPh2, especially in activity (entey 6 vs
entries 7 and 8). The screening of other bases suggested that
Et3N could furtherly improve the enantioselectivity to 99% ee (
With the optimized reaction conditions in hand, we first
investigated substituents on the oxindole ring (Table 2). It was
found that the substrates with a halogen atom at different
positions underwent the [2,3]-rearrangement smoothly to afford
the corresponding products (2b-i) in good to excellent yields (68-
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10.1002/anie.201804080
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Table 3. Substrate scope for substituents at the propargyl ethers.[a]
substituent at the C5 position was also suitable (90% yield, 92%
ee, entry 13). The unprotected oxindole 1n performed the
rearrangement reaction with excellent enantioselectivity but in
lower yield (51% yield, 99% ee, entry 14). Changing the N-
protected group from methyl to isopropyl group, the yield
increased to 83% with maintained ee value (99% ee, entries 15
and 16). For the rearrangement of N-benzyl protected 3-
cinnamyloxyoxindole 1q, excellent yield and ee value with
moderate diastereoselectivity (3.3/1 d.r., 99% ee/97% ee) could
be achieved by using L-PicH/Ni(BF4)2•6H2O complex (entry 17)
and the diastereoisomers could be isolated by flash
chromatography.
Entry
R3
4
Yield [%][b]
ee [%][c]
1
2-ClC6H4 (3a)
3-ClC6H4 (3b)
4-ClC6H4 (3c)
4-FC6H4 (3d)
4-BrC6H4 (3e)
2-MeC6H4 (3f)
3-MeC6H4 (3g)
4-MeC6H4 (3h)
4-EtC6H4 (3i)
4-tBuC6H4 (3j)
4-MeOC6H4 (3k)
4-F3CC6H4 (3l)
4-O2NC6H4 (3m)
3,4-Cl2C6H4 (3n)
1-naphthyl (3o)
2-thienyl (3p)
cyclohexyl (3q)
Me (3r)
4a
4b
4c
4d
4e
4f
92
99
99
99
99
89
72
92
85
91
80
96
77
95
95
71
43
50
99
2
98
Next, the propargyl ether part was evaluated. As
summarized in Table 3, substrates with electron-donating and
withdrawing groups were well tolerated, providing the
corresponding products (3a-3n) in good yields (72-99%) with
excellent enantioselectivities (97->99% ee, entries 1-14). For
naphthyl- substituted substrate, the product 4o was isolated with
95% yield and 99% ee (entry 15). Heteroaromatic substrate 3p
afforded the expected product 4p in 71% yield and 98% ee
(entry 16). Moreover, aliphatic oxyoxindoles were tested, giving
the desired product 4q and 4r in excellent enantioselectivities
(98% ee, entries 17 and 18) albeit in moderate yields (43% and
50%). Additionally, the absolute configuration of the product 4n
was determined to be R by X-ray crystallography.[17]
3
99
4
99
5
98
6
99
7
4g
4h
4i
>99
99
8
9
98
10
11
12
13
14[d]
15
16
17
18
4j
>99
97
4k
4l
During the optimization of the reaction, we recovered the
unreacted starting material 1a. It was found that the recovered
1a was racemic, which probably caused either by non-
stereoselective deprotonation or by an in-situ racemization via
enolization. Based on the envelope-shaped five- membered
96
4m
4n
4o
4p
4q
4r
97
98 (R)
99
98
100
80
60
40
20
0
98
98
[a] All reactions were the same as detailed in Table 2. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis. [d] The absolute
configuration was determined to be R by X-ray crystallography analysis.
0
20
40
60
80
100
ee of L-PiCHPh (%)
2
Scheme 2. Kinetic resolution/chiral transfer/asymmetric [2,3]-Wittig
rearrangement.
99%) with excellent ee values (87-97% ee, entries 2-9).
Generally, substrates with the halogen at the C4 or C6 positions
provided higher enantioselectivities compared to the ones at the
C5 or C7 positions. Electron-donating groups (methyl, methoxy
and dimethyl) were well tolerated and converted to the desired
products (2j-l) in good yields with excellent enantioselectivities
(99->99% ee).[16] Substrate 1m bearing a trifluoromethoxy
Scheme 3. (a) Strong chiral amplification effect. (b) All reactions were carried
out with L-PiCHPh2/Ni(OTf)2 (1:1, 10 mol%, 15% ee), substrate (0.10 mmol)
and Et3N (0.12 mmol) in EtOAc (0.50 mL) at 35 C for 36 h.
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10.1002/anie.201804080
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COMMUNICATION
allenes. Meanwhile, due to the formation of less soluble racemic
L-PiCHPh2/NiII complexes, a strong positive nonlinear effect was
observed, allowing to access enantioenriched products with 15%
ee of ligand. Further studies on other 2,3-rearrangement
reactions are underway.
Experimental Section
A dry reaction tube was charged with Ni(OTf)2 (5 mol%), N,N'-dioxide
ligand L-PiCHPh2 (5 mol%), and the substrate 1a (0.10 mmol), and
EtOAc (0.50 mL) was added and the mixture was stirred at 35 C for 0.5
h. Then Et3N (0.12 mmol) was added. The reaction mixture was stirred at
35 C for 36 h, and the product was purified by flash chromatography on
silica gel (petroleum ether/DCM/EtOAc = 6/2/1) to afford the desired
product 2a.
Scheme 4. (a) Gram-scaled experiment. (b) Transformation of the product 2a.
Acknowledgements
cyclic transition state of [2,3]-Wittig rearrangement and excellent
results obtained above, we envisioned that the possibility of an
asymmetric [2,3]-Wittig rearrangement of 4-phenylbut-3-yn-2-ol
derived 3s taking advantage of chiral transfer by kinetic
resolution (Scheme 2). To our delight, our current catalyst
system could recognize one enantiomer of racemic 3s, which
then underwent a catalytic [2,3]-Wittig rearrangement to afford
chiral allene 4s (51% yield, >19:1 d.r. and 97% ee) by chiral
transfer. The diastereoselectivity of the product was determined
by both stereogenic center of the substrate and chiral catalyst
(for details, see SI). Meanwhile, the unreacted 3s was recovered
in 46% yield, >19:1 d.r. and 95% ee.
We appreciate the National Natural Science Foundation of
China (Nos. 21432006, 21772127) for financial support.
Keywords: allenic compounds • asymmetric catalysis • chiral
amplification • nickel • rearrangement
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To gain insight into the mechanism, the relationship between
the ee value of the ligand L-PiCHPh2 and that of 2a was
investigated (Scheme 3). A strong positive nonlinear effect
(NLE) [18] was observed, and (R)-2a was generated in 90% ee
even by using 15% ee of L-PiCHPh2 (Scheme 3a, see SI for
details). To test the generality of such remarkable chiral
amplification effect, various substrates were examined under 15%
ee catalyst L-PiCHPh2, delivering the corresponding products in
good results (84-92% yield and 87-92% ee). Based on control
experiments, X-ray crystallography data and HRMS analysis
(see SI for details), it was found that the enhancement of the
solution ee values by formation of less soluble racemic L-
PiCHPh2/NiII complexes was responsible for such remarkable
chiral amplification effect.[19]
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To highlight the robustness of this reaction, a gram scale
synthesis of (R)-2a was performed. By treatment of 1.12 g (3.20
mmol) of 1a in the presence of the L-PiCHPh2-Ni(OTf)2 complex
for 48 h, 1.09 g (97% yield) of the isolated (R)-2a with 98% ee
was obtained (Scheme 4a). In addition, the product 2a could be
easily transformed to dihydrofuran 5 in 95% yield and 97% ee by
treating with AgNO3 and CaCO3 on 0.1 mmol scale (Scheme 4b).
In summary, we have successfully realized the highly
effcient [2,3]-Wittig rearrangement of propargylic and allylic
ethers by developing a nickel(II)-N,N′-dioxide catalytic system.
Various 3-substituted 3-hydroxyoxindoles could be obtained in
excellent yields and enantioselectivities under mild conditions.
Kinetic resolution of oxindole derivatives via [2,3]-Wittig
rearrangement was also realized for the first time in high
resolution efficiency and stereoselectivity. This protocol presents
a practical approach to synthetically valuable functionalized
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10.1002/anie.201804080
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
X. Xu, J. L. Zhang, S. X. Dong, L. L. Lin,
X. B. Lin, X. H. Liu and X. M. Feng *
Page No. – Page No.
Nickel(II)-Catalyzed Asymmetric
Propargyl [2,3]-Wittig Rearrangement
of Oxindole Derivatives： A
Remarkable Chiral Amplification
Effect
A highly enantioselective [2,3]-Wittig rearrangement of oxindole derivatives was
developed by using a chiral N,N′-dioxide/NiII catalyst. This approach provides an
efficient access to chiral 3-hydroxy 3-substituted oxindoles bearing allenyl groups in
up to 99% yield and >99% ee. Catalytic kinetic resolution of racemic oxindole
derivatives via [2,3]-Wittig rearrangement was realized in high resolution efficiency
and stereoselectivity for the first time. Moreover, a strong chiral amplification was
observed in the current system.
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