Umpolung of Imines Enables Catalytic Asymmetric Regio-reversed [3+2] Cycloadditions of Iminoesters with Nitroolefins

Article abstract of DOI:10.1002/anie.201802492

A copper-catalyzed regio-reversed asymmetric [3+2] cycloaddition of iminoesters with nitroolefins is disclosed for the first time. This method enables the facile synthesis of polysubstituted chiral pyrrolidines bearing at least one chiral quaternary cente

Full text of DOI:10.1002/anie.201802492

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Accepted Article
Title: Umpolung of Imines Enables Catalytic Asymmetric Regio-
Reversed [3+2] Cycloadditions of Iminoesters with Nitroolefins
Authors: Wen-Jing Xiao, Liang-Qiu Lu, Bin Feng, Jia-Rong Chen, Guo-
Qiang Feng, Bin-Qing He, and Bin Lu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802492
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10.1002/anie.201802492
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COMMUNICATION
Umpolung of Imines Enables Catalytic Asymmetric Regio-
Reversed [3+2] Cycloadditions of Iminoesters with Nitroolefins
Bin Feng,# Liang-Qiu Lu,# Jia-Rong Chen, Guoqiang Feng, Bin-Qing He, Bin Lu, and Wen-Jing Xiao*
Dedicated to Prof. Xiyan Lu on the occasion of his 90th birthday.
Abstract:
A
copper-catalyzed regio-reversed asymmetric [3+2]
asymmetric catalysis; however, to our surprise, this strategy
remains underexploited for catalytic asymmetric umpolung/[3+2]
cycloaddition reactions of iminoesters.[10,11] In this work, with our
ongoing interest in the applications of chiral P,S ligands in
asymmetric synthesis,[12] we describe a highly enantioselective
and regio-reversed [3+2] cycloaddition of iminoesters through
asymmetric Lewis acid catalysis (Figure 1b; Lewis acid = Cu).
This novel protocol provides direct access to important and
structurally diverse chiral pyrrolidines[13] that bear chiral
quaternary stereocenters with high efficiency and excellent
regio-, diastereo- and enantioselectivities.
cycloaddition of iminoesters with nitroolefins was disclosed for the
first time. This protocol allows the facile synthesis of polysubstituted
chiral pyrrolidines bearing at least one chiral quaternary center in
high yields with excellent regio-, diastereo- and enantioselectivities.
The application of chiral P,S-ligands and the unique effect of α-aryl
groups on the iminoesters were the keys to the success of this
method. The practicality and versatility of the reaction methodology
were also demonstrated.
Imines are a family of privileged compounds in organic
chemistry that are involved in more than 50 named reactions
and are widely used in the synthesis of nitrogen-containing
molecules.[1] One reason for their versatility is the inherent and
tunable electrophilicity of imines (Figure 1a, with Nu-). Recently,
reversing this inherent reactivity (the umpolung of imines) has
opened a new pathway for the further development of imine
chemistry (Figure 1a, with E+).[2] To date, many elegant
transformations have been reported that use this umpolung
strategy, including arylation reactions,[3] allylic additions,[4]
nucleophilic additions,[5] and transaminations of imines.[6]
However, most of these works have focused on reactions that
produce a single chemical bond. Further exploitation of this
concept in cycloaddition reactions, especially catalytic
asymmetric processes, will provide additional opportunities for
the construction of important aza-heterocycles.
In recent years, azomethine ylides have been shown to be
important dipolar intermediates that can participate in a series of
[3+2] cycloadditions with various dipolarophiles.[7] Given the
unique imine structure of iminoesters, precursors of azomethine
ylides, the development of regio-reversed catalytic asymmetric
[3+2] cycloadditions of iminoesters using an umpolung strategy
involving imines would enable the efficient synthesis of new
pyrrolidine compounds.[8,9] However, to our knowledge, very few
studies have been reported in this field. In 2009, Gong and co-
workers disclosed the first example of catalytic asymmetric
umpolung/[3+2] cycloaddition reactions of iminoesters and
methyleneindolinone with chiral phosphoric acid as an efficient
catalyst.[9a,b] Two other impressive umpolung/cycloaddition
reactions of ketimines, which were derived from isatins or CF3-
substituted ketones, were subsequently developed using chiral
squaramide catalysts.[9c,d] Analogously to organocatalysis,
asymmetric Lewis acid catalysis is another efficient strategy for
Figure 1. Reaction design: Cu-catalyzed regio-reversed asymmetric [3+2]
cycloadditions. PG: protecting group; Nu-/E+: nucleophile/electrophile.
We began this project with the regio-reversed [3+2]
cycloaddition of 2,4-diphenyl iminoester 1a and nitrostyrene 2a
as a model reaction using 5 mol% chiral Cu complex as the
catalyst and 30 mol% CsOAc as the base. As highlighted in
Table 1, the Cu catalyst with our chiral P,S-ligand (L1a) indeed
promoted this reaction with a high yield albeit with modest
enantioselectivity (Table 1, entry 1, 80% yield, >19:1 dr and -
20% ee). Encouraged by this result, other structurally related
P,S-ligands were evaluated (Table 1, entries 2-4). Ligands L1c
and L1d, which have bulky substituents (i.e., an iodine atom or
a phenyl group) at the 3,3’-positions of the binaphthyl scaffold,
were determined to be super choices as they provided the
desired products in 99% yields with high levels of
enantiocontrol (Table 1, entries 3 and 4). P,S-ligand L2, which
bears an achiral phosphoramidite unit and is known to be
successful in Pd-catalyzed asymmetric decarboxylative [4+2]
cycloadditions, was also evaluated here, but it failed to give
high enantioselectivity. Other commercial chiral P-ligands, N-
ligands and P,N-ligands were also examined for this
cycloaddition, but none of these ligands provided superior
yields and enantioselectivities to chiral P,S-ligands L1c and
[*]
B. Feng, L.-Q. Lu, J.-R. Chen, G. Feng, B.-Q. He, B. Lu, W.-J. Xiao
CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide
& Chemical Biology, Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
E-mail: wxiao@mail.ccnu.edu.cn
[#]
Contributed equally for this work.
Homepage: chem-xiao.ccnu.edu.cn/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xx xxxx.
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10.1002/anie.201802492
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COMMUNICATION
L1d (Table 1, entries 6-10 vs 3 and 4). To our delight,
performing the reaction at -40 °C with an extended reason time
can greatly improve the results (Table 1, entry 10, 94% yield,
>19:1 dr and 97% ee).[14]
Next, we examined the scope of nitroolefin components. As
shown in Table 3, nitroolefins containing a series of electron-
donating and electron-withdrawing substituents on the β-aryl ring
reacted with iminoester 2a very well. Enantioenriched
pyrrolidines with different aryl groups at the 4-positon were
Table 2: Scope of azomethine ylides.[a]
Table 1: Optimization of the reaction conditions[a]
Entry
L
Time [h]
Yield [%][b]
ee [%][c]
-20
60
Entry
1
R
C6H5
R’
C6H5
Product Yield (%)[b] ee (%)[c]
1
L1a
L1b
L1c
L1d
L2
1
1
80
99
3aa
3ba
3ca
3da
3ea
3fa
83
87
84
99
96
99
92
85
99
94
95
85
96
94
87
80
96
84
92
90
86
97
92
95
94
93
96
97
96
99
94
94
96
96
97
94
88
95
91
95
90
97
2
2
p-MeO-C6H4
p-Me-C6H4
p-Br-C6H4
p-NO2-C6H4
p-CN-C6H4
p-CF3-C6H4
o-Me-C6H4
o-Br-C6H4
m-Me-C6H4
m-NO2-C6H4
m,p-(MeO)2-C6H3
1-naphthyl
2-naphthyl
2-furyl
C6H5
3
1
99
87
3
C6H5
4
1
99
88
4
C6H5
5
1
99
30
5[d]
6
C6H5
6
L3
1
94
3
C6H5
7
L4
1
96
22
7
C6H5
3ga
3ha
3ia
8
L5
3
91
35
8
C6H5
9
L6
1
70
0
9
C6H5
10
11[d]
L7
10
8
43
44
10
11[d]
12[d]
13
14[d]
15
16
17[e]
18
19
20
21
C6H5
3ja
L1d
94 (83)[e]
97
C6H5
3ka
3la
[a] Reaction conditions: 2a (0.3 mmol), 3a (0.2 mmol), Cu(CH3CN)4PF6
(5.0 mol%), ligand (5.5 mol%), CsOAc (30 mol%) in MTBE (2.0 mL) at rt.
[b] Determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal
standard; dr >19:1. [c] Determined by chiral HPLC. [d] Performed at -
40 °C. [e] Isolated yield in parentheses. MTBE: methyl tert-butyl ether.
C6H5
C6H5
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
C6H5
C6H5
2-thiophenyl
cyclohexyl
C6H5
C6H5
C6H5
p-Me-C6H4
p-Cl-C6H4
o-Cl-C6H4
2-thiophenyl
C6H5
C6H5
C6H5
3ua
[a] Unless otherwise noted, reactions were carried out as indicated in entry
12, Table 1, dr > 19:1. [b] Isolated yield. [c] Determined by chiral HPLC. [d]
Using chiral ligand L1c at 0 °C. [e] rt.
produced in high yields and good enantioselectivities (Table 3,
entries 1-8, 3ab-3ai: 86-96% yields and 88-97% ee). Fused aryl-
and heteroaryl-substituted nitroolefins were compatible with this
After establishing the optimal conditions, we probed the
generality of this cycloaddition.[15] As summarized in Table 2, we
were glad to find that a wide range of iminoesters with varied
electronic properties and substitution patterns were well-
tolerated and were converted to the corresponding pyrrolidine
products in high yields and excellent enantioselectivities (Table
2, entries 1-12, 3aa-3la: 83-99% yields and 92-99% ee).
Moreover, substrates with fused aromatic rings, such as 1-
napthyl and 2-napthyl derivatives, and heteroaryls, such as 2-
furyl and 2-thiophenyl, were smoothly converted by this reaction
to products 3ma-3pa with high levels of enantiocontrol (Table 2,
entries 13-16: 80-96% yields and 88-97% ee). This catalytic
system has been successfully applied to iminoesters derived
from aliphatic aldehydes. For example, a cyclohexyl-substituted
iminoester was well tolerated in the Cu-catalyzed regio-reversed
[3+2] cycloaddition and provided 5-cyclohexyl-substuted product
3qa in 96% yield and 95% ee (Table 2, entry 17). Furthermore,
iminoesters with different aryl groups at the α-position were
examined for this transformation. Gratifyingly, all were found to
be efficient substrates. This included electron-deficient and
electron-rich aryls as well as heteroaryls; the desired products
were provided in 84-92% yields and 90-97% ee (Table 2, entries
18-21, 3ra-3ua).
Table 3: Scope of nitroolefins.[a]
Entry
1
R
R’
Product
Yield (%)[b]
96
ee (%)[c]
96
p-MeO-C6H4
H
3ab
2
3
p-Me-C6H4
p-Cl-C6H4
o-Me-C6H4
o-Br-C6H4
o-Cl-C6H4
m-Me-C6H4
2,4-Cl2-C6H4
2-naphthyl
2-furyl
H
H
H
H
H
H
H
H
H
H
H
3ac
3ad
3ae
3af
93
86
90
86
94
99
90
99
94
94
81
97
90
95
93
88
91
91
97
97
97
98
4
5
6
3ag
3ah
3ai
7
8
9
3aj
10
11
12
3ak
3al
2-thiophenyl
isopropyl
3am
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10.1002/anie.201802492
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13[d]
14[d]
cyclohexyl
H
3an
82
81
92
93
Scheme 2. A gram-scale reaction and demonstration of synthetic utility of the
product.
C6H5
Me
3ao
[a] Unless otherwise noted, reactions were carried out as indicated in entry 12,
Table 1, dr > 19:1. [b] Isolated yield. [c] Determined by chiral HPLC. [d] Using
chiral ligand L1c at 0 °C.
Regarding the origin of reversed regio-selectivity of this Cu-
catalyzed asymmetric [3+2] dipolar cycloaddition, we envisioned
that the α-aryl group of the iminoester helps stabilize the 2-
azaallyl anion of the azomethine ylide intermediate, thus
promoting the umpolung of iminoester 1. To verify this
hypothesis, control experiments with α-Bn-, α-Me- and α-H-
substituted iminoesters were performed under the standard
conditions. As expected, cycloaddition products with normal
regio-selectivity were observed (Figure 2). In addition, based on
the X-ray structure of the Cu-complex with the chiral P,S-
ligands,[12f] a possible stereoinduction mode was proposed to
account for the observed stereochemistry of the products. As
depicted in Figure 2, a six-membered copper chelate consisting
of the P,S-ligand, Cu core and azomethine ylide might first take
on a distorted tetrahedral geometry. Then, the N-metalated
azomethine ylide can approach the Si-face of the nitroolefin.[17]
The steric hindrance between the imine group and the phenyl
group of the nitroolefin forces the two phenyl group at C4 and
C5 in an anti-conformation thus providing chiral exo-3aa.
reaction system, and the corresponding products were delivered
in excellent yields and enantioselectivities (Table 3, entries 9-11,
3aj-3ak: up to 99% yield and 97% ee). Moreover, alkyl-
substituted nitroolefins, such as the isopropyl- and cyclohexyl-
substituted substrates, were efficient substrates for this reaction
(Table 3, entry 12, 3am: 81% yield and 98% ee; entry 13, 3an:
82%
yield and
92%
ee).
To our
delight,
the
umpolung/cycloaddition reaction of α-methyl nitrostyrene
proceeded well; product 3ao, bearing two vicinal quaternary
stereocenters, was afforded in 81% yield and 93% ee (Table 3,
entry 14). Notably, the success of this Cu-catalyzed regio-
reversed [3+2] cycloaddition could be extended to β-CF3-
substituted alkenes, which can be utilized to prepare
trifluoromethylated pyrrolidines.[16] For example, when β-CF3-
substituted enoate 5a and vinyl sulfone 5b were subjected to the
optimal reaction conditions, products 6aa and 6ab were
generated with high reaction efficiency and excellent regio- and
enantioselectivities (Eqs. 1 and 2).
As presented in Scheme 2a, to demonstrate the practicality
of reaction methodology, we performed a gram-scale experiment
of the model reaction under the optimal conditions. As a result,
1.12 g of chiral pyrroline product 3aa was prepared with high
reaction efficiency and excellent enantioselectivity. Then,
several synthetic transformations were carried out to highlight
the potential uses of this product. For example, the selective
reduction of the ester by LiAlH4 or the nitro group by Zn dust
afforded the corresponding chiral alcohol 7 or amine 8 in high
yields without erosion of the enantiomeric excess (Scheme 2b
and 2c). Furthermore, chiral amine 8 was converted to amino
alcohol 9 in good yield by treatment with LiAlH4 (Scheme 2d).
Figure 2. Control experiments of the iminoesters with varied α-substituted
groups and a proposed stereoinduction mode.
t
Remarkably, treatment of 8 with BuMgCl in THF provided β-
lactam 10 in 88% yield and 97% ee (Scheme 2e).
In summary, we have successfully developed a copper-
catalyzed asymmetric regio-reversed [3+2] cycloaddition of
iminoesters with nitroolefins and CF3-containing alkenes. A wide
range of polysubstituted chiral pyrrolidines bearing at least one
chiral quaternary center were generated in high yields and with
excellent regio-, diastereo- and enantioselectivities. The success
of this reaction in achieving the umpolung of imines can be
attributed to the use of our chiral P,S-ligand and the unique
effect of the α-aryl group of the iminoesters.
Acknowledgements
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10.1002/anie.201802492
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COMMUNICATION
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We are grateful to the NNSFC (No. 21772052, 21772053,
21622201 and 21472057), the Program of Introducing Talents of
Discipline to Universities of China (111 Program, B17019), the
Foundation for the Author of National Excellent Doctoral
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Keywords: umpolung of imines • dipolar cycloaddition • chiral
P,S ligand • azomethine ylide • nitroolefin
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10.1002/anie.201802492
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Heterocycles
Bin Feng,# Liang-Qiu Lu,# Jia-Rong Chen,
Guoqiang Feng, Bin-Qing He, Bin Lu, and
Wen-Jing Xiao*
Page No. – Page No.
Umpolung of Imines Enables Catalytic
Asymmetric Regio-Reversed [3+2]
Cycloadditions of Iminoesters with
Nitroolefins
A copper-catalyzed regio-reversed asymmetric [3+2] cycloaddition of iminoesters with
nitroolefins was disclosed for the first time. This protocol allows the facile synthesis of
polysubstituted chiral pyrrolidines bearing at least one chiral quaternary center in high
yields with excellent regio-, diastereo- and enantioselectivities. The application of chiral
P,S-ligands and the unique effect of α-aryl groups on the iminoesters were the keys to
the success of this method. The practicality and versatility of the reaction methodology
were also demonstrated.
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