Sequential Ir-Catalyzed Allylation/2-aza-Cope Rearrangement Strategy for the Construction of Chiral Homoallylic Amines?

Article abstract of DOI:10.1002/cjoc.202000065

Sequential Ir-catalyzed asymmetric allylation/2-aza-Cope rearrangement of arylidene aminomalonates with allylic carbonates was successfully developed, and a variety of enantioenriched homoallylic amine derivatives were obtained in high yields with good chirality transfer and excellent E/Z-geometry control (up to 99% yield, 96% ee). Compared with previous dual catalytic system established for this transformation, the current mono metal catalytic system provides a simpler and more practical protocol employing the readily available starting materials.

Full text of DOI:10.1002/cjoc.202000065

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Sequential Ir-Catalyzed Allylation/2-aza-Cope Rearrangement Strategy for the
Construction of Chiral Homoallylic Amines
Authors: Ruo-Qing Wang, Chong Shen, Xiang Cheng, Zuo-Fei Wang, Hai-Yan Tao,
Xiu-Qin Dong,* and Chun-Jiang Wang*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000065.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202000065.
ISSN 1001-604X • CN 31-1547/O6
mc.manuscriptcentral.com/cjoc
www.cjc.wiley-vch.de

Sequential Ir-Catalyzed Allylation/2-aza-Cope Rearrangement Strategy
for the Construction of Chiral Homoallylic Amines
Ruo-Qing Wang,a,§ Chong Shen,a,§ Xiang Cheng,a Zuo-Fei Wang,a Hai-Yan Tao,a Xiu-Qin Dong,*a and Chun-Jiang Wang*a,b
a Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan
University, Wuhan, 430072, China.
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, 230021, China.
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion Sequential Ir-catalyzed asymmetric allylation/2-aza-Cope rearrangement of arylidene aminomalonates
with allylic carbonates was successfully developed, and a variety of enantioenriched homoallylic amine derivatives were obtained in high yields with good
chirality transfer and excellent E/Z-geometry control (up to 99% yield, 96% ee). Compared with previous dual catalytic system established for this
transformation, the current mono metal catalytic system provides a simpler and more practical protocol employing the readily available starting materials.
ensuing 2-aza-Cope rearrangement through the release of the
Background and Originality Content
steric hindrance (Scheme 1a).[9] According to the mechanistic
Chiral homoallylic amines and derivatives have been
studies, we found that the stereoselectivity control of chiral copper
represented as an important class of privileged structural units,
catalyst is not indispensable to deliver the final homoallylic amines
which are universally distributed in a number of nature products,
in the dual catalysis system followed by the subsequent acidic
drugs and biologically active molecules.[1] In addition, they can be
hydrolysis. The key role of copper complex is converting aldimine
served as versatile chiral building blocks and key intermediates in
ester under basic condition to form more rigid and nucleophilic
the field of asymmetric synthesis.[2] As a result, highly efficient
metallated azomethine ylide, which initiate the first asymmetric
synthesis of chiral homoallylic amines and derivatives is of
particular interest. Extensive efforts have been made toward the
construction of these scaffolds, and many synthetic strategies have
been studied extensively and well-established.[2a-2b,3-6] Apart from
the traditional reactions of imines with allyl metal reagents or
metalloids under chiral substrate control or by the aid of chiral
auxiliaries,[3] the asymmetric catalytic allylations of imines using
allylic metal[4] or boron reagents[5] have been regarded as the
important synthetic methodologies. However, allylic metal and
boron reagents always required multi-step preparation and are
generally sensitive to air or moisture, which enormously limited
their wide application in organic synthesis. With chiral or achiral
1,1-disubstituted homoallylic amines as the starting materials,
Kobayashi, Rueping, Wulff and Johnson documented chiral
Brønsted acid-catalyzed 2-aza-Cope rearrangement for the
construction of enantioenriched homoallylic amines.[7] Recently, an
allylation[10] step as a nucleophile.[11] In order to make this method
more economical and easy manipulation, it is important to develop
a simple and efficient catalytic system to realize this transformation.
We envisioned that the more active nucleophilic 2-azallyl carbanion
could be readily generated under basic condition in the absence of
copper complex through introducing an additional electron-
withdrawing group at α-position of aldimine esters. Herein, we
successfully developed a sequential Ir-catalyzed asymmetric
allylation/2-aza-Cope rearrangement of easily available arylidene
aminomalonates, affording various enantioenriched homoallylic
amines and derivatives with well chirality transfer and excellent
E/Z-geometry control (Scheme 1b).
Scheme
1
a) Dual Cu/Ir or PTC/Ir-catalyzed allylation/2-aza-Cope
rearrangement; b) Mono metal-catalyzed allylation/2-aza-Cope
rearrangement (This Work).
elegant
Ir-catalyzed
asymmetric
allylation/2-aza-Cope
rearrangement of sterically bulky N-fluorenyl imines to access
chiral homoallylic amines was reported by Niu’s group.[8] Based on
the strategy of synergistic activation, our group developed dual
Cu/Ir and PTC/Ir catalytic system to prepare a series of chiral
homoallylic amines via
a sequential allylation/2-aza-Cope
rearrangement using the sterically bulky α-substituted aldimine
esters as the nucleophiles, which provided the driving force for the
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000065
This article is protected by copyright. All rights reserved.

First author et al.
Report
work:
iBu
or
entry
1
R
base
DBU
solvent
CH2Cl2
3
yield (%)b ee (%)c
Previous
a)
dual Cu/Ir PTC/Ir catalysis
cooperative
Me
CO2
Cu/Ir
iPr (1a)
3aa
90
NR
87
92
88
87
95
80
85
96
NA
93
92
96
96
90
95
95
iBu
NH2
H+
iPr (1a)
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
3aa
3aa
3aa
3aa
3aa
3ba
3ca
3aa
R
N
2
3
N
Me
R'
CO2
R'
R'
R
R
or
PTC/Ir
iPr (1a) Cs2CO3
R
R'
Me
OCO2
work
iPr (1a)
iPr (1a)
iPr (1a)
Et (1b)
tBu (1c)
iPr (1a)
Et3N
TMG
DBU
DBU
DBU
DBU
: mono
R''
This
metal-complex catalysis
4
b)
CO2
5
R''
CO2
R
N
R''
CO2
NH2
Ir
N
R''
R'
H+
6
CO2
7
R
R'
Me
OCO2
8
9d
Results and Discussion
a All reactions were carried out with 0.30 mmol of 1 and 0.20 mmol of 2a in
2 mL of solvent at room temperature within 12 h, then heated in PhMe at
110 °C for 6 h. DBU is 1,8-Diazabicyclo[5.4.0]undec-7-ene, TMG is
1,1,3,3-Tetramethylguanidine. NR = no reaction. NA = not available. b
Yields refer to the isolated products after chromatographic purification.
The ee value was determined by HPLC analysis. d (R,R)-THQ-Phos was used
instead of (S,S,S)-L.
The initial study was began with diisopropyl benzylidene
aminomalonate 1a and methyl cinnamyl carbonate 2a as model
substrates with Ir(I)/(S,S,S)-L complex[12,13] (5 mol%) in CH2Cl2. The
branched allylation product was obtained in good yield with
excellent enantioselectivity (vide infra), then the desired
homoallylic amine derivative 3aa could be readily achieved in high
c
yield with 96% ee through
a stereospecific 2-aza-Cope
With the optimized reaction conditions in hand, we made effort
to investigate the substrate generality of this sequential Ir-
catalyzed allylation/2-aza-Cope rearrangement. A wide range of
diisopropyl arylidene aminomalonates were first examined, and
these results were summarized in Table 2. These arylidene
aminomalonates containing electron-donating (1d-1g, 1m) or
electron-withdrawing (1h-1l, 1n-1o) substituents on the phenyl
ring reacted with cinnamyl carbonate 2a smoothly to give the
corresponding homoallylic amine derivatives (3da-3oa) with
moderate to high yields and excellent enantioselectivities (75%-95%
yields, 89%-96% ee, Table 2, entries 1-12). We found that the
substitution position on the phenyl ring has little effect on the
reactivity and enantioselectivity, and comparable performance was
still achieved for ortho-methyl and ortho-chloro-substituted
aminomalonates (Table 2, entries 3 and 7). The fused 2-
naphthylaldehyde-derived aminomalonate (1p) also worked well,
affording the corresponding product (3pa) with 85% yield and 91%
ee (Table 2, entry 13). Moreover, the heteroaromatic thiophene
aldehyde-derived substrate (1q) was good reaction partner to
provide the desired product (3qa) with 99% yield and 93% ee (Table
2, entry 14). However, alkyl aldehyde-derived aminomalonate was
not compatible in this sequential process probably due to the less
reactivity and fast decomposition of the imine ester.
rearrangement upon heating the allylation intermediate in toluene
o
at 110 C for 6 h (Table 1, entry 1). We found that base played an
important role in Ir-catalyzed allylation step, and no allylation
intermediate was observed in the absence of base (Table 1, entry
2). Subsequently, various bases such as Cs2CO3, NEt3 and TMG,
were inspected in this sequential process (Table 1, entries 3-5), and
DBU was revealed as the best of choice in terms of yield and
enantioselectivity. Variation of ester moiety in benzylidene
aminomalonate was applied to further investigate the reactivity
and enantioselectivity. Although the similar reactivity was
observed with diethyl benzylidene aminomalonate 1b as the
nucleophilic precursor, the enantioselectivity is lower than that
with diisopropyl benzylidene aminomalonate 1a (Table 1, entry 7
vs entry 1). With the bulky di-tert-butyl benzylidene
aminomalonate 1c as the reaction partner, the corresponding
product 3ca was separated with 95% ee albeit with a little lower
yield (Table 1, entry 8). With the chiral ligand (R,R)-THQ-Phos
developed by You’s group,[14] similar level of reactivity and
enantioselectivity was observed (Table 1, entry 9).
Table 1 Optimization reaction conditions for sequential Ir-catalyzed
allylation/2-aza-Cope rearrangement.a
R
CO2
R
CO2
L
S,S,S
Ir(I)/(
(5
)-
%)
Ph
Ph
N
1
+
R
CO2
Table 2 Substrate scope study of imines for sequential Ir-catalyzed
allylation/2-aza-Cope rearrangement.a
PhMe
mol
N
R
CO2
rt
base solvent,
,
110 °C
Ph
Ph
iPr
CO2
Me
OCO2
3
iPr
CO2
2a
-
R'
N
iPr
CO2
L
S,S,S)
Ir(I)/(
(5
N
iPr
CO2
1
mol
PhMe
%)
Ph
N
+
Ph
O
O
rt
110 °C
DBU, CH2Cl2
,
R'
P
N
P
-
Ph
Me
OCO2
3
O
2a
O
Ph
-
entry
R
3
yield (%)b
ee (%)c
L
THQ-Phos
R,R
)
S,S,S
(
)
(
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
1
2
p-MeC6H4 (1d)
m-MeC6H4 (1e)
o-MeC6H4 (1f)
p-tBuC6H4 (1g)
p-ClC6H4 (1h)
3da
3ea
3fa
80
95
76
94
80
75
77
82
80
90
87
91
85
99
95
93
89
93
94
94
90
96
90
92
90
92
91
93
Encouraged by the excellent performance with respect to the
nucleophilic partner, we turned our attention to exploring a variety
of π-allyl precursors for further substrate scope study. As shown in
Table 3, allyl carbonates bearing the substituted groups on the
phenyl ring with diverse electronic properties and different
positions were tolerated well in this sequential transformation,
which led to various enantioenriched homoallylic amine derivatives
(3ab-3am) in high yields and excellent enantioselectivities (89%-99%
yields, 90%-95% ee, Table 3, entries 1-12). The ortho-methyl and
chloro-substituted cinnamyl carbonates (2d, 2i) with steric
hindrance did not react efficiently to obtain the corresponding
products with satisfied yields and enantioselectivities when using
(S,S,S)-L as the chiral ligand. Fortunately, THQ-Phos ligand exhibited
excellent asymmetric induction and catalytic activity for these
ortho-substituted cinnamyl carbonates (Table 3, entries 3 and 8). 2-
Naphthyl substituted allyl carbonate 2n reacted smoothly to
prepare product 3an with 85% yield and 92% ee (Table 3, entry 13).
To our delight, heteroaryl allyl carbonates (2o and 2p) were well
tolerated to deliver the expected products (3ao-3ap) in 65% yield
with 85% ee and in 91% yield with 95% ee, respectively (Table 3,
entries 14 and 15). When methyl crotyl carbonate was tested in this
transformation, only the first allylation step occurred without
further rearrangement probably due to the significantly reduced
steric congestion, and the allylation product 3aq was separated in
86% yield with 93% ee (Table 3, entry 16).
3
4
3ga
3ha
3ia
5
6
m-ClC6H4 (1i)
7
o-ClC6H4 (1j)
3ja
8
p-FC6H4 (1k)
3ka
3la
9
p-BrC6H4 (1l)
10
11
12
13
14
3,5-Me2C6H3 (1m)
2,4-Cl2C6H3 (1n)
p-CF3C6H4 (1o)
2-napthyl (1p)
2-thiophenyl (1q)
3ma
3na
3oa
3pa
3qa
a Unless otherwise noted, all reactions were carried out with 0.30 mmol of
1 and 0.20 mmol of 2a in 2 mL of CH2Cl2 at room temperature within 12-16
h, then heated in PhMe at 110 °C for 6 h. Yields refer to the isolated
products after chromatographic purification. c The ee value was determined
by HPLC analysis.
b
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

Table 3 Substrate scope study of allyl carbonates for sequential Ir-catalyzed allylation/2-aza-Cope rearrangement.a
iPr
CO2
-
iPr
CO2
mol
(5
L
%)
S,S,S)
PhMe
Ir(I)/(
iPrO
N
2C
Ph
+
R''
Me
OCO2
Ph
N
iPr
R''
iPr
rt
,
110 °C
DBU, CH2Cl2
CO2
2
1a
3
iPr
CO2
iPr
iPr
CO2
CO2
CO2
N
iPrO
N
OMe
2C
iPrO
N
iPrO
N
iPrO
2C
2C
Ph
2C
Ph
Ph
Ph
entry 3:
3ad
91%
entry 4: 3ae
entry 1: 3ab
entry 2: 3ac
ee
ee
eeb
ee
94%
94%
93%
93%
89%
97%
91%
yield,
yield,
yield,
iPr
yield,
iPr
CO2
iPr
iPr
CO2
N
CO2
N
CO2
iPrO
N
Cl
2C
Ph
iPrO
iPrO
iPrO
N
2C
2C
2C
Ph
Ph
Ph
OMe
Cl
Cl
entry 5: 3af
entry 6: 3ag
entry 7: 3ah
entry 8:
3ai
ee
ee
ee
eeb
91%
95%
92%
90%
92%
95%
95%
90%
yield,
yield,
yield,
yield,
iPr
CO2
iPr
iPr
iPr
CO2
CO2
N
CO2
Cl
Cl
iPrO
N
Br
F
2C
Ph
entry 12: 3am
iPrO
N
O
O
iPrO
iPrO
N
2C
Ph
2C
2C
Ph
Ph
entry 9: 3aj
entry 10: 3ak
entry 11: 3al
ee
ee
ee
ee
99%
90%
94%
94%
93%
91%
91%
94%
yield,
yield,
yield,
yield,
iPr
iPr
iPr
CO2
N
CO2
CO2
Me
iPrO
iPrO
N
iPrO
2C
N
iPr
2C
2C
Ph
CO2
CO2
Ph
N
iPr
N
S
Ph
Ph
entry 15: 3ap
entry 13: 3an
entry 14: 3ao
entry 16:
3aq
ee
ee
ee
ee
85%
92%
91%
95%
65%
85%
86% 93%
yield,
yield,
yield,
yield,
a Unless otherwise noted, all reactions were carried out with 0.30 mmol of 1a and 0.20 mmol of 2 in 2 mL of CH2Cl2 at room temperature within 12-16 h,
then heated in PhMe at 110 °C for 6 h. Yields refer to the isolated products after chromatographic purification. The ee value was determined by HPLC
analysis. b (R,R)-THQ-Phos was used instead of (S,S,S)-L.
obtained in the first step can be readily converted into compound
In order to reveal the stereochemical outcome of the current
Scheme 2. Ir-catalyzed asymmetric allylation and proposed transition
state for the ensuing 2-aza Cope rearrangement.
sequential
Ir-catalyzed
asymmetric
allylation/2-aza-Cope
rearrangement, the initial branch-selective allylation intermediate
product 3aa' was separated in 92% yield and 96% ee (Scheme 2).
The absolute configuration of 3aa' was deduced to be S-
configuration based on the X-ray crystallography analysis of the
corresponding tert-butyl analogue 3ca'.[15] Therefore, the 2-aza-
Cope rearrangement of (S)-3aa' occurred through six-membered
iPr
CO2
-
L
mol%)
(5
S,S,S)
Ir(I)/
(
Ph
N
iPr
CO2
Ph
Me
OCO2
rt
,
DBU, CH2Cl2
1a
2a
CO2iPr
N
H
chair-like transition state (Zimmerman-Traxler transition state[16]
)
iPrO2C
Ph
Ph
iPr
CO2
Ph
to deliver the homoallylic amine (S)-3aa with well chirality transfer
and excellent E/Z-geometry control.
H
iPr
CO2
iPr
N
CO2
Ph
N
iPr
CO2
Ph
PhMe,
reflux
To demonstrate the synthetic utility of this sequential protocol,
gram-scale reaction of 1a and 2a was conducted under the
optimized reaction condition to afford product 3aa with 82% yield
and 96% ee (Scheme 3, upside). Compound 3aa was easily
transformed to primary homoallylic amine 4 by treatment with
hydroxylamine. The enantioenriched allylation intermediate 3aa'
Ph
90%
3aa'
3aa
ee
ee
96%
yield,
92%
96%
yield,
5 in good yield with maintained enantioselectivity (Scheme 3,
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
downside). Acetylation of 5 in the presence of pyridine furnished
the compound 6. Subsequently, I2-promoted cyclization of 6
provided biologically important pyrrolidine 7 in high yield and high
diastereoselectivity without erosion of enantioselectivity (93%
yield, 9:1 dr, 96% ee).[17]
solvents were removed under vacuum to give a pale yellow solid.
Then, DCM (2 mL), imines 1 (0.3 mmol, 1.5 equiv.), allylic
carbonates 2 (0.2 mmol, 1 equiv.) and DBU (0.20 mmol) were added
sequentially under N2. The mixture was then stirred at rt for 12 h-
16 h. Once allylic carbonate was consumed (monitored by TLC), the
organic solvent was removed and the residue was purified by
column chromatography to afford the desired allylation
intermediate. The obtained intermediate was then dissolved in 2
mL toluene, sealed and stirred for 6 h at 110 °C. After removal of
the solvent, the residue was purified by silica gel flash
chromatography to afford the desired product 3, which was then
directly analyzed by HPLC to determine the enantiomeric excess.
Scheme 3. Gram-scale synthesis and synthetic transformations.
iPr
CO2
-
mol
rt
L
%)
S,S,S)
Ir(I)/(
(5
Ph
Me
OCO2
mmol
Ph
N
iPr
CO2
DBU, CH2Cl2
,
mmol
1a
,
2a
6.0
,
9.0
2.62 g
1.15 g
iPr
CO2
NH2
Ph
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2019xxxxx.
PhMe
NH
2OH•AcOH
N
iPr
CO2
Ph
110 °C
Ph
THF, 50 °C
Ph
3aa
4
,
78%
yield
ee
82%
,
yield
96%
ee
96%
Acknowledgement
iPr
CO2
-
mol
(5
L
%)
S,S,S)
Ir(I)/(
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21525207, 21772147),
Natural Science Foundation of Jiangsu Province (Grant No.
SKB2019041078), Wuhan Morning Light Plan of Youth Science and
Technology (Grant No. 2017050304010307) and the Fundamental
Research Funds for the Central Universities (Grant No.
2042018kf0202). We thank Prof. Shu-Li You at SIOC for generously
providing (R,R)-THQ-Phos. The Program of Introducing Talents of
Discipline to Universities of China (111 Project) is also appreciated.
Ph
Me
OCO2
Ph
N
iPr
CO2
rt
DBU, CH2Cl2
,
1a
2a
Ph
Ph
NH
2OH•AcOH
iPr
CO2
iPr
CO2
iPr
CO2
iPr
CO2
THF, 50 °C
Ph
N
H2N
82%
ee
ee
96%
yield,
3aa'
5
,
92%
96%
,
yield,
AcO
Ph
Ph
rt
iPr
iPr
I2
,
CO2
CO2
References
pyridine/AcCl
rt
iPr
CO2
iPr
CO2
N
H
CH2Cl2
CH2Cl2/H2O
,
AcHN
(a) Doherty, A. M.; Sircar, I.; Kornberg, B. E.; Quin, J., III; Winters, R. T.;
Kaltenbronn, J. S.; Taylor, M. D.; Batley, B. L.; Rapundalo, S. R.; Ryan,
M. J.; Painchaud, C. A. Design and Synthesis of Potent, Selective, and
Orally Active Fluorine-Containing Renin Inhibitors. J. Med. Chem. 1992,
35, 2-14. (b) Puentes, C. O.; Kouznetsov, V. Recent Advancements in
the Homoallylamine Chemistry. J. Heterocyclic. Chem. 2002, 39, 595-
614. (c) Dong, L. M.; Marakovits, J.; Hou, X. J.; Guo, C. X.; Greasley, S.;
Dagostino, E.; Ferre, R.; Johnson, M. C.; Kraynov, E.; Thomson, J.;
Pathak, V.; Murray, B. W. Structure-based Design of Novel Human
Pin1 Inhibitors (II). Bioorg. Med. Chem. Lett. 2010, 20, 2210-2214. (d)
Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and
Applications, Wiley-VCH, Weinheim, Germany, 2010. (e) Guthrie, R.
W.; Kaplan, G. L.; Mennona, F. A.; Tilley, J. W.; Kierstead, R. W.; Mulling,
J. G.; LeMahieu, R. A.; Zawoiski, S.; O’Donnell, M.; Crowley, H.;
Yaremko, B.; Welton, A. F.; J. Med. Chem. 1989, 32, 1820-1835. (f)
Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic
enantioselective formation of C-C bonds by addition to imines and
hydrazones: a ten-year update. Chem. Rev. 2011, 111, 2626-2704.
(a) Yus, M.; González-Gómez, J. C.; Foubelo, F. Diastereoselective
Allylation of Carbonyl Compounds and Imines: Application to the
Synthesis of Natural Products. Chem. Rev. 2013, 113, 5595-5698. (b)
Yus, M.; González-Gómez, J. C.; Foubelo, F. Catalytic Enantioselective
Allylation of Carbonyl Compounds and Imines. Chem. Rev. 2011, 111,
7774-7854. (c) White, J. D.; Hansen, J. D. Total Synthesis of (-)-7-
7
93%
,
6
98%
,
yield
ee
yield
9:1 dr, 96%
Conclusions
In summary, we successfully developed a sequential Ir-
catalyzed asymmetric allylation of readily available arylidene
aminomalonates followed by
a
stereospecific 2-aza-Cope
rearrangement, and a wide range of chiral homoallylic amines and
derivatives could be obtained in high yield with good chirality
transfer and excellent E/Z-geometry control. The sequential
transformations can be performed at gram scale, and the branched
allylation intermediate is readily converted into enantioenriched
pyrrolidine derivative. Compared with our previously reported dual
catalytic systems, the current protocol provides a simpler and more
practical protocol to enantioenriched homoallylic amines.
Experimental
A flame dried Schlenk tube was cooled to rt and filled with N2.
To this flask were added [Ir(COD)Cl]2 (0.005 mmol, 2.5 mol %),
phosphoramidite ligand (S,S,S)-L1 (0.01 mmol, 5 mol %), degassed
THF (0.5 mL) and degassed n-propylamine (0.5 mL). The reaction
mixture was heated at 50 °C for 30 min and then the volatile
Epicylindrospermopsin,
a
Toxic Metabolite of the Freshwater
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
Cyanobacterium Aphanizomenon Ovalisporum, and Assignment of Its
chiral π-allylpalladium catalyst for the allylation of imines.
Tetrahedron Lett. 2000, 41, 131-134. (f) Colombo, F.; Annunziata, R.;
Benaglia, M. Catalytic, enantioselective allylation of α-iminoesters
promoted by silver(I) complexes of chiral imines. Tetrahedron Lett.
2007, 48, 2687-2690. (g) Aydin, J.; Kumar, K. S.; Sayah, M. J.; Wallner,
O. A.; Szabó, K. J. Synthesis and Catalytic Application of Chiral 1,1’-Bi-
2-naphthol- and Biphenanthrol-Based Pincer Complexes:ꢀ Selective
Allylation of Sulfonimines with Allyl Stannane and Allyl Trifluoroborate.
J. Org. Chem. 2007, 72, 4689-4697.
(a) Morrison, R. J.; Hoveyda, A. H. γ-, Diastereo-, and Enantioselective
Addition of MEMO-Substituted Allylboron Compounds to Aldimines
Catalyzed by Organoboron-Ammonium Complexes. Angew. Chem. Int.
Ed. 2018, 57, 11654-11661. (b) van der Mei, F. W.; Miyamoto, H.;
Silverio, D. L.; Hoveyda, A. H. Lewis Acid Catalyzed Borotropic Shifts in
the Design of Diastereo- and Enantioselective γ-Additions of
Allylboron Moieties to Aldimines. Angew. Chem. Int. Ed. 2016, 55,
4701-4706. (c) Jang, H.; Romiti, F.; Torker, S.; Hoveyda, A. H. Catalytic
diastereo- and enantioselective additions of versatile allyl groups to
N-H ketimines. Nat. Chem. 2017, 9, 1269-1275. (d) Silverio, D. L.;
Torker, S.; Pilyugina, T.; Vieira, E. M.; Snapper,M. L.; Haeffner, F.;
Hoveyda, A. H. Simple organic molecules as catalysts for
enantioselective synthesis of amines and alcohols. Nature, 2013, 494,
216-221. (e) Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H.
Enantioselective Synthesis of Homoallylic Amines through Reactions
of (Pinacolato)allylborons with Aryl-, Heteroaryl-, Alkyl-, or Alkene-
Substituted Aldimines Catalyzed by Chiral C1-Symmetric NHC-Cu
Complexes. J. Am. Chem. Soc. 2011, 133, 3332-3335.
(a) Sugiura, M.; Hirano, K.; Kobayashi, S. α-Aminoallylation of
Aldehydes with Ammonia: Stereoselective Synthesis of Homoallylic
Primary Amines. J. Am. Chem. Soc. 2004, 126, 7182-7183. (b) Yeung,
K.; Ruscoe, R. E.; Rae, J.; Pulis, A. P.; Procter, D. J. Enantioselective
Generation of Adjacent Stereocenters in a Copper Catalyzed Three-
Component Coupling of Imines, Allenes, and Diboranes. Angew.
Chem., Int. Ed. 2016, 55, 11912-11916. (c) Wada, R.; Shibuguchi, T.;
Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. Catalytic
Enantioselective Allylation of Ketoimines. J. Am. Chem. Soc. 2006, 128,
7687-7691. (d) Lou, S.; Moquist, P. N.; Schaus, S. E. Asymmetric
Allylboration of Acyl Imines Catalyzed by Chiral Diols. J. Am. Chem. Soc.
2007, 129, 15398-15404. (e) Wu, T. R.; Chong, J. M. Asymmetric
Allylboration of Cyclic Imines and Applications to Alkaloid Synthesis. J.
Am. Chem. Soc. 2006, 128, 9646-9647. (f) Nakamura, K.; Nakamura, H.;
Yamamoto, Y. Chiral π-Allylpalladium-Catalyzed Asymmetric Allylation
of Imines:ꢀ Replacement of Allylstannanes by Allylsilanes. J. Org. Chem.
1999, 64, 2614-2615. (g) Fernandes, R. A.; Yamamoto, Y. The First
Catalytic Asymmetric Allylation of Imines with the Tetraallylsilane-
TBAF-MeOH System, Using the Chiral Bis-π-allylpalladium Complex. J.
Org. Chem. 2004, 69, 735-738. (h) Tan, K. L.; Jacobsen, E. N. Indium-
Mediated Asymmetric Allylation of Acylhydrazones Using a Chiral
Urea Catalyst. Angew. Chem., Int. Ed. 2007, 46, 1315-1317. (i) Zhang,
H.; Gu, Q.; You, S. Recent Advances in Ni-Catalyzed Allylic Substitution
Reactions. Chin. J. Org. Chem. 2019, 39, 15-27.
Absolute Configuration. J. Org. Chem. 2005, 70, 1963-1977. (d)
Lathrop, S. P.; Pompeo, M.; Chang, W. T. T.; Movassaghi, M.
Convergent and Biomimetic Enantioselective Total Synthesis of (-)-
Communesin F. J. Am. Chem. Soc. 2016, 138, 7763-7769.
(a) Schaus, J. V.; Jain, N.; Panek, J. S. Asymmetric Synthesis of
Homoallylic Amines and Functionalized Pyrrolidines via Direct Amino-
Crotylation of In Situ Generated Imines. Tetrahedron. 2000, 56, 10263-
10274. (b) Qiao, X. C.; Zhu, S. F.; Chen, W. Q.; Zhou, Q. L. Palladium-
Catalyzed Asymmetric Umpolung Allylation of Imines with Allylic
Alcohols. Tetrahedron: Asymmetry. 2010, 21, 1216-1220. (c) Vilaivan,
T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. Indium-
Mediated Asymmetric Barbier-Type Allylation of Aldimines in
Alcoholic Solvents: Synthesis of Optically Active Homoallylic Amines. J.
Org. Chem. 2005, 70, 3464-3471. (d) Huber, J. D.; Leighton, J. L. Highly
Enantioselective Imine Cinnamylation with
a
Remarkable
Diastereochemical Switch. J. Am. Chem. Soc. 2007, 129, 14552-14553.
(e) Huber, J. D.; Perl, N. R.; Leighton, J. L. Allylsilane-Vinylarene Cross-
Metathesis Enables a Powerful Approach to Enantioselective Imine
Allylation. Angew. Chem., Int. Ed. 2008, 47, 3037-3039. (f) Liu, M.;
Shen, A.; Sun, X. W.; Deng, F.; Xu, M. H.; Lin, G. Q. Dramatic Lithium
Chloride Effect on the Reaction Stereocontrol in Zn-mediated
Asymmetric Cinnamylation: Highly Practical Synthesis of β-aryl
Homoallylic Amines. Chem. Commun. 2010, 46, 8460-8462. (g) Sirvent,
J. A.; Foubelo, F.; Yus, M. Diastereoselective indium-mediated
allylation of N-tert-butanesulfinyl ketimines: easy access to
asymmetric quaternary stereocenters bearing nitrogen atoms. Chem.
Commun. 2012, 48, 2543-2545. (h) Guo, T.; Song, R.; Yuan, B. H.; Chen,
X. Y.; Sun, X. W.; Lin, G. Q. Highly Efficient Asymmetric Construction of
Quaternary Carbon-Containing Homoallylic and Homopropargylic
Amines. Chem. Commun. 2013, 49, 5402-5404. (i) Grellepois, F.; Jamaa,
A. B.; Rosa, N. S. α-Trifluoromethylated Tertiary Homoallylic Amines:
Diastereoselective Synthesis and Conversion Into β-Aminoesters, γ-
and δ-Aminoalcohols, Azetidines and Pyrrolidines. Org. Biomol. Chem.
2017, 15, 9696-9709. (j) Berger, R.; Duff, K.; Leighton, J. L.
Enantioselective Allylation of Ketone-Derived Benzoylhydrazones:
Practical Synthesis of Tertiary Carbinamines. J. Am. Chem. Soc. 2004,
126, 5686-5687. (k) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. Toward
a Versatile Allylation Reagent: Practical, Enantioselective Allylation of
Acylhydrazones Using Strained Silacycles. J. Am. Chem. Soc. 2003, 125,
9596-9597. (l) Cook, G. R.; Maity, B. C.; Kargbo, R. Highly
Diastereoselective Indium-Mediated Allylation of Chiral Hydrazones.
Org. Lett. 2004, 6, 1741-1743.
(a) Nakamura, H.; Nakamura, K.; Yamamoto, Y. Catalytic Asymmetric
Allylation of Imines via Chiral Bis-π-allylpalladium Complexes. J. Am.
Chem. Soc. 1998, 120, 4242-4243. (b) Gastner, T.; Ishitani, H.; Akiyama,
R.; Kobayashi, S. Highly Enantioselective Allylation of Imines with a
Chiral Zirconium Catalyst. Angew. Chem., Int. Ed. 2001, 40, 1896-1898.
(c) Fernandes, R. A.; Yamamoto, Y. Catalytic Asymmetric
Carbalkoxyallylation of Imines with the Chiral Bis-π-allylpalladium
Complex. J. Org. Chem. 2004, 69, 3562-3564. (d) Fernandes, R. A.;
Stimac, A.; Yamamoto, Y. Chiral Bis-π-allylpalladium Complex
Catalyzed Asymmetric Allylation of Imines:ꢀ Enhancement of the
Enantioselectivity and Chemical Yield in the Presence of Water. J. Am.
Chem. Soc. 2003, 125, 14133-14139. (e) Bao, M.; Nakamura, H.;
Yamamoto, Y. Preparation and application of a polymer-supported
(a) Sugiura, M.; Mori, C.; Kobayashi, S. Enantioselective Transfer
Aminoallylation:ꢀ Synthesis of Optically Active Homoallylic Primary
Amines. J. Am. Chem. Soc. 2006, 128, 11038-11039; (b) Rueping, M.;
Antonchick, A. P. Catalytic Asymmetric Aminoallylation of Aldehydes:
A Catalytic Enantioselective Aza-Cope Rearrangement. Angew. Chem.
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Int. Ed. 2008, 47, 10090-10093; (c) Ren, H.; Wulff, W. D. Direct
Synthesis of (2S,4R)-4-Hydroxyproline from (S)-O-Benzylglycidol by a
Catalytic Asymmetric Aminoallylation of Aldehydes: Synergism of
Chiral and Nonchiral Brønsted Acids. J. Am. Chem. Soc. 2011, 133,
5656-5659; (d) Goodman, C. G.; Johnson, J. S. Asymmetric Synthesis
of β-Amino Amides by Catalytic Enantioconvergent 2-Aza-Cope
Rearrangement. J. Am. Chem. Soc. 2015, 137, 14574-14577; (e)
Novel Cyclization. J. Chem. Soc., Chem. Commun., 1988, 1527-1528.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
Horowitz, R. M.; Geissman, T. A.
A Cleavage Reaction of α-
Allylbenzylamines. J. Am. Chem. Soc. 1950, 72, 1518-1522.
(a) Liu, J.; Cao, C. G.; Sun, H. B.; Zhang, X.; Niu, D. W. Catalytic
Asymmetric Umpolung Allylation of Imines. J. Am. Chem. Soc. 2016,
138, 13103-13106. (b) Wang, Y.; Deng, L.-F.; Zhang, X.; Niu, D. Catalytic
Asymmetric synthesis of α-Tetrasubstituted α-Trifluoromethyl
Homoallylic Amines by Ir-Catalyzed Umpolung Allylation of Imines.
Org. Lett. 2019, 21, 6951-6956. (c) Cao, C.-G.; He, B.; Fu, Z.; Niu, D.
Synthesis of β3-Amino Esters by Iridium-Catalyzed Asymmetric Allylic
Alkylation Reaction. Org. Process Res. Dev. 2019, 23, 1758-1761.
(a) Wei, L.; Zhu, Q.; Xiao, L.; Tao, H.-Y.; Wang, C.-J. Synergistic Catalysis
for Cascade Allylation and 2-aza-cope Rearrangement of Azomethine
Ylides. Nat. Commun. 2019, 10, 1594-1605. (b) Wei, L.; Xiao, L.; Wang,
Z.-F.; Tao, H.-Y.; Wang, C.-J. Ir/PTC Cooperatively Catalyzed
Asymmetric Cascade Allylation/2-aza-Cope Rearrangement: An
Efficient Route to Homoallylic Amines from Aldimine Esters. Chin. J.
Chem. 2020, 38, 82-86. (c) Shi, L.-M.; Sun, X.-S.; Shen, C.; Wang, Z.-F.;
Tao, H.-Y.; Wang, C.-J. Catalytic Asymmetric Synthesis of α-
Trifluoromethyl Homoallylic Amines via Umpolung Allylation/2-Aza-
Cope Rearrangement: Stereoselectivity and Mechanistic Insight. Org.
Lett. 2019, 21, 4842-4848. (d) Shen, C.; Wang, R.-Q.; Wei, L.; Wang, Z.-
F.; Tao, H.-Y.; Wang, C.-J. Catalytic Asymmetric Umpolung Allylation/2-
Aza-Cope Rearrangement for the Construction of α-Tetrasubstituted
α-Trifluoromethyl Homoallylic Amines. Org. Lett. 2019, 21, 6940-6945.
Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen. G.; You, S.-L.
Iridium-Catalyzed Asymmetric Allylic Substitution Reactions. Chem.
Rev. 2019, 119, 1855-1969.
(a) Wei, L.; Zhu, Q.; Xu, S.-M.; Chang, X.; Wang, C.-J. Stereodivergent
Synthesis of α,α-Disubstituted α-Amino Acids via Synergistic Cu/Ir
Catalysis. J. Am. Chem. Soc. 2018, 140, 1508-1513. (b) Huo, X. H.;
Zhang, J. C.; Fu, J. K.; He, R.; Zhang, W. B. Ir/Cu Dual Catalysis: Enantio-
and Diastereodivergent Access to α,α-Disubstituted α-Amino Acids
Bearing Vicinal Stereocenters. J. Am. Chem. Soc. 2018, 140, 2080-2084.
(a) Kiener, C. A.; Shu, C., Incarvito, C.; Hartwig, J. F. Identification of an
Activated Catalyst in the Iridium-Catalyzed Allylic Amination and
Etherification. Increased Rates, Scope, and Selectivity. J. Am. Chem.
Soc. 2003, 125, 14272-14273; (b) Hartwig, J. F.; Stanley, L. M.
Mechanistically Driven Development of Iridium Catalysts for
Asymmetric Allylic Substitution. Acc. Chem. Res. 2010, 43, 1461-1475.
Teichert, J. F.; Feringa, B. L. Phosphoramidites: Privileged Ligands in
Asymmetric Catalysis. Angew. Chem. Int. Ed. 2010, 49, 2486-2528.
Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. Iridium-Catalyzed
Allylic Alkylation Reaction with N-Aryl Phosphoramidite Ligands:
Scope and Mechanistic Studies. J. Am. Chem. Soc. 2012, 134, 4812-
4821.
CCDC 1969230 (3ca') contains the supplementary crystallographic
data for this paper.
Zimmerman, H. E.; Traxler, M. D. The Stereochemistry of the Ivanov
and Reformatsky Reactions. J. Am. Chem. Soc. 1957, 79, 1920-1923.
Takano, S.; Iwabuchi, Y.; Ogasawara, K. Concise Stereoselective
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Entry for the Table of Contents
Page No.
R''
CO2
R''
CO2
Sequential Ir-Catalyzed Allylation/2-aza-Cope
Rearrangement Strategy for the Construction of
Chiral Homoallylic Amines
R'' H
CO2
R
N
R''
CO2
Ir
N
R''
CO2
R''O
R'
R
2C
N
R'
Ir-catalyzed
allylation
2-aza-Cope
rearrangement
R
R'
Me
OCO2
to 99%
to 96%
H
up
up
yield
ee
Sequential Ir-catalyzed asymmetric allylation/2-aza-Cope rearrangement of arylidene amino-
malonates with allylic carbonates was successfully developed, and a variety of enantioenriched
homoallylic amine derivatives were obtained in high yields with good chirality transfer and excellent
E/Z-geometry control (up to 99% yield, 96% ee). Compared with previous dual catalytic system
established for this transformation, the current mono metal catalytic system provides a simpler and
more practical protocol employing the readily available starting materials.
Ruo-Qing Wang,a,§ Chong Shen,a,§ Xiang Cheng,a
Zuo-Fei Wang,a Hai-Yan Tao,a Xiu-Qin Dong,*a and
Chun-Jiang Wang*a,b
a Department, Institution, Address 1
E-mail:
c Department, Institution, Address 3
E-mail:
b Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim
This article is protected by copyright. All rights reserved.