Nickel-Catalyzed Asymmetric Reductive 1,2-Carboamination of Unactivated Alkenes

Article abstract of DOI:10.1002/anie.201913743

Starting from diverse alkene-tethered aryl iodides and O-benzoyl-hydroxylamines, the enantioselective reductive cross-electrophilic 1,2-carboamination of unactivated alkenes was achieved using a chiral pyrox/nickel complex as the catalyst. This mild, modular, and practical protocol provides rapid access to a variety of β-chiral amines with an enantioenriched aryl-substituted quaternary carbon center in good yields and with excellent enantioselectivities. This process reveals a complementary regioselectivity when compared to Pd and Cu catalysis.

Full text of DOI:10.1002/anie.201913743

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Nickel-Catalyzed Asymmetric Reductive 1,2-Carboamination of
Unactivated Alkenes
Authors: Jun He, Yuhang Xue, Bo Han, Chunzhu Zhang, You Wang,
and Shaolin Zhu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913743
Angew. Chem. 10.1002/ange.201913743
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10.1002/anie.201913743
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed Asymmetric Reductive 1,2-Carboamination of
Unactivated Alkenes
Jun He, Yuhang Xue,† Bo Han,† Chunzhu Zhang, You Wang,* and Shaolin Zhu*
Dedicated to the 100th anniversary of the School of Chemistry and Chemical Engineering, Nanjing University
Abstract: Starting from diverse alkene-tethered aryl iodides and O-
benzoyl-hydroxylamines, the enantioselective reductive cross-
electrophilic 1,2-carboamination of unactivated alkenes was
achieved using a chiral pyrox−nickel complex as the catalyst. This
mild, modular, and practical protocol provides rapid access to a
variety of β-chiral amines with an enantioenriched aryl-substituted
quaternary carbon center in good yield and with excellent
postulated that the readily prepared electrophilic nitrogen
source,[10] O-benzoyl-hydroxylamine, could be used with an aryl
halide, another electrophile, to undergo reductive alkene
carboamination producing the desired β-aryl-substituted chiral
amine. As shown in Figure 1c, we anticipated that the
arylnickel(II) species generated through the oxidative addition of
aryl iodide with a nickel catalyst could undergo an asymmetric
enantioselectivity. This process reveals
a
complementary
intramolecular cyclization reaction with
a
tethered 1,1-
regioselectivity when compared to Pd and Cu catalysis.
disubstituted alkene. The resulting alkylnickel(II) species with an
all-carbon quaternary center at the adjacent position could be
reduced in situ to afford the alkylnickel(I) intermediate and
Alkenes are versatile and readily available starting
materials for many types of transformations, including
undergo
a
sequential electrophilic amination reaction[11] to
introduce the desired amine. It is critical to the success of this
design, that the O-benzoyl-hydroxylamine meets two
requirements. First, the intramolecular cyclization must be rapid
compared to the undesired competitive reductive cross-
electrophilic coupling. Second, the O-benzoyl-hydroxylamine
must be stable enough to avoid decomposition under the
reductive conditions.
hydrogenation[1],
hydrofunctionalization[2],
and
difunctionalization[3]. In particular, transition-metal-catalyzed
asymmetric difunctionalization of alkenes,[4,5] leading to
concomitant introduction of two functional groups into a C=C
double bond in a catalytic and enantioselective manner, is a
protocol enabling fast increase in molecular complexity and
direct access to a diverse set of densely functionalized chiral
building blocks from simple starting materials. Substantial efforts
to achieve asymmetric alkene 1,2-carboamination using Pd[6]
and Cu[7] catalysts have been reported but these transformations
produce only α-chiral amines in a highly regioselective fashion.
a
Transition-matal-catalyzed asymmetric alkene 1,2-carboamination
opposite
regioselectivity
R1
Ar
N
or
R1
R2
Pd
Cu
R1
R2
N
Ar
R2
alkene
known
challenge
α-chiral amine
β-chiral amine
Catalytic
asymmetric
carboamination
with
opposite
regioselectivity to access β-chiral amines remains a significant
unexplored challenge (Figure 1a). Recently, β-chiral amines
were obtained from alkenes by Pd[6g] and Cu[7d] catalysts with
moderate ee, but the alkenes were limited to dihydrofurans and
cyclopropenes. β-Chiral amines are common in pharmaceuticals
and natural products, and their direct construction through
enantioselective alkene 1,2-carboamination is highly desirable.
Simultaneous regioselective introduction of an aryl and an amino
group into an unactivated 1,1-disubstituted olefin would lead to
the synthesis of β-chiral amines with an enantioenriched aryl-
substituted quaternary carbon at the β-position, a privileged
b
Representative β-chiral amines with β-aryl-substituted quaternary stereocenter
Natural products:
Pharmaceuticals:
N
H
R
N
N
O
N
H
HO
R = H, horsfiline
R= OMe, amorolfine
(-)-aphanorphine
(-)-meptazinol
(meptid)
c
Modular strategy: Ni-catalyzed asymmetric reductive alkene carboamination
4° stereocenter
Ni
X
R3
N
R4
R2
Ar
R3
R1
R2
R'
+
structure found in
a
number of natural products and
OBz
N
reductive
olefin carboamination
R4
Y
pharmaceuticals (Figure 1b).
Although nickel has been widely used over the past
reductive
elimination
oxidative addition
/cyclization
L*nNi0
decade
in
cross-coupling
chemistry,[9]
Ni-catalyzed
R2
enantioselective alkene difunctionalization has been reported
only rarely.[5a-k] To realize asymmetric 1,2-carboamination[8], we
N
OBz
Ar
NiII
Ar
N
R1
R2
R1
R2
Zn
reduction
NiI
R'
NiIII
OBz
OA
Y
■ β-chiral amine
■ quaternary stereocenter
■ mild/broad scope
[*]
[†]
J. He, Y. Xue, B. Han, C. Zhang, Dr. Y. Wang, and Prof. S. Zhu
State Key Laboratory of Coordination Chemistry, Chemistry and
Biomedicine Innovation Center (ChemBIC), School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing, 210093,
(China)
Figure 1. Design plan: Access to β-chiral amines with a β-aryl-substituted
quaternary stereocenter via Ni-catalyzed reductive alkene carboamination.
E-mail: shaolinzhu@nju.edu.cn; wangyou@nju.edu.cn
These authors contributed equally.
Our investigations began with the enantioselective 1,2-
carboamination of the aryl iodide tethered alkene (1a) with O-
benzoyl-hydroxylamine (2a) (Table 1). After extensive
examination of nickel sources, ligands, reductants, additives,
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201913743
Angewandte Chemie International Edition
COMMUNICATION
solvents, and temperature, we found that the desired β-chiral
amine (3a)[12] could be obtained in 74% isolated yield and 96%
ee under mild conditions in the presence of a Ni/pyrox catalyst
(Table 1, entry 1). Use of other nickel precatalysts, including
Ni(cod)2, led to slightly reduced yields but comparable ee (entry
2). The use of the structurally similar tBu-Pyrox ligand (L2) led to
somewhat lower yield (entry 3) and Ph-Pyrox ligand (L3)
provided a poor yield and ee (entry 4). Use of the bioxazoline
ligands (L4) or (L5) delivered only traces of the desired product
(entry 5). The addition of a co-catalyst, cobalt(II) phthalocyanine
(CoPc),[13] improved the yield (entry 6). Replacement of the
reductant Zn0 by Mn0 led to essentially no coupling product
(entry 7). The reactivity could however be significantly improved
by the addition of TMSCl as an additive (entry 1 vs entry 8). N-
Methyl-2-pyrrolidone (NMP) was shown to be a less effective
solvent and tetrahydrofuran (THF) was shown to be an
unsuitable solvent (entries 9 and 10). Inferior results were
obtained when the cross-coupling was conducted at higher
temperatures or using other amination reagents[14], revealing the
subtle interplay of the reagents in this reaction (entries 11 and
12). A lower catalyst loading could be used, producing only a
slightly reduced yield and comparable ee (entry 13). The
reaction was conducted at the 5 mmol level to determine its
scalability (entry 14). At this scale, only a slightly diminished
yield was observed with unchanged enantioselectivity,
demonstrating the robustness of this catalytic system.
smoothly (Table 2). Both electron-rich (1b–1e) and electron-
deficient (1f–1i) substituents on the aryl ring were well tolerated,
affording the cyclized amination products with good yields and
high enantioselectivity. Of particular interest is that a potential
cross-coupling partner, the aryl bromide (1g), remained intact
and was available for further derivatization. A variety of alkyl-
substituted alkenes were subject to the reaction. These had
linear (1j–1l and 1n–1p) and branched (1m) alkyl groups,
although more steric hindered alkyl group led to a slight lower ee
(1m vs 1j–1l). As anticipated, our protocol is also efficient with
alkene substrates containing a variety of functional groups,
including a furan (1n), ethers (1o, 1p), and an olefin (1p).
Accordingly, alkenes tethered with an all carbon chain (1q–1t)
delivered indanes in good yields with excellent enantioselectivity.
Table 2: Scope of alkene-tethered aryl iodide coupling partners.[a]
I
R2
10 mol% NiI2 , 12 mol% L1
O
R1
10 mol% CoPc
NBn2
R2
+
R1
X
Bn2N
O
Mes
3.0 equiv. Zn
3.0 equiv. TMSCl
DMF (0.20 M), 35 °C, 24 h
X
1
2a (1.5 equiv.)
3
i
Pr
R
NBn2
NBn2
NBn2
O
O
O
Me
MeO
3e 60% yield, 96% ee
NBn2
3b R = Me, 67% yield, 96% ee
3c R = tBu, 66% yield, 96% ee
3d 70% yield, 96% ee
F3C
R
NBn2
NBn2
O
O
O
MeO2C
3f R = F, 52% yield, 94% ee
3g R = Br, 50% yield, 92% ee
Table 1: Variation of reaction parameters.
3h 66% yield, 94% ee
3i 75% yield, 96% ee
R
10 mol% NiI2 , 12 mol% L1
I
NBn2
O
OMe
NBn2
10 mol% CoPc
+
O
O
O
NBn2
Bn2N
O
Mes
3.0 equiv. Zn
3.0 equiv. TMSCl
DMF (0.20 M), 35 °C, 24 h
NBn2
O
3a
3j R = nC5H11, 65% yield, 94% ee
3k R = nC9H19, 68% yield, 94% ee
3l R = Bn, 71% yield, 96% ee
3m R = iPr, 42% yield, 88% ee
1a
2a
O
(1.0 equiv.)
(1.5 equiv.)
carboamination
O
Yield [%][a]
78(74)
69
3n 60% yield, 94% ee
3o 63% yield, 98% ee
Entry
1
2
Variation from standard conditions
none
ee [%][b]
96
96
96
46
–
O
NBn2
NBn2
Ni(cod)2, instead of NiI2
L2, instead of L1
NBn2
R
R
3
4
69
37
O
3q R = H, 68% yield, 96% ee 3s R = OMe, 62% yield, 94% ee
3r R = Me, 65% yield, 98% ee 3t R = F, 64% yield, 94% ee
L3, instead of L1
3p 55% yield, 96% ee
5
6
L4 or L5, instead of L1
w/o CoPc
trace
68
96
–
[a] The isolated yield and enantioselectivity (ee) for each product is given (0.20
mmol scale, average of two runs).
7
Mn, instead of Zn
w/o TMSCl
trace
23
68
8
9
96
96
–
96
96
96
96
NMP, instead of DMF
THF, instead of DMF
45 °C, instead of 35 °C
Bn2NOBz, instead of 2a
5 mol% NiI2, 6 mol% L1
5 mmol-scale
10
11
12
13
14
trace
66
69
A subsequent survey of hydroxylamine esters revealed
that a range of amino groups can be installed (Table 3). Benzyl-
protected hydroxylamine esters were used in most cases
because benzyl groups can be easily removed to give the
corresponding primary and secondary amines. The current
reaction conditions are compatible with a variety of functional
groups, including an aniline (4b), ethers (4b, 4d, and 4e), a
thioether (4c), a nitrile (4h), a boronic acid pinacol ester (4i), a
furan (4j), a thiophene (4k), an alkyne (4l), a Boc carbamate
(4q), an ester (4r), and an olefin (4s). Potential coupling motifs,
including a boronic acid pinacol ester (4i) and an aryl chloride
(4f) remained intact and could serve as convenient handles for
63
68
O
N
O
O
N
O
N
O
O
L2 R = tBu
L3 R = Ph
N
N
N
N
N
tBu
tBu
Ad
R
tBu
tBu
L1
L4
L5
[a] Yields determined by GC using n-dodecane as the internal standard, the
yield in parentheses is the isolated yield (0.20 mmol scale). [b]
Enantioselectivities determined by chiral HPLC analysis; the absolute
configuration determined by X-ray crystallography. Mes=2,4,6-trimethylphenyl;
Ad=1-adamantyl; TMS=trimethylsilyl, DMF=dimethylformamide.
further derivatization. Notably,
a more sterically hindered
amination reagent, substituted with a secondary alkyl group (4n),
was also well tolerated, and a pre-existing adjacent stereocenter
Under the optimal conditions, a broad range of alkene-
tethered aryl iodides were found to undergo this transformation
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10.1002/anie.201913743
Angewandte Chemie International Edition
COMMUNICATION
in the amination reagent was not affected, with the
carboamination reaction proceeding in a completely catalyst-
controlled manner (4u, 4v).
a
Stoichiometric experiments
I
NBn2
+
Ph
+
()2
1.0 equiv. Ni(cod)2
1.0 equiv. L1
1q
3q
3q-1
3q-2
Table 3: Scope of electrophilic amine coupling partner.[a]
+
DMF (0.20 M)
35 °C, 24 h
then quenched
with H2O
O
NiII
+
I
10 mol% NiI2 , 12 mol% L1
Bn2N
O
Mes
R1
O
R1
N
R2
10 mol% CoPc
N
R2
2a (1.5 equiv.)
3q-3
3q-4
3q-3 & 3q-4
formed via:
+
O
O
Mes
3.0 equiv. Zn
3.0 equiv. TMSCl
O
conditions
w/o Zn
3q
3q-3
9%
3q-1
trace
trace
3q-2
none
none
3q-4
88%
16%
1a
2 (1.5 equiv.)
DMF (0.20 M), 35 °C, 24 h
4
none
27%
3.0 equiv. Zn
46%
4c p-MeS, 74% yield, 96% ee
4d p-MeO, 62% yield, 95% ee
4e p-CF3O, 75% yield, 99% ee
4f 3-Cl-4-F, 65% yield, 96% ee
4g p-CF3, 74% yield, 96% ee
4h p-CN, 63% yield, 98% ee
4i m-Bpin, 67% yield, 96% ee
N
R
Bn
b
Control experiment of free amine
N
O
O
I
N
standard conditions
NBn2
+
Bn2NH
4b 78% yield, 94% ee
Bn
O
O
w or w/o Zn
O
1a
(1.5 equiv.)
3a
nBu
N
N
N
c
Reductive cross-electrophile coupling
Bn
X
Bn
Bn
O
O
O
standard conditions
I
NBn2
O
TMS
4j X = O, 64% yield, 96% ee
4k X = S, 58% yield, 96% ee
+
4l 59% yield, 98% ee
4m 59% yield, 96% ee
Bn2N
O
Mes
2a (1.5 equiv.)
5
i
Pr
N
N
Cy
N
Bn
O
Bn
Bn
O
O
Scheme 1. Control experiments.
4n 61% yield, 96% ee
4o 55% yield, 97% ee
4p 74% yield, 98% ee
CO2Et
N
N
N
()2
In summary, we have established a practical and efficient
reductive 1,2-carboamination process that allows the rapid and
enantioselective construction of β-chiral amines with an
enantioenriched aryl-substituted quaternary carbon. Under the
mild conditions used, excellent chemo- and enantioselectivity
was observed for a wide range of both alkene-tethered aryl
Bn
NBoc
Bn
Bn
O
O
O
4q 53% yield, 94% ee
4r 70% yield, 96% ee
4s 55% yield, 98% ee
iBu
N
Bn
N
Bn
N
iBu
Ph
O
Ph
O
O
4t 58% yield, 96% ee
4u 62% yield, >20:1 dr
4v 62% yield, >20:1 dr
iodide
and
O-benzoylhydroxylamine
partners.
Further
[a] Yield and ee are as defined in Table 2.
investigation of the mechanistic details is currently in progress.
The mechanism shown in Figure 1c was proposed and
preliminary experiments were performed to gain support for it.
With stoichiometric amounts of Zn0, both arylnickel(II) and
alkylnickel(II) complexes are known to be reduced to the
corresponding Ni(I) species and we sought to determine if this
reduction process takes place before or after the cyclization.
Accordingly, a stoichiometric amount of nickel(0) was employed
(Scheme 1a). The presence of zinc reductant was found to be
critical for formation of the desired carboamination product,
suggesting that the amination step involves alkylnickel(I)
intermediates, and cyclized side products (3q-3 and 3q-4) were
observed even in the absence of the zinc reductant. We
therefore tentatively propose that cyclization occurs through the
intramolecular migratory insertion of arylnickel(II) into the
tethered-alkene and the reduction process happens after the
cyclization.
To gain insight into the amination step, we first were able
to rule out SN2 type nucleophilic displacement of the potential
alkyl iodide intermediates by the secondary amine, as no
desired carboamination product (3a) was observed when a free
secondary amine was used (Scheme 1b). In addition, no aniline
product (5) was observed when treating simple aryl iodide with
O-benzoyl-hydroxylamines under the standard conditions
(Scheme 1c), suggesting that arylnickel(I) species is not formed
in our system.[15]
Acknowledgements
Support was provided by NSFC (21702102, 21772087), NSF of
Jiangsu Province (BK20190281), and the Fundamental
Research Funds for the Central Universities (020514380182).
Keywords: • alkenes • asymmetric catalysis • carboamination •
nickel • quaternary stereocenter
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This article is protected by copyright. All rights reserved.

10.1002/anie.201913743
Angewandte Chemie International Edition
COMMUNICATION
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in situ, the aniline product (5) could be obtained (see SI for details).
This article is protected by copyright. All rights reserved.

10.1002/anie.201913743
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Jun He, Yuhang Xue,† Bo Han,†
Chunzhu Zhang, You Wang,* and
Shaolin Zhu*
R2
O
R'
I
O
N
R2
R'
cat. Ni(II)/L*, Zn
N
R''
R1
+
R1
N O
Ar
reductive olefin
carboamination
N
R''
X
Ad
X
Page No. – Page No.
(S)-Ad-Pyrox
alkene
hydroxylamine
β-chiral amine
Nickel-Catalyzed Asymmetric
Reductive 1,2-Carboamination of
Unactivated Alkenes
Catalytic enantioselective installation of two unique functional groups into an
unactivated alkene can rapidly increase the molecular complexity of a compound.
Here we report a Ni-catalyzed reductive cross-electrophilic 1,2-carboamination of
terminal alkenes which permits rapid access to a variety of β-chiral amines with an
enantioenriched aryl-substituted quaternary carbon center.
This article is protected by copyright. All rights reserved.