Enantioselective Copper-Catalyzed Alkylation of Quinoline N-Oxides with Vinylarenes

Article abstract of DOI:10.1002/anie.201709411

An asymmetric copper-catalyzed alkylation of quinoline N-oxides with chiral Cu–alkyl species, generated by migratory insertion of a vinylarene into a chiral Cu?H complex, is reported. A variety of quinoline N-oxides and vinylarenes underwent this Cu-catalyzed enantioselective alkylation reaction, affording the corresponding chiral alkylated N-heteroarenes in high yield with high-to-excellent enantioselectivity. This enantioselective protocol represents the first general and practical approach to access a wide range of chiral alkylated quinolines.

Full text of DOI:10.1002/anie.201709411

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Accepted Article
Title: Enantioselective Copper-Catalyzed Alkylation of Quinoline N-
Oxides with Vinylarenes
Authors: Songjie Yu, Hui Leng Sang, and Shaozhong Ge
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709411
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10.1002/anie.201709411
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Copper-Catalyzed Alkylation of Quinoline N-
Oxides with Vinylarenes
Songjie Yu, Hui Leng Sang, and Shaozhong Ge*
Abstract: We report an asymmetric copper-catalyzed alkylation of
quinoline N-oxides with chiral Cu-alkyl species generated by
migratory insertion of vinylarene into a chiral Cu-H complex. A
variety of quinoline N-oxides and vinylarenes underwent this Cu-
catalyzed enantioselective alkylation reaction, affording the
corresponding chiral alkylated N-heteroarenes in high isolated yields
with high to excellent enantioselectivities. This enantioselective
protocol represents the first general and practical approach to
access a wide range of chiral alkylated quinolines.
bis(boryl)alkanes[11] or Grignard reagents.[12] However, the
asymmetric alkylation of quinoline N-oxides to prepare chiral 2-
alkyl quinolines has not been developed yet. To realize this
asymmetric alkylation, we rationalized that the catalytic
generation of a chiral metal alkyl species would be a key step.
A) Stereospecific coupling of pyridine derivatives with chiral reagents
R
Pd catalysts
R
R'
+
X
R'
N
N
N
M
M = Sn, B, or Zn
R
R'
R"
R'
R
R"
Li
+
low T (-78 °C)
N
Bpin
Chiral alkylated N-heteroarenes have found broad applications
in medicinal chemistry, material sciences, and coordination
chemistry.[1] Even though numerous methods have been
developed to prepare alkylated N-heteroarenes,[2] protocols for
asymmetric synthesis of chiral alkylated N-heteroaromatics are
rather limited. Stereospecific cross-coupling reactions of N-
heteroaryl halides with optically pure organotin,[3] organoboron,[4]
and organozinc reagents[5] or lithiated N-heteroarenes with chiral
alkylboronates[6] have been developed to prepare chiral
alkylated N-heteroarenes (Scheme 1A). However, these
stereospecific transformations require stoichiometric amounts of
optically pure reagents and do not create new stereogenic
centers.[7] In 2014, Hou reported a Sc-catalyzed asymmetric
hydroheteroarylation of aliphatic alkenes with 2-substituted
pyridines (Scheme 1B).[8] However, this reaction requires a
highly moisture- and air-sensitive Sc-alkyl catalyst precursor and
the highly electrophilic nature of this Sc-catalyst limits the
reaction scope. Furthermore, quinolines do not undergo this Sc-
catalyzed asymmetric hydroarylation because they show
stronger coordination to scandium center than 2-substituted
pyridines.[8] Very recently, Buchwald and coworkers reported an
asymmetric cross coupling of heteroaryl halides with vinylarenes
and this transformation requires the combination of palladium
B) Enantioselective hydroheteroarylation of alkenes with pyridines
chiral cationic Sc(III) catalyst
R'
+
R'
R
N
R
N
Me
C) Pd/Cu-catalyzed asymmetric coupling of Halopyridines with vinylarenes
Me
Ar
Ar
Me
Cu
Pd/Cu catalysts
X
+
(L*)
N
N
D) Enantioselective heteroarylation of vinylarenes with heteroaromatic N-oxides (this work)
chiral
Ar
(L*)Cu-H
R
Ar
R = H or Alkyl
+
R
N
O
N
R
(L*)
Cu
Ar
Scheme 1. General synthesis of chiral alkylated six-membered nitrogen
heteroaromatic compounds.
Enantioselective insertion of alkenes into a chiral metal-
hydride bond represents a general approach to access chiral
metal-alkyl species.[13] Very recently, chiral Cu-alkyl complexes,
formed by migratory insertion of alkenes into a chiral Cu-H
species,[14] have presented a platform for a wide range of
asymmetric organic reactions and they can readily react with
various electrophiles including hydroxylamine O-benzoylester,[15]
carbonyl compounds,[16] imines[17] and allyl halides.[18] We
envisioned that a chiral Cu-alkyl species, generated by insertion
of alkenes into a chiral Cu-H species, could react with quinoline
N-oxides to produce chiral 2-alkylated quinolines (Scheme 1D).
Challenges to this enantioselective protocol include competitive
reduction of quinoline N-oxides to quinolines by hydrosilanes in
the presence of Cu-H catalyst and the potential catalyst
deactivation by quinolines.[19] Nevertheless, if these challenges
could be met, this strategy would represent a practical protocol
to prepare chiral alkylated quinolines from readily available
quinoline N-oxides and alkenes. Herein, we report a highly
enantioselective Cu-catalyzed alkylation of quinoline N-oxides
with vinylarenes using a chiral Cu-H catalyst.
and copper catalysts.[9] Therefore, the development of
a
practical enantioselective protocol for the synthesis of chiral
alkylated N-heteroarenes from readily accessible starting
materials still remains a challenge.
Challenges in developing metal-catalyzed asymmetric
alkylation of heteroarenes stem from their low electrophilicity
and strong binding affinity to metal catalysts. We reasoned that
the readily available quinoline N-oxides could serve as quinoline
surrogates for the asymmetric alkylation reactions because
oxidizing quinolines into their N-oxides weakens their binding
affinity and enhances their electrophilicity. Accordingly, quinoline
N-oxides have been employed as electrophiles for various
nucleophilic addition reactions.[10] For examples, quinoline N-
oxides undergo a variety of alkylation reactions with gem-
We chose to study the reaction of quinoline N-oxide and 3-
chlorostyrene to identify a chiral copper catalyst and reaction
conditions for this Cu-catalyzed asymmetric transformation. We
tested various chiral bisphosphine ligands, hydrosilanes, and
solvents for this reaction and the experiments are summarized in
Table 1. These reactions were conducted with 5 mol% Cu(OAc)
and 6 mol% chiral ligand in the presence of 2 equivalents of
hydrosilanes at room temperature for 24 h, and 2-alkylated
quinoline 1a was identified as the major product.
[*]
Dr. S. Yu, H. L. Sang, Prof. Dr. S. Ge
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: chmgsh@nus.edu.sg
Homepage: www.geresearchgroup.com
Supporting information for this article is available on the WWW
under http://angewandte.org or from the author.
This article is protected by copyright. All rights reserved.

10.1002/anie.201709411
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COMMUNICATION
Among the reactions conducted with (EtO)3SiH and various
ligands in cyclohexane (entries 1-6), the reaction catalyzed by
Cu(OAc)/(Ra)-DTBM-segphos afforded 1a in high isolated yield
with high enantioselectivity (96% ee, entry 6). Next, we tested
this reaction in various solvents (entries 6-11) and found that the
in high yields (72–95%) with high to excellent enantioselectivities
(84–99% ee). In addition, this protocol was also applied to
benzo[h]quinoline and pyridine N-oxides (1k and 1l) and good
enantioselectivities were achieved, albeit with slightly lower
yields. The reactions of other pyridine N-oxides, such as N-
oxides of pyridine, 2-chloropyridine or 2-methylpyridine,
produced only trace amounts of products. N-oxides of
isoquinoline, 2,2-bypridine, and 1,10-phenanthroline did not
undergo this Cu-catalyzed alkylation under the identified
conditions, probably due to the strong coordination of these N-
heterocycles to the copper center (for inhibition effects of these
solvent does not have
a
significant influence on the
enantioselectivities. The reactions in cyclohexane and hexane
produced 1a in similarly high isolated yields and similarly high
enantioselectivities (entries 6 and 11). Furthermore, we tested a
series of hydrosilanes for this reaction (entries 12-16), and only
the reactions employing alkoxy hydrosilanes afforded product 1a
in high isolated yields and high enantioselectivities (entries 6, 12, N-heterocycles on this alkylation reaction, see SI).
and 13). In addition, the reaction conducted at lower
temperature (5 °C) afforded the product 1a in slightly
Table 2. Scope of quinoline N-oxides[a]
a
Cu(OAc) ( 5 mol%)
Cl
increased yield with similarly high enantioselectivity (entry 17).
(Ra)-DTBM-segphos (6 mol%)
R
(EtO)2MeSiH ( 2 equiv.)
+
R
Table 1. Evaluation of conditions for Cu-catalyzed reaction between 3-
N
O
CyH, 5 °C, 24 h
chlorostyrene with quinoline N-oxide[a]
N
Cl
Me
1a-1n
Cu(OAc) ( 5 mol%)
ligand (6 mol%)
silane (2 equiv.)
Cl
Cl
Cl
Cl
Me
Cl
+
N
O
solvent, tempeature, 24 h
N
Me
N
N
N
1a
Temperature Yield (%)[b] ee (%)[c]
Me
1a, 92% yield; 97% ee
Me
Me
Entry
Silane
Solvent
CyH
Ligand
1a,[b] 94% yield; 97% ee
1b, 86% yield; 95% ee
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
5 °C
1
2
3
(R,R)-quinoxP*
(Ra)-synphos
(R)-Ph-BPE
79
48
61
33
14
67
Cl
Cl
Cl
Me
CyH
CyH
N
Me
N
N
Me
Me
Me
1e, 62% yield; 78% ee
Cl
Me
4
5
6
7
(Ra)-segphos
(Ra)-DM-segphos
CyH
57
64
83
80
12
38
96
91
1c, 80% yield; 94% ee
1d, 92% yield; 96% ee
CyH
Cl
Cl
(Ra)-DTBM-segphos (EtO)3SiH
(Ra)-DTBM-segphos (EtO)3SiH
CyH
F
Br
THF
N
N
N
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
Et2O
8
(Ra)-DTBM-segphos
(Ra)-DTBM-segphos
(Ra)-DTBM-segphos
42
69
63
80
78
85
44
57
23
92
83
90
92
95
95
96
96
92
--
OMe
Me
Me
Me
1f, 79% yield; 84% ee
1g, 75% yield; 99% ee
1h, 85% yield; 98% ee
9
toluene
1,4-dioxane
hexane
CyH
Cl
CH2OTBS Cl
Cl
10
11
12
13
14
15
16
17
MeO2C
(Ra)-DTBM-segphos (EtO)3SiH
N
(MeO)2MeSiH
(Ra)-DTBM-segphos
(Ra)-DTBM-segphos
(Ra)-DTBM-segphos
(Ra)-DTBM-segphos
(Ra)-DTBM-segphos
N
N
Me
Me
Me
(EtO)2MeSiH
Et2SiH2
CyH
1i, 95% yield; 96% ee
1j, 72% yield; 95% ee
1k, 59% yield; 94% ee
CyH
Cl
Cl
Cl
Ph2SiH2
PhSiH3
CyH
N
N
CyH
Ph
N
N
N
97
(Ra)-DTBM-segphos (EtO)2MeSiH
CyH
Me
1l,[c] 44% yield; 87% ee
Me
Me
1m, 21% yield; 69% ee
1n,[c] 14% yield; 49% ee
O
Ph
Me
(Ra)-segphos
O
N
P
tBu
tBu
Ar = C6H5
P
O
O
PPh2
PPh2
O
O
Ph
PAr2
PAr
[a] Conditions: quinoline N-oxide (0.400 mmol), vinylarene (0.200 mmol),
Cu(OAc) (10.0 µmol), (Ra)-DTBM-segphos (12.0 µmol), cyclohexane (1 mL), 5
°C, 24 h; isolated yields, and ee determined by chiral HPLC analysis. [b] (Sa)-
DTBM-segphos was used. [c] 50 oC.
(Ra)-DM-segphos
2 Ar = 3,5-(CH3)2C6H3
Ph
N
P
P
Me
(Ra)-DTBM-segphos
Ar = 3,5-(tBu)2-4-OMe-C6H2
O
O
Ph
(R,R)-Ph-BPE
(R,R)-QuinoxP*
(Ra)-synphos
Table
3
summarized the scope of vinylarenes that
[a] Conditions: quinoline N-oxide (0.400 mmol), 3-chlorostyrene (0.200 mmol),
Cu(OAc) (10.0 µmol), ligand (12.0 µmol), solvent (1 mL), 24 h; [b] isolated
yields; [c] ee was determined by chiral HPLC analysis using the isolated
compound 1a.
underwent this copper-catalyzed asymmetric reaction. In general,
a wide range of vinylarenes containing electronically varied aryl
groups reacted with quinoline N-oxide to afford the
corresponding chiral 2-alkyl quinolines in high isolated yields
with excellent enantioselectivities (1o–1af in Table 3). The
absolute configuration of 1o was assigned as (S) by comparison
of optical rotation with a reported value.[6] Reactive groups, such
as halogens (1t–1w), trifluoromethyl ether (1x), ester (1y), siloxy
(1z), pinacol boronic ester (1aa) and acetal (1ab), were
compatible with the reaction conditions. In addition, a sulfur-
Under the identified conditions (entry 17 in Table 1), we
studied the scope of quinoline N-oxides and vinylarenes that
underwent this asymmetric Cu-catalyzed transformation, and the
results are summarized in Table 2. In general, quinoline N-
oxides with substituents at various positions reacted smoothly
with 3-chlorostyrene to yield the corresponding 2-alkylated
quinolines in high yields and excellent enantioselectivities (1a–
1j). 8-Methyl and 8-methoxyquinoline N-oxides reacted with
decreased enantioselectivities (1e and 1f), which might be due
to the increased steric hindrance around the N-O bond.[20]
Various reactive groups, such as ether (1f), halogen (1g and 1h),
siloxy (1i), and ester (1j), at different positions of quinoline N-
oxides were tolerated, and the alkylation products were isolated
containing
heteroaromatic
alkene
reacted
with
high
enantioselectivity (1ac). (E)-(3-methoxyprop-1-en-2-yl)benzene,
an internal vinylarene, also reacted with good enantioselectivity
(92% ee, 1ad), albeit
Furthermore, we tested the reaction with additional substrates of
a moderate yield was obtained.
mixed quinoline N-oxides and vinyarenes, and these reactions
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10.1002/anie.201709411
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COMMUNICATION
occurred in good yields and excellent enantioselectivities (1ae
and 1af).
chlorostyrene under standard conditions afforded 1a in high
yield with excellent enantioselectivity, but no deuterium was
incorporated into the product (Scheme 2B). However, when
conducted with Ph2SiD2, this reaction afforded 1a-D in high yield
with high enantioselectivity and the deuterium was located in the
methyl group of 1a (Scheme 2C). The results of these
deuterium-labelling experiments support the formation of a Cu-H
intermediate.
To highlight the utility of this enantioselective protocol, we
tested a gram scale reaction of quinoline N-oxide and 3-
chlorostyrene [eq (1)]. This reaction proceeded to full conversion
of 3-chlorostyrene in the presence of 1.5 mol% copper catalyst
and afforded 1a in a high isolated yield and similarly high
enantioselectivity as the reaction run on a smaller scale. In
addition, we demonstrated that the chiral quinoline product 1a
underwent hydrogenation of the pyridine ring, producing a cyclic
amine 2 in high yield and enantioselectivity [eq (2)].
Cu(OAc) (5 mol%)
(Ra)-DTBM-segphos (6 mol%)
40% D
A)
+
Ph2SiD2
N
O
CyH, 5 °C, 24 h
87% yield
N
H/D
Cu(OAc) (5 mol%)
(Ra)-DTBM-segphos (6 mol%)
(EtO)2MeSiH (2 equiv.)
Table 3. Scope of Vinylarenes[a]
Cl
Cl
B)
+
Cu(OAc) ( 5 mol%)
N
O
D
CyH, 5 °C, 24 h
86% yield
N
(Ra)-DTBM-segphos (6 mol%)
(98%D)
Me
R
(EtO)2MeSiH ( 2 equiv.)
+
R
NO deuterium incorporation
N
O
N
CyH, 5 °C, 24 h
Cu(OAc) (5 mol%)
(Ra)-DTBM-segphos (6 mol%)
Ph2SiD2 (96%D) (2 equiv.)
Me
1o-1af
Cl
Cl
+
C)
CF3
Me
N
O
CyH, 5 °C, 24 h
84% yield
N
31% D
C(H/D)3
N
N
N
Me
Me
Me
Scheme 2. Deuterium-labeling experiments
CuOAc + L* + R3SiH
1o, 77% yield; 99% ee
1p, 94% yield; 96% ee
1q, 59% yield; 99% ee
Ph
F
N
N
N
Me
Me
Me
L* = (Ra)-DTBM-segphos
1r, 73% yield; 98% ee
1s, 68% yield; 98% ee
1t, 63% yield; 97% ee
R3SiOH
F
Ar
(L*)CuH
N
F
N
N
Br
Me
Me
Me
1w, 94% yield; 97% ee
1u, 90% yield; 98% ee
1v, 64% yield; 98% ee
R3SiH
OAc
Si(OMe)3
H
Ar
(S)
Me
slow
epimerization
N
Cu(L*)
Cu(L*)
N
OCF3
N
N
R3SiOH
O
(L*)CuOH
SiR3
Ar Me
(S)
Ar
Me
Me
1x, 91% yield; 97% ee
Me
Me
(R)
C
1y, 87% yield; 91% ee
1z, 70% yield; 98% ee
A
A'
R3SiH
path II
Me
O
Bpin
(S)
O
Ar
S
N
path I
H
N
N
N
N
O
Ar
(S)
Me
Me
N
O
Me
Me
Me
1aa, 84% yield; 98% ee
1ab, 64% yield; 99% ee
1ac, 46% yield; 96% ee
Cu(L*)
B
Me
CH2OTBS
F
N
Scheme 3. Proposed catalytic pathways for this Cu-catalyzed asymmetric
alkylation of quinoline N-oxides.
N
N
OMe
Me
Me
1af, 73% yield; 97% ee
1ad, 41% yield; 92% ee
1ae, 66% yield; 99% ee
[a] Conditions: quinoline N-oxide (0.400 mmol), vinylarene (0.200 mmol),
Cu(OAc) (10.0 µmol), (Ra)-DTBM-segphos (12.0 µmol), cyclohexane (1 mL), 5
°C, 24 h; isolated yields, and ee determined by chiral HPLC analysis.
Based on the precedent of the alkylation of quinoline N-
oxides with metal alkyl reagents[12] and the Cu-H-catalyzed
hydrofunctionalization of alkenes,[14] we proposed a possible
catalytic cycle for this Cu-catalyzed asymmetric alkylation
reaction (Scheme 3). Activation of Cu(OAc) with silane in the
presence of (Ra)-DTBM-segphos (L*) generates a chiral Cu-H
species (L*)Cu-H. Enantioselective insertion of vinylarene into
this chiral (L*)Cu-H produces a kinetically formed diastereomer
A with a (S) configuration at the benzylic carbon.[20] This
intermediate A undergoes slow epimerization, by reversible
deinsertion and insertion of vinylarenes into (L*)Cu-H, to form a
thermodynamically more stable diastereomer A’ with a (R)
configuration at the benzylic carbon.[20] Subsequent reaction of A
with quinoline N-oxide via nucleophilic addition generates an
intermediate B. Intermediate B then undergoes aromatization to
release 2-alkylquinoline product and eliminates (L*)CuOH, which
can regenerate (L*)Cu-H by the reaction with hydrosilane
(pathway I in Scheme 3). Alternatively, the intermediate B reacts
with hydrosilane to generate the Cu-H species and a siloxane
intermediate C, which can aromatize to produce the
Cu(OAc) (1.5 mol%)
Cl
(Ra)-DTBM-segphos (1.8 mol%)
Cl
(EtO)2MeSiH (2 equiv.)
+
(1)
(2)
N
O
CyH, 5 °C, 24 h
N
5.0 mmol
Cl
Me
1a, 1.08 g
81% yield; 96% ee
Cl
NaB(CN)H3
HOAc, RT
N
N
H
Me
1a, 97% ee
Me
2, 97% yield, dr = 1.6:1
96% ee (major); 97% ee (minor)
To get a preliminary understanding of this Cu-catalyzed
asymmetric alkylation, we conducted a series of deuterium-
labelling experiments (Scheme 2). The reduction of quinoline N-
oxides with Ph2SiD2 in the presence of chiral copper catalyst let
to 40% deuterium incorporation onto 2-position of quinoline
(Scheme 2A). The reaction of quinoline-2-D N-oxide with 3-
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10.1002/anie.201709411
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COMMUNICATION
[7]
For examples of enantioselective cross-coupling reactions employing a
limited number of heteroaryl halides or boronates, see: a) S. Ge, J. F.
Hartwig, J. Am. Chem. Soc. 2011, 133, 16330; b) N. T. Kadunce, S. E.
Reisman, J. Am. Chem. Soc. 2015, 137, 10480; c) D. Wang, L. Wu, F.
Wang, X. Wan, P. Chen, Z. Lin, G. Liu, J. Am. Chem. Soc. 2017, 139,
6811; d) G. J. Lovinger, M. D. Aparece, J. P. Morken, J. Am. Chem.
Soc. 2017, 139, 3153.
alkylquinoline product (pathway II in Scheme 3). The obtained
(S)-configuration for alkylation products suggests that the
reaction of the chiral alkylcopper species A with quinoline N-
oxide is stereoretentive.
In summary, we have developed the first enantioselective
protocol for alkylation of quinoline N-oxides with vinylrenes to
prepare chiral quinolines using chiral Cu-H catalysts. A variety of
quinoline N-oxides reacted with vinylarenes to produce chiral 2-
alkyl quinolines in high isolated yields with high to excellent
enantioselectivities. In addition, this reaction can be conducted
on a gram scale with a reduced catalyst loading (1.5 mol% Cu).
Therefore, this protocol presents a practical approach to access
optically pure 2-substituted quinolines from readily available
starting materials. Studies to develop a diverse set of other
chiral nucleophiles for asymmetric functionalization of N-
heterocycles will be the subjects of future work.
[8]
[9]
G. Song, W. W. N. O, Z. Hou, J. Am. Chem. Soc. 2014, 136, 12209.
a) S. D. Friis, M. T. Pirnot, S. L. Buchwald, J. Am. Chem. Soc. 2016,
138, 8372; b) S. D. Friis, M. T. Pirnot, L. N. Dupuis, S. L. Buchwald,
Angew. Chem., Int. Ed. 2017, 56, 7242. For a non-asymmetric version
of this reaction, see: K. Semba, K. Ariyama, H. Zheng, R. Kameyama,
S. Sakaki, Y. Nakao, Angew. Chem., Int. Ed. 2016, 55, 6275.
[10] For recent examples: a) L. Bering, A. P. Antonchick, Org. Lett. 2015,
17, 3134; b) H. Wang, Y. Pei, J. Bai, J. Zhang, Y. Wu, X. Cui, RSC Adv.
2014, 4, 26244; c) Y. Lian, S. B. Coffey, Q. Li, A. T. Londregan, Org.
Lett. 2016, 18, 1362; d) H. Yu, C. A. Dannenberg, Z. Li, C. Bolm, Chem.
Asian J. 2016, 11, 54; e) W.-Z. Bi, K. Sun, C. Qu, X.-L. Chen, L.-B. Qu,
S.-H. Zhu, X. Li, H.-T. Wu, L.-K. Duan, Y.-F. Zhao, Org. Chem. Front.
2017, 4, 1595.
[11] a) W. Jo, J. Kim, S. Choi, S. H. Cho, Angew. Chem. Int. Ed. 2016, 55,
9690; b) C. Hwang, W. Jo, S. H. Cho, Chem. Commun. 2017, 53, 7573.
[12] a) H. Andersson, M. Gustafsson, D. Bostrom, R. Olsson, F. Almqvist,
Angew. Chem. Int. Ed. 2009, 48, 3288; b) O. V. Larionov, D. Stephens,
A. Mfuh, G. Chavez, Org. Lett. 2014, 16, 864.
Acknowledgements
This work was supported by the National University of Singapore
(No. R-143-000-614-133) and the Ministry of Education (MOE)
of Singapore (No. R-143-000-635-112). S. Yu thanks Wei Jie
Teo for the assistance with 2H NMR analysis.
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Keywords: asymmetric catalysis • copper • quinoline N-oxide •
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[19] Quinoline N-oxide does not react with (EtO)2MeSiH in the absence of a
copper catalyst. However, quinoline N-oxide was reduced to quinoline
by (EtO)2MeSiH in the presence of a copper catalyst. See SI for the
detailed information.
[3]
[4]
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This article is protected by copyright. All rights reserved.

10.1002/anie.201709411
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Songjie Yu, Hui Leng Sang, and
Shaozhong Ge*
Page No. – Page No.
Enantioselective Copper-Catalyzed
Alkylation of Quinoline N-Oxides with
Vinylarenes
Asymmetric Catalysis: A highly enantioselective copper-catalyzed alkylation of
quinoline N-oxides with vinylarenes using a catalyst generated from Cu(OAc) and
(Ra)-DTBM-segphos was developed. (see the Picture). A wide range of quinoline N-
oxides and vinylarene reacted to afford the corresponding chiral alkylated quinoline
in high isolated yields with excellent enantioselectivities.
This article is protected by copyright. All rights reserved.