Asymmetric Lewis Acid Catalyzed Electrochemical Alkylation

Article abstract of DOI:10.1002/anie.201901801

Lewis-acid catalysis and electrochemistry represent two powerful fields that have found widespread application in organic chemistry. Reported herein is an asymmetric electrosynthesis in combination with a chiral Ni catalyst leading to an intermolecular al

Full text of DOI:10.1002/anie.201901801

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Lewis-Acid-Catalyzed Asymmetric Electrochemical Alkylation
Authors: Qinglin Zhang, Xihao Chang, Lingzi Peng, and Chang Guo
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901801
Angew. Chem. 10.1002/ange.201901801
Link to VoR: http://dx.doi.org/10.1002/anie.201901801
http://dx.doi.org/10.1002/ange.201901801

Angewandte Chemie International Edition
10.1002/anie.201901801
COMMUNICATION
Lewis-Acid-Catalyzed Asymmetric Electrochemical Alkylation
Qinglin Zhang, Xihao Chang, Lingzi Peng, Chang Guo*
Abstract: Lewis-acid catalysis and electrochemistry represent two
powerful fields that have found widespread application in organic
chemistry. Herein, we report an asymmetric electrosynthesis via a
chiral Ni-catalyst leading to an intermolecular alkylation reaction in
good yields with excellent enantioselectivities (up to 97% ee).
Mechanistic studies suggested that the Lewis acid-bound radical
intermediate via a single-electron anodic oxidation selectively reacts
with the benzylic radical species to generate the desired adducts.
electrochemistry can be used to produce benzylic ion
intermediates in non-chiral transformations. Waldvogel group
[
5]
disclosed a very efficient procedure for the electrochemical
functionalization of benzylic groups.[
5e]
Inspired by these
chiral Lewis-acid
important studies, we speculated that
a
catalyzed enolate pathway could be involved in the
electrochemistry to access asymmetric alkylation reaction via
benzylic C-H bond activation, thus offering a unique opportunity
with great synthetic potential (Scheme 1b). Herein, we describe
the successful development of such an asymmetric catalytic
system, proving the alkylation products with good
enantioselectivities.
The advances in chiral catalysts to forge new carbon−carbon
bonds with high levels of stereoselectivity have provided access
to chiral molecular scaffolds that are ubiquitous in the fine
chemical and pharmaceutical industries.[1] Among these reactions,
Lewis-acid-catalyzed asymmetric alkylation is renowned for its
breadth of applicability and has been extensively employed in the
enantioselective synthesis.[2] Although Lewis-acid-catalysts are
known to generate chiral enolate equivalents susceptible to
electrophilic attack, expanding the scope of their utility with
unconventional electrophiles continues to present a formidable
challenge.[3]
Electrochemistry has developed significantly over the past
decades as a platform for the discovery of novel synthetic
transformations, providing the opportunity to generate reactive
radical intermediates.[4,5] Although several strategies using
Scheme 1. Design of Lewis-acid catalyzed asymmetric electrochemical
alkylation.
[
6]
[7]
covalent chiral auxiliaries or chiral electrode have been used
to dictate stereochemistry in electrochemical reactions,
asymmetric catalysis for the directly electrochemical reaction with
high enantioselectivity has been rarely reported.[8] Indeed,
Jørgenson group[ and Luo group[10] have independently
established that organocatalysts could efficiently induce the
enantioselectivity of asymmetric additions under electrochemical
conditions. Recently, Meggers and co-workers reported an
elegant asymmetric electrochemical transformation of 2-acyl
imidazoles with silyl enol ethers involving the use of the rhodium-
bound radical intermediate.[11] However, asymmetric radical C-H
activation/radical cross-coupling reaction remains a significant
challenge via direct enantioselective electrosynthesis.[12]
On the basis of this asymmetric electrochemical plan, we began
our investigations into the proposed chiral Lewis-acid-catalyzed
electrochemical alkylation using 2-acyl imidazole (1a) and
trimethylphenol (2a) (Table 1). By screening different types of
solvents and chiral ligands, we found that the desired alkylation
product (3a) could be forged in good yield and excellent
9]
enantioselectivity using Ni(OAc) as Lewis acid along with chiral
2
diamine ligand A by the bulky 2,6-dichloro-phenyl group under the
electrochemical conditions (entry 1 and Supporting Information
for details).[ In the presence of the Ni(OAc) (10 mol%) but with
14]
2
only 10 mol% of ligand A, the desired product 3a could be
obtained, albeit with a slight decrease in enantioselectivity
(entreis 1 and 2). Importantly, a series of control experiments
verified the necessity of each reaction component. In the absence
One particularly versatile and reactive pathway is the
electrochemistry-mediated benzylic C-H bond activation, which
would provide a facial approach to generate key structural motifs
in
a
range of biologically active natural products and
of ligand, Ni(OAc) or electric current, no product was formed
2
pharmaceuticals, such as Equol and related isoflavonoids
(entries 3-5). These experiments indicate that there is no
Scheme 1a).[
13]
Recently, several groups have shown that
(
contribution from a competitive racemic background process, and
also demonstrates the compatibility of these two important modes.
Indeed, moderate yield was observed in the absence of
quinuclidine (entry 6, 39% yield, 94% ee). When 1a and 2a were
subjected under a constant current of 1.0 mA, comparable yield
and selectivity was observed (entry 7). Further exploration
showed that with Pt as electrodes in the undivided cell 3a could
be converted in 64% yield with 93% ee (entry 8). The use of
[
a]
Q. Zhang, X. Chang, L. Peng, Prof. Dr. C. Guo
Hefei National Laboratory for Physical Sciences at the Microscale,
University of Science and Technology of China
Hefei 230026, China
E-mail:guochang@ustc.edu.cn
Supporting information for this article is given via a link at the end
of the document.
Cu(OAc)
2
as the Lewis acid led to the 3a in only 9% yield with 7%
ee (entry 9). In contrast, further changing the protecting group of
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201901801
COMMUNICATION
1
did not lead to the alkylation product, strongly suggesting that
With the optimal conditions in hand, we next sought to explore
the scope of 2-acyl imidazoles derivatives 1 with trimethylphenol
2a in this asymmetric electrochemical alkylation reaction. As
shown in Table 2, our catalytic reaction can be scaled up to 2-
mmol scale with the formation of 3a in 82% yield with 94% ee.
the Lewis-acid-enolate intermediate is crucial in the
transformation (entry 10).
Table 1. Optimization of the Reaction Conditions.[a]
Moreover,
a diverse array of different substituted 2-acyl
imidazoles, bearing electron-withdrawing (4-9) or electron-
donating (11-13) substituents in the phenyl moiety, performed
well in this transformation to form a series of alkylation products
with excellent enantioselectivity. Substituents at the meta or ortho
positions also worked well to give the corresponding adducts in
good yields and excellent enantioselectivities of 90–94% ee (14-
17). The absolute configuration of the resulting molecule 17 was
Entry
Variation from the standard conditions
Yield [%][b]
ee [%][c]
94
92
-
-
-
94
94
93
7
1
2
3
4
5
6
none
10 mol% A
no ligand A
70
55
nr
nr
nr
39
67
64
9
[15]
assigned by single-crystal X-ray diffraction analysis.
Furthermore, naphthyl or thiophene acyl imidazoles were found to
be competent substrates, demonstrating the diversity of
substituents (19 and 20). The reaction of 2-(phenylthio)acyl
imidazole also proceeded, providing 21 in moderate yield and
enantioselectivity. Notably, we also tested a different class of N-
substituent at the imidazole moiety, giving the desired products in
good yields and excellent enantioselectivities (22-25).
no Ni(OAc)
2
no electric current
no quinuclidine
constant current: 1.0 mA
Pt (+) | Pt(-)
[
d]
7
8
9
2
Cu(OAc) as the Lewis acid
10
1b or 1c as the substrate
nr
-
[
a] Reactions were carried out using 2-acyl substrate 1a (0.1 mmol, 1.0 equiv.),
a (0.2 mmol, 2.0 equiv.), nBu
NPF (0.2 mmol, 2.0 equiv.), quinuclidine (0.05
2
4
6
Table 3. Scope of p-Methylphenol Derivatives 2. [a]
mmol, 0.5 equiv.), toluene/HFIP = 3:1 (8 mL) with 10 mol% Lewis-acid catalyst
at 0 °C, and a constant cell potential of +3 V vs Ag/AgCl in an undivided cell
(
3.36 F/mol). [b] Isolated yields after chromatography are shown. [c] Determined
by HPLC analysis. [d] 2.24 F/mol. HFIP = Hexafluoro-2-propanol. nr = no
reaction.
Table 2. Scope of 2-Acyl Imidazoles 1. [a]
[
a] Reaction conditions: 2-acyl imidazole
methylphenol 2 (0.2 mmol, 2.0 equiv.), Ni(OAc)
mmol, 0.2 equiv.), nBu
NPF
.5 equiv.) in toluene/HFIP = 3:1 (8 mL) at 0 °C for 6-12 h , and a constant cell
1
(0.1 mmol, 1.0 equiv.), p-
2
(0.01 mmol, 0.1 equiv.), A (0.02
4
6
(0.2 mmol, 2.0 equiv.), quinuclidine (0.05 mmol,
0
potential of +3 V vs Ag/AgCl in an undivided cell. [b] Quinuclidine (0.2 mmol, 2
euqiv.) was used. [c] Cresol (0.4 mmol, 4 euqiv.) was used.
Encouraged by these excellent results with various 2-acyl
imidazoles, we then investigated the asymmetric electrochemical
reaction with a range of p-methylphenol derivatives 2 (Table 3). A
variety of p-methylphenols 2 proved to be excellent components
in this reaction, and afforded the desired alkylation adducts in high
yields and excellent enantioselectivities (26-38). It is worth
mentioning that cresol also reacted smoothly with 2-acyl-N-
thiophenimidazole, but with slightly reduced enantioselectivity
(38).
[
a] Reaction conditions: 2-acyl imidazole
trimethylphenol 2a (0.2 mmol, 2.0 equiv.), Ni(OAc)
0.02 mmol, 0.2 equiv.), nBu
NPF (0.2 mmol, 2.0 equiv.), quinuclidine (0.05
6
1
(0.1 mmol, 1.0 equiv.),
2
(0.01 mmol, 0.1 equiv.), A
(
4
mmol, 0.5 equiv.) in toluene/HFIP = 3:1 (8 mL) at 0 °C for 6-12 h, and a constant
cell potential of +3 V vs Ag/AgCl in an undivided cell. [b] 2-mmol scale. [c]
To highlight the synthetic potential of the current method, the
alkylation product 39 can be easily transformed into the
corresponding carboxylic acid 40, which was subsequently
treated with diphenyl phosphorazidate to generate amine 41
(Scheme 2).[16] The latter compound can be converted into a
2
Quinuclidine (0.2 mmol), Ni(OAc) (0.02 mmol) and A (0.04 mmol) were used.
Ellipsoids of 17 are shown at 50% probability, and hydrogen atoms are omitted
for clarity.
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201901801
COMMUNICATION
previously described target compound with antibacterial
activity.[
To gain more information about the possible radical pathway,
we turned our attention to detect the active radical intermediates
13]
(Scheme 3). When (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl
(TEMPO) was used to the reaction mixture of 1a under electrolytic
conditions, the TEMPO-adduct 42 was isolated in 33% yield.
Importantly, no conversion of 42 was observed without the electric
current, which suggests the rationality of the proposed
electrolysis-induced SET process to generate [Ni(A)-1a]·+
intermediate (Supporting Information for details). Furthermore, a
standard electrolytic condition in the presence of TEMPO
provided the TEMPO-trapping product 42 in 11% yield (Scheme
3
a). Moreover, no product was formed under the optimized
condition with or without the electric current when Waldvogel’s
benzylic HFIP ether intermediate 43 was used instead of p-
methylphenol 2a (Scheme 3b).[5e] Dimer product 44 could be
isolated under the electrolytic condition (Supporting Information
for details).
Scheme 2. Derivatization of the Alkylation Product 39. MeOTf = Methyl
trifluoromethanesulfonate, DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene, DPPA =
Diphenyl phosphoryl azide, DIPEA = N,N-Diisopropylethylamine, BnOH =
Benzyl alcohol.
To gain a better understanding of the mechanistic details of this
asymmetric electrochemical alkylation, we wanted to investigate
cyclic voltammetry experiments to study the redox potential of
different reaction components (Figure
1 and Supporting
Information for details). Initially, the oxidation potential of the p-
methylphenol component 2a was observed at 1.98 V (Figure 1a,
oxi
oxi
1
a, E1a = 2.71 V Vs. SCE; 2a, E2a = 1.98 V Vs. SCE; Lewis-acid
o
x
i
o
x
i
catalyst, Ecat. = 2.22 V Vs. SCE; 3a, E3a = 2.0 V Vs. SCE). In
particular, cyclic voltammetry reveals that Lewis acid bound-1a
oxi
(
Figure 1b, Ecat.-1a = 1.80 V Vs. SCE in MeCN) has a significantly
oxi
lower oxidation peak potential than 1a (E1a = 2.71 V Vs. SCE in
MeCN) and Lewis acid (Ecat. = 2.22 V Vs. SCE in MeCN). All of
oxi
Scheme 3. Control experiments.
these cyclic voltammetry results suggest that a SET oxidation of
Lewis acid-enolate under the electrolytic conditions appears
feasible.
To further confirm the radical pathway in this electrochemical
reaction, the electrochemical alkylation reaction was monitored by
electron paramagnetic resonance spectroscopy (EPR) (See
Supporting Information for details). With the addition of DMPO as
free radical spin-trapping agent, signals were observed when 1a
was treated under the catalytic electrochemical conditions, which
+
suggested that the existence of [Ni(A)-1a]· radical intermediate
in the catalytic process. Moreover, signals with six peaks were
observed for the reaction of 2a, suggesting a benzylic radical is
involved through single electron oxidation of the p-methylphenol
compound 2a in the electrochemical conditions.[
16]
Similarly,
signals could also be detected in the standard reaction with the
addition of DMPO. All of these results support that a benzylic
+
radical intermediate and [Ni(A)-1a]· radical intermediate might be
active species in the reaction.
Taking into account the combined results of our mechanistic
studies, a plausible mechanistic cycle, in which electrosynthesis
intertwines with asymmetric Lewis-acid catalysis, is outlined in
Figure 2. The asymmetric electrosynthesis was realized by
combination of [Ni(A)-1a]·+ radical intermediate (III) and an
electrochemistry-oxidatively-driven benzylic radical (IV). The
proposed catalytic cycles begin with the coordination of the Lewis
acid catalyst to the 2-acyl imidazoles (1) to generate the Lewis-
acid-enolate complex (II) upon deprotonation (left cycle). Then
Figure 1. Cyclic voltammetry experiments: Cyclic voltammetry of different
+
[Ni(A)-1a]· intermediate (III) was generated via electrolysis-
reaction components on
temperature with a scan rate at 0.1 V s . (a) Cyclic voltamograms of 1a, 2a,
a glassy carbon electrode in MeCN at room
-
1
induced SET oxidation. In a parallel electrochemical cycle, the
benzylic radical species (IV) was delivered by the anodic
oxidation.[5e,17] Based on the above experimental results and
quinuclidine and 3a. (b) Cyclic voltamograms of 1a, Ni(OAc)
A-1a.
2 2
-A and Ni(OAc) -
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201901801
COMMUNICATION
[
4,12]
previous reports,
radical-radical coupling reaction between III
Angew. Chem. Int. Ed. 2018, 57, 5594; Angew. Chem. 2018, 130, 5694;
g) S. Möhle, M. Zirbes, E. Rodrigo, T. Gieshoff, A. Wiebe, S. R.
Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 6018; Angew. Chem. 2018,
and IV was proposed, affording the corresponding intermediate V.
Moreover, this stereocontrol step was also related to the in situ
generation of radicals with π systems of chiral enamines[18] and
chiral enolates.[12,19] Then release of the Lewis-acid catalyst with
unreacted substrate 1 gives rise to the final product 3.
1
30, 6124; h) S. Tang, Y. Liu, A. Lei, Chem. 2018, 4, 27.
a) R. Hayashi, A. Shimizu, J.-I. Yoshida, J. Am. Chem. Soc. 2016, 138,
400; b) E. J. Horn, B. R. Rosen, Y. Chen, J. Tang, K. Chen, M. D.
[
5]
8
Eastgate, P. S. Baran, Nature 2016, 533, 77; c) D. P. Hruszkewycz, K.
C. Miles, O. R. Thiel, S. S. Stahl, Chem. Sci. 2017, 8, 1282; d) Y.
Kawamata, M. Yan, Z. Liu, D.-H. Bao, J. Chen, J. T. Starr, P. S. Baran,
J. Am. Chem. Soc. 2017, 139, 7448; e) Y. Imada, J. Röckl, A. Wiebe, T.
Gieshoff, D. Schollmeyer, K. Chiba, R. Franke, S. R. Waldvogel, Angew.
Chem. Int. Ed. 2018, 57, 12136; Angew. Chem. 2018, 130, 12312.
a) M. G. M. D’Oca, R. A. Pilli, V. L. Pardini, D. Curi, F. C. M. Comninos,
J. Braz. Chem. Soc. 2001, 12, 507; b) S. S. Libendi, Y. Demizu, Y.
Matsumura, O. Onomura, Tetrahedron 2008, 64, 3935.
[
6]
[
[
7]
8]
B. F. Watkins, J. R. Behling, E. Kariv, L. L. Miller, J. Am. Chem. Soc.
1975, 97, 3549.
a) H. Tanaka, M. Kuroboshi, H. Takeda, H. Kanda, S. Torii, J. Electroanal.
Chem. 2001, 507, 75; b) D. Franco, A. Riahi, F. Henin, J. Muzart, E.
Duñach, Eur. J. Org. Chem. 2002, 2002, 2257; c) B.-L. Chen, H.-W. Zhu,
Y. Xiao, Q.-L. Sun, H. Wang, J.-X. Lu, Electrochem. Commun. 2014, 42,
55; d) D. Minato, H. Arimoto, Y. Nagasue, Y. Demizu, O. Onomura,
Figure 2. Proposed mechanism.
Tetrahedron 2008, 64, 6675.
[
9]
K. L. Jensen. P. T. Franke, L. T. Nielsen, K. Daasbjerg, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2010, 49, 129; Angew. Chem. 2010, 122, 133.
In this study, we have reported
a Lewis-acid catalytic
[
[
10] N. Fu, L. Li, Q. Yang, S. Luo, Org. Lett. 2017, 19, 2122.
asymmetric electrosynthesis. Asymmetric induction can be
realized through the radical-radical coupling of a chiral Lewis-
acid-bound radical with an electrochemical oxidative driven
benzylic radical species. The electrochemical alkylation products
are very useful and have been applied to the synthesis of
described target compound with antibacterial activity. The
combination of chiral Lewis-acid with electricity-driven
intermediates has the potential to be a valuable platform for the
development of a wide range of broadly useful stereocontrolled
reactions.
11] X. Huang, Q. Zhang, J. Lin, K. Harms, E. Meggers, Nat. catal. 2019, 2,
34.
[
[
12] H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh, A. Lei, Chem.
Rev. 2017, 117, 9016.
13] a) R. Griera, C. Cantos-Llopart, M. Amat, J. Bosch, J.-C. Castillo, J.
Huguet, Bioorg. Med. Chem. Lett. 2006, 16, 529; b) N. C. Veitch, Nat.
Prod. Rep. 2007, 24, 417; c) K. Burri, L. Schmitt, K. Islam, PCT Int. Appl.
WO 2003/018017, March 6, 2003; d) K. Drabikova, T. Perecko, R. Nosal,
L. Rackova, G. Ambrozova, A. Lojek, J. Smidrkal, J. Harmatha, V.
Jancinova, Neuroendocrinol. Lett. 2010, 31, 73; e) S. Kotha, D. Deodhar,
P. Khedkar, Org. Biomol. Chem. 2014, 12, 9054.
[
[
14] a) A. Nakamura, S. Lectard, D. Hashizume, Y. Hamashima, M. Sodeoka,
J. Am. Chem. Soc. 2010, 132, 4036; b) Y. Sohtome, G. Nakamura, A.
Muranaka, D. Hashizume, S. Lectard, T. Tsuchimoto, M. Uchiyama, M.
Sodeoka, Nat. Commun. 2017, 8, 14875; c) J. Wang, P. Wang, L. Wang,
D. Li, K. Wang, Y. Wang, H. Zhu, D. Yang, R. Wang, Org. Lett. 2017, 19,
Acknowledgements
The authors acknowledge financial support from the National
Natural Science Foundation of China (grant no. 21702198), the
Anhui Provincial Natural Science Foundation (grant no.
4826.
15] CCDC 1882764 (17) contains the supplementary crystallographic data
for this paper. These data canbe obtained free of charge from the
1
808085MB30), "1000-Youth Talents Plan", and startup funds
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
16] P. Lu, J. J. Jackson, J. A. Eickhoff, A. Zakarian, J. Am. Chem. Soc. 2015,
37, 656.
17] P. Majzlík, L. Omelka, R. Superatová, P. Holubcová, Helv. Chim. Acta.
011, 94, 1260.
Crystallographic
Data
Centre
via
from USTC.
[
[
[
1
Keywords: asymmetric catalysis• Lewis acid • electrochemistry
•
benzylic activation• radical/radical coupling
2
18] a) D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77; b) D. A.
Nagib, M. E. Scott, D. W. C. MacMillan, J. Am. Chem. Soc. 2009, 131,
[
1]
E. N. Jacobsen, A. Pfaltz, H. Eds. Yamamoto, Comprehensive
asymmetric catalysis: Vol. I-III, Suppl. I-II(Springer, New York, 1999).
10875; c) M. Amatore, T. D. Beeson, S. P. Brown, D. W. C. MacMillan,
[
[
2]
3]
K. Zheng, X. Liu, X. Feng, Chem. Rev. 2018, 118, 7586.
Angew. Chem. Int. Ed. 2009, 48, 5121; Angew. Chem. 2009, 121, 5223;
d) H.-W. Shih, M. N. Vander Wal, R. L. Grange, D. W. C. MacMillan, J.
Am. Chem. Soc. 2010, 132, 13600; e) M. Cherevatskaya, M. Neumann,
S. Füldner, C. Harlander, S. Kümmel, S. Dankersreiter, A. Pfitzner, K.
Zeitler, B. König, Angew. Chem. Int. Ed. 2012, 51, 4062; Angew. Chem.
a) G.-S. Chen, Y.-J. Deng, L.-Z. Gong, A.-Q. Mi, X. Cui, Y.- Z. Jiang, M.
C. K. Choi, A. S. C. Chan, Tetrahedron: Asymmetry 2001, 12, 1567; b)
G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007, 317, 496;
c) D. A. Nicewicz, D. W. C. MacMillan, Science 2008, 322, 77; d) Z. T.
Du, Z.-H. Shao, Chem. Soc. Rev. 2012, 42, 1337; e) S. Krautwald, D.
Sarlah, M. A. Schafroth, E. M. Carreira, Science 2013, 340, 1065; f) D.-
F. Chen, Z.-Y. Han, X.-L. Zhou, L.-Z. Gong, Acc. Chem. Res. 2014, 47,
2
012, 124, 4138; f) E. D. Nacsa, D. W. C. MacMillan, J. Am. Chem. Soc.
018, 140, 3322.
2
[
19] a) Z. Gu, A. T. Herrmann, A. Zakarian, Angew. Chem. Int. Ed. 2011, 50,
136; Angew. Chem. 2011, 123, 7274; b) A. T. Herrmann, L. L. Smith, A.
2
365.
a) J.-I. Yoshida, K. Kataoka, R. Horcajada, A. Nagaki, Chem. Rev. 2008,
08, 2265; b) R. Francke, D. Little, Chem. Soc. Rev. 2014, 43, 2492; c)
7
[
4]
Zakarian, J. Am. Chem. Soc. 2012, 134, 6976; c) H. Huo, X. Shen, C.
Wang, L. Zhang, P. Röse, L.-A. Chen, K. Harms, M. Marsch, G. Hilt, E.
Meggers, Nature 2014, 515, 100; d) H. Huo, C. Wang, K. Harms, E.
Meggers, J. Am. Chem. Soc. 2015, 137, 9551; e) X. Huang, R. D.
Webster, K. Harms, E. Meggers, J. Am. Chem. Soc. 2016, 138, 12636.
1
M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017, 117, 13230; d) Y.
Jiang, K. Xu, C. Zeng, Chem. Rev. 2018, 118, 4485; e) S. R. Waldvogel,
S. Lips, M. Selt, B. Riehl, C. J. Kampf, Chem. Rev. 2018, 118, 6706; f)
A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes, S. R. Waldvogel,
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
COMMUNICATION
10.1002/anie.201901801
COMMUNICATION
Qinglin Zhang, Xihao Chang, Lingzi
Peng, Chang Guo*
Page No. – Page No.
Lewis-Acid-Catalyzed Asymmetric
Electrochemical Alkylation
An efficient asymmetric electrosynthesis was developed in high yields with excellent
enantioselectivities via a chiral Ni-catalyst. Mechanistic studies suggested that the
Lewis acid-bound radical intermediate via a single-electron anodic oxidation
selectively reacts with the benzylic radical species to generate the desired adducts.
The electrochemical alkylation products are very useful and have been applied to the
synthesis of described target compound with antibacterial activity.
This article is protected by copyright. All rights reserved.