Cu-Catalyzed Regioselective C-H Alkylation of Benzimidazoles with Aromatic Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c02864

Herein we report a novel Cu-catalyzed regioselective C2-H alkylation of benzimidazoles with aromatic alkenes. The reaction features exclusive regioselectivity and broad substrate scope in the intermolecular alkylation of benzimidazoles with terminal and i

Full text of DOI:10.1021/acs.orglett.0c02864

pubs.acs.org/OrgLett
Letter
Cu-Catalyzed Regioselective C−H Alkylation of Benzimidazoles with
Aromatic Alkenes
Yu-Ting He, Yang-Jie Mao, Hong-Yan Hao, Zhen-Yuan Xu, Shao-Jie Lou,* and Dan-Qian Xu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02864
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein we report a novel Cu-catalyzed regioselec-
tive C2−H alkylation of benzimidazoles with aromatic alkenes. The
reaction features exclusive regioselectivity and broad substrate
scope in the intermolecular alkylation of benzimidazoles with
terminal and internal aromatic alkenes, constituting a modular
access toward benzimidazole-containing 1,1-di(hetero)aryl alkanes.
The intramolecular C2−H alkylation of benzimidazoles with
aromatic alkenes has been achieved in an endo-selective manner.
The enantioselective C2 alkylation of benzimidazoles has also been
realized with moderate to good stereocontrol.
enzimidazoles are among the most important heterocycles
and are widely used in pharmaceuticals and organo-
examples of enantioselective formal C−H alkylation of N-
heterocycles, e.g., pyridine and indazole substrates.10 Ge’s
group also developed an elegant CuH-catalyzed branch-
selective C2 alkylation of quinolines by using quinoline N-
oxides as electrophiles.11 Inspired by these works, we envisaged
that an alkene activation strategy enabled by CuH catalysis
might serve as an efficient alternative for the branch-selective
alkylation of benzimidazoles with aromatic alkenes.
In contrast to the previous C−H activation strategy, the
regioselectivity in this novel strategy should stem from the
selective hydrometalation of the alkene. Thanks to the highly
regioselective 2,1-hydrocupration of aromatic alkenes with
CuH species, the key Cu−alkyl species I is generated in situ
and attacks the electrophilic C2 of benzimidazole, thus
resulting the highly branch-selective C2-alkylated products
(Scheme 1c). On the basis of this rational reaction design, we
report herein a general Cu-catalyzed platform for the
regioselective intermolecular formal C2−H alkylation of
benzimidazoles with terminal and internal styrenes. Moreover,
an endo-selective intramolecular C2 alkylation has also been
developed to give various bicyclic benzimidazoles with
different ring sizes (Scheme 1d).
B
catalysts.1 For instance, many top-selling drugs contain
imidazole moieties, and several chiral benzimidazoles are
used as efficient nucleophilic catalysts. On the other hand, 1,1-
di(hetero)aryl alkanes are widely found in many bioactive
compounds (Scheme 1a).2 Consequently, the rapid and
modular synthesis of benzimidazole-containing 1,1-di(hetero)-
aryl alkanes would be of great interest and importance for drug
discovery. Among the possible approaches, a branch-selective
C−H alkylation of benzimidazoles with aromatic alkenes
would provide the most atom-economical way to construct
these compounds rapidly.3,4 However, such a transformation
has rarely been achieved despite the extensive studies in this
field.5−7 Generally, the previous reports mainly rely on C2−H
bond metalation of benzimidazoles in the presence of various
transition metals, and the regioselectivity usually depends on
subtle ligand or substrate control. To date, the branch-selective
C2−H alkylation of benzimidazoles with terminal aromatic
alkenes has been achieved only by using a Ni−carbene catalysis
platform (Scheme 1b).7a,b,d Notably, the analogous trans-
formation with more challenging internal aromatic alkenes has
not been realized to date. Thus, a novel strategy for the
regioselective C2−H alkylation of benzimidazoles with
aromatic alkenes is still highly desirable.
At the outset of the study, N-methylbenzimidazole (1a) and
styrene (2a) were treated with typical CuH catalytic conditions
(Table 1; also see the Supporting Information for details).12
To our delight, the desired branch-selective product 3a was
CuH catalysis has emerged as a highly efficient method for
the hydrofunctionalization of alkenes in the past few years.8,9
The typical catalytic process includes hydrocupration of the
alkene followed by capture with various electrophiles and
regeneration of the CuH species with a hydrosilane. Although
various electrophiles have been extensively studied, the use of
electron-deficient heterocycles as electrophiles for the hydro-
heteroarylation of alkenes has met with only limited success.
For instance, Buchwald and co-workers reported several
Received: August 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02864
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Synthesis of 1,1-Di(hetero)aryl Alkanes via
Regioselective C−H Alkylation of Benzimidazoles with
Aromatic Alkenes
Table 1. Optimization of the Reaction Conditions for the
Regioselective C2 Alkylation of N-Methylbenzimidazole
a
with Styrene
temp.
(°C)
yield
b
entry
ligand
[Si]−H
solvent
(%)
1
2
3
4
5
6
7
8
9
DCyPE
DCyPE
XantPhos
rac-BINAP
PPh3
(MeO)2MeSiH
(MeO)2MeSiH
(MeO)2MeSiH
(MeO)2MeSiH
(MeO)2MeSiH
(MeO)2MeSiH
(EtO)2MeSiH
(EtO)3SiH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Et2O
50
70
70
70
70
70
70
70
70
70
70
80
87
77
−
−
−
60
68
37
92
84
PBu3
DCyPE
DCyPE
DCyPE
DCyPE
DCyPE
Ph2SiH2
PMHS
PMHS
10
11
a
Conditions: 1a (0.1 mmol), 2a (3.0 equiv), Cu(OAc) (10 mol %),
ligand (12 mol %), and silane (5.0 equiv) in dry solvent (0.25 mL)
b
(see the Supporting Information for details), N2. Determined by
GC−MS.
well-tolerated (3v−aa). A fused benzimidazole was also
compatible with this alkylation reaction but gave a lower
yield (3ab). However, the analogous C2 alkylation of N-
phenyl- or N-toluenesulfonyl-substituted benzimidazole failed
to give the desired products.
obtained directly as the sole product in 87% yield in the
presence of DCyPE and (MeO)2MeSiH at 70 °C (Table 1,
entry 2). Xantphos also gave a comparable result (Table 1,
entry 3). However, BINAP and monophosphine ligands were
inefficient in this transformation (Table 1, entries 4−6),
probably because the CuH species ligated by these ligands
were less reactive. Further switching the silane from
(MeO)2MeSiH to more bench-stable PHMS provided a better
yield of 92% (Table 1, entry 10).
With the optimized conditions in hand, the reaction scope
was investigated next (Scheme 2). A variety of substituted vinyl
arenes were tested first. Generally, both electron-donating and
electron-withdrawing substituents at different positions were
compatible, giving the corresponding products in moderate to
good yields (3a−s). A synthetically useful but sensitive boron
group could survive the reaction conditions (3e). Halo groups
such as chloro and bromo were well-tolerated, providing the
opportunity for further transformation (3j and 3k). A strongly
electron-withdrawing CF3 substituent on the vinylarene did
not significantly influence the efficiency of the reaction (3l).
Vinylthiophene was also accommodated in this reaction,
delivering the alkylated product 3p bearing two different
heterocycles in good yields. In addition, several complex vinyl
arenes were also prepared and tested, which allowed the late-
stage formation of corresponding complicated C2-alkylated
benzimidazoles (3q−s). N-Ethyl- and N-isopropyl-substituted
benzimidazoles were also compatible with the reaction
condition (3t and 3u). Various mono- and disubstituted
benzimidazoles were also prepared and examined. Functional
groups such as ester, methoxy, methyl, and fluoro groups were
Next, we turned our attention to the more challenging
internal vinyl arenes (Scheme 3). To our delight, C2 alkylation
of benzimidazole 1a with trans- or cis-β-methylstyrene gave the
2,1-hydroarylation product in good yield (3ac). Moreover,
oxygen-containing internal aromatic alkenes were also suitable
for this transformation, affording the desired products in
decent yields (3ad−af). Interestingly, the reaction with
endocyclic aromatic alkenes such as dihydrobenzopyran and
1,2-dihydroquinoline took place smoothly, affording the
elaborate complex molecules 3ag and 3ah, respectively. The
remarkable versatility of this alkylation implies potential
applications in the late-stage and modular synthesis of diverse
benzimidazole-containing 1,1-diaryl alkanes, which may play a
pivotal role in discovering pharmaceutical candidates.
Encouraged by the alkylation of benzimidazole with internal
vinyl arenes, we envisaged that an intramolecular C2 alkylation
of benzimidazoles with vinyl arenes should be feasible to
deliver bicyclic benzimidazoles. Despite the success of previous
transition metal catalysis, the regioselectivity of intramolecular
C2 alkylation with alkenes usually exhibits ring-size depend-
ence and requires subtle ligand control. In light of the reaction
mechanism, we believed that the cyclization should proceed in
a highly endo-selective fashion because of the regioselective
hydrocupration of vinyl arenes with CuH species. With this
consideration in mind, N-cinnamylbenzimidazole (4a) was
subjected to the standard conditions (Table 2). To our delight,
B
https://dx.doi.org/10.1021/acs.orglett.0c02864
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Regioselective C2 Alkylation of Benzimidazoles
with Terminal Aromatic Alkenes
Scheme 3. Regioselective C2 Alkylation of Benzimidazoles
with Internal Aromatic Alkenes
a
a
a
Conditions: 1a (0.2 mmol), 2 (3.0 equiv), Cu(OAc) (10 mol %),
DCyPE (12 mol %), PMHS (5.0 equiv), dry PhMe (0.5 mL), N2, 70
b
°C, 24 h. Isolated yields are shown. 48 h.
Table 2. Screening of Conditions for the Regioselective
a
Intramolecular C2 Alkylation of Benzimidazoles
c
entry
[Cu]
[Si]−H
PMHS
(MeO)2MeSiH
(EtO)2MeSiH
(MeO)3SiH
time (h) yield of 5a/6a (%)
1
2
3
4
5
6
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)2
Cu(OAc)2
12
12
12
12
12
24
87/12
90/8
73/26
80/11
69/28
87/11
(MeO)2MeSiH
(MeO)2MeSiH
a
Conditions: 4a (0.1 mmol), Cu(OAc) (10 mol %), DCyPE (12 mol
%), silane (5.0 equiv), dry PhMe (0.25 mL), N2. See the Supporting
b
Information for details. Monitored by TLC until the disappearance
c
of 5a′. Determined by LC.
a
Conditions: 1 (0.2 mmol), 2 (3.0 equiv), Cu(OAc) (10 mol %),
delivering the product in high yield via the formation of a
five-membered ring.
DCyPE (12 mol %), PMHS (5 equiv), dry PhMe (0.5 mL), N2, 70
°C, 24 h. Isolated yields are shown. 1 mmol scale. 48 h. 36 h.
b
c
d
The scope of this intramolecular transformation was then
explored (Scheme 4). Similar to the intermolecular alkylation,
substituted benzimidazoles bearing different vinyl arene units
underwent endo-selective cyclization smoothly (5a−f). More-
over, the cyclization was not limited to the construction of a
five-membered ring, as a bicyclic benzimidazole was also
obtained via six-membered ring formation in an endo-selective
fashion (5g). The present method provides an important
complement to the previous transition-metal-catalyzed intra-
molecular C−H activation/alkylation of benzimidazoles with
alkenes.
the cyclization intermediate 5a′ was detected as a major
product even at room temperature (also see the Supporting
Information).12 After a simple one-pot oxidation with H2O2,
the desired product 5a was obtained in 87% yield along with
the hydrogenated byproduct 6a (Table 2, entry 1). Further
screening of silanes revealed that (MeO)2MeSiH performed
the best among the silanes tested (Table 2, entry 2).
Cu(OAc)2 also gave a comparable result with a prolonged
reaction time (Table 2, entry 6; see the Supporting
Information for detailed information).12 It is noteworthy that
the present cyclization shows exclusive endo selectivity,
To obtain further insight into this CuH-catalyzed C2−H
alkylation of benzimidazoles, several mechanistic experiments
were conducted next. No deuterium incorporation in the final
C
https://dx.doi.org/10.1021/acs.orglett.0c02864
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 4. Regioselective Intramolecular C2 Alkylation of
a
Benzimidazoles
a
Conditions: 4 (0.2 mmol), Cu(OAc) (10 mol %), DCyPE (12 mol
%), (MeO)2MeSiH (5.0 equiv), dry PhMe (0.5 mL), N2, r.t., 12 h.
Figure 1. Possible reaction mechanism.
b
Isolated yields are shown. Monitored by TLC until the
c
d
disappearance of 5′. 24 h. 90 °C, 24 h.
(see the Supporting Information for details).12 Indeed,
asymmetric C2 alkylation of imidazoles could be achieved by
using (S,S)-Ph-BPE as a chiral phosphine ligand (Scheme 6).
product 3a was observed when the C2-deuterated starting
material 1a-D was treated with the standard conditions
(Scheme 5a). When the model reaction was carried out with
Scheme 6. Enantioselective C2 Alkylation of
Benzimidazoles with Aromatic Alkenes
Scheme 5. Mechanistic Studies
For instance, the asymmetric intermolecular alkylation gave an
enantioenriched product 3a with a good stereocontrol (e.r. =
85:15; Scheme 6, top). To the best of our knowledge, this is
the first asymmetric example of intermolecular C2 alkylation of
benzimidazoles with aromatic alkenes. Furthermore, a
moderate enantioselectivity was obtained in the case of
intramolecular alkylation (e.r. = 68:32; Scheme 6, bottom).
In conclusion, we have developed a general CuH-catalyzed
intermolecular and intramolecular C2 alkylation of benzimi-
dazoles with various vinyl arenes. The present method features
excellent regioselectivity, broad substrate scope, and mild
reaction conditions and thus provides an efficient alternative
for the synthesis of benzimidazole-containing 1,1-di(hetero)-
aryl alkanes. Preliminary mechanism studies supported our
reaction design toward the formal C2−H alkylation of
benzimidazoles via an alkene activation strategy. Enantioen-
riched products could also be obtained by using a chiral ligand.
Further application of this protocol in the synthesis of
bioactive compounds and investigation of the asymmetric
transformations are ongoing in our laboratory.
Ph2SiD2, significant deuterium incorporation was observed at
the terminal methyl group of 3a-D (Scheme 5b). Moreover,
the N-silyl cyclization intermediate 5a′ was determined
1
unambiguously by H NMR analysis (Scheme 5c; see the
Supporting Information for details).12 These observations were
fully consistent with our hypothesis on the reaction design.
A possible reaction mechanism was proposed on the basis of
the above results (Figure 1). Regioselective hydrocupration of
4a delivers intermediate I′, which undergoes intramolecular
addition to the CN bond to give dearomative cyclization
intermediate II′. Then the interaction of this copper nitride
intermediate with the silane regenerates the CuH species and
gives the N-silyl intermediate III′ (5a′), which has been
determined by NMR analysis. Further oxidative rearomatiza-
tion of III′ (5a′) gives the product 5a eventually.
ASSOCIATED CONTENT
* Supporting Information
■
Asymmetric CuH catalysis has emerged as a powerful
platform for the synthesis of chiral molecules in the past
decade.8,9 We were also interested in the development of
asymmetric C2 alkylation of benzimidazoles with vinyl arenes
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02864.
D
https://dx.doi.org/10.1021/acs.orglett.0c02864
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Ikpo, C. O.; Adedapo, A. E.; Olanrewaju, I. O. Functionalized
Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in
Therapeutic Medicine. Arch. Pharm. 2016, 349, 475−504. (d) Akhtar,
W.; Khan, M. F.; Verma, G.; Shaquiquzzaman, M.; Rizvi, M. A.;
Mehdi, S. H.; Akhter, M.; Alam, M. M. Therapeutic evolution of
benzimidazole derivatives in the last quinquennial period. Eur. J. Med.
Chem. 2017, 126, 705−753. (e) Ali, I.; Lone, M. N.; Aboul-Enein, H.
Y. Imidazoles as potential anticancer agents. MedChemComm 2017, 8,
1742−1773.
(2) Ameen, D.; Snape, T. J. Chiral 1,1-diaryl compounds as
important pharmacophores. MedChemComm 2013, 4, 893−907.
(3) (a) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G.
Transition-Metal-Catalyzed C-H Alkylation Using Alkenes. Chem.
Rev. 2017, 117, 9333−9403. (b) Evano, G.; Theunissen, C. Beyond
Friedel and Crafts: Directed Alkylation of C-H Bonds in Arenes.
Angew. Chem., Int. Ed. 2019, 58, 7202−7236.
(4) Crisenza, G. E. M.; Bower, J. F. Branch Selective Murai-type
Alkene Hydroarylation Reactions. Chem. Lett. 2016, 45, 2−9.
(5) For selected reviews of C−H addition of imidazoles to alkenes,
see: (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Direct
Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C-H
Bond Activation. Acc. Chem. Res. 2008, 41, 1013−1025. (b) Colby, D.
A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C-C Bond
Formation via Heteroatom-Directed C-H Bond Activation. Chem.
Rev. 2010, 110, 624−655.
(6) For intramolecular C2 alkylation of imidazoles with alkenes, see:
(a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. Annulation of Alkenyl-
Substituted Heterocycles via Rhodium-Catalyzed Intramolecular C-H
Activated Coupling Reactions. J. Am. Chem. Soc. 2001, 123, 2685−
2686. (b) Tan, K. L.; Bergman, R. G.; Ellman, J. A. Intermediacy of an
N-Heterocyclic Carbene Complex in the Catalytic C-H Activation of
a Substituted Benzimidazole. J. Am. Chem. Soc. 2002, 124, 3202−
3203. (c) Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P.
V.; Bergman, R. G.; Ellman, J. A. Synthesis of Potent Bicyclic
Bisarylimidazole c-Jun N-Terminal Kinase Inhibitors by Catalytic C-
H Bond Activation. J. Am. Chem. Soc. 2007, 129, 490−491. (d) Wang,
Y.-X.; Qi, S.-L.; Luan, Y.-X.; Han, X.-W.; Wang, S.; Chen, H.; Ye, M.
Enantioselective Ni-Al Bimetallic Catalyzed exo-Selective C-H
Cyclization of Imidazoles with Alkenes. J. Am. Chem. Soc. 2018,
General experimental details, including procedures,
syntheses and characterization data of new products
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Dan-Qian Xu − Catalytic Hydrogenation Research Center, State
Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Key Laboratory of Green Pesticides and Cleaner
Production Technology of Zhejiang Province, Zhejiang
University of Technology, Hangzhou 310014, P. R. China;
orcid.org/0000-0003-0152-0860; Email: chrc@
zjut.edu.cn
Shao-Jie Lou − Catalytic Hydrogenation Research Center, State
Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Key Laboratory of Green Pesticides and Cleaner
Production Technology of Zhejiang Province, Zhejiang
University of Technology, Hangzhou 310014, P. R. China;
Email: loushaojie@zjut.edu.cn
Authors
Yu-Ting He − Catalytic Hydrogenation Research Center, State
Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Key Laboratory of Green Pesticides and Cleaner
Production Technology of Zhejiang Province, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Yang-Jie Mao − Catalytic Hydrogenation Research Center, State
Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Key Laboratory of Green Pesticides and Cleaner
Production Technology of Zhejiang Province, Zhejiang
University of Technology, Hangzhou 310014, P. R. China;
orcid.org/0000-0003-4101-4030
Hong-Yan Hao − Catalytic Hydrogenation Research Center,
State Key Laboratory Breeding Base of Green Chemistry-
Synthesis Technology, Key Laboratory of Green Pesticides and
Cleaner Production Technology of Zhejiang Province, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
Zhen-Yuan Xu − Catalytic Hydrogenation Research Center,
State Key Laboratory Breeding Base of Green Chemistry-
Synthesis Technology, Key Laboratory of Green Pesticides and
Cleaner Production Technology of Zhejiang Province, Zhejiang
University of Technology, Hangzhou 310014, P. R. China
140, 5360−5364. (e) Loup, J.; Muller, V.; Ghorai, D.; Ackermann, L.
̈
Enantioselective Aluminum-Free Alkene Hydroarylations via C-H
Activation by a Chiral Nickel/JoSPOphos Manifold. Angew. Chem.,
Int. Ed. 2019, 58, 1749−1753. (f) Lou, S.-J.; Mo, Z.; Nishiura, M.;
Hou, Z. Construction of All-Carbon Quaternary Stereocenters by
Scandium-Catalyzed Intramolecular C-H Alkylation of Imidazoles
with 1,1-Disubstituted Alkenes. J. Am. Chem. Soc. 2020, 142, 1200−
1205.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02864
(7) For intermolecular C2 alkylation of imidazoles with alkenes, see:
(a) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. Nickel-
Catalyzed Hydroheteroarylation of Vinylarenes. Angew. Chem., Int. Ed.
2010, 49, 4451−4454. (b) Shih, W.-C.; Chen, W.-C.; Lai, Y.-C.; Yu,
M.-S.; Ho, J.-J.; Yap, G. P. A.; Ong, T.-G. The Regioselective Switch
for Amino-NHC Mediated C-H Activation of Benzimidazole via Ni-
Al Synergistic Catalysis. Org. Lett. 2012, 14, 2046−2049. (c) Lee, W.-
C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.; Ong, T.-G. Tandem
Isomerization and C−H Activation: Regioselective Hydroheteroar-
ylation of Allylarenes. Org. Lett. 2013, 15, 5358−5361. (d) Chen, W.-
C.; Lai, Y.-C.; Shih, W.-C.; Yu, M.-S.; Yap, G. P. A.; Ong, T.-G.
Mechanistic Study of a Switch in the Regioselectivity of Hydro-
heteroarylation of Styrene Catalyzed by Bimetallic Ni-Al through C-H
Activation. Chem. - Eur. J. 2014, 20, 8099−8105. (e) Tran, G.;
Confair, D.; Hesp, K. D.; Mascitti, V.; Ellman, J. A. C2-Selective
Branched Alkylation of Benzimidazoles by Rhodium(I)-Catalyzed C-
H Activation. J. Org. Chem. 2017, 82, 9243−9252. (f) Li, R.-P.; Shen,
Z.-W.; Wu, Q.-J.; Zhang, J.; Sun, H.-M. N-Heterocyclic Carbene
Ligand-Controlled Regioselectivity for Nickel-Catalyzed Hydro-
arylation of Vinylarenes with Benzothiazoles. Org. Lett. 2019, 21,
5055−5058.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the National Natural Science
Foundation of China (21361130021), the China Postdoctoral
Science Foundation (2014M560494), and the Postdoctoral
Science Foundation of Zhejiang Province for financial support.
REFERENCES
■
(1) (a) Zhang, Z.; Xie, F.; Jia, J.; Zhang, W. Chiral Bicycle Imidazole
Nucleophilic Catalysts: Rational Design, Facile Synthesis, and
Successful Application in Asymmetric Steglich Rearrangement. J.
Am. Chem. Soc. 2010, 132, 15939−15941. (b) Yadav, G.; Ganguly, S.
Structure Activity Relationship (SAR) Study of Benzimidazole
Scaffold for Different Biological Activities: A Mini-review. Eur. J.
Med. Chem. 2015, 97, 419−443. (c) Ajani, O. O.; Aderohunmu, D. V.;
E
https://dx.doi.org/10.1021/acs.orglett.0c02864
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(8) For selected reviews, see: (a) Rendler, S.; Oestreich, M.
Polishing a Diamond in the Rough: “Cu−H” Catalysis with Silanes.
Angew. Chem., Int. Ed. 2007, 46, 498−504. (b) Deutsch, C.; Krause,
with a C3-Quaternary Chiral Center Using CuH Catalysis. J. Am.
Chem. Soc. 2020, 142 (23), 10550−10556.
(11) (a) Yu, S. J.; Sang, H. L.; Ge, S. Z. Enantioselective Copper-
Catalyzed Alkylation of Quinoline N-Oxides with Vinylarenes. Angew.
Chem., Int. Ed. 2017, 56, 15896−15900. (b) Yu, S. J.; Sang, H. L.;
Zhang, S.-Q.; Hong, X.; Ge, S. Z. Catalytic asymmetric synthesis of
chiral trisubstituted heteroaromatic allenes from 1,3-enynes. Commun.
Chem. 2018, 1, 64.
N.; Lipshutz, B. H. CuH-Catalyzed Reactions. Chem. Rev. 2008, 108,
̌
́
́
2916−2927. (c) Soradova, Z.; Sebesta, R. Enantioselective Cu-
Catalyzed Functionalizations of Unactivated Alkenes. ChemCatChem
2016, 8, 2581−2588. (d) Pirnot, M. T.; Wang, Y.-M.; Buchwald, S. L.
Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes.
Angew. Chem., Int. Ed. 2016, 55, 48−57. (e) Jordan, A. J.; Lalic, G.;
Sadighi, J. P. Coinage Metal Hydrides: Synthesis, Characterization,
and Reactivity. Chem. Rev. 2016, 116, 8318−8372. (f) Chen, J.; Lu, Z.
Asymmetric hydrofunctionalization of minimally functionalized
alkenes via earth abundant transition metal catalysis. Org. Chem.
Front. 2018, 5, 260−272. (g) Wang, H.; Buchwald, S. L. Copper-
Catalyzed, Enantioselective Hydrofunctionalization of Alkenes. Org.
Rec. 2019, 100, 121.
(12) See the Supporting Information for more detailed descriptions.
(9) (a) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed
Intermolecular Regioselective Hydroamination of Styrenes with
Polymethylhydrosiloxane and Hydroxylamines. Angew. Chem., Int.
Ed. 2013, 52, 10830−10834. (b) Miki, Y.; Hirano, K.; Satoh, T.;
Miura, M. Copper-Catalyzed Enantioselective Formal Hydroamina-
tion of Oxa- and Azabicyclic Alkenes with Hydrosilanes and
Hydroxylamines. Org. Lett. 2014, 16, 1498−1501. (c) Yang, Y.; Shi,
S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Catalytic asymmetric
hydroamination of unactivated internal olefins to aliphatic amines.
Science 2015, 349, 62−66. (d) Niu, D.; Buchwald, S. L. Design of
Modified Amine Transfer Reagents Allows the Synthesis of α-Chiral
Secondary Amines via CuH-Catalyzed Hydroamination. J. Am. Chem.
Soc. 2015, 137, 9716−9721. (e) Nishikawa, D.; Hirano, K.; Miura, M.
Asymmetric Synthesis of α-Aminoboronic Acid Derivatives by
Copper-Catalyzed Enantioselective Hydroamination. J. Am. Chem.
Soc. 2015, 137, 15620−15623. (f) Niljianskul, N.; Zhu, S.; Buchwald,
S. L. Enantioselective Synthesis of α-Aminosilanes by Copper-
Catalyzed Hydroamination of Vinylsilanes. Angew. Chem., Int. Ed.
2015, 54, 1638−1641. (g) Ascic, E.; Buchwald, S. L. Highly
Diastereo- and Enantioselective CuH-Catalyzed Synthesis of 2,3-
Disubstituted Indolines. J. Am. Chem. Soc. 2015, 137, 4666−4669.
(h) Yang, Y.; Perry, I. B.; Buchwald, S. L. Copper-Catalyzed
Enantioselective Addition of Styrene-Derived Nucleophiles to Imines
Enabled by Ligand-Controlled Chemoselective Hydrocupration. J.
Am. Chem. Soc. 2016, 138, 9787−9790. (i) Liu, R. Y.; Yang, Y.;
Buchwald, S. L. Regiodivergent and Diastereoselective CuH-
Catalyzed Allylation of Imines with Terminal Allenes. Angew. Chem.,
Int. Ed. 2016, 55, 14077−14080. (j) Han, J. T.; Jang, W. J.; Kim, N.;
Yun, J. Asymmetric Synthesis of Borylalkanes via Copper-Catalyzed
Enantioselective Hydroallylation. J. Am. Chem. Soc. 2016, 138,
15146−15149. (k) Wang, Y.-M.; Buchwald, S. L. Enantioselective
CuH-Catalyzed Hydroallylation of Vinylarenes. J. Am. Chem. Soc.
2016, 138, 5024−5027. (l) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig,
J. F. Regioselective, Asymmetric Formal Hydroamination of
Unactivated Internal Alkenes. Angew. Chem., Int. Ed. 2016, 55,
776−780. (m) Bandar, J. S.; Ascic, E.; Buchwald, S. L.
Enantioselective CuH-Catalyzed Reductive Coupling of Aryl Alkenes
and Activated Carboxylic Acids. J. Am. Chem. Soc. 2016, 138, 5821−
5824. (n) Yang, Y.; Perry, I. B.; Lu, G.; Liu, P.; Buchwald, S. L.
Copper-catalyzed asymmetric addition of olefin-derived nucleophiles
to ketones. Science 2016, 353, 144−150. (o) Wang, H.; Yang, J. C.;
Buchwald, S. L. CuH-Catalyzed Regioselective Intramolecular Hydro-
amination for the Synthesis of Alkyl-Substituted Chiral Aziridines. J.
Am. Chem. Soc. 2017, 139, 8428−8431. (p) Zhou, Y.; Bandar, J. S.;
Buchwald, S. L. Enantioselective CuH-Catalyzed Hydroacylation
Employing Unsaturated Carboxylic Acids as Aldehyde Surrogates. J.
Am. Chem. Soc. 2017, 139, 8126−8129.
(10) (a) Gribble, M. W., Jr; Guo, S.; Buchwald, S. L. Asymmetric
Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines
without Preactivation of the Heterocycle or Nucleophile. J. Am.
Chem. Soc. 2018, 140, 5057−5060. (b) Ye, Y.; Kevlishvili, I.; Feng, S.;
Liu, P.; Buchwald, S. L. Highly Enantioselective Synthesis of Indazoles
F
https://dx.doi.org/10.1021/acs.orglett.0c02864
Org. Lett. XXXX, XXX, XXX−XXX