Construction of All-Carbon Quaternary Stereocenters by Scandium-Catalyzed Intramolecular C-H Alkylation of Imidazoles with 1,1-Disubstituted Alkenes

Article abstract of DOI:10.1021/jacs.9b12503

The exo-selective C-H cycloaddition of imidazoles to 1,1-disubstituted alkenes has been achieved for the first time by using half-sandwich scandium catalysts. A wide range of imidazole compounds bearing various 1,1-disubstituted aliphatic alkenes, styrenes, dienes, and enynes have been selectively converted in high yields to the corresponding bicyclic imidazole derivatives bearing β-all-carbon-substituted quaternary stereocenters. By using a chiral half-sandwich scandium catalyst, the asymmetric exo-selective cyclization has also been achieved with a high level of enantioselectivity.

Full text of DOI:10.1021/jacs.9b12503

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Communication
Construction of All-Carbon Quaternary Stereocenters by Scandium-Catalyzed
Intramolecular C-H Alkylation of Imidazoles with 1,1-Disubstituted Alkenes
Shao-Jie Lou, Zhenbo Mo, Masayoshi Nishiura, and Zhaomin Hou
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12503 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Construction of All-Carbon Quaternary Stereocenters by Scandium-
Catalyzed Intramolecular CH Alkylation of Imidazoles with 1,1-
Disubstituted Alkenes
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
†
†,‡
,†,‡
Shao-Jie Lou, Zhenbo Mo, Masayoshi Nishiura, and Zhaomin Hou*
†Advanced Catalysis Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-
198, Japan;
0
‡Organometallic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama 351-0198,
Japan
Supporting Information Placeholder
addition to alkenes. Herein, we report the first example of exo-
ABSTRACT: The exo-selective CH cycloaddition of imidazoles
selective CH cycloaddition of imidazoles to 1,1-disubstituted
alkenes by half-sandwich scandium catalysts, which constitutes an
efficient protocol for the construction of -all-carbon quaternary
centers via either 5- or 6-membered ring formation (Scheme 1b).
Moreover, asymmetric cyclization has also been successfully
achieved in high enantioselectivity by using a chiral half-sandwich
scandium catalyst.
to 1,1-disubstituted alkenes has been achieved for the first time by
using half-sandwich scandium catalysts. A wide range of imidazole
compounds bearing various 1,1-disubstituted aliphatic alkenes,
styrenes, dienes and enynes have been selectively converted in high
yields to the corresponding bicyclic imidazole derivatives bearing
-all-carbon-substituted quaternary stereocenters. By using a chiral
half-sandwich scandium catalyst, the asymmetric exo-selective
cyclization has also been achieved with a high level of
enantioselectivity.
Scheme 1. Catalytic C‒H Cycloaddition of Imidazoles to
1,1-Disubstituted Alkenes
a. Previous studies: Rh- and Ni-catalyzed endo-selective cyclization
R1
N
N
R1
R2
[
Rh]
N
N
H
Organic molecules containing all-carbon-substituted quaternary
stereocenters usually show unique bioactivities due to the rigid
three-dimensional structure, and therefore, the efficient and
selective construction of all-carbon quaternary stereocenters has
R2
endo-selective
five-membered ring formation
R
R
R1
R2
N
N
R1
R2
[Ni]
N
N
H
1
,2
received intensive attention in the past decades. Imidazoles are
among the most important heterocycles that show a wide range of
endo-selective
six-membered ring formation
R
R
3
biological activities and clinical applications. The synthesis of
b. This work: Sc-catalyzed exo-selective cyclization leading to
imidazole compounds bearing all-carbon quaternary stereocenters
is consequently of great interest and importance. Among possible
approaches, the Markovnikov-selective CH addition of imidazole
compounds to 1,1-disubstituted alkenes is, in principle, the most
atom-efficient way for the synthesis of the imidazole derivatives
bearing all-carbon quaternary stereocenters. However, despite
extensive studies and recent advances in the CH activation and
construction of all-carbon quanternary stereocenters
R1
N
N
R1
N
H
[Sc]
R2
R
N
R
exo-selective
five- and six-membered ring formation
R2
n
n
n = 1, 2
R = alkyl, aryl, alkenyl, alkynyl, H
4
-6
transformation of imidazoles, the construction of an all-carbon
quaternary stereocenter by the CH addition of an imidazole group
to a 1,1-disubstituted alkene unit has remained unknown to date. It
has been previously reported that Rh and Ni catalysts could
efficiently promote the CH cycloaddition of imidazoles to 1,1-
disubstituted alkenes, but the CC bond formation proceeded all in
At first, half-sandwich scandium catalysts with different Cp
ligands were examined for the cyclization of an alkenyl-substituted
benzimidazole compound 1a (Table 1; see also SI). In the presence
C Me -ligated Sc complex Sc-1 (4 mol %)10 and
a
5 5
of
[Ph C][B(C F ) ] (4 mol %) at room temperature, only a trace
3
6 5 4
amount of the cyclization product 2a was observed after 36 h
(Table 1, Entry 1). When the reaction temperature was raised to 100
°C, the yield of 2a increased to 22% (Table 1, Entry 2). To our
delight, further raising the temperature to 110 °C led to almost
quantitative formation of the desired product 2a (Table 1, Entry 3).
Remarkably, the CH addition of the imidazole moiety to the 1,1-
disubstituted alkene unit in 1a to give 2a proceeded in an exo-
selective fashion, efficiently yielding an all-carbon-substituted
quaternary stereocenter. This is in sharp contrast to the analogous
Rh- and Ni-catalyzed reactions reported previously, which all gave
an endo-selective fashion without forming
stereocenter (Scheme 1a).
a quaternary
6
Rare-earth catalysis has recently emerged as a powerful
7
methodology for CH activation and functionalization. In
particular, half-sandwich rare-earth catalysts often showed unique
activity and regio- and stereoselectivity in CH addition to alkenes,
8,9
including asymmetric transformations.
These results have
prompted us to examine the potential of rare-earth catalysts for the
construction of all-carbon quaternary stereocenters via CH
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
the endo-cyclization products without forming a quaternary
Table 2. Exo-Selective C‒H Cycloaddition of Imidazoles to
1,1-Disubsituted Alkenes by Sc-1
6
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stereocenter (see also Scheme 1a). The use of a further sterically
demanding C Me SiMe -ligated complex Sc-2 did not hamper the
reaction (Table 1, Entry 4), while a smaller C -coordinted analog
Sc-3 showed almost no catalytic activity under the same conditions
Table 1, Entry 5), in agreement with the catalyst activity observed
5
4
3
R1
Sc-1 (4 mol%)
H
5
N
N
R1
R2
N
N
5
H
[Ph3C][B(C6F5)4] (4 mol%)
R2
R
Toluene
R
(
n
n
7a,11
n = 1, 2
previously in olefin polymerization.
2
1
R = Alkyl
Table 1. Exo-Selective C‒H Cycloaddition of
a
Scope of 6-membered ring formation
Benzimidazole moiety to a 1,1-Disubstituted Alkene Unit by
N
nBu
N
N
7
C H
N
N
N
N
15
Ph
a
Sc Catalysts Bearing Different Cp Ligands
N
Ph
2
a, 96%
2b, 96%
2c, 94%
[
Sc] (4 mol%)
2d, 95%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
nBu
Br
H
[Ph3C][B(C6F5)4] (4 mol%)
Toluene, 36 h
nBu
N
N
N
N
O
F
1
a
2a
N
o
Entry
[Sc]
Temp. ( C)
Yield (%)
e, 96%b
2
2f, 94%
1
2
Sc-1
Sc-1
20
trace
22
I
100
N
N
N
N
N
N
3
4
5
Sc-1
Sc-2
Sc-3
110
110
> 99
> 99
O
N
N
H
H
nPr
110
trace
2j, 94%b
2
g, 96%
2h, 95%
2i, 95%
SiMe3
Me
Me
N
nBu
Cl
Cl
Br
N
N
nBu
N
N
nBu
N
nBu
Sc
Sc
N
Sc
N
N
N
N
N
N
N
2
k, 96%
2l, 93%
2m, 91%
2n, 95%
Sc-1
Sc-2
Sc-3
N
N
nBu
Ph
Ph
N
N
nBu
Ph
Ph
N
N
aReaction conditions: 1a (0.1 mmol), [Sc] (4 mol %),
Ph C][B(C ] (4 mol %), toluene (1.0 mL), indicated
temperature, 36 h, NMR yield using CH Br as an internal standard.
Br
[
3
6
F
5
)
4
H
2
p, 96%c
2q, 95%c
2o, 96%
2
2
Br
The imidazole substrate scope was then examined by using the
Sc-1 catalyst under the optimized reaction conditions. Some
representative results are summarized in Table 2. Benzimidazoles
bearing various 1,1-disubstituted alkene units were easily cyclized
in an exo-selective fashion, affording the all-carbon-substituted
quaternary stereocenters in almost quantitative yields. Heteroatoms
such as oxygen, nitrogen and sulfur in the side chain did not hamper
the reaction (2e-2g and 2v-2y). Aromatic halides (F, Cl, Br, I) could
survive the reaction conditions (2e-2g, 2l, 2n, 2o, 2s, 2v, and 2w),
providing the possibility for further transformations. Exocyclic
alkenes were well accommodated in this transformation, leading to
the formation of the polycyclic imidazole derivatives in excellent
yields (2h and 2i). An imidazole compound with contiguous all-
carbon quaternary centers (2j) could be easily constructed in this
way. Besides benzimidazoles, the cyclization of other disubstituted
imidazoles and polycyclic aromatic imidazoles also took place
smoothly (2p-2s). The solid structure of the cyclization product 2q
was confirmed by a single crystal X-ray diffraction analysis. In
addition to six-membered ring formation, the construction of five-
membered ring products (2t-2y) could also be achieved in an exo-
selective fashion, demonstrating again the highly general scope of
this transformation.
Scope of 5-membered ring formation
N
nBu
N
N
N
Ph
N
N
Me
Me
N
N
Ph
Br
2t, 96%c
2u, 96%c
r, 94%c
2s, 96%c
2
Br
Ph
Ph
N
N
OBn
Cl
Ph
Ph
N
N
S
N
O
N
Cl
N
O
N
2w, 95%
2x, 94%c
2y, 93%
2v, 95%
R  Alkyl
N
N
Ph
N
N
N
N
N
N
H
H
H
H
Ph
Me
c
2ac, 96% ;
2z, 96%c
2aa, 96%c
2ab, 96%c
d.r.= 1.6 / 1
Styrene:
Diene:
Enyne:
N
Ph
Ph
N
N
Ph
N
N
Ph
N
N
tBu
N
Ph
Ph
Ph
2
ad, 96%b
2ae, 96%
2af, 96%c
2ag, 96%c
aReaction conditions:
[Ph C][B(C F ) ] (4 mol %), toluene (1.0 mL), 110 °C, 36 h, unless
1 (0.1 mmol), Sc-1 (4 mol %),
3
6 5 4
b
otherwise noted. Percentages represent isolated yields. Sc-1 (8 mol
), [Ph C][B(C F ) ] (8 mol %), 120 °C, 72 h. 6 h.
3 6 5 4
Besides 1,1-dialkyl-substituted alkenes, imidazoles with mono-
substituted terminal alkenes also underwent cyclization in an exo-
selective fashion (2z and 2aa-2ac). The reaction of imidazoles
bearing 1,1-disubstituted styrene units efficiently afforded the all-
carbon quaternary centers with two different aromatic substituents
c
%
Scheme 2. C‒H Cycloaddition of Imidazole to
Trisubstituted Alkene Unit
a
(
2ad and 2ae). Diene and enyne units were well accommodated in
this transformation, yielding the quaternary stereocenters with
alkenyl (2af) and alkynyl (2ag) substituents, respectively. The CH
cycloaddition of an imidazole group to a tri-substituted alkene unit
3) also occurred smoothly, efficiently affording a non-methyl
substituted all-carbon quaternary stereocenter (4) (Scheme 2).
Ph
Ph
Sc-1
(8 mol%)
N
N
Ph
Ph
N
N
H
[Ph3C][B(C6F5)4] (8 mol%)
Et
(
Toluene, 120 oC, 72 h
Et
3
4, 95%
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
Scheme 3. Transformation of a Cyclization Product 2a
Table 3. Asymmetric exo-Selective C‒H Cycloaddition of
1
2
3
4
5
6
7
8
9
Imidazoles to 1,1-Disubsituted Alkenes by a Chiral Sc
OAc
nBu
Pd(OAc)2 (5 mol%)
PhI(OAc)2 (1.5 equiv.)
a
N
Catalyst
(a)
N
AcOH / Ac2O (1/1, 1.0 mL),
110 oC, 6 h
OTBDPS
H
nBu
R1
R2
TBDPS-Sc (5 mol%)
N
N
N
N
2a-OAc, 80 %
R1
R2
H
[Ph C][B(C F ) ] (5 mol%)
N
N
3
6 5 4
[
Cp*IrCl2]2 (2.5 mol%)
AgNTf2 (15 mol%)
PivOH (3.0 equiv.)
Ph2IOTf (2.0 equiv.)
R
R
Toluene-d8
Sc
R
n
R
n
OTBDPS
2a
n = 1, 2
N
nBu
2
t
TBDPS = Si BuPh ; R = CH C H NMe -o
2
2
6
3
2
1
(b)
TBDPS-Sc
200 mg 4Å MS
N
cyclohexane, 100 oC, 12 h
R = Alkyl
Ph
N
N
Ph
Ph
N
N
Ph
Ph
N
N
2a-Ph, 73 %
nBu
I
C7H15
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
Ph
In attempts to explore the elaboration of the present cyclization
products, the C(sp )H functionalization of the methyl group in 2a
3
(R)-2p, 96%,
e.r. = 96 : 4
(R)-2ah, 96%,
e.r. = 95 : 5
(R)-2ai, 94%,
e.r. = 84 : 16
was examined by using the imidazole moiety as an intrinsic
directing group. The Pd-catalyzed methyl CH acetoxylation of 2a
easily afforded the acetoxylated derivative 2a-OAc (Scheme 3,
F
Ph
Ph
N
N
Ph
Ph
N
Ph
Ph
N
O
S
N
O
N
1
2
a), and the Ir-catalyzed CH arylation of 2a gave the arylated
(R)-2x, 93%,
e.r. = 92 : 8
(R)-2aj, 94%,
e.r. = 94 : 6
(R)-2ak, 95%,
e.r. = 97: 3
1
3
product 2a-Ph in good yield (Scheme 3, b). These results
demonstrate that the application scope of the present Sc-catalyzed
imidazole CH addition protocol may be further broadened to the
synthesis of more diversified all-carbon-substituted quaternary
stereocenters through the transition-metal-catalyzed methyl
Me
Br
Ph
Ph
N
N
N
nBu
O
N
Me
3
14
C(sp )H functionalization of the resulting cyclization products.
(R)-2al, 93%,
e.r. = 96 : 4
(R)-2am, 96%,
e.r. = 95 : 5
Having established the achiral reactions, we next examined if
the construction of all-carbon quaternary stereocenters could be
achieved in an asymmetric fashion by using a chiral scandium
catalyst. The asymmetric cyclization of a wide range of 4,5-
disubstituted imidazole substrates were successfully realized by
using a chiral half-sandwich scandium catalyst TBDPS-Sc (Table
MeO
MeO
F
Br
N
N
N
N
N
N
nBu
nBu
nBu
F
Br
Br
(
R)-2an, 93%,
e.r. = 92 : 8
(R)-2ao, 95%,
e.r. = 90 : 10
(R)-2ap, 95%,
e.r. = 91 : 9
1
; see also SI). The reaction generally took place at 70 °C in toluene,
affording the bicyclic imidazole derivatives bearing chiral all-
carbon quaternary stereocenters in high yields (92-96%) and high
enantioselectivity (up to 97:3 e.r.). Similar to the achiral
transformations, fluoro, bromo, and iodo functional groups
remained intact during the reaction ((R)-2ai, (R)-2aj and (R)-2al).
Oxygen and sulfur atoms in the side chain did not hamper the
enantioselectivity in the formation of both five-membered ring and
six-membered ring ((R)-2ai, (R)-2x, and (R)-2aj-2al). Imidazole
moiety with highly fused aromatic rings was also well compatible
R  Alkyl
Ph
Ph
N
N
nBu
N
N
N
N
H
H
Br
(R)-
2r, 94%,
(S)-2ab, 95%,
e.r. = 88 : 12
(S)-2aq, 95%,
e.r. = 89 : 11
e.r. = 88 : 12
Ph
Ph
N
N
Ph
Ph
Ph
Ph
N
N
N
N
tBu
1
5
with the asymmetric transformation ((R)-2r). The absolute
configuration of an annulation product (R)-2al was confirmed by
the single crystal X-ray diffraction analysis. The asymmetric
hydroimidazolylation of monosubstituted terminal alkenes also
took place with good stereocontrol ((S)-2ab and (S)-2aq). The
construction of chiral all-carbon quaternary stereocenters bearing
phenyl ((R)-(2ae), alkynyl ((R)-2ag), and alkenyl ((R)-2ar) groups
was achieved as well with no erosion of enantioselectivity.
Me
(R)-2ar,b 92%,
e.r. = 96 : 4
(R)-2ae,b,c 96%,
(R)-2ag, 95%,
e.r. = 94 : 6
e.r. = 94 : 6
aReaction conditions: 1 (0.05 mmol), TBDPS-Sc (5 mol %),
[Ph C][B(C ] (5 mol %), toluene-d (0.5 mL), 70 °C, 24-48 h,
unless otherwise noted. Percentages represent isolated yields. The
3
6
F
5
)
4
8
b
e.r. was determined by HPLC. TBDPS-Sc (8 mol %),
c
[Ph
3
C][B(C
6
F
5
)
4
] (8 mol %). 85 °C, 72 h.
To gain information on the reaction mechanism, the deuterium-
labelling experiments were carried out. The reaction of the C2-
deuterated imidazole compound 1a-D at 110 °C for 24 h afforded
the corresponding cyclization product 2a-D in 21% yield with 75%
deuterium incorporation at the resulting methyl group and 5%
deuterium incorporation at the C3 position (Scheme 4, a). The
deuterium incorporation at the C3 position of the recovered
uncyclized benzimidazole compound (1a-D’) was also observed.
These results suggest that deprotonative metalation could occur at
both the C2 and C3 positions of the benzimidazole moiety of 1a.
Heating a 1:1 mixture of 1a-D and a 4,5-dichlorobenzimidazole
compound 1l at 110 °C for 36 h led to deuterium incorporation at
the methyl group and the C3 position of both of the cyclization
products 2a-D’ and 2l-D (Scheme 4, b). The relative ratio of the
initial rates of two parallel reactions using 1a and 1a-D,
respectively, was determined to be 2.2, indicating that C‒H bond
cleavage might be involved in the rate-determining step (see SI).
On the basis of the above experimental results, a possible
mechanism of the cyclization of 1a is shown in Scheme 5. The
deprotonative C‒H activation by the Sc‒R species could take place
at either the C2 or C3 position of 1a, affording I or I’, respectively.
The intermediates I and I’ may be interconverted by the similar
reaction with another molecule of 1a. The intramolecular insertion
(
cyclization) of the C=C unit into the Sc‒imidazolyl bond in I via
II would give III. The exo-selectivity in this transformation should
11
be governed by both the steric and electronic effects. The
hydrogen abstraction of 1a by the Sc‒C -bond in III would release
2
a and regenerate I or I’.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Scheme 4. Deuterium-Labelling Experiments
AUTHOR INFORMATION
Page 4 of 6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a. Reaction of D-labeled 1a
Corresponding Author
*houz@riken.jp
0.05 D
0.75 D
0.06 D
H
H/D
H/D
0.96 D
0
.99 D
D
C3
Sc-1 (4 mol%)
N
N
N
N
nBu
N
[
Ph3C][B(C6F5)4] (4 mol%)
D
C2
D
nBu
nBu
+
N
Toluene-d8, 110 oC, 24 h
ORCID
2
a-D, 21%
1a-D', 73%
.10 D
H/D
0.10 D
1a-D
Shao-Jie Lou: 0000-0003-3700-6812
Zhenbo Mo: 0000-0002-5021-9540
Masayoshi Nishiura: 0000-0003-2748-9814
Zhaomin Hou: 0000-0003-2841-5120
0
b. Cross deuterium exchange
H/D
0
.99 D
N
N
N
N
nBu
D
nBu
Sc-1 (4 mol%)
Notes
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[Ph3C][B(C6F5)4] (4 mol%)
2a-D'
1
a-D (0.05 mmol)
+
Toluene-d8, 110 oC, 36 h
+
The authors declare no competing financial interests.
0.19 D
H/D
Cl
Cl
N
H
N
>
99% NMR yield
H/D
0.09 D
nBu
Cl
Cl
N
nBu
ACKNOWLEDGMENT
N
1
l (0.05 mmol)
This work was supported in part by JSPS KAKENHI Grants (Nos.
JP19H00897, JP17H06451, JP17K05824). We thank Mrs. Akiko
Karube and Dr. Takemichi Nakamura for high resolution mass
spectrometry (HRMS) analyses.
2l-D
Scheme 5. Possible Reaction Mechanism
[Ph3C][B(C6F5)4]
Ph3C-R
1a
Sc
REFERENCES
Sc
Sc
N
N
R
R
R
1a
R-H
+1a / -1a
H
(1) Selected reviews: (a) Corey, E. J.; Guzman-Perez, A. The Catalytic
Enantioselective Construction of Molecules with Quaternary Carbon
Stereocenters. Angew. Chem. Int. Ed. 1998, 37, 388. (b) Douglas, C. J.;
Overman, L. E. Catalytic Asymmetric Synthesis of All-carbon Quaternary
Stereocenters. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (c) Quasdorf,
K. W.; Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary
Carbon Stereocenters. Nature 2014, 516, 181. (d) Liu, Y.; Han, S.-J.; Liu,
W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary
Stereocenters: Assembly of Key Building Blocks for the Synthesis of
Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740. (e) Zeng,
X.-P.; Cao, Z.-Y.; Wang, Y.-H.; Zhou, F. Zhou, J. Catalytic
Enantioselective Desymmetrization Reactions to All-Carbon Quaternary
Stereocenters. Chem. Rev. 2016, 116, 7330. (f) Newton, C. G.; Wang, S.-
G.; C. Oliveira, C.; Cramer. N. Catalytic Enantioselective Transformations
Involving C-H Bond Cleavage by Transition-Metal Complexes. Chem. Rev.
2017, 117, 8908. (g) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G.
Transition-Metal-Catalyzed C-H Alkylation Using Alkenes. Chem. Rev.
R-H
Me2N
I'
nBu
R =
+
1a / -1a
N
Sc
2a
N
nBu
I
1a
‡
Sc
N
Sc
1a
N
nBu
nBu
I'
N
N
2a
II
III
2
017, 117, 9333. (h) Feng, J.; Holmes, M.; Krische, M. J. Acyclic
Quaternary Carbon Stereocenters via Enantioselective Transition Metal
Catalysis. Chem. Rev. 2017, 117, 12564. (i) Li, Y.; Xu, S. Transition Metal-
Catalyzed C-H Functionalization for Construction of Quaternary Carbon
Centers. Chem. Eur. J. 2018, 24, 16218. (j) Ping, Y.; Li, Y.; Zhu, J.; Kong,
W. Construction of Quaternary Stereocenters by Palladium-Catalyzed
Carbopalladation-Initiated Cascade Reactions. Angew. Chem. Int. Ed. 2019,
In summary, by using a half-sandwich scandium catalyst such
as Sc-1, we have achieved for the first time the exo-selective C‒H
cycloaddition of imidazoles to various alkenes, offering a
convenient route for the synthesis of polycyclic imidazole
derivatives containing -all-carbon quaternary stereocenters. This
protocol features unprecedented exo-selectivity, broad substrate
scope, excellent yield, and 100 % atom-efficiency. By using a
chiral scandium catalyst, the asymmetric construction of all-carbon
quaternary stereocenters has also been accomplished with a high
5
8, 1562.
(2) Selected examples: (a) Li, Q.; Yu, Z.-X. Enantioselective Rhodium-
Catalyzed Allylic C-H Activation for the Addition to Conjugated Dienes.
Angew. Chem. Int. Ed. 2011, 50, 2144. (b) Ye, B.; Donets, P. A.; Cramer,
N. Chiral Cp-Rhodium(III)-Catalyzed Asymmetric Hydroarylation of 1,1-
Disubstituted Alkenes. Angew. Chem. Int. Ed. 2014, 53, 507. (c) Zhang, C.;
Santiago, C. B.; Crawford, J. M.; Sigman, M. S. Enantioselective
Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles
to Construct Quaternary Stereocenters. J. Am. Chem. Soc. 2015, 137, 15668.
3
level of enantioselectivity. The easy C(sp )‒H functionalization of
the methyl group in the resulting cyclization products such as 2a
via Pd and Ir catalysis demonstrated that further diversified all-
carbon-substituted quaternary stereocenters can be efficiently
constructed based on this protocol.
(3) (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.
ASSOIATED CONTENT
Supporting Information
2
010, 132, 15939. (b) Worthy, A. D.; Sun, X.; Tan, K. L. Site-Selective
Catalysis: Toward a Regiodivergent Resolution of 1, 2-Diols. J. Am. Chem.
Soc. 2012, 134. 7321. (c) 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.
The Supporting Information is available free of charge on the ACS
Publications website.
(d) Ajani, O. O.; Aderohunmu, D. V.; 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. (e) 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. (f) Denny, R. A.; Flick, A. C.; Coe, J.; Langille, J.;
Basak, A.; Liu, S.; Stock, I.; Sahasrabudhe, P.; Bonin, P.; Hay, D. A.;
Detailed experimental procedures, spectroscopic data for all new
compounds (PDF)
Crystallographic data for 2e, 2q and (R)-2al (CCDC 1958516-
958518) (CIF)
1
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
Brennan, P. E.; Pletcher, M.; Jones, L. H.; Chekler, E. L. P. Structure-Based
2016, 7, 6429. (h) Shi, X.; Nishiura, M.; Hou, Z. C-H Polyaddition of
Dimethoxyarenes to Unconjugated Dienes by Rare Earth Catalysts. J. Am.
Chem. Soc. 2016, 138, 6147. (i) Luo, Y.; Ma, Y.; Hou, Z. α-C-H Alkylation
of Methyl Sulfides with Alkenes by a Scandium Catalyst. J. Am. Chem. Soc.
2018, 140, 114.
Design of Highly Selective Inhibitors of the CREB Binding Protein
Bromodomain. J. Med. Chem. 2017, 60, 5349. (g) Ali, I.; Lone, M. N.;
Aboul-Enein, H. Y. Imidazolesaspotentialanticanceragents. MedChemComm
1
2
3
4
5
6
7
8
9
2
017, 8, 1742.
(4) Selected reviews on C‒H addition of imidazoles to alkenes: (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.
(9) (a) Song, G.; Wylie, W. N. O.; Hou, Z. Enantioselective C–H Bond
Addition of Pyridines to Alkenes Catalyzed by Chiral Half-Sandwich Rare-
Earth Complexes. J. Am. Chem. Soc. 2014, 136, 12209. (b) Teng, H.-L.;
Luo, Y.; Wang, B.; Zhang, L.; Nishiura, M.; Hou, Z. Synthesis of Chiral
Aminocyclopropanes by Rare-Earth-Metal-Catalyzed Cyclopropene
Hydroamination. Angew. Chem., Int. Ed. 2016, 55, 15406. (c) Luo, Y.; Teng,
H.-L.; Nishiura, M.; Hou, Z. Asymmetric Yttrium-Catalyzed C(sp )-H
Addition of 2-Methyl Azaarenes to Cyclopropenes. Angew. Chem. Int. Ed.
2017, 56, 9207. (d) Teng, H.-L.; Luo, Y.; Nishiura, M.; Hou, Z.
2
008, 41, 1013. (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.
3
(5) (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. (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. (c) Tan, K. L.;
Vasudevan, A.; Bergman, R. G.; Ellman, J. A.; Souers, A. J. Microwave-
Assisted C-H Bond Activation:ꢀ A Rapid Entry into Functionalized
Heterocycles. Org. Lett. 2003, 5, 2131. (d) 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. (e)
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, 140, 5360.
(6) (a) Tsai, A. S.; Wilson, R. M.; Harada, H. Bergman, R. G.; Ellman, J.
A. Rhodium Catalyzed Enantioselective Cyclization of Substituted
Imidazoles via C-H bond Activation. Chem. Commun. 2009, 3910. (b) Loup,
J.; Müller, 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. (c) Diesel, J.;
Grosheva, D.; Kodama, S.; Cramer, N. A Bulky Chiral N-Heterocyclic
Carbene Nickel Catalyst Enables Enantioselective C-H Functionalizations
of Indoles and Pyrroles. Angew. Chem. Int. Ed. 2019, 58, 11044.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Diastereodivergent
Asymmetric
Carboamination/Annulation
of
Cyclopropenes with Aminoalkenes by Chiral Lanthanum Catalysts. J. Am.
Chem. Soc. 2017, 139, 16506. (e) Teng, H.-L.; Ma, Y.; Zhan, G.; Nishiura,
M.; Hou, Z. Asymmetric C(sp)-H Addition of Terminal Alkynes to
Cyclopropenes by a Chiral Gadolinium Catalyst. ACS Catal. 2018, 8, 4705.
(f) Zhan, G.; Teng, H.-L.; Luo, Y.; Lou, S.-J.; Nishiura, M.; Hou, Z.
Enantioselective Construction of Silicon-Stereogenic Silanes by Scandium-
Catalyzed Intermolecular Alkene Hydrosilylation. Angew. Chem. Int. Ed,
2018, 57, 12342. (g) Kundu, A.; Inoue, M.; Nagae, H.; Tsurugi, H.;
Mashima, K. Direct ortho-C–H Aminoalkylation of 2-Substituted Pyridine
Derivatives
Catalyzed
by
Yttrium
Complexes
with N,N′-
Diarylethylenediamido Ligands. J. Am. Chem. Soc. 2018, 140, 7332.
(10) Li, X.; Nishiura, M.; Mori, K.; Mashiko, T.; Hou, Z. Cationic scandium
aminobenzyl complexes. Synthesis, structure and unprecedented catalysis
of copolymerization of 1-hexene and dicyclopentadiene. Chem. Commun.
2007, 4137.
(11) (a) Wang, C.; Luo, G.; Nishiura, M.; Song, G.; Yamamoto, A.; Luo,
Y.; Hou, Z. Heteroatom-assisted olefin polymerization by rare-earth metal
catalysts. Sci. Adv. 2017, 3, e1701011. (b) Wang, H.; Yang, Y.; Nishiura,
M.; Higaki, Y.; Takahara, A.; Hou, Z. Synthesis of Self-Healing Polymers
by
Scandium-Catalyzed
Copolymerization
of
Ethylene
and
(7) Selected reviews: (a) Nishiura, M.; Guo, F.; Hou, Z. Half-Sandwich
Rare-Earth-Catalyzed Olefin Polymerization, Carbometalation, and
Hydroarylation. Acc. Chem. Res. 2015, 48, 2209; b) Gandeepan, P.; Müller,
T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for
C-H Activation. Chem. Rev. 2019, 119, 2192. c) Loup, J.; Dhawa, U.;
Pesciaioli, F.; Wencel-Delord, J.; Ackermann, L. Enantioselective C-H
Activation with Earth-Abundant 3d Transition Metals. Angew. Chem. Int.
Ed. 2019, 58, 12803; d) Woźniak, Ł.; Cramer, N. Enantioselective C-H
Bond Functionalizations by 3d Transition-Metal Catalysts. Trends Chem.
Anisylpropylenes. J. Am. Chem. Soc. 2019, 141, 3249. (c) Wang, H.; Zhao,
Y.; Nishiura, M.; Yang, Y.; Luo, G.; Luo, Y.; Hou, Z. Scandium-Catalyzed
Regio- and Stereoselective Cyclopolymerization of Functionalized  -
Dienes and Copolymerization with Ethylene. J. Am. Chem. Soc. 2019, 141,
12624.
(12) Desai, L. V.; Hull, K. L.; Sanford, M. S. Palladium-Catalyzed
3
Oxygenation of Unactivated sp C-H Bonds. J. Am. Chem. Soc. 2004, 126,
9542.
(13) Gao, P.; Guo, W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z.
Iridium(III)-Catalyzed Direct Arylation of C-H Bonds with Diaryliodonium
Salts. J. Am. Chem. Soc. 2015, 137, 12231.
2
019, 1, 471.
(8) (a) Guan, B.-T.; Hou, Z. Rare-Earth-Catalyzed C–H Bond Addition of
Pyridines to Olefins. J. Am. Chem. Soc. 2011, 133, 18086. (b) Oyamada, J.;
Hou, Z. Regioselective C–H alkylation of anisoles with olefins catalyzed
by cationic half-sandwich rare earth alkyl complexes. Angew. Chem. Int. Ed.
(14) Selected reviews on transition-metal catalyzed C(sp )H bond
3
functionalization: (a) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q.
Palladium-Catalyzed Transformations of Alkyl C-H Bonds. Chem. Rev.
2017, 117, 8754. (b) Chu, J. C. K.; Rovis, T. Complementary Strategies for
2
012, 51, 12828. (c) Guan, B.-T.; Wang, B.; Nishiura, M.; Hou, Z. Yttrium-
Catalyzed Addition of Benzylic C–H Bonds of Alkyl Pyridines to Olefins.
Angew. Chem. Int. Ed. 2013, 52, 4418. (d) Song, G.; Wang, B.; Nishiura,
M.; Hou, Z. Catalytic C-H Bond Addition of Pyridines to Allenes by a Rare-
Earth Catalyst. Chem. Eur. J. 2015, 21, 8394. (e) Nagae, H.; Shibata, Y.;
Tsurugi, H.; Mashima, K. Aminomethylation Reaction of ortho-Pyridyl
C−H Bonds Catalyzed by Group 3 Metal Triamido Complexes. J. Am.
Chem. Soc. 2015, 137, 640. (f) Song, G.; Luo, G.; Oyamada, J.; Luo, Y.;
Hou, Z. ortho-Selective C-H addition of N,N-dimethyl anilines to alkenes
by a yttrium catalyst. Chem. Sci. 2016, 7, 5265. (g) Nako, A. E.; Oyamada,
J.; Nishiura, M.; Hou, Z. Scandium-catalysed intermolecular
hydroaminoalkylation of olefins with aliphatic tertiary amines. Chem. Sci.
Directed C(sp )-H Functionalization: A Comparison of Transition-Metal-
3
Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene
Transfer. Angew. Chem. Int. Ed. 2018, 57, 62.
(15) Unsubstituted benzimidazole unit (1a) did not undergo the cyclization
reaction by TBDPS-Sc, probably because of the smaller steric hindrance
which may allow stronger interaction between the metal center and the N
atom(s) of the substrate, and thus hamper the access of the C=C unit to the
catalyst metal center. Similar steric influence has been observed previously
in the rare-earth-catalyzed C‒H alkylation of pyridines (see ref 8a).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R1
R1
R2
N
N
N
N
H
Sc
R
R2
R
n
n
n = 1, 2
excellent yield & up to 97:3 e.r.
R = alkyl, aryl, alkenyl, alkynyl, H


Exo-selectivity & high enantioselectivity  100% atom-efficiency
All-carbon-substituted quanternary center  Broad substrate scope
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
ACS Paragon Plus Environment