Asymmetric Alkyl and Aryl/Azolation of Alkenes via a Single Cu(I) Complex

Article abstract of DOI:10.1021/acscatal.0c05576

The copper-catalyzed, highly enantioselective alkyl and aryl/azolation of alkenes is reported. The employment of the chiral carbazole-based bisoxazoline (Cbzbox) ligand is critical to the success of this chemistry. Anionic tridentate ligands improve the reducibility of copper complexes, facilitating alkyl/aryl radical generation and providing good enantiocontrol in the azolation. The three-component coupling reactions feature mild reaction conditions and tolerate broad range of functional groups. This strategy allows straightforward introduction of valuable azole functionalities into a elaborated molecular system through direct C-H functionalization.

Full text of DOI:10.1021/acscatal.0c05576

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Research Article
Asymmetric Alkyl and Aryl/Azolation of Alkenes via a Single Cu(I)
Complex
Xiaodong Ma and Guozhu Zhang*
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ABSTRACT: The copper-catalyzed, highly enantioselective alkyl
and aryl/azolation of alkenes is reported. The employment of the
chiral carbazole-based bisoxazoline (Cbzbox) ligand is critical to
the success of this chemistry. Anionic tridentate ligands improve
the reducibility of copper complexes, facilitating alkyl/aryl radical
generation and providing good enantiocontrol in the azolation. The
three-component coupling reactions feature mild reaction con-
ditions and tolerate broad range of functional groups. This strategy
allows straightforward introduction of valuable azole functionalities
into a elaborated molecular system through direct C−H
functionalization.
KEYWORDS: copper catalysis, asymmetric C−H functionalization, multicomponent reaction, difunctionalization, azoles
he 1,2-difunctionalization of alkenes has been established
Tto be a versatile approach to derivatization of hydro-
carbons which allows the direct introduction of two functional
groups within a single transformation.1 In contrast to the
tremendous progress achieved in asymmetric difunctionaliza-
tion of alkenes with two electron redox catalysis, the
development of general methods that form bonds from
radical-based electrophiles, typically readily available alkyl
(pseudo) halides, lags far behind, partially due to their slow
oxidative addition with metal and downstream β-H elimination
of resulting alkyl metal species.2 Among established methods,
copper-catalyzed asymmetric radical difunctionalization of
alkenes via a Cu(I) species has shown unique potential.3
With respect to nucleophilic coupling partners in alkene
difunctionalization chemistry, as far as we know, there were no
successful examples by the use of simple (hetero)arenes with
acidic C(sp2)−H bonds as nucleophiles despite that
prefunctionalized (hetero)aryl reagents have been employed
as coupling partners in two-component coupling reactions.4
Owing to the important role in many compounds of biological
and molecular systems and medicines, azoles have drawn much
attention of organic chemists and pharmaceutists.5 Obviously,
replacing prefunctionalized (hetero)aryl reagents with simple
(hetero)arenes will significantly improve practicality of this
method, considering material accessibility, atom economy, and
operational simplicity. Racemic radical cross-coupling of alkyl
electrophiles with heteroarene C(sp2)−H bonds has seen
limited success, the asymmetric variants are even more
challenging with reported catalysis, largely ascribed to the
use of strong base at high temperature, resulting in the
racemization of the obtained α-chiral alkyl (hetero)arenes,
particularly with electron-deficient heteroarenes.6 Thus, new
systems enabling the asymmetric three-component carboazo-
lation of alkene would be highly desired.
Our and Liu’s group recently discovered the catalytic system
of copper(I) and chiral anionic ligand to realize enantiocon-
vergent cross-coupling of alkyne with common racemic alkyl
electrophiles7 and asymmetric alkylation of benzyl bromide
with azoles (Scheme 1, eq a).8 The significance of this series of
work lies in: (1) the identification of the anionic multidentate
ligand to significantly enhance the reducing capability of the
copper−Nu complx, which reduces carboelectrophiles under
mild conditions; (2) the use of chiral oxazoline allows the
ready access of both enantiomers of the product;3p,9 (3) the
use of simple terminal alkynes and azoles as nucleophiles by
facile formation of copper−nucleophilic species, which leads to
much improved functional group compatibility as well as opens
up new routes for the introduction of other nucleophiles with
acidic C−H bonds, not limited to traditional organometallic
reagents.
We envisioned that an asymmetric three-component
coupling of alkenes, alkyl halides, and (hetero)arenes with
acidic C(sp2)−H bonds might be viable under Cu(I)/N,N,N-
ligand catalysis (Scheme 1, eq b). In this manuscript, we
Received: December 20, 2020
Revised: March 30, 2021
Published: April 13, 2021
https://doi.org/10.1021/acscatal.0c05576
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Scheme 1. (a) Asymmetric Biscomponent Azolation (b) This Work: Enantioselective Alkyl and Aryl/Azolation of Alkenes
describe our initial efforts in achieving enantioconvergent
three-component coupling of a variety of alkyl halides/diaryl
iodonium salts, styrenes, and azole C(sp2)−H bonds using the
Cbzbox−Cu catalytic system. The reaction is allowing a facile
incorporation of valuable functionalities including ester,
ketone, acetylene, difluoro acetate, and phenyl into the azole-
containing elaborated molecular skeleton. In addition,
mechanistic studies support that our Cu(I)/N,N,N-ligand
catalyst sufficiently reduces the carboelectrophiles to carbo
radicals to initiate the reaction at lower reaction temperature
which also prevents the racemization of sensitive tertiary
stereocenter in the α-chiral alkylated azole product. Inspired by
Liu’s work on employing activated tertiary halide as the alkyl
radical precursor,3p we selected benzoxazole 1a, styrene 2a,
and ethyl 2-bromo-2-methylpropanoate 3a to test the three-
component coupling reactions. After extensive experiments of
tuning various reaction parameters, we found that the reaction
with chiral tBuCbzbox10 L1 as the ligand and 5 mol % CuBr as
the catalyst gave a good yield and enantioselectivity of a1
(Table 1, entry 3).
6), and product was racemic when using BOPA as the ligand
(Table 1, entry 7−9). Notably, Pybox (L8) and Box (L9)
ligands were not effective for the current reaction (Table 1,
entry 10 and 11), suggesting that the anion coordination site in
Cbzbox might be necessary for this reaction. With identifying
the optimal ligand, we next turned our attention to other
elements in this three-component coupling reaction. More
benzoxazole (1a) and less halohydrocarbon (3a) led to better
yield (99%) but less ee value (87%) (Table 1, entry 12).
Lowering temperature improved enantioselectivity but gave
significantly diminished yield (40%) (Table 1, entry 13). Other
copper salts like Cu(CN)4PF6 and CuCN could gave same ee
value but lower yield (Table 1, entry 14 and 15). Switching the
base from tBuOLi to others like MeOLi was also detrimental
to the reaction as no desired product was observed (Table 1,
entry 16).
With the optimized conditions in hand (Table 1, entry 1),
substrate scope of alkenes for this asymmetric reaction was
then explored (Table 2). A range of styrenes bearing mono-
substituents on the aryl ring were initially investigated. Weak
electron-donating groups such as Me and tBu groups in the
para position facilitate this transformation as the corresponding
products were obtained in good yields and good ees (92, 95%)
(a2, a3), while the halogen gave moderate yield (28−66%) and
good enantioselectivity (87−88%) (a4−a6). For the styrenes
with strong electron-donating groups (OMe), the reactions
Encouraged by this preliminary result, we tested a variety of
Cbzbox with different substituents (L2−L4) and BOPA (L5−
L7). The latter contains a flexible backbone11 and gave good
result in the former multicomponent alkynylation reactions.7
However, further changing of the substituents on the Cbzbox
ligand resulted in a moderate stereo control (Table 1, entry 4−
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Table 1. Optimization of the Reaction Conditions
a
b
c
entry
deviation
yield (%)
ee (%)
1
2
none
85
0
89
without chiral ligand
L1
L2
L3
L4
L5
L6
L7
de
,
3
75
40
43
11
35
32
9
88
de
,
4
de
,
5
11
12
de
,
6
de
,
7
de
,
8
de
,
9
de
,
10
11
12
13
14
15
16
L8
L9
0
0
de
,
e
3 equiv of 1a
99
40
64
39
0
87
91
88
89
0 °C instead of RT
Cu(CN)4PF6 instead of CuBr
CuCN instead of CuBr
MeOLi instead of tBuOLi
de
,
de
,
d
a
Standard reaction conditions: 5 mol % CuBr, 5 mol % tBuCbzbox, 0.15 mmol of tBuOLi in 0.5 mL of DCE, room temperature, reaction time = 24
b
h. The absolute configuration of the product was assigned by comparison with the single-crystal X-ray analysis of an analogue. NMR yield.
c
d
e
Determined by HPLC, see the Supporting Information for further details. Reaction time = 16 h. 1 equiv of 3a.
proceeded well to provide the products in good yields (89%)
and slightly dropped ees (80%) (a7), and electron-with-
drawing groups (CF3) led to diminished yield (30%) and
moderate enantioselectivity (73%) (a8). Styrene containing
chloromethyl in the para position gave products in the modest
yield and ee (a9). The alkyl meta-substitution like methyl led
to comparable yield and ee value (a10). However, the aryl
alkenes with meta halogen substitution on the aryl ring gave
products in decreased yields (42, 64%) and moderate ees (40,
72%) (a11, a12). For the styrenes with disubstituents on the
benzene ring, the reaction provided the product with further
dropped yield (32%) due to the steric congestion but
comparable ee (89%) (a13). Other aromatic alkenes, like
naphthyl and biphenyl, were compatible with current reaction
conditions (a14, a15). Surprisingly, an enantiomeric excess
was obtained for a16. This result suggests that the weak
interaction of the copper species with the styrene double bond
before the alkylation might be possible. More detailed
mechanistic research in the enantiodetermining step and
ligand interaction would be helpful for the explanation of an
interesting phenomenon and further development of asym-
metric azolations.
Benzoxazoles with different substitutions could also be
alkylated in moderate yields with good ee (b1−b9) (Table 3).
Alkyl (methyl) and halides (F, Cl, and Br) were all tolerated at
different positions on the benzoxazole ring (b1−b5). Both
electron-donating group (b6) and electron withdrawing group
(b7) were compatible with current reaction conditions.
Oxazoles with elongated conjugation, such as naphtho[2,3-
d]oxazole and naphtho[1,2-d]oxazole, were capable substrates
as well, providing the products in moderate yields with good
ees (b8, b9). Oxadiazole were also examined, and the
moderate result was obtained (b10). Moreover, the oxazole
with an electron-withdrawing group could give low yield and
moderate enantioselectivity (b11), and benzothiazole provided
products with moderate yield and comparable enantioselectiv-
ity (b12−b14). Our efforts to expand the three-component
coupling to other heteroaromatics, including thiophene with
EWG,14 were unsuccessful, possibly due to the less acidic C−H
bond of heteroarenes and the insufficient reducibility of the
corresponding Cu-complex.
The scope of alkyl radical precursors was then investigated
(Table 4), the secondary alkyl ester gave the desired products
as a 1.3:1−5.7:1 mixture of diastereomers with good yields and
enantioselectivities (c1−c4). 2-Chloropropanenitrile could
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a
Table 2. Substrate Scope Studies of Alkenes
a
Reaction condition: 5 mol % CuBr, 5 mol % tBuCbzbox, 0.15 mmol of tBuOLi in 0.5 mL of DCE at room temperature for 24 h. Isolated yield.
b
Determined by HPLC. Performed at 0 °C for 48 h.
react with moderate result (c5). Importantly, α-bromo ketones
were also compatible with the reaction, giving moderate yield
and good ee value (c6−c9). The difluoroacetate was tolerated
under current reaction conditions, leading to the product in
reasonable yields and fare ees (c10). Furthermore, the
asymmetric reaction proceeded smoothly with 3-bromo-1-
trimethylsilyl-1-propargyne to give c11 in 52% yield and 84%
ee. 1-Bromoethyl benzene did not provide the three-
component coupling product c12, a trace amount of
compound derived from the coupling of benzoxzole and
bromide was detected by GC−MS.
Encouraged by the success of alkyl/azolation of alkenes, we
started to explore other potential aryl radical precursors for
asymmetric aryl/azolation of alkenes. Motivated by our
previous study on asymmetric aryl/alkynylation of alkenes
using diaryliodonium salt as an aryl radical precursor,7b we
found that the reaction of benzoxazole 1a with styrene 2a and
diaryliodonium trifluoromethyl sulfonate13 using tBuCbzbox as
the ligand indeed provided the desired product (Table 5).
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a
Table 3. Substrate Scope Studies of Heterocycle Systems
a
Reaction condition: room temperature, 5 mol % CuBr, 5 mol % tBuCbzbox, 0.15 mmol of tBuOLi in 0.5 mL of DCE for 24 h. Isolated yield.
Determined by HPLC.
After extensive experiments of screening various reaction
parameters, d1 was obtained in 62% yield with 89% ee. With
these optimized conditions in hand, the generality of this
transformation is established in Table 5. Styrenes with mono
para-substituted aryl groups that were weak electron donating
(d2, d3), halides (d4−d6), and strong electron donating (d7)
reacted well to provide the products in moderate yields and
good ees. Interestingly, a reactive benzyl chloride could also be
tolerated (d8), thus providing a good handle for further
transformations. 2-Vinylnaphthalene and 4-vinylbiphenyl were
good substrates as well (d9, d10). The copper-catalyzed
method was further applied to the other oxazole system. The
three-component addition of 5-substitution benzoxazole
including methyl, halide, and methoxy with aryl alkene
performed well and produced α,β-diarylation benzoxazole
(d11−d14) in moderated yields with good ees (83−90%).
Finally, we tested the established reaction with a range of
diaryliodonium salts. A variety of aryl-substituted iodonium
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a
Table 4. Substrate Scope Studies of Alkyl Halohydrocarbons
a
b
Reaction condition: 5 mol % CuBr, 5 mol % tBuCbzbox, 0.15 mmol of tBuOLi in 0.5 mL of DCE. Isolated yield. Determined by HPLC. 1 equiv
of bromide hydrocarbons.
salts proved to be good substrates for this reaction, leading to
diversified products (d15−d17).
ring-opening took place, leading to product f1 via difunction-
alization across the extended carbon chain in low ee. Notably,
no side product with the cyclopropyl group intact was
observed, those results are consistent with that of a typical
radical process involving the secondary alkyl precursor.7c We
also tested the benzyl bromide as the radical initiator8b and
could only observe biscomponent coupling product comprising
oxazole and benzyl groups (Scheme 2, eq d), which suggests
the incapability of the benzyl radical in the current three-
component reaction system. In addition, the reaction of
benzoxazole and ethyl 2-bromopropanoate did not give the
coupling product, suggesting the critical role of aromatic alkene
for the success of the radical three-component coupling
reaction (Scheme 2, eq e).
Several control experiments were chosen to elucidate the
possible mechanism of this copper-catalyzed three-component
coupling reaction (Scheme 2). No reaction occurred in the
absence of L1 (Table 1, entry 2), suggesting that the ligand-
coordinated copper benzoxazole complex facilitates the
reduction of alkyl halides for reaction initiation. Treatment
of 1a with tBuOLi at r.t. for 2 h, followed by CD3OD, a 85% of
H/D exchange ratio was observed, suggesting that the
formation of the [Li+oxazole−] complex is quite efficient
(Scheme 2, eq a). The following ligand exchange to form
[Cu+oxazole−] is viable.14
Upon the addition of the radical scavenger TEMPO, the
reaction was totally shut down, indicating a radical mechanism
(Scheme 2, eq b). A radical clock experiment was further
conducted (Scheme 2, eq c), 2b with a cyclopropyl group was
subjected to the standard conditions in place of styrene, and
Based on the literature3d−o,7c,12 and these findings, a
tentative reaction mechanism is shown in Figure 1. After
deprotonation in the presence of a base, the azole coordinates
with copper to form the [LCu(I)(azole)]− Li+ (A) in situ14
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a
Table 5. Substrate Scope Studies of Reactions with Diaryliodonium Salts
a
Reaction condition: 10 mol % CuBr, 10 mol % tBuCbzbox, 0.5 mmol of tBuOLi in 2 mL of DCE. Isolated yield. Determined by HPLC.
that serves as the reductive species, and the anionic ligand
could potentially enhance the reductive ability of the copper
complex. This intermediate converts alkyl halide to alkyl
radical (R●) with simultaneous generation of [LCu(II)-
(azole)] (B). The alkyl bromides (MeO2CCH(CH3)2Br)
have reduction potential E1/2 = −0.43 V versus SCE15 which
is sufficiently lower than that of reported anionic ligand−
copper complex.3p,7a,b Those results suggest that the SET
process may be viable. Then, the addition of an organic radical
to styrene results in a stabilized benzylic radical (C), which
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Scheme 2. Mechanism Investigation
Figure 1. Proposed catalytic cycle.
combines with catalytic species (B) and gives the key
intermediate (D). Eventually, the Cu(III) species affords the
product after the process of reductive elimination and
regenerates the catalyst LCuIX.
Copper-catalyzed aryl-azolation might proceed through an
analogous pathway, leading to [LCu(I)(azole)]− Li+ (A),
which could be oxidized by diaryliodonium salt to provide an
aryl radical with a simultaneous formation of copper(II)
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species LCu(II)(azole) (B).7b The Ph2I+/PhI+Ph have an
sufficient reduction potential E = −0.7 versus SCE.16 A similar
radical addition and LCu-controlled enantioselective azolation
are followed, leading to arylated compounds.
Molecular Synthesis, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, Shanghai 200032, P.
R. China; orcid.org/0000-0002-2222-6305;
Email: guozhuzhang@sioc.ac.cn
With the single-crystal structure, experiment results, and
former studies,3p,17 we tentatively proposed the transition state
when the chiral center forms. Accordingly, two enantiodiscri-
mination transition states of pentacoordinated Cu(III)
complexes, leading to two enantiomers, were inferred, as
shown in Figure 2. The steric repulsion between the aryl group
Author
Xiaodong Ma − State Key Laboratory of Organometallic
Chemistry, Shanghai Institute of Organic Chemistry, Center
for Excellence in Molecular Synthesis, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05576
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to NSFC-21772218, 21821002,
XDB20000000, the “Thousand Plan” Youth program, State
Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
for financial support.
Figure 2. Proposed transition state.
in the substrate and the tert-butyl group in the ligand makes
the re-transition state unfavorable. On the contrary, the Si-
transition state with smaller spatial repulsion leads to the
formation of (S)-product, which is consistent with the
experimental results.
REFERENCES
■
(1) For some difunctional reactions reviews: (a) Egami, H.;
Sodeoka, M. Trifluoromethylation of Alkenes with Concomitant
Introduction of Additional Functional Groups. Angew. Chem., Int. Ed.
2014, 53, 8294−8308. (b) Zhang, J.-S.; Liu, L.; Chen, T.; Han, L.-B.
Transition-Metal-Catalyzed Three-Component Difunctionalizations
of Alkenes. Chem.Asian J. 2018, 13, 2277−2291. (c) Kolb, H. C.;
Van Nieuwenhze, M. S.; Sharpless, K. B. Catalytic Asymmetric
Dihydroxylation. Chem. Rev. 1994, 94, 2483−2547. (d) Guo, H.-C.;
Ma, J.-A. Catalytic Asymmetric Tandem Transformations Triggered
by Conjugate Additions. Angew. Chem., Int. Ed. 2006, 45, 354−366.
(e) Wang, K.; Kong, W. Recent Advances in Transition Metal-
Catalyzed Asymmetric Radical Reactions. Chin. J. Chem. 2018, 36,
247−256.
(2) For some reviews: (a) Lan, X.-W.; Wang, N.-X.; Xing, Y. Recent
Advances in Radical Difunctionalization of Simple Alkenes. Eur. J.
Org. Chem. 2017, 5821−5851. (b) McDonald, R. I.; Liu, G.; Stahl, S.
S. Palladium(II)-catalyzed Alkene Functionalization via Nucleopalla-
dation: Stereochemical Pathways and Enantioselective Catalytic
Applications. Chem. Rev. 2011, 111, 2981−3019. (c) Yin, G.; Mu,
X.; Liu, G. Palladium (II)-Catalyzed Oxidative Difunctionalization of
Alkenes: Bond Forming at a High-Valent Palladium Center. Acc.
Chem. Res. 2016, 49, 2413−2423. . For some representative examples
catalysed by Pd, Ni, Cr, Au: (d) Qi, X.; Yu, F.; Chen, P.; Liu, G.
Palladium-Catalyzed Intermolecular Arylcarbonylation of Unactivated
Alkenes: Incorporation of Bulky Aryl Groups at Room Temperature.
Angew. Chem., Int. Ed. 2017, 56, 12692−12696. (e) Li, X.; Chen, P.;
Liu, G. Intermolecular Palladium-Catalyzed Oxidative Fluorocarbo-
nylation of Unactivated Alkenes: Efficient Access to β-Fluorocarbox-
ylic Esters. Angew. Chem., Int. Ed. 2018, 57, 15871−15876. (f) Liao,
L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. A Palladium-Catalyzed
Three-Component Cross-Coupling of Conjugated Dienes or
Terminal Alkenes with Vinyl Triflates and Boronic Acids. J. Am.
Chem. Soc. 2011, 133, 5784−5787. (g) Wu, X.; Lin, H.-C.; Li, M.-L.;
Li, L.-L.; Han, Z.-Y.; Gong, L.-Z. Enantioselective 1,2-Difunctional-
ization of Dienes Enabled by Chiral Palladium Complex-Catalyzed
Cascade Arylation/Allylic Alkylation Reaction. J. Am. Chem. Soc.
2015, 137, 13476−13479. (h) Derosa, J.; Tran, V. T.; Boulous, M. N.;
Chen, J. S.; Engle, K. M. Nickel-Catalyzed β,γ-Dicarbofunctionaliza-
tion of Alkenyl Carbonyl Compounds via Conjunctive Cross-
Coupling. J. Am. Chem. Soc. 2017, 139, 10657−10660. (i) Gao, P.;
Chen, L.-A.; Brown, M. K. Nickel-Catalyzed Stereoselective Diary-
In summary, we report here the enantioselective radical
alkyl/aryl azolation of styrene enabled by a single Cbzbox−
Cu(I) complex. In the alkylation reaction, Cbzbox−Cu(I) with
benzoxazole serves as the reducing species and the
enantiomeric induction source. With the same copper catalyst,
an enantioselective arylalkynylation of styrene using diary-
liodonium salt has been realized. Different from the former
reports about copper-catalyzed aryl difunctionalization involv-
ing alkenes and diaryliodonium salts through aryl−Cu(III)
species, Cbzbox−Cu catalysis may proceed through a phenyl
radical pathway, according to the preliminary mechanistic
studies. Highly valuable azole products could be obtained from
a series of benzoxazoles, substituted aryl alkenes, and alkyl
halides/diaryliodonium salts under mild-reaction conditions.
This efficient asymmetric coupling reaction through C−H
functionalization of benzoxazoles should open new possibilities
for the application of abundant metals and carbohalides in
heterocyclic chemistry and offer new opportunities for
diaryliodonium salts in radical redox coupling reactions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05576.
■
sı
Experimental procedures and spectra data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Guozhu Zhang − College of Chemistry, Central China Normal
University (CCNU), Wuhan, Hubei 430079, P. R. China;
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Center for Excellence in
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Research Article
lation of Alkenylarenes. J. Am. Chem. Soc. 2018, 140, 10653−10657.
(j) Xu, C.; Yang, Z.-F.; An, L.; Zhang, X. Nickel-Catalyzed
Difluoroalkylation-Alkylation of Enamides. ACS Catal. 2019, 9,
8224−8229. (k) Li, J.; Luo, Y.; Cheo, H. W.; Lan, Y.; Wu, J.
Photoredox-Catalysis-Modulated, Nickel Catalyzed Divergent Difunc-
tionalization of Ethylene. Chem 2019, 5, 192−203. (l) Xiong, Y.;
Zhang, G. Enantioselective 1,2-Difunctionalization of 1,3-Butadiene
by Sequential Alkylation and Carbonyl Allylation. J. Am. Chem. Soc.
2018, 140, 2735−2738. (m) Zhang, S.; Wang, C.; Ye, X.; Shi, X.
Intermolecular Alkene Difunctionalization via Gold Catalyzed Oxy-
arylation. Angew. Chem., Int. Ed. 2020, 59, 20470−20474.
62, 1529−1536. (s) Cheng, Y.-F.; Liu, J.-R.; Gu, Q.-S.; Yu, Z.-L.;
Wang, J.; Li, Z.-L.; Bian, J.-Q.; Wen, H.-T.; Wang, X.-J.; Hong, X.;
Liu, X.-Y. Catalytic Enantioselective Desymmetrizing Functionaliza-
tion of Alkyl Radicals via Cu(i)/CPA Cooperative Catalysis. Nat.
Catal. 2020, 3, 401−410.
(4) (a) You, S. L. Asymmetric Functionalization of C−H Bonds; RSC:
Cambridge, 2015; Vol. 92. (b) Wencel-Delord, J.; Colobert, F.
Asymmetric C(sp2)-H Activation. Chem.Eur. J. 2013, 19, 14010−
14017. (c) Zheng, C.; You, S.-L. Recent Development of Direct
Asymmetric Functionalization of Inert C-H Bonds. RSC Adv. 2014, 4,
6173−6214. (d) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer,
N. Catalytic Enantioselective Transformations Involving C-H Bond
Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117,
8908−8976. (e) Gao, D.-W.; Gu, Q.; Zheng, C.; You, S.-L. Synthesis
of Planar Chiral Ferrocenes via Transition-Metal-Catalyzed Direct C-
H Bond Functionalization. Acc. Chem. Res. 2017, 50, 351−365.
(f) Saint-Denis, T. G.; Zhu, R. Y.; Chen, G.; Wu, Q. F.; Yu, J. Q.
Enantioselective C(sp3)-H Bond Activation by Chiral Transition
Metal Catalysts. Science 2018, 359, No. eaao4798.
(5) (a) Seregin, I. V.; Gevorgyan, V. Direct Transition Metal-
Catalyzed Functionalization of Heteroaromatic Compounds. Chem.
Soc. Rev. 2007, 36, 1173−1193. (b) Alberico, D.; Scott, M. E.;
Lautens, M. Aryl-Aryl Bond Formation by Transition-Metal-Catalyzed
Direct Arylation. Chem. Rev. 2007, 107, 174−238. (c) Ackermann, L.;
Vicente, R. n.; Kapdi, A. R. Transition-Metal-Catalyzed Direct
Arylation of (Hetero) Arenes by C-H Bond Cleavage. Angew.
Chem., Int. Ed. 2009, 48, 9792−9826. (d) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Palladium- and Copper-Catalyzed Arylation of Carbon-
Hydrogen Bonds. Acc. Chem. Res. 2009, 42, 1074−1086.
(3) For some review: (a) Li, Z.-L.; Fang, G.-C.; Gu, Q.-S.; Liu, X.-Y.
Recent Advances in Copper-Catalysed Radical-Involved Asymmetric
1, 2-Difunctionalization of Alkenes. Chem. Soc. Rev. 2020, 49, 32−48.
. Gu, Q. S. (b) Gu, Q.-S.; Liu, X. Y. Copper(I)-Catalyzed Asymmetric
Reactions Involving Radicals. Acc. Chem. Res. 2020, 53, 170−181.
(c) Tian, Y.; Chen, S.; Gu, Q.-S.; Lin, J.-S.; Liu, X.-Y. Amino- and
Azidotrifluoromethylation of Alkenes. Tetrahedron Lett. 2018, 59,
203−215. . For some representative reactions catalysed by Cu:
(d) Zhu, R.; Buchwald, S. L. Enantioselective Functionalization of
Radical Intermediates in Redox Catalysis: Copper-Catalyzed Asym-
metric Oxytrifluoromethylation of Alkenes. Angew. Chem., Int. Ed.
2013, 52, 12655−12658. (e) Zhu, R.; Buchwald, S. L. Versatile
Enantioselective Synthesis of Functionalized Lactones via Copper-
Catalyzed Radical Oxyfunctionalization of Alkenes. J. Am. Chem. Soc.
2015, 137, 8069−8077. (f) Wang, F.; Wang, D.; Wan, X.; Wu, L.;
Chen, P.; Liu, G. Enantioselective Copper-Catalyzed Intermolecular
Cyanotrifluoromethylation of Alkenes via Radical Process. J. Am.
Chem. Soc. 2016, 138, 15547−15550. (g) Wang, D.; Wu, L.; Wang, F.;
Wan, X.; Chen, P.; Lin, Z.; Liu, G. Asymmetric Copper-Catalyzed
Intermolecular Aminoarylation of Styrenes: Efficient Access to
Optical 2,2-Diarylethylamines. J. Am. Chem. Soc. 2017, 139, 6811−
6814. (h) Wu, L.; Wang, F.; Wan, X.; Wang, D.; Chen, P.; Liu, G.
Asymmetric Cu-Catalyzed Intermolecular Trifluoromethylarylation of
Styrenes: Enantioselective Arylation of Benzylic Radicals. J. Am. Chem.
Soc. 2017, 139, 2904−2907. (i) Wang, D.; Wang, F.; Chen, P.; Lin,
Z.; Liu, G. Enantioselective Copper-Catalyzed Intermolecular Amino-
and Azidocyanation of Alkenes in a Radical Process. Angew. Chem.,
Int. Ed. 2017, 56, 2054−2058. (j) Wu, L.; Wang, F.; Chen, P.; Liu, G.
Enantioselective Construction of Quaternary All-Carbon Centers via
Copper-Catalyzed Arylation of Tertiary Carbon-Centered Radicals. J.
Am. Chem. Soc. 2019, 141, 1887−1892. (k) Fu, L.; Zhou, S.; Wan, X.;
Chen, P.; Liu, G. Enantioselective Trifluoromethylalkynylation of
Alkenes via Copper-Catalyzed Radical Relay. J. Am. Chem. Soc. 2018,
140, 10965−10969. (l) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.;
Tan, B.; Liu, X.-Y. A Dual-Catalytic Strategy to Direct Asymmetric
Radical Aminotrifluoromethylation of Alkenes. J. Am. Chem. Soc.
2016, 138, 9357−9360. (m) Lin, J.-S.; Wang, F. L.; Dong, X. Y.; He,
W. W.; Yuan, Y.; Chen, S.; Liu, X. Y. Catalytic Asymmetric Radical
Aminoperfluoroalkylation and Aminodifluoromethylation of Alkenes
to Versatile Enantioenriched-fluoroalkyl Amines. Nat. Commun. 2017,
8, 14841. (n) Wang, F.-L.; Dong, X.-Y.; Lin, J.-S.; Zeng, Y.; Jiao, G.-
Y.; Gu, Q.-S.; Guo, X.-Q.; Ma, C.-L.; Liu, X.-Y. Catalytic Asymmetric
Radical Diamination of Alkenes. Chem 2017, 3, 979−990. (o) Li, X.-
T.; Gu, Q.-S.; Dong, X.-Y.; Meng, X.; Liu, X.-Y. A Copper Catalyst
with a Cinchona-Alkaloid-Based Sulfonamide Ligand for Asymmetric
Radical Oxytrifluoromethylation of Alkenyl Oximes. Angew. Chem.,
Int. Ed. 2018, 57, 7668−7672. (p) Dong, X.-Y.; Cheng, J.-T.; Zhang,
Y.-F.; Li, Z.-L.; Zhan, T.-Y.; Chen, J.-J.; Wang, F.-L.; Yang, N.-Y.; Ye,
L.; Gu, Q.-S.; Liu, X.-Y. Copper-Catalyzed Asymmetric Radical 1,2-
Carboalkynylation of Alkenes with Alkyl Halides and Terminal
Alkynes. J. Am. Chem. Soc. 2020, 142, 9501−9509. (q) Lin, J.-S.; Li,
T.-T.; Liu, J.-R.; Jiao, G.-Y.; Gu, Q.-S.; Cheng, J.-T.; Guo, Y.-L.; Hong,
X.; Liu, X.-Y. Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric
Three-Component Radical-Initiated 1,2-Dicarbofunctionalization of
Alkenes. J. Am. Chem. Soc. 2019, 141, 1074−1083. (r) Zeng, Y.; Liu,
X.-D.; Guo, X.-Q.; Gu, Q.-S.; Li, Z.-L.; Chang, X.-Y.; Liu, X.-Y. Cu/
Chiral Phosphoric Acid-Catalyzed Radical-Initiated Asymmetric
Aminosilylation of Alkene with Hydrosilane. Sci. China Chem. 2019,
(6) Ohmiya, H.; Zhang, H.; Shibata, S.; Harada, A.; Sawamura, M.
Construction of Quaternary Stereogenic Carbon Centers through
Copper-Catalyzed Enantioselective Allylic Alkylation of Azoles.
Angew. Chem., Int. Ed. 2016, 55, 4777−4780.
(7) (a) Zhang, Y.; Sun, Y.; Chen, B.; Xu, M.; Li, C.; Zhang, D.;
Zhang, G. Copper-Catalyzed Photoinduced Enantioselective Dual
Carbofunctionalization of Alkenes. Org. Lett. 2020, 22, 1490−1494.
(b) Lei, G.; Zhang, H.; Chen, B.; Xu, M.; Zhang, G. Copper-
Catalyzed Enantioselective Arylalkynylation of Alkenes. Chem. Sci.
2020, 11, 1623−1628. (c) Mo, X.; Chen, B.; Zhang, G. Copper-
Catalyzed Enantioselective Sonogashira Type Couplings of Alkynes
with α-Bromoamide. Angew. Chem., Int. Ed. 2020, 59, 13998−14002.
(8) (a) Su, X. L.; Ye, L.; Chen, J. J.; Liu, X. D.; Jiang, S. P.; Wang, F.
L.; Liu, L.; Yang, C. J.; Chang, X. Y.; Li, Z. L.; Gu, Q. S.; Liu, X. Y.
Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic
Alkyl Bromides with Azole C(sp2)−H Bonds. Angew. Chem., Int. Ed.
2021, 60, 380−384. (b) Li, C.; Chen, B.; Ma, X.; Mo, X.; Zhang, G.
Light-Promoted Copper-Catalyzed Enantioselective Alkylation of
Azoles. Angew. Chem., Int. Ed. 2021, 60, 2130−2134.
(9) (a) Dong, X.-Y.; Zhang, Y.-F.; Ma, C.-L.; Gu, Q.-S.; Wang, F.-L.;
Li, Z.-L.; Jiang, S.-P.; Liu, X.-Y. A General Asymmetric Copper-
Catalysed Sonogashira C(sp3)-C(sp) coupling. Nat. Chem. 2019, 11,
1158−1166. (b) Xia, H. D.; Li, Z. L.; Gu, Q. S.; Dong, X. Y.; Fang, J.
H.; Du, X. Y.; Wang, L. L.; Liu, X. Y. Photoinduced Copper-Catalyzed
Asymmetric Decarboxylative Alkynylation with Terminal Alkynes.
Angew. Chem., Int. Ed. 2020, 59, 16926−16932. (c) Li, X.-T.; Lv, L.;
Wang, T.; Gu, Q.-S.; Xu, G.-X.; Li, Z.-L.; Ye, L.; Zhang, X.; Cheng,
G.-J.; Liu, X.-Y. Diastereo- and Enantioselective Catalytic Radical
Oxysulfonylation of Alkenes in β, γ-Unsaturated Ketoximes. Chem
2020, 6, 1692−1706.
(10) (a) Inoue, M.; Suzuki, T.; Nakada, M. Asymmetric Catalysis of
Nozaki-Hiyama Allylation and Methallylation with A New Tridentate
Bis(oxazolinyl)carbazole Ligand. J. Am. Chem. Soc. 2003, 125, 1140−
1141. (b) Chen, W.; Yang, Q.; Zhou, T.; Tian, Q.; Zhang, G.
Enantioselective Synthesis of α-exo-Methylene γ-Butyrolactones via
Chromium Catalysis. Org. Lett. 2015, 17, 5236−5239.
(11) For some work about BOPA: (a) McManus, H. A.; Guiry, P. J.
Coupling of Bulky, Electron-Deficient Partners in Aryl Amination in
the Preparation of Tridentate Bis(oxazoline) Ligands for Asymmetric
Catalysis. J. Org. Chem. 2002, 67, 8566−8573. (b) McManus, H. A.;
5117
https://doi.org/10.1021/acscatal.0c05576
ACS Catal. 2021, 11, 5108−5118

ACS Catalysis
pubs.acs.org/acscatalysis
Research Article
Cozzi, P. G.; Guiry, P. J. Application of Tridentate Bis(oxazoline)
Ligands in Catalytic Asymmetric Nozaki-Hiyama Allylation and
Crotylation: An Example of High Enantioselection with a Non-
Symmetric Bis(oxazoline) Ligand. Adv. Synth. Catal. 2006, 348, 551−
558. (c) Hargaden, G. i. C.; McManus, H. A.; Cozzi, P. G.; Guiry, P. J.
The Application of Bis(oxazoline) lLigands in the Catalytic
Enantioselective Methallylation of Aldehydes. Org. Biomol. Chem.
2007, 5, 763−766.
(12) Ma, X.; Zhang, G. Visible Light-Induced Copper-Catalyzed C-
H Arylation of Benzoxazoles. Chin. J. Chem. 2020, 38, 1299−1303.
(13) (a) Merritt, E. A.; Olofsson, B. Diaryliodonium Salts: A Journey
from Obscurity to Fame. Angew. Chem., Int. Ed. 2009, 48, 9052−9070.
(b) Martín, F. M. Copper-Catalyzed Arylation with Diaryliodonium
Salts. Synthesis 2017, 49, 1905−1930. (c) Phipps, R. J.; Grimster, N.
P.; Gaunt, M. J. Cu(II)-Catalyzed Direct and Site-Selective Arylation
of Indoles Under Mild Conditions. J. Am. Chem. Soc. 2008, 130,
8172−8174. (d) Phipps, R. J.; Gaunt, M. J. A Meta-Selective Copper-
Catalyzed C-H Bond Arylation. Science 2009, 323, 1593−1597.
(e) Phipps, R. J.; McMurray, L.; Ritter, S.; Duong, H. A.; Gaunt, M. J.
Copper-Catalyzed Alkene Arylation with Diaryliodonium Salts. J. Am.
Chem. Soc. 2012, 134, 10773−10776. (f) Kumar, D.; Pilania, M.;
Arun, V.; Pooniya, S. C-H Arylation of Azaheterocycles: a Direct
Ligand-Free and Cu-Catalyzed Approach using Diaryliodonium Salts.
Org. Biomol. Chem. 2014, 12, 6340−6344.
(14) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Copper-Catalyzed
Direct Carboxylation of C-H Bonds with Carbon Dioxide. Angew.
Chem., Int. Ed. 2010, 49, 8670−8673.
(15) Isse, A. A.; Lin, C. Y.; Coote, M. L.; Gennaro, A. Estimation of
Standard Reduction Potentials of Halogen Atoms and Alkyl Halides. J.
Phys. Chem. B 2011, 115, 678−684.
(16) Romanczyk, P. P.; Kurek, S. S. The Reduction Potential of
Diphenyliodonium Polymerisation Photoinitiator Is Not -0.2V vs.
SCE. A Computational Study. Electrochim. Acta 2017, 255, 482−485.
(17) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.;
Stahl, S. S.; Liu, G. Enantioselective Cyanation of Benzylic C-H Bonds
via Copper-Catalyzed Radical Relay. Science 2016, 353, 1014−1018.
5118
https://doi.org/10.1021/acscatal.0c05576
ACS Catal. 2021, 11, 5108−5118