Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic Alkyl Bromides with Azole C(sp2)?H Bonds

Article abstract of DOI:10.1002/anie.202009527

The development of enantioconvergent cross-coupling of racemic alkyl halides directly with heteroarene C(sp²)?H bonds has been impeded by the use of a base at elevated temperature that leads to racemization. We herein report a copper(I)/cinchona-alkaloid-derived N,N,P-ligand catalytic system that enables oxidative addition with racemic alkyl bromides under mild conditions. Thus, coupling with azole C(sp²)?H bonds has been achieved in high enantioselectivity, affording a number of potentially useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4-triazoles, for drug discovery. Mechanistic experiments indicated facile deprotonation of an azole C(sp²)?H bond and the involvement of alkyl radical species under the reaction conditions.

Full text of DOI:10.1002/anie.202009527

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Copper-Catalyzed Enantioconvergent Cross-Coupling of
Racemic Alkyl Bromides with Azole C(sp2)–H Bonds
Authors: Xiao-Long Su, Liu Ye, Ji-Jun Chen, Xiao-Dong Liu, Sheng-
Peng Jiang, Fu-Li Wang, Lin Liu, Chang-Jiang Yang, Xiao-
Yong Chang, Zhong-Liang Li, Qiang-Shuai Gu, and Xin-Yuan
Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009527
Link to VoR: https://doi.org/10.1002/anie.202009527

10.1002/anie.202009527
Angewandte Chemie International Edition
RESEARCH ARTICLE
Copper-Catalyzed Enantioconvergent Cross-Coupling of Racemic
Alkyl Bromides with Azole C(sp2)–H Bonds
Xiao-Long Su+, Liu Ye+, Ji-Jun Chen+, Xiao-Dong Liu+, Sheng-Peng Jiang, Fu-Li Wang, Lin Liu, Chang-
Jiang Yang, Xiao-Yong Chang, Zhong-Liang Li, Qiang-Shuai Gu, and Xin-Yuan Liu*
Dedicated to Professor Ilhyong Ryu on the occasion of his 70th birthday
[*]
Dr. X.-L. Su[+]
Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering
Baoji University of Arts and Sciences, Baoji, Shaanxi 721013 (China)
Dr. X.-L. Su,[+] Dr. J.-J. Chen,[+] Dr. X.-D. Liu,[+] Dr. S.-P. Jiang, Dr. F.-L. Wang, Dr. L. Liu, Dr. C.-J. Yang, Dr. X.-Y. Chang, Prof. Dr. X.-Y. Liu
Shenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis
Southern University of Science and Technology, Shenzhen 518055 (China)
E-mail: liuxy3@sustech.edu.cn
Homepage: https://liuxy.chem.sustech.edu.cn
Dr. L. Ye,[+] Dr. Z.-L. Li, Dr. Q.-S. Gu
Academy for Advanced Interdisciplinary Studies and Department of Chemistry
Southern University of Science and Technology, Shenzhen 518055 (China)
[+]
These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.2020XXXX.
Abstract: The development of enantioconvergent cross-coupling of
racemic alkyl halides directly with heteroarene C(sp2)–H bonds has
been impeded by the commonly necessary use of base at elevated
ready material availability, operational simplicity, and high atom
economy of C−H functionalization.[7,8] Nonetheless, the usually
inevitable use of base at elevated temperature (typically 80–
160 °C)[8–10] in racemic coupling of alkyl electrophiles with
heteroarene C(sp2)–H bonds poses a remarkable challenge for
enantioconvergent synthesis: racemization might readily occur
(Scheme 1B), particularly with electron-deficient heteroarenes.
temperature that leads to racemization. We herein report
a
copper(I)/cinchona-alkaloid-derived N,N,P-ligand catalytic system
that enables oxidative addition with racemic alkyl bromides under mild
conditions. Thus, the coupling with azole C(sp2)–H bonds has been
achieved in high enantioselectivity, affording a number of potentially
useful α-chiral alkylated azoles, such as 1,3,4-oxadiazoles, oxazoles,
and benzo[d]oxazoles as well as 1,3,4-triazoles, for drug discovery.
Mechanistic experiments indicated facile deprotonation of an azole
C(sp2)–H bond and the involvement of alkyl radical species under the
reaction conditions.
Introduction
α-Chiral alkyl heteroarenes are common structural motifs in
many drugs, bioactive small molecules, and natural products.[1]
Synthetically, transition metal-catalyzed enantioconvergent
radical C(sp3)–C cross-coupling of racemic alkyl (pseudo)halides
has received much attention over the past two decades.[2] In this
context,
enantioconvergent
(hetero)arylation
of
alkyl
(pseudo)halides via coupling with
a
diverse array of
prefunctionalized (hetero)aryl reagents has emerged as a
powerful method for the efficient construction of α-chiral alkyl
(hetero)arene scaffolds with high levels of stereocontrol (Scheme
1A).[3–6] Thus, a variety of chiral catalysts based on first-row
transition metals such as Ni, Co, and Fe have been utilized to
convert racemic alkyl electrophiles to prochiral alkyl radicals, a
strategy pioneered by Fu, Reisman and others.[2–5] Although
impressive results have been achieved with this approach, the
direct use of heteroarenes in place of these prefunctionalized
heteroaryl reagents would be more desirable considering the
Scheme 1. Enantioconvergent heteroarylation of racemic alkyl electrophiles.
As a part of our research program on asymmetric chemistry
involving alkyl radical species,[11] we recently discovered that
1
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10.1002/anie.202009527
Angewandte Chemie International Edition
RESEARCH ARTICLE
chiral alkaloid-derived multidentate N,N,P-ligand greatly
enhanced the reducing capability of copper catalyst.[12] Thus, the
resulting chiral copper catalyst readily reduced alkyl halides to
alkyl radicals under ambient conditions. In view of the
aforementioned racemization issue as well as the importance of
azole in drug discovery (Scheme S1 in the Supporting
Information),[1] we envisioned that our Cu(I)/N,N,P-ligand catalyst
might promote the desired enantioconvergent coupling of alkyl
Next, we examined the scope of alkyl bromides in this reaction
(Table 1). Thus, benzyl bromides featuring linear and branched
purely aliphatic side chains were all suitable substrates for this
reaction (3–6). In addition, substituents such as terminal alkene
(7 and 8), ether (9), silyl-protected alcohol (10), and primary
chloride (11) on the alkyl side chains were tolerated. On the other
hand, various functional groups of either electron-donating or -
withdrawing properties on the phenyl rings of benzyl bromides
halides with azole C(sp2)–H bonds under mild conditions. As such, were compatible with the reaction conditions, delivering product
the remaining challenges would be: i. efficient inhibition of
homocoupling of heterocycles[13] and/or alkyl halides;[14] ii.
enantiocontrol over the heteroarylation of alkyl radicals. If
successful, this method would provide not only an excellent
12–19 in moderate to good yield with good enantioselectivity.
Interestingly, medicinally relevant heteroaryl substituents such as
furanyl (20), thiophenyl (21, 22, and 24), and pyrrolyl (23)
appended on the phenyl rings were also applicable to the reaction.
In addition, bicyclic 2-naphthalenyl- and heterocyclic 3-
thiophenyl-substituted alkyl bromides were viable substrates,
leading to products 25 and 26, respectively, in moderate yield and
good enantioselectivity. Interestingly, a mixture of regioisomeric
allylic bromides also gave rise to the coupling product as a single
regioisomer in good yield with promising enantioselectivity
(Scheme S3), of which the result is currently under further
complementary
approach
to
the
previous
reported
enantioselective heteroarene C(sp2)–H alkylation,[15] but also an
immediate access to enantioenriched α-chiral alkylated azoles for
potential drug discovery (Scheme S1).[1] Herein, we describe the
development of a mild copper(I)/cinchona alkaloid-derived N,N,P-
ligand catalytic system for an asymmetric radical C(sp3)–C(sp2)
cross-coupling of racemic alkyl bromides with azole C(sp2)–H
bonds (Scheme 1C).
Table 1: Substrate scope of alkyl bromides.[a,b,c]
Results and Discussion
Initially we found that the desired coupling product 3 was
formed in 24% yield with 49% ee from racemic 1a and 1,3,4-
oxadiazole 2a under the catalysis of CuBH4(PPh3)2 and L*1 in
presence of LiOtBu in DMA (N,N-dimethylacetamide) at room
temperature (Scheme 2 and Table S1, entry 1 in the Supporting
Information). The addition of two equivalents of H2O greatly
increased the yield of
3 to 58% without affecting the
enantioselectivity (49% ee) (Table S1, entry 4), possibly due to
enhanced transmetalation for the formation of a C–Cu bond
(Scheme S2).[16] Besides, the presence of H2O also rendered the
reaction results readily repeatable. Further screening of solvents,
ligands L*1–L*3, base additives, copper salts, and reaction
temperatures identified the optimal conditions as follows (Scheme
2 and Table S1, entry 19): (±)-1a (2 equiv), 2a (1 equiv),
CuBH4(PPh3)2 (10 mol%), L*3 (12 mol%), H2O (2 equiv), and
LiOtBu (4.5 equiv) in DMA/DCM (2/1, 0.60 mL) at 10 °C under
argon, affording 3 in 90% NMR yield and 90% ee. The absolute
configuration of 3 was determined to be R by X-ray[17] structural
analysis (Scheme 2 and Figure S1 in the Supporting Information)
and those of other products in this work were assigned by analogy.
PMP
CuBH4(PPh3)2 (10 mol%), L*3 (12 mol%)
H2O (2.0 equiv), LiOtBu (4.5 equiv)
PMP
N
N
N
Br
O
+
O
N
Ph
(±)-1a
Et
DMA/DCM (2/1), 10 °C
H
Ph
Et
2a
3, 90%, 90% ee
(PMP: para-methoxyphenyl)
OMe
OMe
N
N
N
Ar2P HN
NH PAr 2
N
O
O
L*1, Ar = Ph
L*2
L*4, Ar = 9-Phen
X-ray structure of 3
[a] Reaction conditions: 1 (2.0 equiv), 2a (0.10 mmol), CuBH4(PPh3)2 (10 mol%),
L*3 (12 mol%), H2O (2.0 equiv) and LiOtBu (4.5 equiv) in DMA/DCM (2/1, 1.05
mL) at 10 °C. [b] Isolated yield. [c] The ee value was determined by HPLC. [d]
The enantiomer of 3, i.e., ent-3, was obtained using L*4 (see Scheme 2 for
structure) in 78% with 89% ee. [e] 1 (2.5 equiv). [f] 1 (3.0 equiv), H2O (3.0 equiv),
and LiOtBu (3.5 equiv). [g] 1 (3.0 equiv). [h] 2a (0.20 mmol) and LiOtBu (3.8
equiv) were used. TBDPS: tert-butyldiphenylsilyl.
, Ar = 3,5-(OMe)2-C6H3
L*3, Ar = 9-Phen
Scheme 2. Reaction development.
2
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10.1002/anie.202009527
Angewandte Chemie International Edition
RESEARCH ARTICLE
optimization. Nonetheless, alkyl bromides α to carbonyl groups
have so far failed to provide the desired products in spite of high
conversions.
Table 2: Scope of azoles and transformation.[a,b,c]
L*3
CuBH4(PPh3)2/
H2O/LiOtBu
N
Z
Y
N
Br
Y
As for the scope of azoles (Table 2), a variety of 2-phenyl-
substituted 1,3,4-oxadiazoles smoothly underwent the desired
alkylation reaction (27–34). Further, 1,3,4-oxadiazoles bearing
naphthalenyl, pyridinyl, and furanyl substituents also delivered the
desired coupling products 35, 36, and 37, respectively, in good
enantioselectivity. Notably, replacing the (hetero)aryl substituents
with alkyl groups did not obviously affect the reaction efficiency or
stereoselectivity and the products 38 and 39 were forged in
moderate yield with good to excellent ee. Interestingly,
unsubstituted 1,3,4-oxadiazoles delivered bis-alkylated product
40 in high enantioselectivity and moderate diastereoselectivity.
The reaction is not limited to 1,3,4-oxadiazoles and structurally
similar and medicinally important oxazoles and benzo[d]oxazoles
were suitable heteroarylation reagents,[1] too, providing products
41–44 in moderate yield and excellent enantioselectivity. In
addition, benzo[d]thiazole was also applicable to the reaction and
the corresponding product 45 was obtained in 87% ee albeit of
low yield. However, many other azoles and cyanothiophenes
either remained intact or underwent decomposition under the
reaction conditions (see Scheme S4 for structures). Importantly,
the enantioenriched 1,3,4-oxadiazole product 3, obtained in the
preparative scale reaction of 2a, was readily converted to 1,2,4-
triazole 46 without obvious loss of enantiopurity, thus indicating
the synthetic potential of the current method towards this kind of
pharmaceutically useful heterocycles.[1] Additionally, the good
chemoselectivity observed in substrates containing additional
potentially reactive halides (11, 19, 30, and 33), which are
amenable to follow-up manipulations, further strengthens the
synthetic potential.
+
H
Z
Ph
(±)-
Et
1a
DMA/DCM, 10 °C
2
Ph
Et
27 45
–
tBu
Br
1,3,4-oxadiazole
Ph
N
N
N
N
O
N
O
N
O
N
O
N
30
27
28
72%, 89% ee[d]
29
69%, 90% ee[d]
67%, 89% ee[d]
F3C
75%, 87% ee[e]
Cl
N
N
N
N
N
O
N
O
N
O
N
O
31
47%, 78% ee[f]
32
33
34
49%, 85% ee
57%[g], 79% ee[h]
51%, 85% ee
N
O
Bn
N
N
N
N
O
N
O
N
O
N
O
N
35
36
37
38
73%[g], 85% ee[h]
25%, 75% ee[i]
34%, 82% ee[i]
55%, 81% ee
oxazole
CF3
F3C
Et
F
F3C
tBu
N
Ph
N
O
N
O
N
O
N
O
N
Control experiments at higher reaction temperatures indicated
drastically diminished enantioselectivity starting at around 50 °C
(Table S1, entries 20 and 21). In addition, obvious racemization
of an enantioenriched alkylation product was observed at 60 °C
while only marginal racemization occurred at 40 °C under the
otherwise standard conditions (Tables S2 and S3). Besides, other
common bidentate or tridentate ligands only provided less than
15% yield and poor enantioselectivity under the otherwise
identical conditions (Table S1, entries 22–24). All these results
strongly support the indispensable role of our ligand in enabling
facile oxidative addition at around ambient temperature for
suppressing product racemization. In regard to the overall
reaction mechanism, control experiments indicated that copper,
ligand, and base are all indispensable for the reaction to provide
the desirable product 3 (Table S4). Further, we observed facile
D/H exchange of the C5–H in substrate 2a with an excessive
amount of D2O at room temperature in the presence or absence
of copper (Scheme S2). Thus, the C5–H should be acidic enough
for direct deprotonation without the need for copper. The
subsequent radical trap experiment with 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) led to the formation of TEMPO-trapped
product 47 while providing no desired product 3 (Scheme 3A). In
addition, benzyl bromide (±)-1b tethered with an alkene moiety
underwent tandem 5-exo-trig cyclization and C(sp3)–C(sp2)
coupling, delivering 49 in addition to 48 (Scheme 3B; no
corresponding cyclization side products were observed for
products 7 and 8). Collectively, these results strongly support the
involvement of alkyl radical species in the reaction. Further radical
clock experiment with 2b provided only alkylation product 50 with
39
47%, 93% ee[j]
40
41
51%[g], 95% ee[l]
42
35%, 85% ee[m]
43%, 97% ee[k]
6:1 dr
benzo[d]oxazole
OMe
benzo[d]thiazole
Ph
O
N
O
N
S
N
43
30% yield, 91% ee[n]
44
45
12%, 87% ee[o]
63%[g], 93% ee
1,2,4-triazole
transformation to
PMP
PMP
PMP
N
preparative scale
reaction
N
N
N
PhNH2, p-TsOH
80 °C
O
N
N
O
N
Ph
H
Ph
Et
Ph
Et
[p]
2a
3
46
, 90%, 93% ee
, 1.0 mmol
, 94% ee
[a] Reaction conditions: 1a (2.0 equiv), 2 (0.10 mmol), CuBH4(PPh3)2 (10 mol%),
L*3 (12 mol%), H2O (2 equiv) and LiOtBu (4.5 equiv) in DMA/DCM (2/1, 1.05
mL) at 10 °C. [b] Isolated yield. [c] The ee value was determined by HPLC. [d]
1a (3.0 equiv) and LiOtBu (2.5 equiv). [e] 1a (3.0 equiv) and 2 (0.20 mmol). [f]
1a (3.0 equiv) at rt. [g] Yield based on recovered starting material. [h] 1a (3.0
equiv) and H2O (3 equiv) in DMA/PhCF3 (1/2, 1.05 mL) at rt. [i] 1a (3.0 equiv)
and LiOtBu (2.5 equiv) in DMA/PhCF3 (1/2, 1.05 mL) at rt. [j] 1a (3.0 equiv) and
LiOtBu (3.0 equiv). [k] 1a (10 equiv). Mono-alkylated product 40′ was obtained
in 34% with 77% ee. [l] 1a (3.0 equiv) and Cu(iPrCO2)2 (10 mol%). [m] 1a (3.0
equiv) and CuI (10 mol%) at rt. [n] 1a (2.5 equiv) and Cu(acac)2 (10 mol%). [o]
1a (2.5 equiv) and CuI (10 mol%) at rt. [p] 1a (2.5 equiv), 2a (1.0 mmol),
CuBH4(PPh3)2 (10 mol%), L*3 (12 mol%), H2O (2.0 equiv), and LiOtBu (2.5
equiv) in DMA/DCM (2/1, 10 mL) at 10 °C. Acac: acetylacetonate.
3
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10.1002/anie.202009527
Angewandte Chemie International Edition
RESEARCH ARTICLE
an intact cyclopropane ring (Scheme 3C). Accordingly, the direct
addition of alkyl radical to the azole ring is unlikely under our
conditions.[18] On the basis of the experimental results as well as
our previous works,[11,12a,12b] a working mechanism was proposed,
shown in Scheme 3D. In the presence of base, the CuIL* complex
I first forms and further reacts with azole 2, giving CuI intermediate
II. This intermediate next reduces alkyl bromide (±)-1 to alkyl
radical III and itself transforms to CuII complex IV. Finally, C(sp3)–
scope to other heteroarenes as well as arenes and on
investigating the reaction mechanism in details are currently
undergoing in this lab.
Acknowledgements
Financial support from the National Natural Science Foundation
of China (Nos. 21722203, 21831002, 21702093, and 21801116),
Guangdong Provincial Key Laboratory of Catalysis (No.
2020B121201002), Guangdong Innovative Program (No.
C(sp2) coupling occurs possibly via formation of
a
CuIII
intermediate[19] and its subsequent reductive elimination (see
Figure S2 for a tentative stereodiscrimination proposal via the
copper(III) intermediate). Nonetheless, we currently have no solid
experimental or theoretical evidence supporting this CuIII
intermediate and thus, are carrying out further studies on this step.
2019BT02Y335),
Shenzhen
Special
Funds
(No.
JCYJ20180302174416591), Shenzhen Nobel Prize Scientists
Laboratory Project (No. C17783101), SUSTech Special Fund for
the Construction of High-Level Universities (No. G02216303), the
Shaanxi Provincial Key Laboratory Project (No. 19JS007), the
Project of Science and Technology Department of Shaanxi
Province (No. 2020JQ-894), Baoji University of Arts and Sciences
(No. 209040030), and the China Postdoctoral Science
Foundation (No. 2019M662155) is greatly appreciated. The
authors acknowledge the assistance of the SUSTech Core
Research Facilities for technical support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation • asymmetric radical reaction • azole •
copper • racemic alkyl bromides
[1]
a) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57,
10257; b) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451;
c) A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical
Substances: Syntheses, Patents and Applications of the most relevant
APIs, 5th ed., Thieme Chemistry, 2009.
[2]
[3]
a) J. Choi, G. C. Fu, Science 2017, 356, eaaf7230; b) G. C. Fu, ACS
Cent. Sci. 2017, 3, 692; c) A. H. Cherney, N. T. Kadunce, S. E. Reisman,
Chem. Rev. 2015, 115, 9587.
For selected recent examples using Ni catalysis: a) H. Yin, G. C. Fu, J.
Am. Chem. Soc. 2019, 141, 15433; b) A. Varenikov, M. Gandelman, Nat.
Commun. 2018, 9, 3566; for a selected example using Co catalysis: c) J.
Mao, F. Liu, M. Wang, L. Wu, B. Zheng, S. Liu, J. Zhong, Q. Bian, P. J.
Walsh, J. Am. Chem. Soc. 2014, 136, 17662; for a selected example
using Fe catalysis: d) M. Jin, L. Adak, M. Nakamura, J. Am. Chem. Soc.
2015, 137, 7128.
Scheme 3. Mechanistic experiments and proposal.
[4]
For selected representative enantioconvergent reductive cross-coupling
examples: a) H. Guan, Q. Zhang, P. J. Walsh, J. Mao, Angew. Chem. Int.
Ed. 2020, 59, 5172; Angew. Chem. 2020, 132, 5210; b) K. E. Poremba,
N. T. Kadunce, N. Suzuki, A. H. Cherney, S. E. Reisman, J. Am. Chem.
Soc. 2017, 139, 5684; c) N. T. Kadunce, S. E. Reisman, J. Am. Chem.
Soc. 2015, 137, 10480.
Conclusion
In summary, the use of N,N,P-ligand has enabled the
realization of direct enantioconvergent coupling of racemic alkyl
bromides with azole C(sp2)–H bonds. And the enhanced reducing
power of copper by the N,N,P-ligand is key to lower the reaction
temperature close to room temperature, thus effectively
suppressing undesired racemization of the newly formed chiral
stereocenters. This method provides a convenient access to a
range of enantioenriched α-chiral alkylated azoles, such as 1,3,4-
oxadiazoles, oxazoles, and benzo[d]oxazoles as well as 1,3,4-
triazoles, all of which are common structural motifs in many
bioactive molecules and drugs. Further studies on expanding the
[5]
[6]
For selected representative enantioconvergent cross-coupling examples
using alkyl radical precursors other than alkyl halides: a) Z. Zuo, H. Cong,
W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan, J. Am. Chem. Soc. 2016,
138, 1832; b) O. Gutierrez, J. C. Tellis, D. N. Primer, G. A. Molander, M.
C. Kozlowski, J. Am. Chem. Soc. 2015, 137, 4896.
For selected non-radical enantioconvergent C(sp3)–C(sp2) coupling
examples: a) M. Sidera, S. P. Fletcher, Nat. Chem. 2015, 7, 935; b) P.
Schäfer, T. Palacin, M. Sidera, S. P. Fletcher, Nat. Commun. 2017, 8,
15762; c) F. W. Goetzke, M. Mortimore, S. P. Fletcher, Angew. Chem.
Int. Ed. 2019, 58, 12128; Angew. Chem. 2019, 131, 12256; d) J.
González, P. Schäfer, S. P. Fletcher, Organometallics 2019, 38, 3991.
4
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10.1002/anie.202009527
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RESEARCH ARTICLE
[7]
For selected reviews on asymmetric (hetero)arene C(sp2)–H
functionalization: a) J. Loup, U. Dhawa, F. Pesciaioli, J. Wencel-Delord,
L. Ackermann, Angew. Chem. Int. Ed. 2019, 58, 12803; Angew. Chem.
2019, 131, 12934; b) C. G. Newton, S.-G. Wang, C. C. Oliveira, N.
Cramer, Chem. Rev. 2017, 117, 8908; c) C. Zheng, S.-L. You, RSC Adv.
2014, 4, 6173; d) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu,
Chem. Soc. Rev. 2009, 38, 3242.
For selected reviews on racemic (hetero)arene C(sp2)–H
functionalization: a) P. Gandeepan, T. Müller, D. Zell, G. Cera, S.
Warratz, L. Ackermann, Chem. Rev. 2019, 119, 2192; b) G. Evano, C.
Theunissen, Angew. Chem. Int. Ed. 2019, 58, 7558; Angew. Chem. 2019,
131, 7638; c) Y. Yang, J. Lan, J. You, Chem. Rev. 2017, 117, 8787; d)
C. Liu, J. Yuan, M. Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015,
115, 12138; e) X.-X. Guo, D.-W. Gu, Z. Wu, W. Zhang, Chem. Rev. 2015,
115, 1622.
M. Sawamura, Angew. Chem. Int. Ed. 2016, 55, 4777; Angew. Chem.
2016, 128, 4855; k) C. M. Filloux, T. Rovis, J. Am. Chem. Soc. 2015, 137,
508; l) P.-S. Lee, N. Yoshikai, Org. Lett. 2015, 17, 22; m) J. Llaveria, D.
Leonori, V. K. Aggarwal, J. Am. Chem. Soc. 2015, 137, 10958; n) G.
Song, W. W. N. O, Z. Hou, J. Am. Chem. Soc. 2014, 136, 12209; o) C.
S. Sevov, J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 2116.
[16] T. Xiong, Y. Li, X. Bi, Y. Lv, Q. Zhang, Angew. Chem. Int. Ed. 2011, 50,
7140; Angew. Chem. 2011, 123, 7278.
[8]
[17] CCDC 1999436 (3) contains the supplementary crystallographic data for
this paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
[18] a) D. Li, W.-C. Yang, Tetrahedron Lett. 2019, 60, 1792; b) C. Theunissen,
J. Wang, G. Evano, Chem. Sci. 2017, 8, 3465.
[19] For C–C bond formation via copper(III) intermediates, see: S. Liu, H. Liu,
S. Liu, Z. Lu, C. Lu, X. Leng, Y. Lan, Q. Shen, J. Am. Chem. Soc. 2020,
142, 9785 and references cited therein.
[9]
For selected examples of racemic cross-coupling of alkyl halides with
azole C(sp2)–H: a) W. Li, A. Varenikov, M. Gandelman, Eur. J. Org.
Chem. 2020, 2020, 3138; b) X. Wu, C. Lei, G. Yue, J. Zhou, Angew.
Chem. Int. Ed. 2015, 54, 9601; Angew. Chem. 2015, 127, 9737; c) X. Wu,
J. W. T. See, K. Xu, H. Hirao, J. Roger, J.-C. Hierso, J. Zhou, Angew.
Chem. Int. Ed. 2014, 53, 13573; Angew. Chem. 2014, 126, 13791; d) P.
Ren, I. Salihu, R. Scopelliti, X. Hu, Org. Lett. 2012, 14, 1748; e) L.
Ackermann, S. Barfüsser, C. Kornhaass, A. R. Kapdi, Org. Lett. 2011,
13, 3082; f) L. Ackermann, B. Punji, W. Song, Adv. Synth. Catal. 2011,
353, 3325; g) O. Vechorkin, V. Proust, X. Hu, Angew. Chem. Int. Ed.
2010, 49, 3061; Angew. Chem. 2010, 122, 3125; h) T. Yao, K. Hirano, T.
Satoh, M. Miura, Chem. Eur. J. 2010, 16, 12307; i) D. Lapointe, K.
Fagnou, Org. Lett. 2009, 11, 4160.
[10] For
a selected example of racemic azole alkylation with N-
tosylhydrazones: X. Zhao, G. Wu, Y. Zhang, J. Wang, J. Am. Chem. Soc.
2011, 133, 3296.
[11] For selected summaries: a) Q.-S. Gu, Z.-L. Li, X.-Y. Liu, Acc. Chem. Res.
2020, 53, 170; b) Z.-L. Li, G.-C. Fang, Q.-S. Gu, X.-Y. Liu, Chem. Soc.
Rev. 2020, 49, 32; for selected examples: c) C.-J. Yang, C. Zhang, Q.-S.
Gu, J.-H. Fang, X.-L. Su, L. Ye, Y. Sun, Y. Tian, Z.-L. Li, X.-Y. Liu, Nat.
Catal. 2020, 3, 539; d) X.-T. Li, L. Lv, T. Wang, Q.-S. Gu, G.-X. Xu, Z.-L.
Li, L. Ye, X. Zhang, G.-J. Cheng, X.-Y. Liu, Chem 2020, 6, 1692; e) Y.-F.
Cheng, J.-R. Liu, Q.-S. Gu, Z.-L. Yu, J. Wang, Z.-L. Li, J.-Q. Bian, H.-T.
Wen, X.-J. Wang, X. Hong, X.-Y. Liu, Nat. Catal. 2020, 3, 401; f) L. Ye,
Y. Tian, X. Meng, Q.-S. Gu, X.-Y. Liu, Angew. Chem. Int. Ed. 2020, 59,
1129; Angew. Chem. 2020, 132, 1145; g) J.-S. Lin, X.-Y. Dong, T.-T. Li,
N.-C. Jiang, B. Tan, X.-Y. Liu, J. Am. Chem. Soc. 2016, 138, 9357.
[12] a) X.-Y. Dong, Y.-F. Zhang, C.-L. Ma, Q.-S. Gu, F.-L. Wang, Z.-L. Li, S.-
P. Jiang, X.-Y. Liu, Nat. Chem. 2019, 11, 1158; b) X.-Y. Dong, J.-T.
Cheng, Y.-F. Zhang, Z.-L. Li, T.-Y. Zhan, J.-J. Chen, F.-L. Wang, N.-Y.
Yang, L. Ye, Q.-S. Gu, X.-Y. Liu, J. Am. Chem. Soc. 2020, 142, 9501; for
an elegant work of ligand design for copper-catalyzed radical
enantioconvergent reaction: c) H. Iwamoto, K. Endo, Y. Ozawa, Y.
Watanabe, K. Kubota, T. Imamoto, H. Ito, Angew. Chem. Int. Ed. 2019,
58, 11112; Angew. Chem. 2019, 131, 11229.
[13] X. Qin, B. Feng, J. Dong, X. Li, Y. Xue, J. Lan, J. You, J. Org. Chem.
2012, 77, 7677.
[14] A. C. P. F. d. Sá, G. M. A. Pontes, J. A. L. d. Anjos, S. R. Santana, L. W.
Bieber, I. Malvestiti, J. Braz. Chem. Soc. 2003, 14, 429.
[15] For selected reviews on enantioselective Friedel-Crafts alkylation of
heteroarenes, see: a) M. M. Heravi, V. Zadsirjan, B. Masoumi, M.
Heydari, J. Organomet. Chem. 2019, 879, 78; b) Y. Zhang, X. Liu, L. Lin,
X. Feng, Prog. Chem. 2018, 30, 491; c) V. Terrasson, R. Marcia de
Figueiredo, J. M. Campagne, Eur. J. Org. Chem. 2010, 2010, 2635; for
selected enantioselective alkylation of heteroarenes using other
strategies: d) R. S. J. Proctor, H. J. Davis, R. J. Phipps, Science 2018,
360, 419; e) X. Liu, Y. Liu, G. Chai, B. Qiao, X. Zhao, Z. Jiang, Org. Lett.
2018, 20, 6298; f) X. Bao, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2017,
56, 9577; Angew. Chem. 2017, 129, 9705; g) J. Loup, D. Zell, J. C. A.
Oliveira, H. Keil, D. Stalke, L. Ackermann, Angew. Chem. Int. Ed. 2017,
56, 14197; Angew. Chem. 2017, 129, 14385; h) M. Odachowski, A.
Bonet, S. Essafi, P. Conti-Ramsden, J. N. Harvey, D. Leonori, V. K.
Aggarwal, J. Am. Chem. Soc. 2016, 138, 9521; i) B. M. Trost, L. Debien,
Chem. Sci. 2016, 7, 4985; j) H. Ohmiya, H. Zhang, S. Shibata, A. Harada,
5
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10.1002/anie.202009527
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
R1
R
N
> 40 examples
up to 85% yield
up to 95% ee
R1
I L*
Cu /
N
Z
Y
N
+
R2
H
*
N
Y
R2 Br
(±)
10 °C, base
Z
Y = C, N; Z = O, S
NH PAr2
O
Y
N
+
L*
IIL*
Cu
Z
R2 R1
suppressed racemization thanks to facile oxidative addition
Racemization-free: The use of cinchona-alkaloid-derived N,N,P-ligand leads to the realization of direct enantioconvergent coupling
of racemic alkyl bromides with azole C(sp2)–H bonds by copper catalysis. The key to success is the ligand-enabled facile oxidative
addition at around room temperature that suppresses the otherwise product racemization at elevated temperature. This method
provides a range of enantioenriched α-chiral alkylated azoles.
6
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