A Cobalt-Catalyzed Enantioconvergent Radical Negishi C(sp3)-C(sp2) Cross-Coupling with Chiral MultidentateN,N,P-Ligand

Article abstract of DOI:10.1021/acs.organomet.1c00190

A cobalt-catalyzed enantioconvergent radical Negishi C(sp³)-C(sp²) cross-coupling of racemic benzyl chlorides with arylzinc reagents has been developed in good yield with moderate enantioselectivities. This strategy provides an expedient access toward a range of enantioenriched 1,1-diarylmethanes. Key to this discovery is the utilization of a chiral multidentate anionicN,N,P-ligand to strongly coordinate with the cobalt catalyst and tune its chiral environment, thus achieving the enantiocontrol over the highly reactive prochiral alkyl radical species.

Full text of DOI:10.1021/acs.organomet.1c00190

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A Cobalt-Catalyzed Enantioconvergent Radical Negishi C(sp3)−
C(sp2) Cross-Coupling with Chiral Multidentate N,N,P‑Ligand
Zhuang Li,§ Xian-Yan Cheng,§ Ning-Yuan Yang, Ji-Jun Chen, Wen-Yue Tang, Jun-Qian Bian,
Yong-Feng Cheng, Zhong-Liang Li, Qiang-Shuai Gu,* and Xin-Yuan Liu*
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ABSTRACT: A cobalt-catalyzed enantioconvergent radical Negishi
C(sp3)−C(sp2) cross-coupling of racemic benzyl chlorides with
arylzinc reagents has been developed in good yield with moderate
enantioselectivities. This strategy provides an expedient access
toward a range of enantioenriched 1,1-diarylmethanes. Key to this
discovery is the utilization of a chiral multidentate anionic N,N,P-
ligand to strongly coordinate with the cobalt catalyst and tune its
chiral environment, thus achieving the enantiocontrol over the highly reactive prochiral alkyl radical species.
ransition metal catalyzed enantioconvergent C(sp3)−
Scheme 1. Design of Chiral Ligand in Cobalt-Catalyzed
Enantioconvergent C(sp3)−C(sp2) Cross-Coupling
2
TC(sp ) cross-coupling of racemic alkyl electrophiles and
organometallic reagents represents a powerful tool in the
synthesis of enantioenriched three-dimensional molecules.1
Recent emphasis on sustainability and economy has led to the
use of an earth-abundant transition metal catalyst as a new
horizon in the cross-coupling reactions.2 In this context, the
first-row transition metals (Ni, Co, Fe, and Cu) have high-spin
electronic configurations and easily convert racemic alkyl
electrophiles to the prochiral alkyl radical species via a single-
electron transfer process, thus providing a general mechanism
for enantioconvergence.2 As such, tremendous progress has
been made by Fu and others in developing chiral nickel
catalysis to realize the enantioconvergent C(sp3)−C(sp2)
cross-coupling of racemic alkyl electrophiles in the past two
decades (Scheme 1).3,4 Very recently, the chiral iron and
copper catalysis have been designed for such transforma-
tions.5−7 Owing to the earth-abundant, low-cost, and nontoxic
nature of cobalt catalyst, it has been widely used in the cross-
coupling of alkyl electrophiles with organometallic reagents in
the past three decades.8,9 However, the enantioconvergent
cross-coupling has been much less developed. The main reason
might be that the cobalt-catalyzed C(sp3)−C cross-coupling
occurs easily even in the absence of any ligand, and this
background reaction would thwart the development of a chiral
ligand-induced enantioconvergent process.8b,10 It is thus a
challenging task to design suitable chiral ligands to promote
the enantioconvergent cross-coupling. Until now, only limited
examples have been demonstrated by using chiral bisoxazoline
ligands in the enantioconvergent C(sp3)−C(sp2) cross-
coupling of racemic α-bromo esters or fluorinated benzyl
bromides since the seminal work of Zhong and Bian.11
Therefore, the development of new chiral ligands to tune the
chiral environment of cobalt catalyst and realize the
enantioconvergent cross-coupling of more alkyl halides is
highly desirable.
Special Issue: Organometallic Solutions to Challenges
in Cross-Coupling
Received: March 29, 2021
Published: May 14, 2021
https://doi.org/10.1021/acs.organomet.1c00190
© 2021 American Chemical Society
Organometallics 2021, 40, 2215−2219
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Communication
a
Our group has focused on designing new chiral anionic
ligands to develop the first-row transition metal catalyzed
enantioconvergent C(sp3)−C cross-coupling of racemic alkyl
halides with diverse nucleophiles.6 During this course, we
found that a chiral multidentate anionic N,N,P-ligand could
tune the chiral environment of the copper catalyst to realize
the enantiocontrol over the in situ generated prochiral alkyl
radical species.6 We speculated that such a multidentate
anionic ligand might coordinate strongly with the cobalt
catalyst to realize the enantioconvergent C(sp3)−C cross-
coupling of racemic alkyl halides. The success of this strategy
would open new vistas for the development of cobalt-catalyzed
enantioconvergent cross-coupling. Given the importance of
chiral 1,1-diarylalkanes in drug discovery,12 we herein report
the first application of quinine-derived N,N,P-ligand in the
cobalt-catalyzed enantioconvergent Negishi C(sp3)−C(sp2)
cross-coupling of racemic benzyl chlorides with arylzinc
reagents. Notably, this is also the first time that the more
stable alkyl chlorides rather than bromides,11 are used in the
cobalt-catalyzed enantioconvergent C(sp3)−C(sp2) cross-cou-
pling.
In order to verify our hypothesis, we first investigated the
cross-coupling between racemic 3-(1-chloroethyl)benzonitrile
1a and 4-methoxyarylzinc reagent 2a in the presence of
catalytic amount of CoBr2. The initial attempts showed that
the reaction proceeded smoothly to afford coupling product 3a
without the addition of any ligand in THF even at 0 °C, which
supported the background Negishi cross-coupling (Table 1,
entry 1). We then lowered down the reaction temperature to
−20 °C and found that the background reaction could be
inhibited (Table 1, entry 2). As such, we examined chiral
bisoxazoline ligand L1 which was previously utilized in cobalt-
catalyzed asymmetric cross-coupling11 and found that L1 was
not effective for the reaction of benzyl chlorides 1a. We then
investigated the effect of our developed multidentate electron-
rich N,N,P-ligand L2,6b and found that it not only greatly
promoted the reaction but also afforded the coupling product
3a in 50% yield with an enantiomeric ratio (e.r.) of 77:23
(Table 1, entry 4). Encouraged by this result, we systematically
screened the reaction parameters. We first modified the
structure of ligands with different steric and electronic
properties at different positions of the P-aryl ring (Table 1,
entries 5−11). The screening results indicated that the
electron-withdrawing substituents on 3,5-position of the P-
aryl ring (L3) provided 3a with a lower e.r. than the electron-
donating groups (L4), albeit with a similar yield (Table 1,
entries 5 and 6). While the reaction with phenyl-substituted
ligand L5 provided 3a with a comparable enantioselectivity, it
provided the product in a much lower yield than that of L4
(Table 1, entry 7). The electron-donating substituents on the
para position of the P-aryl ring (L6) gave 3a in 65% yield with
a 79:21 e.r. (Table 1, entry 8). Although the para phenyl-
substituted ligand L7 gave a similar yield with L6, the
enantiomeric ratio is lower (Table 1, entry 9). The ortho-
substituent of the P-aryl ring (L8) has a deleterious effect on
the reaction efficiency, suggesting that the steric environment
on the cobalt is crucial to the cross-coupling reaction (Table 1,
entry 10). The reaction with a naphthyl-substituted ligand L9
gave a poor result as well (Table 1, entry 11). Considering the
reaction efficiency and the enantioselectivity, we chose L6 as
the best ligand for the subsequent reaction optimization. The
results showed that 3a was generated in 90% yield with a 77:23
e.r. at 0 °C, and this retention of e.r. revealed that the chiral
Table 1. Screening of Reaction Conditions
b
c
entry
[Co]
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
CoBr2
L*
solvent
T/°C
yield
e.r.
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
DCM
DMF
EtOAc
0
−20
−20
−20
−20
−20
−20
−20
−20
−20
−20
0
rt
0
0
0
0
0
0
75%
0%
L1
L2
L3
L4
L5
L6
L7
L8
L9
L6
L6
L6
L6
L6
L6
L6
L6
15%
50%
41%
35%
19%
65%
63%
trace
21%
90%
45%
95%
93%
99%
76%
87%
98%
50:50
77:23
54:46
82:18
80:20
79:21
70:30
9
10
11
12
13
14
15
16
17
18
19
57:43
77:23
50:50
76:24
75:25
75:25
74:26
69:31
74:26
CoBr2
Co(salen)
Co(PPh3)2Cl2
CoBr2
CoBr2
CoBr2
CoBr2
a
Reaction conditions: ( )-1a (0.05 mmol), 2a (0.15 mmol), [Co]
(10 mol %), and L* (15 mol %), in solvent (0.50 mL) for 72 h under
argon. Yield was based on H NMR analysis of the crude product
b
1
c
using 1,3,5-trimethoxybenzene as an internal standard. The e.r.
values were determined by HPLC analysis.
N,N,P-ligand/cobalt catalysis could suppress the background
reaction and promote the enantioconvergent process (Table 1,
entries 1 and 12). However, the reaction afforded 3a with no
e.r. at room temperature (Table 1, entry 13). Further screening
of different cobalt salts and solvents showed that the reaction
provided the best yield with a slightly decreased e.r. in toluene
(Table 1, entries 14−19). Finally, we identified the optimal
reaction conditions as follows: The reaction of 1a and 2a in a
molar ratio of 1:3 in the presence of 10 mol % of CoBr2 and 15
mol % of L6 in toluene afforded 3a in 99% yield, with 75:25
e.r. at 0 °C.
With the optimal reaction conditions established, we then
examined the scope of benzylic chlorides (Table 2). The
reaction of benzyl chloride without any substituent on the aryl
ring provided 3b in 61% yield with 71.5:28.5 e.r.. The chlorine-
substituted substrates both afforded desired products 3c and
3d in good yields, and the meta-substituted one gave a higher
yield and enantioselectivity than the para-substituted one. The
fluorine-substituted substrates provided 3e and 3f in a similar
yield and e.r. The substrate with a trifluoromethyl group
provided 3g with the best enantioselectivity (80:20 e.r.). To
investigate the functionality tolerance, we studied the cross-
coupling reaction of carbonyl-substituted benzyl chloride, the
reaction delivered product 3h as well, albeit with a lower yield
(40%). In addition, the substrates with an ester substituent
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Communication
a
a
Table 2. Scope of Benzyl Chlorides
Table 3. Scope of Arylzinc Reagents
a
Reaction conditions: ( )-1a (0.20 mmol), 2 (0.60 mmol), CoBr2
(10 mol %), and L6 (15 mol %), in toluene (2.0 mL) for 72 h under
argon. Isolated yields were based on 1a and e.r. values were
b
determined by HPLC analysis. THF (2.0 mL) was used as the
solvent.
a
Reaction conditions: ( )-1 (0.20 mmol), 2a (0.60 mmol), CoBr2
(10 mol %), and L6 (15 mol %), in toluene (2.0 mL) for 72 h under
argon. Isolated yields were based on 1 and e.r. values were determined
b
by HPLC analysis. THF (2.0 mL) was used as the solvent.
trifluoromethylated arylzinc reagent was amenable to the
reaction to give 3x in 98% yield with 72:28 e.r. The arylzinc
reagent containing the 1,3-benzodioxole group worked as well
to give desired product 3y.
To verify the hypothesis of a radical process, we carried out
the radical-inhibiting experiment with TEMPO ((2,2,6,6-
tetramethylpiperidin-1-yl)oxyl). The result showed a complete
inhibition of the desired cross-coupling reaction of 1b and
TEMPO-trapped product 4 was obtained in 35% yield, which
supported the formation of the alkyl radical species (Scheme
2A). On the basis of the literature reports,8d,14 we proposed a
either at meta or para positions of the aryl ring are also suitable
for the reaction to provide 3i and 3j. However, the substrates
with an electron-donating (Me) and a phenyl group gave
products 3k and 3l with a poor yield and enantioselectivity.
The absolute configuration of 3l was determined to be R by
comparing its HPLC spectrum and optical rotation with those
reported in literature,13 and the stereochemistry of other
products was determined in reference to 3l. Moreover, the
naphthyl-substituted benzyl chloride was also a viable substrate
to furnish desired product 3m in 50% yield with 70.5:29.5 e.r.
In addition, we investigated the possibility of introducing a
heterocycle to the 1,1-diarylalkane skeleton and found that the
substrate with a pyridyl group was applicable to the current
strategy to afford 3n in 90% yield with 72:28 e.r..
Scheme 2. Mechanistic Study and Proposed Reaction
Pathway
Encouraged by the above results, we next evaluated the
scope of arylzinc reagents (Table 3). We first investigated the
effect of electron-donating groups on the aryl ring. The
methoxyl group at the meta position of aryl ring did not affect
the reaction efficiency, and the reaction provided 3o in 93%
yield, albeit with a lower e.r. than that of 3a. Besides, the
phenoxyl group was also tolerable in the reaction to generate
3p in excellent yield with 72:28 e.r.. Furthermore, the amino-
substituted arylzinc reagent reacted well to afford 3q in 90%
yield with a moderate enantioselectivity. Further investigation
revealed that the alkyl-substituted arylzinc reagents reacted
smoothly to provide 3r and 3s. In addition to the electron-
donating groups, the unfunctionalized arylzinc reagent was also
suitable for the reaction to deliver 3t in 68% yield with 70:30
e.r. We then studied the influence of electron-withdrawing
substituents of the arylzinc reagents on the reaction. The
halogen (Cl, F) substituents are tolerated to afford 3u−3w
under the standard reaction conditions. More significantly, the
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Communication
plausible mechanism as shown in Scheme 2B. The precatalyst
CoII was first be reduced by the arylzinc reagent to the active
catalytic species LnCom for the initiation of the reaction. The
low-valent LnCom species would then undergo a single-
electron transfer with the benzyl chloride 1 to generate
prochiral benzyl radical I and the LnCom+1 species. A
transmetalation between the LnCom+1 species and arylzinc
reagent 2 would provide complex II, which subsequently
recombined with prochiral benzyl radical I to deliver Com+2
complex III. A final reductive elimination of complex III
furnished coupling product 3 and regenerate the active catalyst
for the next catalytic cycle.
In sum, we have developed a cobalt-catalyzed enantiocon-
vergent radical Negishi C(sp3)−C(sp2) cross-coupling of
racemic benzyl chlorides, providing an access to enantioen-
riched 1,1-diarylmethanes in good yields with moderate
enantioselectivities. Critical to the success was the first
utilization of a chiral multidentate anionic N,N,P-ligand to
tune the chiral environment of cobalt catalyst to achieve the
enantiocontrol over the highly reactive prochiral alkyl radical
species. It constitutes an important complement to the
developed Co/chiral bisoxazoline catalysis, and we believe
that it will open new vistas for cobalt-catalyzed enantiocon-
vergent cross-coupling. Further designing of more robust chiral
multidentate anionic ligand is still ongoing in our laboratory to
realize the cobalt-catalyzed enantioconvergent cross-coupling
in high enantioselectivity.
Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China
Ji-Jun Chen − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China
Wen-Yue Tang − Shenzhen Grubbs Institute and Department
of Chemistry, Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China
Jun-Qian Bian − Shenzhen Grubbs Institute and Department
of Chemistry, Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China
Yong-Feng Cheng − Shenzhen Grubbs Institute and
Department of Chemistry, Guangdong Provincial Key
Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China
Zhong-Liang Li − Academy for Advanced Interdisciplinary
Studies and Department of Chemistry, Southern University of
Science and Technology, Shenzhen 518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00190
Author Contributions
§Z.L. and X.-Y.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
■
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ACKNOWLEDGMENTS
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00190.
■
Financial support is from the National Natural Science
Foundation of China (21831002, 22025103, 22001109, and
22001111), Guangdong Provincial Key Laboratory of Catalysis
(2020B121201002), Guangdong Innovative Program
(2019BT02Y335), Guangdong Basic and Applied Basic
Research Foundation (2019A1515110822), Shenzhen Special
Funds (JCYJ20200109141001789), Shenzhen Key Laboratory
of Small Molecule Drug Discovery and Synthesis
(ZDSYS20190902093215877), SUSTech Special Fund for
the Construction of High-Level Universities (G02216303),
and Special Funds for the Cultivation of Guangdong College
Students’ Scientific and Technological Innovation.(“Climbing
Program” Special Funds.) (pdjh2020b0524). The authors
appreciate the assistance of SUSTech Core Research Facilities.
Experimental procedures and characterization of com-
pounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Qiang-Shuai Gu − Shenzhen Key Laboratory of Small
Molecule Drug Discovery and Synthesis and Academy for
Advanced Interdisciplinary Studies and Department of
Chemistry, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0002-3840-
425X; Email: guqs@sustech.edu.cn
Xin-Yuan Liu − Shenzhen Grubbs Institute and Department of
Chemistry, Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen 518055, China; orcid.org/0000-0002-6978-
6465; Email: liuxy3@sustech.edu.cn
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