Streamlined Construction of Silicon-Stereogenic Silanes by Tandem Enantioselective Ca'H Silylation/Alkene Hydrosilylation

Enantioselective C −H Silylation/Alkene Hydrosilylation

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Streamlined Construction of Silicon-Stereogenic Silanes by Tandem

Delong Mu, Wei Yuan, Shuyou Chen, Na Wang, Bo Yang, Lijun You, Bing Zu, Peiyuan Yu,

and Chuan He*

Cite This: https://dx.doi.org/10.1021/jacs.0c04863

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ABSTRACT: A rhodium-catalyzed tandem enantioselective C−H

silylation/alkene hydrosilylation of dihydrosilanes, which enables the

streamlined construction of a wide range of silicon-stereogenic

silanes, is successfully developed. This process involves a SiH₂-

steered highly enantioselective C−H silylation to furnish the

corresponding desymmetric monohydrosilanes, which are subse-

quently trapped with alkenes in a stereospeciﬁc fashion to build

functionally diverse asymmetrically tetrasubstituted silanes. This

general strategy combines readily available dihydrosilanes and

alkenes to construct various enantioenriched silicon-stereogenic

silanes, including 9-silaﬂuorenes, Si-bridged ladder compounds, and

benzosilolometallocenes, in a single step with good to excellent

yields and enantioselectivities.

INTRODUCTION

via selective desymmetrization of dihydrosilanes or tetraorga-

■

1g,5

nosilanes (Scheme 1a).

These approaches can provide

The development of new chemical transformations based on

asymmetric catalysis for the construction of silicon-stereogenic

silanes is of great importance and a challenge. Despite many

organosilicon compounds having been prepared by synthetic

chemists, which display valuable and desirable properties that

have led to their broad applications in synthetic chemistry,

enantioenriched silicon-stereogenic silanes, but not without

limitations, such as (1) the relatively poor substrate scope,

functional-group tolerance or enantiomeric excess (ee); (2)

lack of a streamlined method to construct architecturally

complex and functionally diverse silicon-stereogenic silanes

from simple starting materials with operational simplicity and

eﬃcacy.

materials science, and pharmaceuticals, the creation of silicon-

stereogenic centers in enantioenriched forms has been

signiﬁcantly less explored. The inherently longer C−Si bond

prevents the formation of compact transition states; and the

silicon atom is usually bonded with relatively similar groups,

making discrimination of enantiotopic faces or groups

In recent years, the development of transition-metal-

catalyzed silylation of C−H bonds has emerged as a powerful

tool for the synthesis of organosilicon compounds. Usually,

the reaction is initiated by oxidative addition of the Si−H bond

to the metal center in which the metal atom is oriented to the

diﬃcult. Moreover, the availability of empty 3d orbitals of

proximal C−H bond site, allowing selective and eﬃcient C−H

silicon makes it easy to form hypervalent ﬁve- or six-

6b,7

bond cleavage.

As part of an overarching goal to develop

coordinated intermediates. Traditionally, the preparation of

silicon-stereogenic silanes in enantiopure or enantioenriched

form is restricted to optical and kinetic resolution with chiral

new modes for catalytic enantioselective C−H bond

functionalization, we questioned whether the silyl group is

not only served as a directing group, but also stands as a

silicon-stereogenic center during the enantioselective C−H

functionalization, which would provide a more eﬃcient and

straightforward manner for the construction of silicon-

a,b,d,4

auxiliary,

which severely hamper the discovery and

development of this important class of molecules. Therefore,

the exploration of eﬃcient and straightforward asymmetric

catalysis methods that enable the streamlined construction of

enantioenriched highly functionalized silicon-stereogenic si-

lanes from simple starting materials would have far-reaching

implications for both the synthetic and the materials chemistry

communities. In the past 2 decades, a number of research

eﬀorts have been dedicated to the use of chiral transition-metal

catalysts that can perform catalytic asymmetric transformation

of tailored silanes to enantioenriched silicon-stereogenic silanes

Received: May 4, 2020

XXXX American Chemical Society

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

Article

Scheme 1. Construction of Silicon-Stereogenic Silanes

stereogenic silanes in a single step with good to excellent yields

and enantioselectivities (Scheme 1d).

RESULTS AND DISCUSSION

■

Reaction Development. We commenced our studies of

the enantioselective C−H silylation with dihydrosilane 1 as the

substrate, which could presumably undergo SiH -steered C−H

bond activation via a six-membered metallocycle intermediate

in the presence of an appropriate transition-metal catalyst. A

number of rhodium(I) and iridium(I) catalyst precursors with

various chiral ligands were tested in the reaction. However,

only a trace of the desired C−H silylation monohydrosilane

product was observed, and the dihydrosilane starting material

was decomposed in many cases. To address the decomposition

problem of the potentially formed monohydrosilane, we

employed several reaction partners in the reaction. After

many eﬀorts, we found that when dihydrosilane 1 was treated

with 4 mol % Rh(cod)Cl dimer catalyst precursor with

bidentate phosphine ligands such as BINAP (L1) or Segphos

(

L2) in the presence of 1.2 equiv of 3,3-dimethylbut-1-ene, a

tetrasubstituted silicon-stereogenic silane product 2 was

obtained in 60−75% ee, albeit in low yields (Table 1, entries

and 2). It is noteworthy that alkene participates in the

reaction as a coupling partner rather than the hydrogen

Table 1. Development of the Enantioselective C−H

Silylation for Biaryl Dihydrosilane Substrate

stereogenic silanes with many exciting opportunities. To

achieve this idea, a silyl group with two Si−H bonds

(

−SiH ) is required to conduct the enantioselective C−H

bond functionalization via a desymmetrization strategy.

However, the main obstacle when using dihydrosilanes is the

facile decomposition and nonselective hydrosilylation in the

presence of highly active transition metals. So far, there is

only one example involving enantioselective C−H activation of

dihydrosilanes reported by Takai, Kuninobu, and co-workers,

which enables the synthesis of spirosilabiﬂuorene derivatives

entry

[Rh]

ligand

solvent

yield (%)

ee (%)

[Rh(cod)Cl]₂

[Rh(cod)OH]₂

[Rh(nbd)Cl]₂

toluene

THF

77 (75)

from bis(biphenyl)silanes (Scheme 1b). To explore the

toolbox of SiH -steered enantioselective C−H activation for

the streamlined construction of diverse silicon-stereogenic

silanes, we propose that reaction of an appropriate chiral

transition-metal catalyst with a general dihydrosilane substrate

would allow a SiH -steered enantioselective C−H silylation

aﬀording the corresponding desymmetric monohydrosilane.

To avoid the potential decomposition or racemization of the

newly formed monohydrosilane, one could use appropriate

reaction partners to trap the monohydrosilane instantly and

deliver the asymmetrically tetrasubstituted silicon-stereogenic

silanes in one pot (Scheme 1c). Nevertheless, the precise

control of the sequence of this one-pot process could be rather

challenging. Herein, we report the development of an

enantioselective C−H silylation/alkene hydrosilylation of

various dihydrosilanes, which enables the streamlined con-

struction of a wide range of architecturally complex and

functionally diverse asymmetrically tetrasubstituted silicon-

[Rh(CO) Cl]₂

[Rh(cod)Cl]₂

DCE

Et O

Conditions: 1 (0.1 mmol), [Rh] (4 mol %), ligand (8 mol %), 3,3-

dimethylbut-1-ene (1.2 equiv), in 1.0 mL of solvent under an argon

atmosphere at 60 °C for 12 h. The yield was determined by H NMR

using 1,1,2,2-tetrachloroethane as the internal standard; the yield in

brackets is the isolated yield. The ee values were determined by chiral

HPLC.

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Scheme 2. Control Experiments

Scheme 3. Preliminary Mechanistic Studies

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Table 2. Scope of Silicon-Stereogenic Silanes Containing 9-Silaﬂuorene Scaﬀold

See Supporting Information for experimental procedures. Isolated yields. The ee values were determined by chiral HPLC.

acceptor, and no extra oxidant is needed in this dehydrogen-

ative silylation process. To the best of our knowledge, this is

the ﬁrst example of a tandem enantioselective silylation of C−

H bond/alkene hydrosilylation enabling the construction of a

tetraorganosilicon stereocenter from a simple dihydrosilane.

Further condition optimization and ligand screening found

that one of the commercially available Josiphos ligands (L6)

improved the yield to 75% with 91% ee (Table 1, entries 3−9).

Other rhodium(I) catalyst precursors reduced the yields

signiﬁcantly (Table 1, entries 10−12). Changing the solvent

to THF, DCE, or Et O also gave lower yields and ee (Table 1,

entries 13−15). Under the optimized conditions, switching to

the dihydrosilane substrate 3 containing a methyl-substituted

group on the same aromatic ring of the silyl group gave

another enantiomer 4 with a comparable 90% ee (Scheme 2a).

No monohydrosilane 5 or direct hydrosilylation 6 byproduct

was observed in this highly selective one-pot process.

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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b,7

Article

Mechanistic Studies. This interesting transformation

displayed a remarkable selectivity that encouraged us to

elucidate the reaction mechanism. Usually, hydrosilylation of

alkenes with dihydrosilanes is facile under appropriate

of hydrosilane, which undergoes oxidative addition into one

of the Si−H bonds of dihydrosilane, aﬀording the key

intermediate B. Then reductive elimination of dihydrogen

from intermediate B generates a Rh(I) silyl complex C, which

subsequently undergoes enantioselective C−H bond activa-

tion, aﬀording intermediate D. Then reductive elimination of

intermediate D occurs to form the C−Si bond and Rh(I)

hydride species, which instantly proceeds oxidative addition

into the second Si−H bond, furnishing intermediate E. Finally,

insertion of alkene into intermediate E, followed by reductive

elimination from intermediate F, completes the catalytic cycle,

and it regenerates the catalytically active Rh(I) species. To

elucidate the origin of the enantioselectivity, we conducted

preliminary DFT calculations (see Supporting Information,

section 7.6). We were able to locate the C−H activation

transition states TS-major and TS-minor, which lead to the

two enantiomeric products. Various coordination types and

conformations were considered to ensure that the most

favorable transition states are located. TS-major is 5.0 kcal/

mol more favorable than TS-minor in terms of free energy at

room temperature, which is consistent with the observed

enantioselectivity. Nonetheless, these DFT results are very

preliminary and further detailed studies on the whole reaction

pathway is in progress, which will be disclosed in due course.

Substrate Scope. On the basis of the optimized conditions

and the preliminary mechanistic studies, we next explored the

substrate scope of this process. As the created silicon-

stereogenic centers are decorated with four groups, here we

used four colors to assess the scope of this reaction (Table 2).

First, biaryl dihydrosilane substrates bearing a wide range of

substituents on either the reacting C−H bond side of the

aromatic ring (light blue) or the silyl group tethered aromatic

ring (yellow) at diﬀerent positions all reacted smoothly with

5f,m,n,9

transition-metal-catalyzed conditions,

and the generated

hydrosilylation monohydrosilanes can reasonably undergo the

C−H activation/silylation reaction. Therefore, a control

experiment in the absence of alkene was reinvestigated.

Under the optimized conditions only without the alkene

partner, the monohydrosilane product 5 could be obtained in

7% yield via C−H activation/silylation (Scheme 2b). Despite

low yield, the comparable 95% ee of 5 clearly indicates that the

stereodetermining step is the SiH -steered C−H activation/

silylation process. Further treatment of the resulting

enantioenriched monohydrosilane 5 with 3,3-dimethylbut-1-

ene under the Rh-catalyzed conditions using either (R,Sp)-

Josiphos L6 or (S,Rp)-Josiphos L6 or (racemic)-Josiphos L6

furnished the identical tetrasubstituted silane product 4 with

retention of the absolute conﬁguration (see Supporting

Information , section 7.2). When a racemic monohydrosilane

was subjected to the reaction conditions using (R,Sp)-

Josiphos L6, a racemic product 4 was obtained (Scheme 2c).

Moreover, the racemic monohydrosilane 6 was prepared and

also subjected to the standard reaction conditions. In this case,

no reaction occurred (Scheme 2d). These results further

suggest that monohydrosilane 5 is the key intermediate in the

reaction, and the chirality of the silicon-stereogenic center of 5

is induced in the ﬁrst SiH -steered C−H activation/silylation

process, which leads to the formation of the ﬁnal product 4. It

should be noted that the key intermediate monohydrosilane 5

is not stable under the Rh-catalyzed conditions, and the one-

pot trap of it with alkenes in a stereospeciﬁc fashion stabilized

the silicon-stereogenic center, providing a perfect strategy for

5m,10

the construction of asymmetrically tetrasubstituted silanes.

,3-dimethylbut-1-ene to aﬀord the desired asymmetrically

To the best of our knowledge, this is also the ﬁrst example of

rhodium-catalyzed stereospeciﬁc intermolecular hydrosilyla-

tion of alkene with retention of the silicon-stereogenic center.

In addition, this tandem C−H silylation/alkene insertion

tetrasubstituted silane products in high yields (55−88%) with

good to excellent enantioselectivities (81−99% ee). Electron-

donating groups, such as methyl, tert-butyl, methoxy groups

7−9, 19), and electron-withdrawing groups, such as

triﬂuoromethyl group (10) and halogen substituents (11, 17,

8), were well tolerated. Interestingly, compound 11 and

(

process also suggests that the SiH -steered intramolecular C−

H activation of dihydrosilane is more favored than the

intermolecular alkene hydrosilylation.

compound 17 are also a pair of enantiomers in this

transformation. Extended aromatic groups and heterocycles

such as furan, thiophene, and indole (12−16, 20) could also

be transformed into the 9-silaﬂuorene scaﬀold successfully.

Next, changing the third substituents (green) on the

dihydrosilane substrates into functionalized aromatic rings,

heterocycles, and aliphatic methyl group also produced the

corresponding products in good yields without the loss of

enantioselectivities (21−26). For the scope of alkenes (blue),

we ﬁnd that besides 3,3-dimethylbut-1-ene, other types of

alkenes containing adamantyl group, aromatic rings, amino

group, styrene, vinylsilane, and vinylgermane were competent

substrates, providing the desired highly functionalized silane

products in good yields with excellent enantioselectivities

(27−30, 32, 33). However, because of the unselective

hydrosilylation of carbonyl groups, ester or ketone functional

groups gave poor results in the transformation (31). In

addition, linear aliphatic alkenes (34) and vinyl ethers are not

very compatible with biaryl dihydrosilane substrates in the

tandem process. In these cases, direct hydrosilylation of the

Next, two parallel kinetic isotope eﬀect (KIE) experiments

were carried out using 1-H and 1-D , as shown in Scheme 3a.

The reactions gave rise to a k /k value of 1.08. The lack of a

kinetic isotope eﬀect rules out C−H bond cleavage occurring

during the turnover-limiting step in this tandem process.

Moreover, the reaction of dihydrosilane 3 with [Rh(cod)Cl]

and Josiphos L6 in toluene-d was monitored by P and H

NMR at room temperature (Scheme 3b). Two doublets of

doublets at 101.3 ppm (dd, J_R_h₋_P= 140.9 Hz, J_P₋_P= 32.6 Hz,

P(tBu) ) and 28.9 ppm (dd, J

= 136.5 Hz, J_P₋_P= 32.6 Hz,

Rh−P

P(Ph) ) were observerd in the P NMR spectrum. And two

broad rhodium hydride species (−6.28 and −3.32 ppm) were

observed in the H NMR spectrum (see Supporting

Information , section 7.5). These signals suggested the

formation of the rhodium silyl dihydride intermediate B,

which was proposed to be the catalyst resting state in the

catalytic cycle. On the basis of the results described above,

we propose that this SiH -steered tandem enantioselective C−

H silylation/alkene hydrosilylation process occurs by the

mechanism as shown in Scheme 3c. First, Rh(I) hydride

phosphine active catalyst species A is generated from precursor

Rh(cod)Cl dimer and chiral phosphine ligand in the presence

less hindered alkene is more favored than SiH -steered C−H

activation/silylation (see Supporting Information, section 6).

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Scheme 4. Construction of Enantiopure Silicon-Bridged Ladder π-Conjugated Systems

It is noteworthy that 9-silaﬂuorene derivatives have attracted

increasing attention as promising components of novel

advanced functional materials because of their low LUMO

excellent enantiocontrol (90−99% ee). Ferrocene dihydrosi-

lane substrates bearing a number of electron-donating or

-withdrawing substituents, such as methyl, ﬂuoro, chloro,

methoxy, triﬂuoromethyl, OTBS, and amino functional groups

on the silyl group tethered aromatic rings (yellow and green)

at diﬀerent positions were all well accommodated in this

transformation to deliver the corresponding benzosilolome-

tallocene products in 62−95% yields with 93−99% ee (47−54,

2i−l

energy level via the σ*−π* conjugation.

Herein, this

methodology provides streamlined access to functionally

diverse silicon-stereogenic 9-silaﬂuorene derivatives in a chiral

version of untapped potential, which could be highly attractive

to organic materials chemists as novel chiral building blocks.

Moreover, given that silicon-bridged ladder π-conjugated

systems are also an important class of scaﬀolds for organic

8−62). Dihydrosilanes containing a naphthalene ring and

14a

benzofuran, as well as ruthenocene (light blue), were viable

substrates giving decent yields and ee (55, 56, and 63).

Notably, this process was eﬀective with a broad series of

alkenes (blue), including aliphatic alkenes, vinyl ethers, vinyl

amines, styrenes, vinyl ferrocene, and vinylsilane (64−74),

which enables the facile construction of complex enantiopure

benzosilolometallocenes displaying structural and functional

features relevant to fragment-based lead identiﬁcation pro-

grams. It is worth mentioning that linear aliphatic alkene is

compatible with the ferrocene dihydrosilane substrate in this

i−l

electronics,

the construction of such molecules in an

enantiopure form should be a powerful demonstration of the

utility of this process, which would lead to their broad

applications in materials science. To test this strategy, we

selected four bis-dihydrosilane substrates (35−38) and

subjected them to the reaction conditions (Scheme 4). Each

of these bis-dihydrosilanes underwent smooth C−H silylation/

alkene hydrosilylation to furnish the target silicon-bridged

ladder π-conjugated products (39, 41, 43, 45) in good yields

with excellent ee, albeit minor meso products were also

observed.

tandem process (66), which indicates that the SiH -steered

C−H activation/silylation of metallocene is still more favored

than direct alkene hydrosilylation, even with less hindered

alkene. To further illustrate the utility of this transformation,

we examined this reaction employing the core structures of

several bioactive molecules, pharmaceuticals, or materials

building blocks, such as (+)-α-tocopherol (75), D-ribofurano-

side (76), β-estradiol (77), (−)-menthol (78), phenothiaine

Since this SiH -steered C−H silylation/alkene hydro-

silylation enables facile access to silicon-stereogenic 9-

silaﬂuorene derivatives in high enantioselectivity, we ques-

tioned whether we could expand this process with the

metallocene system, producing benzosilolometallocenes con-

taining silicon-stereogenic centers, given that metallocenes are

an important class of useful compounds in materials sciences as

(

79), pitavastatin fragment (80), and liquid crystal building

block (81). We were delighted to ﬁnd that the corresponding

benzosilolometallocene products could be obtained in good

yields with excellent stereoselectivities, irrespective of existing

diverse functional groups and complex molecular structures.

well as in bioorganometallic chemistry, and chiral metal-

locene derivatives are also important and privileged units in

catalysts and ligands for asymmetric catalysis. On the basis of

the established reaction conditions, simply changing the

Josiphos ligand into Segphos (L2 ) (for a detailed account of

the optimization study, see Supporting Information , Tables S2

and S3), a wide range of ferrocene dihydrosilanes displaying a

variety of substituents were found to be suitable substrates for

this process (Table 3). The asymmetrically tetrasubstituted

benzosilolometallocenes containing both silicon-centered and

CONCLUSION

■

Taken together, we develop a tandem highly enantioselective

C−H silylation/alkene hydrosilylation methodology, that

combines readily available dihydrosilanes and alkenes to

construct architecturally complex and functionally diverse

enantioenriched tetrasubstituted silicon-stereogenic silanes in a

planar chiralities are obtained as single diastereomers with

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Table 3. Scope of Silicon-Stereogenic Silanes Containing Metallocene Scaﬀold

See Supporting Information for experimental procedures. Isolated yields. The ee values were determined by chiral HPLC. All the

benzosilolometallocenes are obtained as single diastereomers (dr > 20:1).

single step with good to excellent yields and enantioselectiv-

ities. We expect that the operational simplicity, eﬃcacy, and

broad scope of this asymmetrically tetrasubstituted silanes

displaying architectural complexity and functional diversity will

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society

https://pubs.acs.org/10.1021/jacs.0c04863

Article

ﬁnd widespread use in the ﬁelds of synthetic chemistry,

medicinal chemistry, and also materials science. Moreover, we

believe that the convenience of this method generating

Guangdong 518055, China; orcid.org/0000-0002-4367-

6866

Complete contact information is available at:

underexplored SiH -directed enantioselective C−H bond

activation will inspire further advances in asymmetric catalysis.

Author Contributions

D.M. and W.Y. contributed equally to this work.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.0c04863.

■

Notes

The authors declare no competing ﬁnancial interest.

Crystallographic data for compound 7; crystallographic

data for compound 11; crystallographic data for

compound 43; crystallographic data for compound

ACKNOWLEDGMENTS

■

We are grateful for ﬁnancial support from the National Natural

Science Foundation of China (21901104), the Thousand

Talents Program for Young Scholars, the start-up fund from

Southern University of Science and Technology, the Shenzhen

Nobel Prize Scientists Laboratory Project (C17783101),

Guangdong Provincial Key Laboratory of Catalysis (No.

2020B121201002), and China Postdoctoral Science Founda-

tion (2019M651153), and Shenzhen Clean Energy Research

Institute (No. CERI-KY-2019-003). We also thank Dr. Xiao-

Yong Chang for assistance in solving the X-ray structures.

(

R,Rp-48); crystallographic data for compound (S,Sp-

8 ); crystallographic data for compound (R,Rp-48-SiH)

ZIP)

Materials and methods; experimental procedures;

optimization studies; characterization data; mechanistic

studies; H, C, and F NMR spectral data; HPLC

spectra; and mass spectrometry data of new compounds

(PDF )

REFERENCES

AUTHOR INFORMATION

Corresponding Author

Chuan He − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China; orcid.org/0000-0002-9983-

■

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Authors

Delong Mu − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

Wei Yuan − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

Shuyou Chen − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

Na Wang − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

Bo Yang − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

Lijun You − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

Bing Zu − Shenzhen Grubbs Institute and Department of

Chemistry, Guangdong Provincial Key Laboratory of Catalysis,

Southern University of Science and Technology, Shenzhen,

Guangdong 518055, China

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