Rhodium(I)-Catalyzed Enantioselective C(sp3)—H Functionalization via Carbene-Induced Asymmetric Intermolecular C—H Insertion?

DOI: 10.1002/cjoc.202100040

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Chinese Journal of Chemistry p. 1911 - 1915 (2021)

Update date:2022-08-11

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Authors:

Liu, Bo Liu, Bo

Xu, Ming-Hua

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Article abstract of DOI:10.1002/cjoc.202100040

Transition-metal-catalyzed C—H insertion of metal-carbene represents an excellent and powerful approach for C—H functionalization. However, despite remarkable advances in metal-carbene chemistry, transition metal catalysts that are capable of enantioselective intermolecular carbene C—H insertion are mainly constrained to dirhodium(II) and iridium(III)-based complexes. Herein, we disclose a new version of asymmetric carbene C—H insertion reaction with rhodium(I) catalyst. A highly enantioselective rhodium(I) complex-catalyzed C(sp³)—H functionalization of 1,4-cyclohexadienes with α-aryl-α-diazoacetates was successfully developed. By using chiral bicyclo[2.2.2]-octadiene as ligand, rhodium(I)-carbene-induced asymmetric intermolecular C—H insertion proceeds smoothly at room temperature, allowing access to a diverse variety of α-aryl-α-cyclohexadienyl acetates and gem-diaryl-containing acetates in good yields with good to excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the reaction was highlighted by facile synthesis of a novel cannabinoid CB₁ receptor ligand. This method may offer a new opportunity for the development of therapeutically exploitable cannabinoid receptor type ligands in medicinal chemistry.

Full text of DOI:10.1002/cjoc.202100040

Chinese Journal

of Chemistry

CJC

中国化学 - An International Journal

Accepted Article

Title: Rhodium(I)-Catalyzed Enantioselective C(sp³)-H Functionalization via

Carbene-Induced Asymmetric Intermolecular C-H Insertion

Authors: Bo Liu, and Ming-Hua Xu*

This manuscript has been accepted and appears as an Accepted Article online.

This work may now be cited as: Chin. J. Chem. 2021, 39, 10.1002/cjoc.202100040.

The final Version of Record (VoR) of it with formal page numbers will soon be

published online in Early View: http://dx.doi.org/10.1002/cjoc.202100040.

ISSN 1001-604X • CN 31-1547/O6

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Xu Ming-Hua (Orcid ID: 0000-0002-1692-2718)

Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX

Rhodium(I)-Catalyzed Enantioselective C(sp³)-H Functionalization

via Carbene-Induced Asymmetric Intermolecular C-H Insertion

Bo Liu,^{a, b}and Ming-Hua Xu*^,a

^aShenzhen Grubbs Institute and Department of Chemistry, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science

and Technology, 1088 Xueyuan Boulevard, Shenzhen 518055, China

^bShanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-chongzhi Road, Shanghai 201203, China

Keywords

Asymmetric catalysis | C-H functionalization | Rhodium carbene | C-H insertion | Chiral diene ligand

Main observation and conclusion

Transition-metal-catalyzed C-H insertion of metal-carbene represents an excellent and powerful approach for C-H functionalization.

However, despite remarkable advances in metal-carbene chemistry, transition metal catalysts that capable of enantioselective inter-

molecular carbene C-H insertion are mainly constrained to dirhodium(II) and iridium(III)-based complexes. Here we disclose a new

version of asymmetric carbene C-H insertion reaction with rhodium(I) catalyst. A highly enantioselective rhodium(I) complex-catalyzed

C(sp³)-H functionalization of 1,4-cyclohexadienes with α-aryl-α-diazoacetates was successfully developed. By using chiral bicyclo[2.2.2]-

octadiene as ligand, rhodium(I)-carbene-induced asymmetric intermolecular C-H insertion proceeds smoothly at room temperature,

allowing access to a diverse variety of α-aryl-α-cyclohexadienyl acetates and gem-diaryl-containing acetates in good yields with good

to excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the reaction was highlighted by the facile synthesis

of a novel cannabinoid CB₁receptor ligand. This method may offer a new opportunity for the development of therapeutically exploitable

cannabinoid receptor type ligands in medicinal chemistry.

Comprehensive Graphic Content

R^'

CO₂

N₂

R¹

R²

via C-H insertion

diene*

Rh(I)/

R^'

CO₂

R²

99%

to 90%

yield,

R' Me,

CH₂CF₃CH CCl

R^'

CO₂

R^'

CO₂

R¹

MeO

cannabinoid CB₁

R²

receptor

ligand

*E-mail: xumh@sustech.edu.cn

This paper is dedicated to the 10th anniversary of Department of Chemistry,

Southern University of Science and Technology.

View HTML Article

Supporting Information

Chin. J. Chem. 2021, 39, XXX－XXX©

2021

SIOC,

CAS,

Shanghai,

WILEY-VCH

GmbH

This article has been accepted for publication and undergone full peer review but has not been

through the copyediting, typesetting, pagination and proofreading process which may lead to

differences between this version and the Version of Record. Please cite this article as doi:

10.1002/cjoc.202100040

First author et al.

Concise Report

phenyldiazoacetate (1a) and 1,4-cyclohexadiene (2a) as model sub-

strates under the conditions of [Rh(C₂H₄)₂Cl]₂(2.5 mol %) in di-

chloromethane at room temperature using C₁-symmetric bicy-

clo[2.2.2]-octadiene L1 as ligand. To our delight, the expected in-

sertion product 3aa was obtained in moderate yield (53%) with a

Background and Originality Content

C-H functionalization represents an attractive and ideal strat-

egy for organic synthesis. In recent years, transition metal-cata-

lyzed C-H functionalization has received significant attention be-

cause it enables the transformation of the most fundamental C-H

bonds in a wide array of organic molecules.^[1]Apart from C-H acti-

vation, metal-carbene-induced C-H insertion has also proven to be

a wonderful means of C-H functionalization,^[2]rendering reaction

site-selectivity typically under mild conditions. However, despite

remarkable advances in metal-carbene chemistry,^[3]transition

metal catalysts that capable of enantioselective intermolecular car-

bene C(sp³)–H insertion are mainly constrained to dirhodium(II)^[3e-

^h,4]and iridium(III)^[5]-based complexes. The development of new ef-

fective chiral catalyst for carbene insertion into C–H bonds remains

an interesting topic.

1, 4-Cyclohexadiene is a versatile chemical intermediate con-

taining both allylic C-H bonds and C=C double bonds in the molecule.

Interestingly, Davies^[6a,b]and Muller^[6c]independently found that

stereoselective C(sp³)-H insertions into the allylic positions of 1, 4-

cyclohexadiene could be the predominant pathway in donor/ac-

ceptor carbenoid reactions by using chiral dirhodium(II) carbox-

ylate catalysts. In 2009, Katsuki^[5a]first disclosed that iridium(III)-

salen complexes could also catalyze this asymmetric car-bene C-H

insertion in a highly enantioselective manner. Subsequently, Che^[5b]

and Blakey^[5c]reported their successful development of chiral irid-

ium(III)-porphyrin and iridium(III)-bis(oxazolinyl)phenyl complexes

as catalysts. These works demonstrated the new reactivity mode of

rhodium(II) and iridium(III)-carbenes. On the other hand, the

abovementioned carbene C–H insertion products are useful chiral

precursors towards the construction of enantioenriched gem-di-

aryl-containing pharmaceuticals (Figure 1).

Table 1 Conditions Optimization for Intermolecular C-H Insertion of 1,4-Cy-

clohexadiene ^a

N₂

catalyst

Rh(I)

DCM,

CO₂

Ar¹

H₃

Ar¹

H₅

C₆

3,5-(CF_{3 2}

)

Ar²4-Me H₄

C₆

Ar²

H₃

Ar²

C₆

3,5-(CF_{3 2}

)

Ar²4-CF

H₄

Ar²

H₅

C₆

₃C₆

Ar¹

Ar²

H₃

C₆

3,5-F₂

H₃

C₆

3,5-(MeO)₂

Ar²

H₃

H₂

C₆

3,5-(CF_{3 2}

3,4,5-F₃

)

Entry

Catalyst

[Rh]+L1

[Rh]+L2

[Rh]+L3

[Rh]+L4

[Rh]+L5

[Rh]+L6

[Rh]+L7

[Rh]+L8

T (ºC)

Yield (%)

Ee (%)

12^b

14^c

16^d

17^d,e

18^d,f

19^d,g

ⁱPr

MeHN

ⁱPr

sertraline

tolterodine

dihydrexidine

[Rh(L8)Cl]₂

H₂N

MeHN

• HCl

indatraline

nomifensine

diclofensine

Figure 1 Representative gem-diaryl-containing pharmaceuticals.

^aReactions were performed with 1 (0.1 mmol), 2a (10.0 equiv), 2.5 mol %

[Rh(C₂H₄)₂Cl]₂in dry solvent (1.0 mL). The reaction time was 12 h. CHCl₃

as solvent. ^d0.5 mL DCM was used. ^e2a (5.0 equiv) was used. ^f2a (2.0 equiv)

was used. ^g1.5 mol % [Rh(C₂H₄)₂Cl]₂was used.

Over the past few years, we have been interested in the design

of chiral olefin ligands for asymmetric catalysis.^[7]Recently, we ac-

complished the first rhodium(I)-catalyzed highly enantioselective

carbene B–H and Si–H insertion reactions with diazo esters using a

C1-symmetric chiral diene ligand.^[8]Different from rhodium(II)-car-

bene chemistry, asymmetric transformations via rhodium(I)-car-

bene intermediate have been much less explored.^[9]Motivated by

the promising catalytic reactivity and stereoselectivity of rho-

dium(I)-diene complexes, we sought to carry out carbenoid C-H in-

sertion reaction to expand the utility of this rhodium(I) catalyst sys-

tem. We disclose herein that the rhodium(I)-chiral diene complexes

are effective catalysts for carbenoid-induced enantioselective inter-

molecular C–H functionalization of 1,4-cyclohexadiene using α-aryl-

α-diazoacetate.

decent enantioselectivity (89% ee) (Table 1, entry 1). This result

suggests that our rhodium(I)-diene catalyst could promote this C-H

insertion process efficiently. To investigate the electronic effect of

aromatic substituents in diene ligands, we replaced 3,5-(CF₃)₂C₄H₃

to 3,4,5-F₃C₆H₂(L2), C₆H₅(L3), and 3,5-(OMe)₂C₄H₃(L4). Interest-

ingly, the enantioselectivity and yield was found to likely depend on

the electronic nature of the olefin ligand. L1 with more electron-

deficient olefins provided higher yield and higher ee value (entries

2-4). To further improve the yield and enantioselectivity, we then

evaluated a series of bicyclo[2.2.2] diene ligands with 3,5-

(CF₃)₂C₄H₃as Ar¹, combining electronically diverse array of aryl sub-

stituents Ar²(L5-8). Similar to the previous results, an observable

improvement in both yield and ee was attained by employing L6, L7

and L8, suggesting that the introduction of electron-withdrawing

Results and Discussion

Inspired by the previous success in the asymmetric B–H and Si–

H insertion reactions, we commenced our reaction with methyl

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Chin. J. Chem. 2021, 39, XXX－XXX

Enantioselective C(sp³)-H Functionalization

Chin. J. Chem.

substituent(s) on the phenyl ring is beneficial in terms of catalytic

activity and stereocontrol performance (entries 5-8). Among them,

C₂-symmetric chiral diene ligand L8 delivered the best result of 79%

yield and 94% ee (entry 8). Subsequently, investigation of R group

at the ester moiety of the diazo substrates was carried out (entries

9-11). The use of more sterically bulky iso-propyl provided the de-

sired C-H insertion product 3aa with an exciting enantioselectivity

(97% ee), however, a large decrease of the reaction yield was also

observed (entry 11). In view of both yield and enantioselectivity, we

continued our optimization using methyl phenyldiazoacetate (1a).

A survey of reaction temperature and solvent revealed that no su-

perior results were obtained (entries 12-14). Gratifyingly, the use

of pre-prepared rhodium complex [Rh(L8)Cl]₂significantly im-

proved the reaction yield to 88%, while maintaining the same level

of enantioselectivity (95% ee) (entry 15). Performing the reaction

at a higher concentration led to a slightly improved yield (entry 16).

Additionally, lowering the amount of cyclohexadiene from 10 equiv

to 5 equiv did not influence the reaction yield (entry 17). Notably,

the reaction can also proceed well with the use of only 2 equiv of

cyclohexadiene, albeit with a slight drop of the yield (entry 18). Fi-

nally, we were delighted to find that the catalyst loading could be

reduced to 1.5 mol% without affecting the reaction yield and enan-

tioselectivity (entry 19).

With the optimized conditions in hand, we sought to explore

the substrate scope of the reaction. As shown in Scheme 1, various

α-diazoarylacetates were suitable for the C-H insertion of 1,4-cyclo-

hexadiene, providing a wide variety of chiral 2-arylacetates bearing

an α-cyclohexa-2,5-dienyl substituent with good to excellent enan-

tioselectivities. In general, both electron-donating and electron-

withdrawing substituents on the phenyl ring had little impact on the

enantioselectivity. For example, diazo substrates bearing meta-

chloro and meta-methoxy provided the desired products 3ha and

3ja with a same ee value (97%). However, diazo with 3,4-dimethoxy

phenyl group resulted in a decrease of the enantioselectivity (3ma,

83% ee) while 3,4-dichloro-containing substrate could give much

higher enantioselectivity (3la, 95% ee). Notably, optically active 3la

was known as a key intermediate for asymmetric synthesis of drug

indatraline,^[10]a nonselective monoamine reuptake inhibitor that

has been shown to block the reuptake of dopamine, norepineph-

rine, and serotonin with effects similar to those of cocaine. Among

them, the absolute configuration of product 3ja was unambigu-

ously assigned as (R) by comparing the optical rotation [α]_Dwith the

literature value.^[5c]Furthermore, trifluoroethyl and trichloroethyl

diazoacetates were proved to be suitable substrates, affording the

corresponding insertion products (3na, 3oa, 3pa) in good yields

with up to 99% ee.

Scheme 1 Rh(I)-Catalyzed Asymmetric C-H Functionalization of 1,4-Cyclo-

hexadiene

Scheme 2 Rh(I)-Catalyzed C-H Insertion into Substituted Cyclohexadienes:

Construction of Chiral α, α-Diarylacetates

R¹

R²

N₂

mol

R¹

R²

1.5

[Rh( )(Cl)]₂

CO₂R^'

mol%), DCM,

CO₂R

[Rh( )(Cl)]₂(1.5

DCM,

CO₂R

toluene,

DDQ

(2.0 equiv),

CO₂R^'

CO₂Me

CO₂

CO₂Me

3aa

95%

3ba

96%

3ca

96%

yield,

81%

85%

90%

yield,

MeO

4db

4qb

4ab

93%

88%

yield,

88%

91%

82%

95%

yield,

CO₂

CO₂Me

3da

94%

3ea

95%

3fa

CO₂CH₂CF₃

CO₂CH₂CCl₃

96%

yield,

CO₂CH₂CCl₃

83%

84%

81%

62%

79%

61%

85%

yield,

4nb

4ob

4oc

94%

78%

96%

81%

96%

85%

yield,

CF₃

MeO

CO₂Me

3ha

3ia

3ga

72%

95%

97%

93%

yield,

MeO

yield,

CO₂

CO₂Me

4dc

4ad

4jc

ee^b

92%

56%

76%

85%

84%

MeO

94%

yield,

MeO

yield,

CO₂Me

CO₂

CO₂Me

MeO

3ka

3la

3ja

95%

91%

97%

82%

yield,

MeO

CO₂Me

ee^b

CO₂CH₂CCl₃

CO₂Me

58%

MeO

4oe

90%

4de

4je

95%

CO₂CH₂CX₃

CO₂CH₂CCl₃

CO₂Me

ee^b

54%

53%

95%

yield,

MeO

3na & 3oa

3ma

3pa

ee^b

81%

97%

yield,

99%

yield,

83% 92%

80%

83%

yield,

^aReactions were performed with 1 (0.1 mmol), 2a (0.5 mmol) and 1.5 mol %

catalyst in dry DCM (0.5 mL) at room temperature. Then oxidation process

was conducted with DDQ (0.2 mmol) in toluene (2 mL) at room temperature.

^bReaction was performed at 0 °C.

Cl, 78%

^aReactions were performed with 1 (0.1 mmol), 2a (0.5 mmol) and 1.5 mol %

catalyst in dry DCM (0.5 mL) at room temperature for 2 h. The reaction

was performed at 0 °C for 12 h.

Chin. J. Chem. 2021, 39, XXX－XXX

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First author et al.

Concise Report

Encouraged by the above results, we next sought to explore the

feasibility of this C-H insertion with substituted cyclohexadienes. As

expected, the reaction was well-tolerated with 1,4-cyclohexadi-

enes containing substituent(s) at the olefin moiety. A series of en-

antioenriched α,α-biarylacetates 4 bearing a gem-diaryl stereocen-

ter were successfully obtained after subsequent oxidation of the

insertion products with DDQ (Scheme 3). It should be mentioned

that the C–H insertion takes place solely at the less hindered allylic

position. Although it is difficult to control the diastereoselectivity,^[11]

single regioisomers could be obtained in good yields with high en-

antioselectivities after simple oxidation. Thus, this method pro-

vides an alternative enantioselective way to access various highly

optically active gem-diarylacetates.

transformations. By employing this protocol, a diverse variety of

gem-diaryl-containing highly enantiomerically enriched acetates

can be easily obtained, which may offer an opportunity for the de-

velopment of therapeutically exploitable cannabinoid CB₁& CB₂re-

ceptors. We believe that this method will find broad application in

organic synthesis and medicinal chemistry.

Experimental

General experimental procedures for the asymmetric C-H func-

tionalization of cyclohexadiene

Under Ar atmosphere, a solution of diazo 1 (0.1 mmol) and

diene 2 (0.1 mmol) in DCM (0.5 mL) was introduced into a dried

Schlenk tube equipped with the catalyst [Rh(L)Cl]₂(2.0 mg, 0.003

mmol, 1.5 mol %), and the resulting mixture was stirred at room

temperature and monitored by TLC. After the reaction was com-

pleted, solvent was removed under reduced pressure and the resi-

due was purified by silica gel column chromatography using petro-

leum ether/ethyl acetate to afford the corresponding insertion

products 3.

Scheme 3 Scale-Up and Transformation of the Product

N₂

Standard Conditions

CO₂Me

3ea

mmol

95%

yield,

990

82%

mg,

Supporting Information

Pd/C, H₂

CH₃OH

DDQ

toluene

CO₂Me

The supporting information for this article is available on the

WWW under https://doi.org/10.1002/cjoc.2021xxxxx.

CO₂Me

3ea

95%

yield,

98%

96%

95%

yield,

Acknowledgement

toluene

DDQ,

Zn, AcOH

We thank Dr. Diao Chen for his very initial attempt on this work

and Dr. Takeshi Yamakawa for helpful discussion. Financial support

from the National Natural Science Foundation of China (21971103,

21672229), the National Science & Technology Major Project “Key

New Drug Creation and Manufacturing Program”, China

(2018ZX09711002-006), and Guangdong Provincial Key Laboratory

of Catalysis (2020B121201002) is gratefully acknowledged. We are

especially grateful to Dr. Stefan Abele in Idorsia Pharmaceuticals

Ltd., Switzerland for his very generous donation of the key interme-

diate (1R,4R)-5-phenylbicyclo[2.2.2]oct-5-en-2-one for diene prep-

aration.

HATU, Et N

CO₂CH₂CCl₃

MeO

82%

92%

MeO

yield,

NH₂

3pa

cannabinoid CB1

receptor

ligand

To demonstrate the practicality of this method, a gram-scale

reaction between methyl phenyldiazoacetate (1e) and 1,4-cyclo-

hexadiene(2a) was carried out (Scheme 3a). Under the standard

conditions, the reaction proceeded smoothly and gave 3ea in good

yield (82%) with no appreciable loss of enantioselectivity (95% ee).

Similarly, this insertion product was readily transformed into α,α-

biphenylacetate 5 by DDQ oxidation in toluene at room tempera-

ture. On the other hand, the cyclohexadiene framework was re-

duced under hydrogen atmosphere in the presence of catalytic

amount of Pd/C, giving α-cyclohexyl substituted α-arylacetate 6

with 95% ee (Scheme 3b). To further showcase the synthetic utility

of the reaction, we carried out the asymmetric synthesis of a can-

nabinoid CB₁receptor ligand^[12](7). As illustrated in Scheme 3c,

DDQ oxidation of the C-H insertion product 3pa, followed by

Zn/AcOH reduction and amination with 3,3-diphenylpropanamine

in the presence of HATU and Et₃N, could give the target molecule 7

in overall 82% yield with 92% ee. Thus, this approach can be used

for synthesis of a series of this cannabinoid receptor type ligands

with ease.

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Chin. J. Chem.

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(The following will be filled in by the editorial staff)

Manuscript received: XXXX, 2021

Manuscript revised: XXXX, 2021

Manuscript accepted: XXXX, 2021

Accepted manuscript online: XXXX, 2021

Version of record online: XXXX, 2021

Chin. J. Chem. 2021, 39, XXX－XXX

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