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Rh(III)-Catalyzed Atroposelective Synthesis of Biaryls via C-H

Activation and Intermolecular Coupling with Sterically Hindered

Alkynes

Fen Wang, Zisong Qi, Yuxia Zhao, Shuailei Zhai, Guangfan Zheng, Ruijie Mi, Zhiyan Huang, Xiaolin

Zhu, Xiaoming He, Xingwei Li*

Dedication ((optional))

[a] Dr. F. Wang, Y, Zhao, Dr. Z. Qi, Shuailei Zhai, Dr. Guangfan Zheng, R. Mi, Dr. Z. Huang, Dr. X. Zhu, Prof. Dr. X. He, Prof. Dr. X. Li

School of Chemistry and Chemical Engineering

Shaanxi Normal University (SNNU)

Xi’an 710062 (China)

E-mail: lixw@snnu.edu.cn

Supporting information for this article is given via a link at the end of the document.

Abstract: Chiral biaryls make important synthetic building blocks and

privileged ligands for asymmetric catalysis. Reported herein is

atroposelective synthesis of biaryl NH isoquinolones via Rh(III)-

catalyzed C-H activation of benzamides and intermolecular [4+2]

annulation with a broad scope of 2-substituted 1-alkynylnaphthalenes

as well as sterically hindered, symmetric diarylacetylenes. The axial

chirality is constructed based on dynamic kinetic transformation of the

alkyne in redox-neutral annulation with benzamides, with alkyne

insertion being stereo-determining. The reaction accommodates both

benzamides and heteroaryl carboxamides and proceeds in excellent

regioselectivity (if applicable) and enantioselectivities (average 91.8%

ee). An enantiomerically and diastereomerically pure rhodacyclic

complex has been prepared and offers insight into enantiomeric

control of the coupling system, and the steric interactions between the

amide directing group and the alkyne substrate serve to dictate both

the regio- and enantioselectivity.

Introduction

Biaryls are prominent linkages in numerous natural products,

and they are also prevalent structural motifs in privileged ligands

in a large number of catalytic reactions.[1] Consequently,

increasing efforts have been devoted to asymmetric synthesis of

biaryls.[2] While atropoisomeric biaryls can be efficiently accessed

by metal catalysis using various transition meals,[3] from the

perspective of atom- and step-economy, C-H bond activation

offers an attractive strategy for construction of value-added

organics, including atropoisomeric biaryls.[4,5] In this regard, two

general strategies are known for biaryl synthesis.[5] C-H arylation

of arenes using aryl halides,[6a,b] aryl boron reagents,[6c] quinone

diazides,[6d,e] and ortho-nucleophile-substituted alkynes[7] as

arylating reagents provides direct access to atropoisomeric

biaryls (Scheme 1a). Alternatively, dynamic kinetic

transformations of arenes serve as a common strategy to access

biaryls by locking a preformed axis via introduction of an ortho

functional group (Scheme 1b).[8] One notable example was

recently reported by Wang in Rh(III)-catalyzed asymmetric

synthesis of biaryls via [2+2+2] annulation of amides with two

alkynes as a result of twofold C-H activation.[9] Despite increasing

reports of asymmetric C-H activation catalyzed by chiral Rh(III)

cyclopentadienyls,[4d,10] examples of atroposelective synthesis of

biaryls remain limited.[6d,e,7a,9]

Scheme 1. Atroposelective Synthesis of Biaryls via C-H Activation

Axial chirality can be delivered by restricting conformation of the

coupling partner using a nascent arene ring generated via

annulation with the adjacent bond (Scheme 1c). This strategy

differs from that in Scheme 1b in that the biaryl axis in the product

originates from a C-C bond of the coupling partner instead of the

arene. Alkynes are typical -coupling partners, and rhodium(III)-

catalyzed C-H activation-[n+2] annulation of alkynes has allowed

direct construction of a diverse array of fused (hetero)arenes.[11]

Although alkynes[12,13] have been previously employed in

Rh(III)/Ir(III)-catalyzed asymmetric C-H activation, they are mostly

limited to (oxidative) [3+2] annulation or arene desymmetrization,

in which reductive elimination generally constitutes the stereo-

determining as well as the product-forming step. We rationalized

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that migratory insertion of the Rh-C(aryl) bond into the alkyne is

stereo-determining in our design, affording an atropomerically

stable biaryl-like rhodacyclic intermediate that eventually leads to

biaryl products following the annulation with retention of axial

chirality (Scheme 1c). This stereo-determining insertion have

been elegantly exemplified by Tan and Liu in Ni(0)-oxazoline

catalyzed asymmetric [4+2] coupling of triazinones and

chloroalkyl-substituted alkynes by way of N-N cleavage.[14] In

2018, the group of Antonchick and Waldmann reported Rh(III)-

catalyzed intramolecular C-H activation of alkyne-tethered N-

alkoxylbenzamides for enantioselective synthesis of 4-

arylisoquinolones bearing a specific alcohol tail (Scheme 1c,

top).[13] Despite the great advances, the ortho position of the

benzamide substrate needs to be blocked to ensure high

enantioselectivity and reactivity. The intramolecularity of their

system also circumvented and simplified the important issue of

regioselectivity with respect to both C-H activation and alkyne

insertion. In general, the enantioselectivity of intramolecular C-H

functionalization reactions seems relatively easily controlled. [13,15]

The demand for structurally diverse chiral biaryls as functional

molecules and ready availability of arenes and alkynes in

separate entities call for asymmetric biaryl synthesis via

intermolecular C-H activation. Despite the design in Scheme 1c,

the following challenges should be properly addressed: (1) the

alkyne and should be judiciously selected to ensure

regioselectivity of alkyne insertion; (2) the enantioselectivity of the

alkyne insertion needs to be well controlled; and (3) the directing

group should be tightly bound to the Rh in the 7-memebered

rhodacycle to ensure atropomeric stability and subsequent

chirality transfer. This in turn requires a suitable chiral Rh(III)

catalyst. As a continuation of our investigation of Rh(III)-catalyzed

asymmetric C-H activation of arenes, we now report highly regio-

(if applicable) and enantioselective synthesis of chiral

isoquinolones via annulation of benzamides with both

symmetrical and nonsymmetrical alkynes.

Results and Discussion

The intermolecular reaction of benzamide bearing an oxidizing

N-O group[11b] and a 2-substituted 1-alkynylnaphthalene was

optimized using the (R)-Rh-1 catalyst in the presence of a

catalytic amount of AgOAc in MeOH (Table 1). It was found that

the 2-OMOM-substituted naphthalene-alkyne coupled with N-

methoxy benzamide to afford the desired biaryl in moderate yield

and enantioselectivity (entry 1). Essentially no improvement was

made when an N-OEt, -OBoc, or -OBz group was used (entries

2-4). As expected, moving to N-OPiv benzamide (1a) resulted in

slight increase of the enantioselectivity (entry 5), which was

further improved when the temperature was lowered to 0 oC (entry

7). No further enhancement of enantioselectivity was made until

the Rh-3 catalyst was used (87% ee, entry 9). The 2-substituent

in the naphthalene ring had profound impact on the

enantioselectivity under the optimal conditions. Gratifyingly, the

coupling of 2-OBn-substituted naphthalene (2a) afforded the

corresponding product in 82% isolated yield and 94% ee (entry

10). In contrast, poor or no enantioselectivity was observed when

a -OH, -OMe, or -OAc group was present. Removal of the 2-

substituent also resulted in poor regio- and enantioselectivity and

a regioisomeric mixture has been obtained for the reaction of 2-

OH and 2-OMe substituted alkynes (Supporting Information)..

Table 1. Optimization Studies of Atroposelective Annulation[a,b]

Entry R R’ Cat. T [oC]

Yield [%]

ee [%]

1 Me MOM Rh-1 28 56 44

2 Et MOM Rh-1 28 <5 nd

3 Boc MOM Rh-1 28 48 4

4 Bz MOM Rh-1 28 78 45

5 Piv MOM Rh-1 28 75 48

6 Piv MOM Rh-1 0 67 55

7 Piv MOM Rh-2 0 56 26

8 Piv MOM Rh-3 0 79 87

9 Piv MOM Rh-3 -10 68 87

10 Piv Bn Rh-3 0 82 94

11 Piv H Rh-1 28 87 26[c]

12 Piv Me Rh-1 28 69 22[d]

13 Piv Ac Rh-1 28 85 7

[a] Reaction Conditions: amide (0.1 mmol), alkyne (0.12 mmol), chiral Rh(III)

catalyst (3 mol%), AgOAc (0.3 equiv), and PivOH (0.2 mmol) in MeOH (1 mL)

at 28 oC (24 h) or a lower temperature (72 h), isolated yield, > 20:1 unless stated.

[b] The ee was determined by HPLC using a chiral stationary phase. [c] r.r. =

2.5:1/ [d] r.r. = 7.7:1.

The scope of this atroposelective annulation system was

explored after the optimzation studies. The scope of the

benzamide was examined using 2-OBn-substituted alkyne (2a) as

coupling partner (Scheme 2). Benzamides bearing a diverse array

of electron-donating, -withdrawing, and halogen groups at the

para-position all coupled in consistently excellent

enantioselectivity (3ba-3ka, 93-99% ee), and the reaction was

readily scaled up to 1 mmol (3aa and 3ba). Consistently excellent

enantioselectivity was also attained for several meta-substituted

benzamides(3la-3na), and the C-H functionalization occurred at

the less hindered ortho site (>20:1 r.r.). ortho-Fluoro and -oxygen-

functionalized benzamides also proved viable (products 3oa and

3ra), with comparable reactivity and enantioselectivity (89-93%

ee). Significantly, the amide substrate was extended to heteroaryl

carboxamides (3pa and 3qa). In particular, the coupling of 3-

thiophenecarboxamide underwent selective C(2)-H annulation in

94% ee (3pa). In all cases, the alkyne insertion is regiospecific,

and the regiochemistry stays complementary to that in Tan and

Liu’s report.[14]

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Scheme 2. Scope of amides in asymmetric [4+2] annulation.[a,b] [a] Reaction

conditions: amide 1 (0.1 mmol), alkyne 2 (1.2 equiv), Rh-3 (3 mol%), AgOAc

(0.3 equiv), and PivOH (2.0 equiv) in MeOH (1 mL) at 0 °C for 72 h. [b] Isolated

yield. [c] 1 mmol scale. [d] r.t.

We next explored the scope of the alkyne using benzamide 1a

as an arene (Scheme 3). The absolute configuration of product

3ab (CCDC1978297) was determined by X-ray crystallography.

Extension of the naphthalene ring to other O-protected (-OCbz

and -OMs) 2-naphthols proved successful (3ac and 3ad). The

substate was not limited to protected naphthols; naphthalenes

bearing 2-phenyl (3ae) and 2-CH2OAc (3af) groups were fully

tolerated, and the former rendered excellent enantioselectivity.

The scope with respect to the alkyne terminus was then examined.

Phenylacetylenes bearing a large range of electron-donating, -

withdrawing, and halogen groups at different positions of the

benzene ring were fully compatible, affording 3ag-3an in 92-95%

ee. The alkyne terminus was further extended to 2-thienyl (3ao),

-cyclopropyl (3ap), and -alkyl (3aq), although the latter was

isolated in relatively lower enantioselectivity. Moreover, variations

of substituents at the 3-, 6-, and 7- positions of the naphthalene

ring allowed smooth isolation of products 3ar-3au in acceptable

yield and high enantioselectivity. The sterically hindered

naphthalene ring in the alkyne was further smoothly extend to an

indolyl (3av) and to a 2,6-disubstituted phenyl (3aw), although the

enantioselectivity was moderate for the latter. In contrast, a nitro-

substituted alkyne failed to undergo any coupling (3ax).

Scheme 3. Scope of alkynes in asymmetric [4+2] annulation.[a] [a] See Scheme

2 for reaction conditions. [b] 1 mmol scale.

To better explore the generality of alkyne substrates, we next

moved to sterically hindered diarylacetylenes that are devoid of a

naphthalene moiety. Symmetrically substituted alkynes such as

di[(2-phenyl)phenyl]acetylene (4a) were examined to simplify the

regioselectivity. N-methoxybenzamide turned out to be the

optimal benzamide substrate when catalyzed by the Rh-1 catalyst

in the presence of NaOAc as a base at 10 oC (see Table S2 in the

Supporting Information), which delivered isoquinolone 5aa in 90%

isolated yield and 89% ee (Scheme 4). In contrast to the high

efficiency of the Rh-3 catalyst in the coupling of 1-

alkynylnaphthlenes, poor efficiency was observed when it was

used for the coupling of these symmetrical alkynes. The scope of

the benzamide was briefly explored at 5 or 10 oC. Benzamides

bearing diversified electron-donating and -withdrawing

substituents at the para position all coupled smoothly with 4a,

affording products 5aa-5ga in good yields and 88-99% ee. Thus,

the reaction enantioselectivity seems insensitive to electronic

perturbation of the benzamide substrate. The presence of meta

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Br group was also tolerated. The reaction also tolerated an ortho

Me group, and the product (5ia) were obtained in 84% ee. In

addition, the arene substrate has been extended to thiophene

rings (5ja), although the enantioselectivity tends to be slightly

lower. The conformational stability of product 5aa has been

examined and essentially no decay of enantiopurity was observed

when a sample was heated at 80 oC for 12 h. In the 1H and 13C

NMR spectra of most products, broadened signals have been

detected. This is likely due to partially hindered rotation of the C-

aryl bond that is proximal to the NH group.

Scheme 4. Scope of benzamides in asymmetric [4+2] annulation with a

symmetrical alkyne.[a,b] [a] Reaction conditions: N-methoxy benzamide (0.1

mmol), alkyne 4a (1.1 equiv), (R)-Rh-1 (4 mol%), and NaOAc (2 equiv) in MeOH

(2 mL) at 5 (Conditions B) or 10 °C (Conditions A) for 72 h under air. [b] Isolated

yield.

The scope of the symmetrical alkynes was next briefly explored

Scheme 5). Alkynes with the biphenyl group functionalized by

electron-donating (OMe) and halogen (Cl) group at the para and

ortho positions of the distal phenyl ring all underwent smooth

coupling with N-methoxy para-methoxybenamide at 5 oC,

affording products 5ab-5ad in good yield and 88-92% ee.

Variation of several substituents (F, OMe, and Me) in the proximal

phenyl ring of the biphenyl unit was also well tolerated (5ae-5ag,

84-99% ee). Thus, such para substituents seem to have strong

influence on the enantioselectivity, and an electron-donating

group tends to give higher enantioselectivity. Besides, di(o-

tolyl)acetylene that bears two ortho-methyl groups was also viable

for this coupling, affording product 5ah in excellent yield and the

absolute configuration was further determined by X-ray

crystallography (CCDC 1993100).

Synthetic applications of products of both series have been

demonstrated (Scheme 6). Deprotection of the OBn group of 3aa

afforded 2-naphthol 6 in 93% yield. Treatment of 3aa with

MeI/Cs2CO3 gave the N-methylation product 7 in excellent yield.

O-Triflation (8) of the NH isoquinolone with Tf2O followed by

Suzuki coupling with p-TolB(OH)2 afforded product 9 in high yield.

To take advantage of the pendent phenyl group in product 5,

oxidative C-N cyclization using PhI(OAc)2 as an oxidant under

palladium catalysis[16] afforded annulated isoquinolones 10a, 10c,

and 10f in high yield and 86-92% ee. With their conformational

rigidity, no signal broadening was observed in the NMR spectra

of these annulated products. In all cases, only slight erosion of

enantiopurity was detected.

Scheme 5. Scope of symmetric alkynes in enantioselective [4+2] annulation

with a benzamide.[a,b] [a] Reaction conditions: N-methoxy benzamide (0.1 mmol),

alkyne (1.1 equiv), Rh-1 (4 mol%), and NaOAc (2 equiv) in MeOH (2 mL) at 5

for 72 h under air. [b] Isolated yield. PMP = para-methoxphenyl

Scheme 6. Synthetic Applications of a Coupled Product.

The photophysical properties of five products were briefly

investigated. The absorption band of these products ranges from

ca. 280 to 425 nm (Figure 1), which can be ascribed to the

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localized π−π* transition or charge-transfer transition. These

compounds exhibit deep blue to sky blue emission. The

fluorescent emission maxima appeared in a range of 405-451 nm

(Table 2), with a quantum yield up to 0.39 (product 3aj). These

results may indicate their potentiality for applications as

photoelectronic materials.

Figure 1. [a] Normalized absorption and [b] emission spectra of 3ia, 3ka, 3pa,

3fa, and 3aj in DCM (1 × 10−5 M).

Table 2. Photophysical Properties of Selected Products (1 × 10−5 M in DCM).

Compound abs[a] (nm) em

[b] (nm) F[c]

3ia 297, 334 (sh) 405 0.02

3ka 297, 367, 388

(sh)

445 0.15

3pa 282, 297, 334 420 0.03

3fa 298, 337(sh) 420 0.10

3aj 296 (sh), 326,

335

451 0.39

[a] Absorption maxima. [b] Fluorescent emission maxima. [c] Absolute quantum

yields (determined with an integrating sphere system).

Several experiments have been carried out to explore the

reaction mechanism. Stoichiometric C-H activation of N-OPiv

benzamide with Rh-1 in the presence of AgOAc followed by

addition of PPh3 allowed isolated of rhodacycle 11 in high yield

(Scheme 7a).[17, 18] Complex 11 was characterized by NMR

spectroscopy and X-ray crystallography (CCDC1978298). In the

crystal structure, the less hindered benzene ring of the benzamide

is disposed toward the chiral ligand for minimized steric

interactions, which sets up a chiral environment for the incoming

alkyne (vide infra).[10] Complex 11 is catalytically active for the

coupling of 1a and 2a (42% yield, 60% ee, see Supporting

Information). This C-H activation process was further studied by

KIE measurements of the coupling of N-OPiv benzamide

(Scheme 7b), and the kH/kD value of 2.5 at a low conversion

suggests that the C-H cleavage is probably involved in the

turnover-limiting process.

The regio- and enantioselective outcomes of this coupling

system are rationalized in Scheme 7c. The steric bias between

the arene and the amide directing groups results in categorical

orientation of the ligated DG-arene upon cyclometalation.

Subsequently, the alkyne substrate approaches with the

naphthalene ring pointed backward and the OR’ group upward

(intermediate A).[10] This leads to minimized steric repulsion

between the naphthalene ring and the N-OPiv directing group,

which eventually leads to the (R)-product. Indeed, this model also

accounts for the observed nearly racemic products when 2-OH

and 2-OMe-substituted naphthalenes were used. Analogously,

introduction of a 7-Ph or 7-Me group increases the steric

interactions between the naphthalene ring and the amide DG in

A, leading to attenuated enantioselectivity (3at, 3au). The

unobserved regioselectivity of that corresponds to frontward

orientation of the naphthalene ring during alkyne insertion is

disfavored by steric repulsion (intermediates C and D).

Analogously, in the case of the coupling of N-methoxy

benzamides and symmetrical alkynes (Scheme 7d), the

cyclorhodated intermediate undergoes alkyne coordination with

both ortho aryl groups in the alkyne sticking upward for minimized

steric interactions toward subsequent migratory insertion of the

Rh-aryl bond (E). This also eventually leads to the (R) configured

product.

Scheme 7. Mechanistic Studies and Rationale of the Reaction Selectivities (Si

= TIPS, R = Piv).

Conclusion

In summary, we have realized atroposelective synthesis of NH

isoquinolones via Rh(III)-catalyzed C-H activation of benzamides

and [4+2] annulation with sterically hindered alkynes with different

structural platforms such as 1-alkynylnaphthalenes and

symmetrical diarylalkynes. In contrast to previously adopted

strategies in asymmetric biaryl synthesis via C-H activation using

alkynes, dynamic kinetic transformation of the alkyne is fulfilled as

a rarely explored strategy, with alkyne insertion being

stereodiscriminant. The coupling system is highly regio- and

enantioselective, and a broad scope of alkynes as well as

carboxamides has been defined. The steric interactions between

the amide directing group and the alkyne substrate serve to

dictate both the regio- and enantioselectivity. Synthetic

applications and photophysical properties of selected products

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have been explored. Future studies will be directed to asymmetric

synthesis of biayls by other C-H activation strategies for delivering

complex molecular scaffolds with functional applications.

Acknowledgements

Financial support from the NSFC (21525208) is acknowledged.

We thank Dr. Huaming Sun, Dr. Lingheng Kong, Xi Han, Tingting

Qiu, Shuang Yang, Junjie Ma, and Huan Gao for preparation of

some substrates.

Keywords: axial chirality • asymmetric C-H activation • rhodium

• amide • alkyne

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2890.

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Rh(III)-Catalyzed Atroposelective Synthesis of Biaryls via C-H Activation and Intermolecular

Coupling with Sterically Hindered Alkynes

Dr. F. Wang, Dr. Z. Qi, Y. Zhao, S. Zhai, Dr. G. Zheng, R. Mi, Dr. Z. Huang, Dr. X. Zhu, Prof. Dr. X. He, Prof. Dr. X. Li*

Rhodium(III)-catalyzed atroposelective synthesis of biaryls has been realized via intermolecular annulation of benzamides with

symmetric and nonsymmetric sterically hindered alkynes. The reaction proceeded via C-H activation and dynamic kinetic transformation

of the alkyne with regiospecificity and excellent enantioselectivity.

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