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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: [email protected]
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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RESEARCH ARTICLE
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RESEARCH ARTICLE
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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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