Rhodium(III)-Catalyzed Direct C-H Arylation of Various Acyclic Enamides with Arylsilanes

Article abstract of DOI:10.1021/acs.orglett.0c03578

The stereoselective β-C(sp2)-H arylation of various acyclic enamides with arylsilanes via Rh(III)-catalyzed cross-coupling reaction was illustrated. The methodology was characterized by extraordinary efficacy and stereoselectivity, a wide scope of substrates, good functional group tolerance, and the adoption of environmentally friendly arylsilanes. The utility of this present method was evidenced by the gram-scale synthesis and further elaboration of the product. In addition, Rh(III)-catalyzed C-H activation is considered to be the critical step in the reaction mechanism.

Full text of DOI:10.1021/acs.orglett.0c03578

pubs.acs.org/OrgLett
Letter
Rhodium(III)-Catalyzed Direct C−H Arylation of Various Acyclic
Enamides with Arylsilanes
Xiaolan Li, Kai Sun, Wenjuan Shen, Yong Zhang, Ming-Zhu Lu, Xuzhong Luo, and Haiqing Luo*
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ABSTRACT: The stereoselective β-C(sp2)−H arylation of various acyclic enamides with arylsilanes via Rh(III)-catalyzed cross-
coupling reaction was illustrated. The methodology was characterized by extraordinary efficacy and stereoselectivity, a wide scope of
substrates, good functional group tolerance, and the adoption of environmentally friendly arylsilanes. The utility of this present
method was evidenced by the gram-scale synthesis and further elaboration of the product. In addition, Rh(III)-catalyzed C−H
activation is considered to be the critical step in the reaction mechanism.
Scheme 1. Strategies for the Direct C−H Arylation of
namides are widely used as building blocks and efficient
Eintermediates in organic synthesis, which could undergo
diverse synthetic transformations to expedite synthesis of
bioactive molecules and drugs.1 Accordingly, the highly
regioselective and stereoselective functionalization of enamides
has aroused great concern in the field of synthetic organic
chemistry.2 Recently, the direct functionalization of enamides
via olefinic β-C(sp2)−H bond activation has attracted
immense attention. A variety of direct C−H functionalization
reactions such as alkylation,3 allylation,4 alkynylation,5
trifluoromethylation,6 acylation,7 arylation,8 and sulfonylation9
have been successively realized. Despite the significant
advances achieved in the β-C(sp2)−H arylation of enamides,
these reactions are usually limited to cyclic enamides. In
contrast, very few methods were proposed for the direct C−H
arylation of acyclic enamides. Innovatively, Loh and co-
workers performed the C−H arylation of enamides with simple
arenes using a palladium(II) catalyst in 2012 (Scheme 1a).10
However, the use of a large excess of simple arenes as the aryl
source and the confined substrate scope significantly hampered
the synthetic applications of this transformation, especially the
preparation of synthetically valuable intermediates, drug
molecules, and complicated natural products inappropriate
for overuse. Therefore, the development of a more efficient
and pragmatic method for the C(sp2)−H arylation of acyclic
enamides is highly desirable.
Acyclic Enamides
insensitivity of arylsilanes to various functional groups.11,12
Tremendous effort has been dedicated to silicon-based cross-
coupling reactions through the C−H activation strategy,13
which was recently demonstrated in the chelation-assisted C−
H arylation reactions with arylsilanes catalyzed by diverse
transition metals.14−18 Particularly, the study of rhodium(III)-
catalyzed C−H Hiyama cross-coupling reactions for control-
lable regioselectivity, wide scope of substrates, and extra-
Received: October 27, 2020
Hiyama cross-coupling reaction is an attractive synthetic tool
to forge the C−C bond in modern organic synthesis due to the
conspicuous advantages of organosilicon reagents such as weak
toxicity, good availability, environmental benignity, and
https://dx.doi.org/10.1021/acs.orglett.0c03578
© XXXX American Chemical Society
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A

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Letter
ordinary compatibility of functional groups toward rhodium
catalysis proved the remarkable advantages of the method
compared to the other catalytic systems.19 To realize the
feasibility of C−H arylation of acyclic enamides with user-
friendly arylsilanes and develop our interest in cross-coupling
reactions involving organosilicon reagents,20 the effective
Rh(III)-catalyzed process for the olefinic β-C(sp2)−H
arylation of acyclic enamides with arylsilanes featuring different
steric and electronic traits was demonstrated (Scheme 1b).
Such a silicon-based strategy accommodates a wide scope of
substrates, excellent functional group tolerance, and supply of
the β-C(sp2)−H arylation products up to excellent yields.
Initially, N-benzyl-N-(1-phenylvinyl)acetamide 1a and
triethoxy(phenyl)silane 2a were used as model coupling
partners for optimizing the reaction conditions. A series of
F− sources (3.0 equiv) such as AgF, KF, CsF, and
tetrabutylammonium fluoride (TABF) were employed as the
activation reagent for the C−Si bond in the presence of
[Cp*RhCl2]2 (2.0 mol %) and Cu(OAc)2 (3.0 equiv) in
dioxane at 100 °C (Table 1, entries 1−4). Interestingly, AgF
desired product. However, only trace amounts of the product
3a could be detected by using Cu(OTf)2 or AgOAc. AgF and
CuF2, acting as an the oxidant as well as the F− source, were
used as the additives to test the reaction (Table 1, entries 9−
10). The results revealed that readily available CuF2 was the
best additive for the reaction, which worked as a bifunctional
silane activator and catalyst reoxidant, as introduced by the
Szostak group,15a affording the arylation product 3a in 66%
yield.21 In order to further improve the yield of the product,
different solvents were screened in this study (Table 1, entries
10−18). To our delight, N,N-dimethylformamide (DMF) was
found to be the most suitable for the reaction, and the required
product 3a was obtained with an outstanding yield (92%).
Additionally, this reaction was performed by reducing the
amount of CuF2 (Table 1, entry 19) or 2a (Table 1, entry 20),
which showed a negative effect on the yield. Further study
revealed that a slight drop in the yield of 3a was obtained as
the temperature was lowered to 80 °C (Table 1, entry 21).
Under the optimal reaction conditions, the substrate scope
was amplified using diverse different functionalized acyclic
enamides 1. As summarized in Scheme 2, a series of acyclic
enamides bearing both electron-rich and electron-deficient
groups on the phenyl rings were tolerated, affording the
desired arylated products in good to excellent yields. Most of
the functional groups showed compatibility with the protocol,
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Rhodium(III)-Catalyzed Direct C−H Arylation
entry
oxidant
F− source
solvent
yield (%)
a b
,
of Acyclic Enamides 1 with Trimethoxyphenylsilane 2a
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Ag2CO3
KF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
i-PrOH
DCE
0
0
0
CsF
TABF
AgF
AgF
AgF
AgF
AgF
64
trace
18
47
trace
15
66
28
45
71
32
30
50
22
92
63
86
88
Ag2O
AgOAc
9
AgF (3.0 equiv)
10
11
12
13
14
15
16
17
18
19
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
CuF2 (2.0 equiv)
CuF2 (3.0 equiv)
CuF2 (3.0 equiv)
THF
CH3CN
toluene
DMSO
H2O
DMF
DMF
c
20
d
DMF
DMF
21
a
Reaction conditions: N-benzyl-N-(1-phenylvinyl)acetamide 1a (0.27
mmol), triethoxy(phenyl)silane 2a (0.81 mmol), [Cp*RhCl2]2
(0.0054 mmol, 2 mol %), oxidant (3.0 equiv), F− source (3.0
b
c
d
equiv), solvent (2.0 mL). Isolated yield. 0.54 mmol 2a was used. T
= 80 °C.
was the sole additive suitable for the reaction, delivering the
expected arylated enamide 3a in 64% yield. The X-ray
crystallographic analysis has unambiguously confirmed the Z-
configuration of the product 3a. The H and 13C nuclear
1
a
magnetic resonance (NMR) data of the arylated product were
consistent with the literature report.10 Subsequently, other
oxidants were also optimized (Table 1, entries 5−8). It was
found that Ag2CO3 and Ag2O were both effective in giving the
Reaction conditions: acyclic enamides 1 (0.27 mmol), triethoxy-
(phenyl)silane 2a (0.81 mmol, 3.0 equiv), [Cp*RhCl2]2 (0.0054
mmol, 2 mol %), CuF2 (0.81 mmol, 3.0 equiv), DMF (2.0 mL), at
b
100 °C for 24 h. Isolated yields.
B
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such as methyl (3b), alkyloxy (3c−h), trifluoromethyl (3n),
cyano (3o), nitro(3p), and aryl (3q) groups. Notably, the
reaction showed excellent tolerance to halogen substituents,
except the iodo group on the phenyl rings, as observed in
fluoro (3i), chloro (3j), and bromo (3k−m) compounds.
Besides, the reaction was well tolerated by the incorporation of
para-, ortho-, and meta-methoxy (3c−e) or bromo (3k−m)
substituents on the aromatic rings of the enamides, indicating
the little influence of steric effect on the reactivity. To our
satisfaction, high yields of desired products were obtained by
using substrates with di- or multisubstituents on the phenyl
ring (3f−h). When the aryl substituent was changed to a
methyl group, the product 3r was obtained in 46% yield.
Substrates with different substitutents at the N atom were also
used to test the reaction. To our delight, the desired products
(3s−u) were obtained in excellent yields when using other N-
benzyl and -methyl substituted enamides. In addition, the
replacement of the acetyl group by propionyl functionality
afforded a smooth reaction to yield the desired product in 86%
(3v). Unfortunately, the free enamide (3w) was incompatible
to the current catalytic system.
(naphthalen-1-yl)-silane was the suitable coupling partner to
give the product in 90% yield. Finally, heteroarylsilanes bearing
thiophenyl and pyridinyl structural motifs were also examined,
but only the former was found to show good reactivity toward
the obtainment of the product in a yield of 48% (4p).
To prove the synthetic utility of the strategy, gram-scale C−
H arylation of enamide 1a (1.01 g, 4 mmol) and triethoxy-
(phenyl)silane 2a (2.89 g, 12 mmol) was performed in the
presence of 1 mol % Cp*Rh(III) in 20 mL of DMF (Scheme
4a). We are pleased to find that the reaction proceeded
Scheme 4. Gram-Scale Synthesis of 3a and Its
Transformations
For further evaluation of the substrate scope, a diversity of
arylsilanes with various substituents on the aryl ring were
subjected to the reaction. Initially, the use of trimethoxyphe-
nylsilane afforded the product 3a in 97% yield. As shown in
Scheme 3, the direct arylation of acyclic enamide has shown
smoothly by the use of half the Rh catalyst loading without
compromising the reaction efficiency. Furthermore, Pd/C-
catalyzed hydrogenation of enamide 3a was successfully
conducted, affording the desired benzylamine 5 in 88% yield.
Meanwhile, the C−H arylation product 3a underwent Suzuki
coupling reaction to provide the access to the tetrasubstituted
enamide product 6 in 61% yield (Scheme 4b).
Scheme 3. Rhodium(III)-Catalyzed Direct C−H Arylation
a b
,
of Acyclic Enamide 1a with Various Arylsilanes 2
To understand the relevant reaction mechanism better,
some control experiments were performed using the model
substrates. The ratio of 1.2 between the intermolecular
competitive reactions of 1f and 1i revealed the higher
reactivity of electron-deficient enamides over the electron-
rich ones (Scheme 5a). The deuterium kinetic isotope effect of
Scheme 5. Mechanistic Studies
a
Reaction conditions: N-benzyl-N-(1-phenylvinyl)acetamide 1a (0.27
mmol), arylsilanes 2 (0.81 mmol, 3.0 equiv), [Cp*RhCl2]2 (0.0054
mmol, 2 mol %), CuF2 (0.81 mmol, 3.0 equiv), DMF (2.0 mL), at
b
100 °C for 24 h. Isolated yields.
excellent functional group tolerance, covering both electron-
rich and electron-deficient groups such as alkyl (4b−g),
alkyloxy (4h−j), fluoro (4k), chloro (4l), trifluoromethyl
(4m), and aryl (4n) groups on the phenyl ring. Triethoxyar-
ylsilanes with ortho-, meta-, and para- methyl substituents
tolerated the production of the desired products in comparably
high yields, indicating the inconspicuousness of steric
hindrance on the reaction. Additionally, triethoxy-
the reaction was investigated. The intermolecular competition
reaction of 1a and deuterio-1a with 2a resulted in a kH/kD of
1.25 (Scheme 5b), suggesting the inability of C−H cleavage in
determining the rate of the reaction.
On the basis of experimental findings and former literature
reports,22 a plausible catalytic cycle for this C−H arylation was
C
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Authors
proposed as shown in Scheme 6. The cycle was initiated by the
prior cyclometalation of enamide 1a with the cationic
Xiaolan Li − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China
Scheme 6. Proposed Reaction Mechanism
Kai Sun − Department of Chemistry & Chemical Engineering,
Gannan Normal University, Ganzhou 341000, China
Wenjuan Shen − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China
Yong Zhang − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China; orcid.org/0000-0001-8911-4650
Ming-Zhu Lu − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China; orcid.org/0000-0002-6333-0803
Xuzhong Luo − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China; orcid.org/0000-0002-5719-9407
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03578
Notes
Cp*Rh(III) complex to generate the six-membered rhodacy-
clic intermediate A via C(sp2)−H bond activation. This was
followed by the transmetalation process promoted by the
fluoride anion nucleophilic attack of silicon, resulting in the
formation of Cp*Rh(III)-aryl intermediate B, which led to the
arylated product 3a through reductive elimination. The
catalytic cycle was accomplished by the reoxidation of
Cp*Rh(I) to Cp*Rh(III) using the Cu(II) salt.
In summary, a Cp*Rh(III)-catalyzed, direct arylation of
acyclic enamides via C(sp2)−H bond activation has been
established. The transformation was featured with high
efficiency, excellent stereoselectivity (only Z configuration),
wide scope of substrates, good functional group tolerance, and
utilization of environmentally friendly arylsilanes. The protocol
provides a highly efficient and pragmatic strategy applicable to
the synthesis of diverse arylated acyclic enamide derivatives.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (No. 21762002), the Jiangxi Provincial
Department of Science and Technology Fund
(20192BAB213007), and the Natural Science Foundation of
Jiangsu Province (BK20181066).
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03578.
Experimental details, characterization data, and NMR
spectra (PDF)
Accession Codes
CCDC 2034821 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
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Corresponding Author
(3) (a) Ding, R.; Huang, Z.-D.; Liu, Z.-L.; Wang, T.-X.; Xu, Y.-H.;
Loh, T.-P. Palladium-Catalyzed Cross-Coupling of Enamides with
Sterically Hindered α-Bromocarbonyls. Chem. Commun. 2016, 52,
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Q.; Zhao, K.; Loh, T.-P. Photoredox-Catalyzed Stereoselective
Haiqing Luo − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China; orcid.org/0000-0003-2159-8403;
Email: luohaiq@sina.com
D
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