RhIII-Catalyzed C-H (Het)arylation/Vinylation of N-2,6-Difluoroaryl Acrylamides

Article abstract of DOI:10.1021/acs.orglett.0c03688

RhIII-catalyzed sp2 C-H cross-coupling of acrylamides with organoboron reactants has been accomplished using a commercially available N-2,6-difluoroaryl acrylamide auxiliary. A broad range of aryl and vinyl boronates as well as a variety of heterocyclic boronates with strong coordinating ability can serve as the coupling partners. This transformation proceeds under moderate reaction conditions with excellent functional group tolerance and high regioselectivity.

Full text of DOI:10.1021/acs.orglett.0c03688

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Letter
RhIII-Catalyzed C−H (Het)arylation/Vinylation of N‑2,6-Difluoroaryl
Acrylamides
Huai-Wei Wang,* Yu-Han Qiao, Jia-Xue Wu, Qiu-Ping Wang, Meng-Xin Tian, Yong-Fei Li,
Qing-Xia Yao, Da-Cheng Li, Jian-Min Dou,* and Yi Lu*
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ABSTRACT: RhIII-catalyzed sp2 C−H cross-coupling of acrylamides with organoboron reactants has been accomplished using a
commercially available N-2,6-difluoroaryl acrylamide auxiliary. A broad range of aryl and vinyl boronates as well as a variety of
heterocyclic boronates with strong coordinating ability can serve as the coupling partners. This transformation proceeds under
moderate reaction conditions with excellent functional group tolerance and high regioselectivity.
innamamide derivatives and related substituted dienes
Care renown for the exhibition of fungicidal and biological
activities in agrochemicals as well as their recent specific optical
properties as fluorescent probes in organic materials.1 There-
fore, developing efficient and facile protocols for the
construction of these compounds is highly desirable. Much
effort has been focused on their rapid synthesis from
commercially available raw materials under mild conditions
with high regioselectivity. Over the past several decades,
transition-metal-catalyzed C−H functionalization has demon-
strated great potential in building essential structural motifs in
a simple and atom-economical fashion.2,3 Various metal
catalysts (for instance, Co,4 Ir,5 Pd,6 Fe,7 Cu,8 and Mn9)
have been explored in this capacity via the cross-coupling
reaction between acrylic acid derivatives and organometallic
nucleophiles such as aryl halides, organoborons, or Grignard
reagents. Despite significant progress in these reactions,
heterocycle coupling partners are not compatible.6c The
heteroarylation of acrylamide derivatives could provide an
efficient method for the preparation of diversified heterocyclic
drug molecules.10 However, the strong coordinating ability of
hetercycles can often outcompete substrates in binding the
metal catalysts, resulting in the inhibition of catalytic turnover
in C−H functionalization.
(Scheme 1a).12 Quite recently, Zhu’s group reported a RhIII-
catalyzed C−H functionalization of cycloalkene-1-carboxa-
mides with aryl boronates to synthesize cycloalkaquinolinones
(Scheme 1b).13 Inspired by these pioneering results and our
previous work,14 we demonstrated a facile RhIII-catalyzed sp2
C−H (het)arylation/vinylation of alkenes with boronates
Scheme 1. RhIII-Catalyzed C−C Cross-Coupling between
Acrylamide Derivatives and Organometallic Reagents
Recently, RhIII salt has been developed as an one of the most
effective catalysts to be used for improving the reactivity and
site selectivity of the catalytic systems.11 However, the RhIII-
catalyzed C−H (het)arylation of acrylamide derivatives still
remains rare so far. In 2013, Glorius’ group developed a RhIII-
catalyzed dehydrogenative cross-coupling between alkenes and
arenes affording Z-selective β-arylated acrylamide derivatives
Received: November 6, 2020
Published: January 14, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03688
© 2021 American Chemical Society
Org. Lett. 2021, 23, 656−662
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using weakly coordinating N-2,6-difluoroaryl acrylamides as
directing groups.
We initiated a preliminary investigation by using model
substrate N-2,6-difluoroaryl acrylamide 1a and 4-carbomethox-
yphenylboronic acid pinacolate 2a with [Cp*Rh(MeCN)3]-
(SbF6)2 catalyst (Table 1). Encouragingly, we discovered that
system, the desired product could be obtained in 88% yield
(Table S1, entries 2−10). Unprotected amino acids and
phosphine ligands were also investigated; however, lower yields
were obtained (Table S1, entries 11−16).
To confirm the importance of the N-2,6-difluoroaryl
acrylamides directing group (T), we then investigated the
effect of other auxiliaries (Scheme S1). No reaction occurred
when acrylic acid (T1) and N-methoxyacrylamide (T2) were
applied as the directing groups. Furthermore, the use of the
weakly acidic N-phenylacrylamide (T3) afforded a lower yield
of 67%. The previously reported strongly acidic directing group
(T4) decreased the yield to 56%, which may be due to the
weak stability of the substrate in this catalytic system. The N-
2,6-difluoroaryl acrylamide directing group possesses an
optimal balance of electronic properties and substrate stability
in this system.
a
Table 1. Optimizations of the Model Reaction
b
entry
oxidant
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
Ag2O
K2CO3
Na2CO3
K3PO4
KF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
DCM
THF
MeCN
MeCN
MeCN
MeCN
28
12
NR
13
11
36
15
26
9
20
56
19
8
Having identified the optimal reaction conditions for the
cross-coupling (Table S1, entry 5), we proceeded to investigate
the acrylamide substrate scope using 2a as the coupling reagent
(Scheme 2). Nonactivated acrylate derivatives with alkyl
CsF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
a b
,
Scheme 2. Scope of Acrylamides Substrates
AgF
9
Ag3PO4
AgOTf
AgOPiv
AgOPiv
AgOPiv
AgOPiv
AgOPiv
-
10
11
12
13
14
15
16
17
18
45
66
NR
NR
49
c
d
AgOPiv
AgOPiv
e
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (0.01 mmol), oxidant (0.2 mmol), and base (0.2
mmol) in dry solvent (2 mL), nitrogen atmosphere, 4 h, 60 °C.
b
Yields were calculated from 1H NMR using 1,3,5-trimethoxybenzene
c
d
as the internal standard. AgOPiv(0.3 mmol). Without catalyst.
e
[Cp*RhCl2]2(0.005 mmol)/AgSbF6 (0.02 mmol).
the combination of K2CO3, Ag2CO3, and MeCN facilitated the
desired product 3a in a 28% yield (entry 1). The Z
configuration of the desired product 3a was unambiguously
notarized by nuclear Overhauser effect spectroscopy (NOESY)
(see the Supporting Information) as well as by X-ray
crystallographic studies (CCDC 2017009). Next, we screened
the base additives and found K2CO3 to be optimal (entries 2−
5). Further experiments, including the investigation of various
oxidants and solvents (entries 6−14), showed that a
combination of AgOPiv and K2CO3 gave a 56% yield.
Increasing the amount of AgOPiv to 3 equiv enhanced the
yield to 66% (entry 15). The control experiments without
AgOPiv or the catalyst (entry 16 or 17, respectively) exhibited
no transformation, confirming that both of them were crucial
to this reaction. Additionally, the application of [Cp*RhCl2]2/
AgSbF6 as a cocatalyst decreased the yield to 49% (entry 18).
To further ameliorate the reaction efficiency, we attempted
to screen various ligands, including MPAAs (mono-N-
protected amino acids), which could evidently accelerate the
C−H cleavage step and promote the subsequent cross-
coupling step via potentially regulating the electronic and
steric properties of the catalytic center (Table S1).15 By
introducing N-acetyl-leucine (Ac-leucine) into the reaction
a
Reaction conditions: 1a−1n (0.1 mmol), 2a (0.2 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (0.01 mmol), AgOPiv (0.3 mmol), K2CO3 (0.2
mmol), and N-Ac-leucine (0.02 mmol) in dry MeCN (2 mL),
b
nitrogen atmosphere, 4 h, 60 °C. Isolated yield.
substituents at the α position reacted favorably to provide
the corresponding products in good yields (3b−3f, 72−82%).
For the tested α-aryl acrylamides, the desired products were
obtained in acceptable yields with good tolerance toward
various functional groups at the para- position (3g−3i).
Moreover, the cyclic olefinic substrates readily participated in
this transformation, delivering the corresponding arylated
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products (3j and 3k) in satisfying yields (71 and 66%,
respectively). However, when α,β-dimethyl, α-methyl-β-ethyl,
and α-methyl-β-phenyl acrylamides were subjected to the
reaction system, lower yields were delivered (38−42%). The
steric and electronic effects of the substituents at the β-position
of the vinylic C−H bond may lead to the much lower reactivity
of the substrates (1l−1n).
To further scrutinize the scope of this arylation trans-
formation, various functionalized arylboronic acid pinacol
esters were then evaluated to determine their influence on the
overall reactivity (Scheme 3). In general, this C−H
functionalization methodology was appropriate for a large
range of arylboronic acid pinacol esters bearing electron-rich
and electron-deficient substituents, affording the products in
moderate to excellent yields (60−93%). Arylboronic acid
pinacol esters bearing para- and meta- alkyl groups provided
yields from 60 to 83% (4b−4f). 4-Biphenyl- and phenyl-
boronic acid pinacol esters performed well and gave 82 and
80% yields (4g and 4h), respectively. A variety of electron-
deficient para-substituted substrates, including the halogen,
trifluoromethyl, and nitrile groups, delivered the desired
arylated products in excellent yields (4i−4m, 83−91%).
Notably, the coupling partner containing an acetamide group
could also undergo the transformation smoothly to achieve the
desired product in 75% yield (4n). Moreover, the use of meta-
substituted as well as disubstituted electron-withdrawing
arylboronates was allowed in this protocol to give the yields
from 71 to 93% (4o−4r). Additionally, 2-naphthyl boronate
also delivered the corresponding product in a yield of 82%
(4s).
The successful application of arylboronic acid pinacol esters
inspired us to examine the compatibility of this transformation
to vinylboron reagents. To our delight, the arylation condition
was compatible with various vinylboron reagents in the
reaction of 1a (Scheme 4). Cyclic vinyl boronates as coupling
a b
,
Scheme 3. Scope of Arylation Reagents
a b
,
Scheme 4. Scope of Vinylboron Reagents
a
Reaction conditions: 1a (0.1 mmol), 5a−5f (0.2 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (0.01 mmol), AgOPiv (0.3 mmol), K2CO3 (0.2
mmol), and N-Ac-leucine (0.02 mmol) in dry MeCN (2 mL),
b
nitrogen atmosphere, 4 h, 60 °C. Isolated yield.
partners were also well tolerated in this protocol, which gave
the corresponding arylated products 6a−6c in a 46−63% yield.
Furthermore, heterocyclic alkenyl boronates 5d and 5e gave
the desired functionalized products 6d and 6e in moderate
yields (50 and 56%), respectively. In addition, the
disubstituted vinyl boronate 5f is also suitable for this
transformation.
With our highly efficient auxiliary in hand, we were delighted
to find that the scope of this reaction can be further extended
to the heterocyclic boronates (Scheme 5). In these reactions,
the use of KHCO3 as an alternative to the combination of
K2CO3 and N-Ac-leucine is necessary to ensure higher activity.
Using the weakly coordinating furan and thiophene hetero-
arylboronic acid pinacol esters as the coupling partners, the
desired products were selectively afforded in yields from 52 to
73% (8a−8d). For the strongly coordinating pyridines and 3-
substituted pyridines bearing electron-rich and electron-
deficient groups, the corresponding heteroarylated products
were obtained in a 52−66% yield (8e−8g). For less strongly
coordinating 2-substituted pyridines containing a variety of
electron-withdrawing and electron-donating groups, satisfying
yields (57−81%) of heteroarylated products could be
a
Reaction conditions: 1a (0.1 mmol), 2b−2s (0.2 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (0.01 mmol), AgOPiv (0.3 mmol), K2CO3 (0.2
mmol), and N-Ac-leucine (0.02 mmol) in dry MeCN (2 mL),
b
nitrogen atmosphere, 4 h, 60 °C. Isolated yield.
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a b
,
S2c). To confirm the necessity of the syn-coplanar C−H bond
for activation, we conducted a control experiment using (Z)-N-
(2,6-difluorophenyl)-2-methylbut-2-enamide (1o) as the sub-
strate under optimal conditions (Scheme S2d). No corre-
sponding product was obtained, demonstrating that the syn-
coplanar bond to Rh is necessary for this transformation.
According to the above results and previous reports, a
plausible mechanism for this reaction is illustrated in Scheme
6. Initially, the RhIII catalyst coordinates with amide 1a to give
Scheme 5. Scope of Heteroarylation Reagents
Scheme 6. Proposed Reaction Pathway
a five-membered rhodacycle species 2 via C−H bond
activation. Subsequently, arylboronic acid pinacol esters
coordinated to the RhIII center lead to rhodium species 4.
Next, the process of C−C reductive elimination gives the
arylated product 3a and a RhI species, which could be oxidized
to RhIII via AgOPiv.
a
Reaction conditions: 1a (0.1 mmol), 7a−7n (0.2 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (0.01 mmol), AgOPiv (0.3 mmol), and KHCO3
(0.2 mmol) in dry MeCN (2 mL), nitrogen atmosphere, 4 h, 60 °C.
In conclusion, a RhIII-catalyzed sp2 C−H functionalization of
acrylamide derivatives with organoboron reactants using a
commercially available N-2,6-difluoroaryl acrylamides auxiliary
has been successfully developed. This protocol demonstrates a
broad substrate scope with excellent regioselectivity and
excellent functional group compatibility. The achievement of
heteroarylation could provide a potential application for the
synthesis of heterocyclic drug molecules.
b
Isolated yield.
delivered, exhibiting excellent functional group compatibility
(8h−8n).
Furthermore, treatment of the template reaction on a gram
scale with the reaction time prolonged to 6 h afforded 3a in
81% yield, exhibiting the potential large-scale industrial
application of this protocol. Meanwhile, the arylated product
4b obtained in this transformation could readily remove the
directing group, converting to the corresponding methyl esters
9b. (See the Supporting Information.)
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03688.
A sequence of control experiments has been carried out to
explore the possible mechanism of the transformation. 41%
Deuterium incorporation was observed for 1a using excess
D2O, indicating that C−H activation might involve a reversible
cyclo-metalation process during the reaction (Scheme S2a). A
competitive experiment between 2a and 2b was conducted to
ascertain the electronic preference of the reaction, which
revealed that the electron-deficient coupling partner was more
reactive in this reaction with a ratio of 3.2:1 (Scheme S2b).
Preliminary kinetic isotope effect (KIE) studies gave an
intermolecular KIE value of 2.3, which disclosed that the C−
H activation step might be the rate-determining step (Scheme
X-ray crystallographic data, characterization data, ex-
perimental details, and NMR spectra (PDF)
Accession Codes
CCDC 2017009 (3a), 2017010 (3e), 2017011 (4c) and
2035959 (8g) contain 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: + 44 1223 336033.
659
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AUTHOR INFORMATION
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Corresponding Authors
Huai-Wei Wang − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China;
Email: wanghuaiwei@lcu.edu.cn
Jian-Min Dou − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China; Email: jmdou@
lcu.edu.cn
Yi Lu − Coordination Chemistry Institute, State Key
Laboratory of Coordination Chemistry, School of Chemistry
and Chemical Engineering, Nanjing National Laboratory of
Microstructures, Collaborative Innovation Center of
Advanced Microstructures, Nanjing University, Nanjing
210023, China; orcid.org/0000-0002-8767-7801;
Email: luyi@nju.edu.cn
Authors
Yu-Han Qiao − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Jia-Xue Wu − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Qiu-Ping Wang − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Meng-Xin Tian − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Yong-Fei Li − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Qing-Xia Yao − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Da-Cheng Li − Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, School
of Chemistry and Chemical Engineering, Liaocheng
University, Liaocheng 252000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03688
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21801108 and 21671093), Shandong Provincial Natural
Science Foundation (ZR2019PB001), and Research Fund for
the Doctoral Program of Liaocheng University (318051726)
for financial support.
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