Meta-dehydrogenative alkylation of arenes with ethers, ketones, and esters catalyzed by ruthenium

Article abstract of DOI:10.1021/acs.orglett.0c02698

A meta-dehydrogenative alkylation of arenes with cyclic ethers, ketones, and esters catalyzed by ruthenium is achieved in the presence of a di-tert-butyl peroxide (DTBP) oxidant. Interestingly, when quinoline and isoquinoline are employed as the directing group, or a chain ether as alkylation reagent, the system produces Minisci reaction products. Mechanistic study indicates that meta-dehydrogenative alkylation is a radical process initiated by DTBP with the assistance of a C_Ar-Ru bond ortho/para-directing effect.

Full text of DOI:10.1021/acs.orglett.0c02698

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Letter
Meta-Dehydrogenative Alkylation of Arenes with Ethers, Ketones,
and Esters Catalyzed by Ruthenium
Gang Li,* Yuan Gao, Chunqi Jia, Shichong Wang, Bingxu Yan, Yu Fang, and Suling Yang
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ABSTRACT: A meta-dehydrogenative alkylation of arenes with cyclic
ethers, ketones, and esters catalyzed by ruthenium is achieved in the
presence of a di-tert-butyl peroxide (DTBP) oxidant. Interestingly, when
quinoline and isoquinoline are employed as the directing group, or a chain
ether as alkylation reagent, the system produces Minisci reaction products.
Mechanistic study indicates that meta-dehydrogenative alkylation is a
radical process initiated by DTBP with the assistance of a CAr−Ru bond
ortho/para-directing effect.
ketones, and esters in the presence of a di-tert-butyl peroxide
fficient and convenient construction of a C−C bond is
Eone of the most important goals for organic chemists. (DTBP) oxidant.
Based on the radical mechanism for Ru-catalyzed meta-CAr−
Compared with the traditional cross-coupling reaction using a
prefunctionalized organic metal or organic halogen as a
substrate to construct the C−C bond, cross-dehydrogenative
coupling (CDC) has obvious advantages in atom efficiency
and synthesis step efficiency.1 With the development of
transition metal (TM) catalyzed C−H bond functionalization
in recent years, many ortho-position cross-dehydrogenative
coupling reactions have been realized with the assistance of a
directing group and have been used in organic synthesis.2
Recently, breakthroughs have also been made in the TM-
catalyzed meta-selective CAr−H bond functionalization
through various ingenious strategies such as the use of steric
and electronic effects,3 traceless directing groups,4 end-on
templates,5 norbornene ferry boats,6 and copper-catalyzed
meta-CAr−H bond arylation.7 In these transformations, the
coupling reagents are usually prefunctionalized organic metals
or organic halogens. However, meta-CAr−H bond cross-
dehydrogenation coupling is still scarce.8
Ruthenium has unique catalytic properties. It can not only
promote the ortho-CAr−H bond functionaliza-tion9 but also
the remote (meta or para) CAr−H bond functionalization.
Under the catalysis of ruthenium, meta-CAr−H bond alkylation
using alkyl halide as reagent,10 nitration,11 sulfonation,12
halogenation,13 difluoromethylation,14 carboxymethylation,15
and benzoylation16 have been realized. Notably, Zhao and Shi,
respectively, reported Ru-catalyzed meta-position dehydrogen-
ative benzylation and alkylation of arenes with toluene and
cycloalkane.17 These are efficient methods to introduce a
functional group at the meta-position of an aromatic ring.
Ethers, ketones, and esters are all common and cheap
multifunctional organic molecules, and they are used widely
as solvents in the chemical industry. Herein, we achieved a
meta-cross-dehydrogenation coupling of arenes with ethers,
H bond functionalization, we proposed that an ether, which
can easily form an alkyl radical in the presence of peroxide,18
should be a good coupling reagent in the process. To achieve
Ru-catalyzed meta-selective dehydrogenative alkylation of
arenes with ethers, commercially available 2-phenylpyridine
was selected as a typical substrate, and the common ether
tetrahydrofuran (THF) was both the alkylation reagent and
solvent to screen and optimize the reaction conditions. The
reaction was conducted at 120 °C for 12 h in a thick-walled
Schlenk reaction tube in N2 atmosphere, as shown in Table 1.
Employing [Ru(p-cymene)Cl2]2 as a catalyst and DTBP as the
radical initiator and oxidant, the desired product was obtained
in a moderate yield, and a large amount of starting material
remained (entry 1). To increase the reaction yield, various
promoters were added into the standard reaction system. To
our delight, when K3PO4 was used as a promoter (entry 2), the
desired product was obtained in a good yield, and the starting
material was almost completely consumed. Other promoters,
such as Na3PO4, K2HPO4, Cu(OAc)2, KPF6, and AgSbF6, were
unable to improve the yield, and even inhibited the reaction
(entries 3−7). An examination of the oxidant indicated that a
small amount of the desired product was obtained when using
TBHP and DCP (entries 8 and 9), while BPO, AgNO3, and
PhI(OAc)2 were unfavorable for the alkylation (entries 10−
12). When Ru(p-cymene)(OAc)2 was used as the catalyst in
Received: August 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02698
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Table 1. Conditions Screening for Meta-Dehydrogenative
Alkylation of Arenes with Ethers
Scheme 1. Scope of the Meta-Dehydrogenative Alkylation of
Arenes with Ethers
a
a
entry
catalyst
oxidant
additive
yield (%)
1
2
3
4
5
6
7
8
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)(OAc)2]
RuCl3
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCP
48
73
22
0
0
0
31
13
28
0
0
0
34
0
0
0
0
K3PO4
Na3PO4
K2HPO4
Cu(OAc)2
KPF6
AgSbF6
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
9
10
11
12
13
14
15
16
17
BPO
AgNO3
PhI(OAc)2
DTBP
DTBP
DTBP
DTBP
DTBP
Ru(PPh)3Cl2
Ru3(CO)12
a
DTBP: di-tert-butyl peroxide; TBHP: tert-butyl hydroperoxide;
DCP: dicumyl peroxide; BPO: benzoyl peroxide.
the reaction, the target product was obtained in a lower yield
than when [Ru(p-cymene)Cl2]2 was used as the catalyst (entry
13). The product was not obtained when Ru3(CO)12,
Ru(PPh3)3Cl2, RuCl3, and no catalyst were added into the
system (entries 14−17).
a
Reaction conditions: 1 (0.2 mmol), ether (0.5 mL), DTBP (1.2
equiv), [Ru(p-cymene)Cl2]2 (5 mol %), K3PO4 (20 mol %), N2, 120
°C, 12 h. Isolated yield. DTBP (3 equiv). Ru(2,2′-bipyridine)3Cl2
(10 mol %).
b
c
With the optimized conditions in hand, various 2-phenyl-
pyridine analogues and ethers were selected as reactants to
examine the scope and limitations of the Ru-catalyzed meta-
selective dehydrogenative alkylation of arenes with ethers, as
shown in Scheme 1. First, 2-phenylpyridine analogues bearing
different substituent groups at the phenyl ring were employed
as reactants. The 2-phenylpyridines with an alkyl and aryl
group were suitable reactants for the meta-dehydrogenative
alkylation and gave the desired products in moderate yield
(3ba, 3ca). Halogens (Cl, Br, F) could also be tolerated in the
dehydrogenative alkylation (3da−3fa), which provided a good
opportunity to further introduce other functional groups in the
aromatic ring. The experimental results showed that both 2-(4-
methoxyphenyl)pyridine bearing a strong electron-donating
substituent (−OCH3, 3ga) and 2-(4-(trifluoromethyl)phenyl)-
pyridine bearing a strong electron-withdrawing (−CF3, 3ha)
functional group were suitable reactants in the process,
although the electron-withdrawing group was unfavorable for
the transformation. The directing group survey indicated that
other nitrogen-containing groups, such as pyridines bearing a
methyl group (3ia, 3ja), pyrimidine (3ka), and pyrazole (3la),
were all effective assistant groups to give the corresponding
target products in moderate to good yields. Two products (7-
(tetrahydrofuran-2-yl)benzo[h]quinoline and 9-(tetrahydrofur-
an-2-yl)benzo[h]quinoline) were obtained at the same time
when a benzo[h]quinoline with two different meta-positions
was selected as the substrate (3ma, 3na). Remarkably, the
meta-selective dehydrogenative alkylation of a naphthalene ring
with ethers was also able to proceed smoothly under standard
conditions (3oa). When the amount of DTBP was increased in
the system, di-meta-selective dehydrogenative alkylation
products were mainly obtained under the standard conditions
(3pa−3ra). The screening of the ether indicated that other
cyclic ethers, such as tetrahydropyran (3ab), p-dioxane (3ac),
and 2, 3-dihydrobenzofuran (3ad), were effective alkylation
reagents in the process. Interestingly, when quinoline and
isoquinoline were employed as the directing group (3sa, 3ta),
or a chain ether as the alkylation reagent (3ae), the products
were not the desired meta-dehydrogenative alkylation product
but rather the Minisci reaction product, where the alkylation
took place on the directing group.19
Moreover, additional experiments showed that a function-
alized ketone and ester were also effective coupling reagents for
the ruthenium-catalyzed meta-dehydrogenative alkylation of
arenes under similar conditions (Scheme 2), and they provided
products with diverse reactivity.20 Unexpectedly, when an ester
was employed as a reactant, the reaction site was a methylene
and not the methyl group connected with a carbonyl group.
The ruthenium catalyzed meta-dehydrogenative alkylation of
arenes with ethers proceeded smoothly in the gram-scale
experiment, as shown in Scheme 3. The target product was
afforded in moderate yield by increasing only the reaction time.
This development provides a convenient and efficient method
to introduce cyclic ethers to the meta-position of an aromatic
ring.
Furthermore, designed experiments were carried out to
explore the mechanism of the meta-dehydrogenative alkylation
B
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Scheme 2. Acetone and Ester for Ru-Catalyzed Meta-
Scheme 4. Designed Experiment
Dehydrogenative Alkylation of Arenes
Scheme 3. Gram-Scale Experiment
of arenes with ethers catalyzed by ruthenium, as shown
Scheme 4. First, when 2-(2,6-dimethylphenyl)pyridine bearing
a methyl group at the two ortho sites on the phenyl ring was
used, the meta-dehydrogenative alkylation did not proceed
under the standard conditions (Scheme 4, a). This result
indicated that ortho-CAr−H cycloruthenation is a necessary
step to realize the meta-CAr−H functionalization. Second,
when the five-membered ruthenacycle intermediate I, which
was synthesized through the reaction of 2-phenypyridine with
[Ru(p-cymene)Cl2]2 in CH2Cl2 at room temperature for 18 h,
was employed as the substrate and catalyst in the trans-
formation, the target product was afforded in a yield of 56%
(Scheme 4, b). This implied that the five-membered
ruthenacycle intermediate I is a key active species in the
dehydrogenative alkylation. Third, when 10 equiv of D2O was
added into the standard reaction, an obvious H/D exchange at
the ortho-position directing group was observed in the residue
material and product (Scheme 4, c). This phenomenon
showed that ortho-CAr−H ruthenation with the assistance of
a directing group is reversible, whereas meta-CAr−H function-
alization is not. Fourth, the target product was not obtained
when free radical inhibitors (TEMPO or BQ) were added into
the reaction system (Scheme 4, d), which further supported
that the Ru-catalyzed meta-CAr−H functionalization is a classic
radical process. Fifth, the electrical effect was significant in the
dehydrogenative alkylation. An electron-rich substrate was
more favorable than an electron-deficient substrate in the
process (Scheme 4, e). The product 3ga or 3ba was mainly
obtained when a competitive reaction of electron-rich arenes
(−CH3 or −OCH3) and electron-deficient arenes (−CF3)
bearing an electron-withdrawing group was carried out in one
pot, respectively.
Scheme 5. Proposed Reaction Mechanism
reacted with [Ru(p-cymene)Cl2]2 to provide five-membered
ruthenacycle complex A via pyridyl-assisted ortho-CAr-H
ruthenation. The α-H abstraction of THF produced an ether
radical in the presence of DTBP. In the CAr−Ru bond ortho/
para-directing effect assistance, the ether radical attacked the
meta-position of the pyridyl directing group to give active
complex B, followed by deprotonation−aromatization to afford
stable complex C. Finally, complex C exchanged a ligand with
According to our experimental results and the pioneering
literature,10−16 a plausible mechanism was proposed to explain
the ruthenium-catalyzed meta-dehydrogenative alkylation of
arenes with ethers, as is shown in Scheme 5. The substrate 1a
C
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reactant 1a to give the alkylated product and the active
complex A for the next cycle.
TIT035), Henan Joint Fund of National Natural Science
Foundation of China (U1804188), for financial support of this
work.
In conclusion, we have developed a ruthenium-catalyzed
meta-dehydrogenative alkylation of arenes with ethers, ketones,
and esters employing DTBP as the oxidant and initiator.
Experimental studies showed that this alkylation is a radical
process initiated by DTBP with the assistance of a CAr−Ru
bond ortho/para-directing effect. Furthermore, the application
of the Ru-catalyzed meta-dehydrogenative alkylation of arenes
with ethers in synthetic chemistry is currently underway.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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Experimental procedures, references, and H and 13C
NMR spectra (PDF)
1
AUTHOR INFORMATION
Corresponding Author
■
Gang Li − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P.R. China; orcid.org/0000-0002-1609-449X;
Email: ligang@aynu.edu.cn
Authors
Yuan Gao − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P.R. China
Chunqi Jia − Engineering Research Center of Molecular Medicine
of Ministry of Education, Key Laboratory of Fujian Molecular
Medicine, Key Laboratory of Xiamen Marine and Gene Drugs,
School of Biomedical Sciences, Huaqiao University, Xiamen
361021, P.R. China
Shichong Wang − College of Chemistry and Chemical
Engineering, Henan Province Key Laboratory of New
Optoelectronic Functional Materials, Anyang Normal
University, Anyang 455002, P.R. China
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Bingxu Yan − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P.R. China
Yu Fang − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P.R. China
Suling Yang − College of Chemistry and Chemical Engineering,
Henan Province Key Laboratory of New Optoelectronic
Functional Materials, Anyang Normal University, Anyang
455002, P.R. China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02698
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the Program of Science and
Technology Innovation Talents of Henan Province (19HAS-
■
D
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Direct α-Arylation of Ethers through the Combination of Photoredox-
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