Ruthenium-catalyzed meta -C-H bond alkylation of aryl 2-pyridyl ketones

Article abstract of DOI:10.1039/c9cc08624b

The first example of meta-selective C_Ar-H bond functionalization of aryl 2-pyridyl ketones has been developed using [Ru(p-cymene)Cl₂]₂ as the catalyst and alkyl bromide as the coupling reagent. This development provides an efficient strategy for modifying the meta-position of aryl 2-pyridyl ketone skeletons, which are found in various functional molecules.

Full text of DOI:10.1039/c9cc08624b

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Ruthenium-catalyzed meta-C–H bond alkylation
of aryl 2-pyridyl ketones†
Cite this: Chem. Commun., 2020,
6, 293
5
ab
c
ab
ab
ab
Gang Li,
*
Chunqi Jia,‡ Xiaofeng Cai,‡ Lei Zhong, Lei Zou and
c
Received 5th November 2019,
Accepted 28th November 2019
Xiuling Cui*
DOI: 10.1039/c9cc08624b
rsc.li/chemcomm
The first example of meta-selective CAr–H bond functionalization of group. Meanwhile, a practical and efficient approach to remote
aryl 2-pyridyl ketones has been developed using [Ru(p-cymene)Cl meta-selective C –H functionalization of arenes remains
as the catalyst and alkyl bromide as the coupling reagent. This challenging.
2 2
]
Ar
development provides an efficient strategy for modifying the meta-
Ruthenium complexes are not only inexpensive and have
position of aryl 2-pyridyl ketone skeletons, which are found in high catalytic activity, but also have a unique catalytic character.
various functional molecules.
Intriguingly, ruthenium can catalyze meta-selective C–H bond
functionalization through the Ru–CAr bond ortho/para-directing
1
0
11
Aromatic ketones and their derivatives are essential compounds effect, in addition to ortho-CAr–H bond transformation.
that are not only present in various pharmaceutical chemicals, Herein, we achieved the first example of meta-selective C –H
Ar
bioactive natural products, agricultural chemicals, and many bond functionalization of aryl 2-pyridyl ketones employing a
newly developed functional materials, but also used as key inter- ruthenium complex as a catalyst.
1
mediates for the synthesis of various functional molecules. To
To explore the feasibility of Ru-catalyzed meta-selective CAr–H
date, numerous methods for synthesizing aromatic ketones have bond functionalizations of aryl 2-pyridyl ketones, commercially
been reported. A classical method for preparing aromatic ketone available phenyl(pyridin-2-yl)methanone (1a) and methyl 2-bromo-
derivatives involves introducing substituents into aromatic propanoate (2a) were used as classical substrates for screening and
ketones via electrophilic aromatic substitution reactions. This optimizing the reaction conditions. The reaction was conducted at
approach is efficient and has been applied in laboratory synth- 110 1C for 24 h in a sealed thick-walled Schlenk reaction tube under
esis and the chemical industry. As carbonyls are strong deacti- a N atmosphere, as shown in Table 1. Using [Ru(p-cymene)Cl ] as
2
2 2
vating groups, electrophilic aromatic substitution is limited to a catalyst, KOAc as a base, and toluene as a solvent, the product was
methods such as nitration and sulfonation, while Friedel–Crafts obtained in 26% isolated yield (entry 1). When carboxylic acids were
2
alkylation and acylation cannot proceed.
added into the system, the reaction efficiency improved dramatically
In recent years, in addition to the increase in TM-catalyzed (entries 2–5). In particular, when 1-AdCOOH was used as an
3
3d,4
5
C–H bond functionalization, arylation, alkenylation,
nitration,
6
7
8
9
amidation, alkoxylation, acylation, and halogenation of aryl
-pyridyl ketones, C –H bonds have been achieved in the
2
Ar
presence of various transition metals (Scheme 1). However, these
approaches have been limited to the ortho-position of the pyridyl
a
College of Chemistry and Chemical Engineering, Anyang Normal University,
Anyang 455000, P. R. China
b
Henan Province Key Laboratory of New Optoelectronic Functional Materials,
Anyang Normal University, Anyang 455002, P. R. China
c
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. E-mail: cuixl@hqu.edu.cn
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc08624b
These authors contributed equally.
Scheme 1 TM-catalyzed
CAr–H functionalization of aryl 2-pyridyl
‡
ketones.
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Table 1 Optimization of the reaction conditions for meta-selective
C
Ar–H alkylation of aryl 2-pyridyl ketones
Entry Catalyst
Base
Ligand
—
Ac-Leu-OH Toluene
MesCOOH Toluene
1-AdCOOH Toluene
Solvent
Yield (%)
1
2
3
)
5
6
7
8
9
1
1
1
1
1
1
1
1
[Ru(p-cymene)CI
2
2
2
2
2
2
2
2
2
2
2
2
2
]
]
]
]
]
]
]
]
]
]
]
]
]
2
2
2
2
2
2
2
2
2
2
2
2
2
KOAc
KOAc
KOAc
KOAc
KOAc
Toluene
26
35
34
53
43
37
12
32
27
43
18
0
0
19
0
0
0
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
[Ru(p-cymene)CI
PivOH
Toluene
K
Na
CS
2
CO
3
1-AdCOOH Toluene
1-AdCOOH Toluene
1-AdCOOH Toluene
2
CO
3
2
CO
3
NaOAc 1-AdCOOH Toluene
0
1
2
3
4
5
6
7
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
1-AdCOOH Benzene
1-AdCOOH Xylene
1-AdCOOH Acetonitrile
1-AdCOOH DMF
1-AdCOOH Toluene
1-AdCOOH Toluene
1-AdCOOH Toluene
1-AdCOOH Toluene
RuCI
Ru (CO)12
3
3
Pd(OAc)
—
2
Scheme 2 Scope and generality of Ru-catalyzed meta-CAr–H alkylation
of aryl 2-pyridyl ketones with alkyl bromides.
additive, the desired product was obtained in 53% isolated yield
3
entry 4). Base screening indicated that K CO , Na CO , Cs CO ,
directing group in the process (3j). To our delight, when 2-(2-
naphthyl)pyridine was used as a reactant, the desired product
was obtained (3k). Various other alkyl bromides were also
subjected to the optimized conditions, with the results indicat-
ing that the other 2-bromocarboxylates were suitable alkylation
reagents, affording the desired products in good isolated yields
(
2
3
2
3
2
and NaOAc were also effective for Ru-catalyzed meta-selective
CAr–H bond functionalization (entries 6–9), but gave the desired
product in lower yields. The solvent also played an important
role. The desired product was also obtained in aromatic solvents
other than toluene, such as benzene and xylene (entries 10
and 11). However, acetonitrile and DMF were ineffective solvents
for the transformation (entries 12 and 13). A small amount of the
(3h, 3i, 3l–3o). Unfortunately, the other brominated alkanes were
not tolerated in the process.
In a gram-scale experiment, the desired product was only
obtained by extending the reaction time (Scheme 3). Therefore,
3
product was obtained when RuCl was used as a catalyst (entry 14).
When Ru (CO) , Pd(OAc) , or no metal catalyst was added to the
3
12
2
the present Ru-catalyzed meta-C –H alkylation provided an
Ar
system, the reaction did not proceed (entries 15–17).
efficient and practical approach to modification and functio-
nalization at the meta-position of aryl 2-pyridyl ketones.
Furthermore, a series of experiments were designed and
conducted to explore the mechanism of the Ru-catalyzed meta-
With the optimized conditions in hand, the generality and
scope of the Ru-catalyzed meta-C–H alkylation of aryl 2-pyridyl
ketones was examined using various aryl 2-pyridyl ketones and
alkyl bromides as substrates, as shown in Scheme 2. Initially,
various aryl 2-pyridyl ketones bearing different substituents on
the phenyl ring were used as substrates under the optimized
conditions. Phenyl(pyridin-2-yl)methanones bearing a methyl
or phenyl group on the benzene ring were suitable substrates
for the Ru-catalyzed meta-CAr–H alkylation, affording the corres-
ponding products in moderate yields (3b and 3c). Notably, halogen
substituents were tolerated well in the process, providing the
opportunity for further transformations to produce highly func-
tionalized derivatives (3d and 3e). Further experimental results
indicated that the electronic nature markedly affected the reac-
tion efficiency. Although the desired products were obtained
using substrates bearing both electron-withdrawing substituents
CAr–H alkylation of aryl 2-pyridyl ketones, as shown in Scheme 4.
First, (2,6-dimethylphenyl)(pyridin-2-yl)methanone, bearing two
methyl groups blocking both ortho-positions on the phenyl ring,
did not react with the alkyl bromide under the optimized condi-
tion (Scheme 4a), supporting that the directing group-assisted
ortho-CAr–H metalation was indispensable in the Ru-catalyzed
alkylation process. Next, significant H/D-exchange at the ortho-
2
position was observed when D O was added to the model
reaction, indicating that ortho-CAr–H metalation was a reversible
3 3
(–CF , 3f) and electron-donating substituents (–OCH , 3g–3i),
electron-donating substituents were better suited to Ru-catalyzed
meta-CAr–H alkylation compared with electron-withdrawing sub-
stituents. A 2-pyridyl-bearing methyl group was also an efficient Scheme 3 Gram-scale synthesis.
2
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key active six-membered ruthenacycle species (A) via reversible
ortho-CAr–H bond metalation. Next, aided by the CAr–Ru s-bond
ortho/para-directing effect, an alkyl radical, formed from alkyl
bromide via a ruthenium-mediated SET process, attacks species
A at the meta-position to the pyridyl group, providing an active
species B. The deprotonation of species B assisted by ruthenium(III)
and K CO generates a stable species C. Finally, the species C
2 3
exchanged a ligand with the aryl 2-pyridyl ketone to provide the
final product and recycle the active catalyst species.
In conclusion, we have achieved the first meta-CAr–H func-
tionalization of aryl 2-pyridyl ketones using alkyl bromides in
the presence of a ruthenium complex catalyst. Mechanistic
studies suggested that this meta-C –H bond functionalization
Ar
might involve a ruthenium-mediated SET. This method pro-
vides an efficient approach to the modification and functiona-
lization at the meta-position of aryl 2-pyridyl ketones.
We gratefully acknowledge the Program of Science and Tech-
nology Innovation Talents of Henan Province (19HASTIT035) for
providing financial support for this work.
Scheme 4 Preliminary mechanistic studies.
Conflicts of interest
process and that the Ru-catalyzed meta-CAr–H functionalization There are no conflicts to declare.
was water-tolerant (Scheme 4b). Furthermore, when radical inhi-
bitors, such as TEMPO and BQ, were separately added to the Notes and references
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