Ruthenium-Catalyzed meta-CAr–H Bond Difluoroalkylation of 2-Phenoxypyridines

Article abstract of DOI:10.1002/ejoc.201901883

A ruthenium-catalyzed meta-selective C_Ar–H bond difluoroalkylation of 2-phenoxypyridine using 2-bromo-2,2-difluoroacetate has been developed. Mechanistic studies indicated that this difluoroalkylation might involve a radical process. Furthermore, a new method is reported for the synthesis of 2-(meta-difluoroalkylphenoxy)pyridine derivatives, which are present in many pharmaceuticals and other functional compounds.

Full text of DOI:10.1002/ejoc.201901883

A Journal of
Accepted Article
Title: Ruthenium-catalyzed meta-CAr–H bond difluoroalkylation of 2-
phenoxypyridines
Authors: Gang Li, Chunqi Jia, Shichong Wang, Xulu Lv, Gang Li, Lei
Zhong, Lei Zou, and Xiuling Cui
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901883
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901883
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10.1002/ejoc.201901883
European Journal of Organic Chemistry
COMMUNICATION
Ruthenium-catalyzed meta-CAr–H bond difluoroalkylation of 2-
phenoxypyridines
Chunqi Jia,[a] Shichong Wang,[b] Xulu Lv,[b] Gang Li,*[b] Lei Zhong,[b] Lei Zou[b] and Xiuling Cui *[a]
[a] Dr. Chunqi Jia, Prof. Dr. Xiuling Cui
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
[b] Bs. Shichong Wang, Bs. Xulu Lv, Prof. Dr. Gang Li, Bs. Lei Zhong, Bs. Lei Zou
College of Chemistry and Chemical Engineering, Henan Province Key Laboratory of New Optoelectronic Functional Materials, Anyang Normal University,
Anyang 455000, P. R. China.
E-mail: ligang@aynu.edu.cn
Supporting information for this article is given via a link at the end of the document.
Table 1. Optimization of reaction conditions for meta-CAr–H difluoroalkylation
of 2-phenoxypyridine.
Abstract:
difluoroalkylation
difluoroacetate has been developed. Mechanistic studies indicated
that this difluoroalkylation might involve radical process.
A
ruthenium-catalyzed meta-selective CAr–H bond
of 2-phenoxypyridine using 2-bromo-2,2-
a
Furthermore, a new method is reported for the synthesis of 2-(meta-
difluoroalkylphenoxy)pyridine derivatives, which are present in many
pharmaceuticals and other functional compounds.
2-Phenoxypyridine derivatives are common in various
pharmaceuticals, agrochemicals, and bioactive natural
compounds.1 Modifications and functionalizations of
common 2-phenoxypyridine are convenient methods for
preparing its derivatives.2 Electrophilic aromatic substitution
is
a
traditional and effective route to introducing
substituents onto an aromatic ring. The site selectivities of
reactions on aromatic rings are determined by substituents.
For phenol derivatives, electrophilic aromatic substitution
mainly affords ortho/para-modified product because the
pyridoxy group acts as an ortho/para director.3 With the
increase
functionalizations
in
transition-metal-catalyzed
reported in recent
C–H
years,
bond
2-
phenoxypyridine derivatives have been prepared via
transition-metal-catalyzed CAr–H functionalizations.
To explore the possibility of a ruthenium(III)-catalyzed meta-CAr–
H bond difluoroalkylation of phenol derivatives, readily available
2-phenoxypyridine (1a) and ethyl 2-bromo-2,2-difluoroacetate
(2a) were selected as representative substrates to screen
reaction conditions. The reaction was conducted at 110  C for
24 h in a sealed Schlenk tube under a N2 atmosphere, as shown
in Table 1. Pleasingly, when RuCl3 was employed as catalyst,
K2CO3 as base and DCE as solvent, the desired product was
obtained in 10% yield (entry 1). When carboxylic acids, which
are often used to promote Ru-catalyzed organic reactions, were
added to the system, the conversion improved greatly (entries
2–5). In particular, when 1-AdCOOH was used as an additive,
the desired product was obtained in a 63% isolated yield (entry
2). Solvent also played a vital role in this reaction. A small
amount of the desired product was also obtained when 1,4-
dioxane and toluene were employed as solvent (entries 6 and 7).
However, acetonitrile and DMF were ineffective reaction
solvents (entries 8 and 9). Base screening indicated that K2CO3
was highly efficient in the system, while KOAc, Cs2CO3, and
Na2CO3 resulted in poor or no reactivity (entries 10–12). Using
However, these methods have been mainly limited to ortho-
CAr–H bond functionalizations. Recently, with the help of the
strong ortho/para-directing character of Ru–CAr -bonds, we
have achieved meta-C–H alkylation and sulfonylation of 2-
phenoxypyridine.4
The introduction of fluorine into organic molecules uniquely
affects their chemical, biological, and physical properties, such
as metabolic stability, lipophilicity, mimic effect, and
bioavailability.5 In particular, the difluoromethylene group (CF2),
which can be employed as a bioisostere for oxygen atoms and
lipophilic hydrogen bond donor, has unique applications in
biologically active molecules.6 In this study, based on the
ortho/para-directing character of Ru–CAr -bonds and ruthenium-
catalyzed meta-CAr–H functionalization,7 we have developed a
ruthenium-catalyzed
meta-selective
CAr–H
bond
difluoroalkylation of 2-phenoxypyridine using 2-bromo-2,2-
difluoroacetate.
1
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10.1002/ejoc.201901883
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Ru3(CO)12 and Ru(PPh3)3Cl2 as catalysts afforded the desired
product in low yields (entries 13–15). When [Ru(p-cymene)Cl2]2
and Pd(OAc)2 were employed as catalysts, the reaction did not
proceed (entries 16 and 17).
tetramethylpiperidin-1-yl)oxyl or butylated hydroxytoluene was
added to the system, which suggests that this process might
involve a single-electron transfer mechanism (Scheme 2b).
Finally,
a
competitive difluoroalkylation between 2-(4-
methoxyphenyl)pyridine, bearing an electron-donating group,
Scheme 1. Scope and generality of the Ru-catalyzed meta-CAr–H
difluoroalkylation of 2-phenoxypyridine.
Scheme 2. Preliminary mechanistic studies.
and 2-(4-(trifluoromethyl)phenyl)pyridine, bearing an electron-
withdrawing group, was conducted to study the impact of
substrate electronic properties on the transformation. The result
indicated that electron-rich substrates were better suited to this
reaction than electron-deficient substrates, supporting the
classification of Ru(III)-catalyzed difluoroalkylation as a base-
assisted electrophilic C-H activation process (Scheme 2c).8
Accoding to the experimental observations and previous studies
on Ru-catalyzed meta-selective CAr–H bond functionalizations,7
a
plausible catalytic mechanism was proposed for this
Under the optimized conditions, the scope and generality of this
difluoroalkylation reaction. As shown in Scheme 3, the CAr–H
functionalization is usually initiated by divalent ruthenium.
Divalent RuCl2Ln is obtained from RuCl3 via a strange redox
process. Combination of RuCl2Ln with 2-phenoxypyridine initially
provides six-membered ruthenacycle species A via nitrogen-
assisted ortho-CAr–H bond metalation. Next, assisted by the
ortho/para-directing effect of the CAr−Ru -bond, the
difluoromethyl radical attacks at the meta-position of the 2-
Ru-catalyzed meta-CAr–H difluoroalkylation were examined
using
various
2-phenoxypyridine
substrates
and
difluoroalkylation reagents, as shown in Scheme 1. Initially,
several 2-phenoxypyridines bearing various substituents on the
phenyl ring were used as substrates. 2-Phenoxypyridines
bearing alkyl and aryl groups on the benzene ring were suitable
substrates for this transformation, affording the desired products
in moderate yields (3b and 3c). Halogen substituents were also
compatible with this transformation (3d–3f), providing the
opportunity for further transformations to afford highly
functionalized derivatives. These results indicated that electronic
properties dramatically affected the reaction efficiency. Although
the desired products were obtained using substrates bearing
both electron-donating (–OCH3, 3h, CCDC: 1957610) and
electron-withdrawing (–CF3, 3g) substituents, electron-
withdrawing substituents (-CF3) were unfavorable for the meta-
CAr–H difluoroalkylation. Methyl-substituted 2-pyridyloxy groups
were also efficient directing groups in this transformation (3i and
pyridoxyl group to give active species B. Meanwhile,
a
difluoromethyl radical forms via ruthenium-mediated single-
Scheme 3. Proposed catalytic mechanism.
3j), while 2-bromo-2,2-difluoroacetamide was
difluoroalkylation reagent (3k).
a
good
Various experiments were also conducted to investigate the
mechanism of this Ru(III)-catalyzed meta-CAr–H bond
difluoroalkylation, as shown in Scheme 2. First, difluoroalkylation
did not proceed when 2-(2,6-dimethylphenoxy)pyridine bearing
two methyl groups was used as a reactant to block the two
ortho-positions on the phenyl ring, which suggests that ortho-
CAr–H metalation was indispensable in the meta-
difluoroalkylation process (Scheme 2a). Next, the model reaction
was inhibited when radical trapping agent 2,2,6,6-
2
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10.1002/ejoc.201901883
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electron transfer. Aided by ruthenium(III) and K2CO3, species B
is deprotonated to give more stable intermediate C. Finally,
ligand exchange of intermediate C with 2-phenoxypyridine gives
the final difluoroalkylation product and regenerates the active
ruthenium catalyst species for further cycling.
In conclusion, we have developed ruthenium-catalyzed meta-
selective C–H bond difluoroalkylation of 2-phenoxypyridines.
This development offers a new strategy for the preparation of 2-
(meta-difluoroalkylphenoxy)pyridine derivatives. Further studies
to expand the substrate scope and apply this difluoroalkylation
method to chemical synthesis are underway.
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Acknowledgements
We gratefully acknowledge the Program of Science and
Technology Innovation Talents of Henan Province
(19HASTIT035) for providing financial support for this
work
.
Keywords: Ruthenium • C-H activation • meta-CAr–H •
Difluoroalkylation • Phenoxypyridine
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3
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Difluoroalkylation
A ruthenium-catalyzed meta-selective CAr–H bond difluoroalkylation of 2-phenoxypyridine using 2-bromo-2,2-difluoroacetate has been
developed, which provide a new method to synthesize 2-(meta-difluoroalkylphenoxy)pyridine derivatives, which are present in many
pharmaceuticals and other functional compounds.
4
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