Ruthenium-catalyzed ortho/meta-selective dual C-H bonds functionalizations of arenes

Article abstract of DOI:10.1021/acs.orglett.7b02439

The first example of transition-metal-catalyzed ortho/metaselective dual C-H functionalizations of arenes in one reaction is described. In this transformation, ortho-C-H chlorination and meta-C-H sulfonation of 2-phenoxypyri(mi)dines were achieved simultaneously under catalysis by [Ru(p-cymene)Cl₂]₂. The other reactant, namely, an arylsulfonyl chloride, played the role of both a sulfonation and chlorination reagent. More importantly, the arylsulfonyl chloride was also an oxidant in the process. Mechanistic studies indicated that six-membered ruthenacycles were the key intermediate in the reaction.

Full text of DOI:10.1021/acs.orglett.7b02439

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed ortho/meta-Selective Dual C−H Bonds
Functionalizations of Arenes
Gang Li,*,†,‡ Biao Zhu,†,§ Xingxing Ma,†,§ Chunqi Jia,†,§ Xulu Lv,† Junjie Wang,†,‡ Feng Zhao,†,‡
Yunhe Lv,†,‡ and Suling Yang†,‡
†College of Chemistry and Chemical Engineering Anyang Normal University, Anyang 455002, PR China
‡Henan Province Key Laboratory of New Optoelectronic Functional Materials, Anyang Normal University, Anyang 455002, PR
China
S
* Supporting Information
ABSTRACT: The first example of transition-metal-catalyzed ortho/meta-
selective dual C−H functionalizations of arenes in one reaction is described.
In this transformation, ortho-C−H chlorination and meta-C−H sulfonation of
2-phenoxypyri(mi)dines were achieved simultaneously under catalysis by
[Ru(p-cymene)Cl2]2. The other reactant, namely, an arylsulfonyl chloride,
played the role of both a sulfonation and chlorination reagent. More
importantly, the arylsulfonyl chloride was also an oxidant in the process. Mechanistic studies indicated that six-membered
ruthenacycles were the key intermediate in the reaction.
romatic compounds widely exist in pharmaceuticals,
natural products, and various functional materials. The
meta-CAr−H bonds to CAr−X bonds via alternative strategies
(Scheme 1c),3 such as inherent sterics,4 electronic effects,5
remote directing groups,6 norbornene mediation,7 copper-
catalyzed four-membered-ring transition states,8 and ortho/
para-directing effects of Ru−CAr σ-bonds.9
In all the above CAr−H functionalization processes, the
reactions usually convert one type of CAr−H bond with
controlled selectivity.10 The selective transformation of dual
CAr−H bonds of different types to different CAr−X bonds in
one reaction remains elusive. Herein, we report the first
example of the transition-metal-catalyzed ortho/meta-selective
dual C−H functionalization of arenes. Using [Ru(p-cymene)-
Cl2]2 as catalyst, we achieved ortho-chlorination and meta-
sulfonation of 2-phenoxy-pyri(mi)dines with various arylsul-
fonyl chlorides (Scheme 1d). Removal of the pyri(mi)dine
directing groups enabled the facile preparation of 2-chloro-5-
(arylsulfonyl)phenol.11
A
direct transformation of aryl C−H bonds to CAr−X bonds
provides a convenient strategy for the synthesis of complex
aromatic molecules. Thus, far, there are two major routes to
transform aryl C−H bonds to CAr−X bonds: one is
electrophilic aromatic substitution, such as nitration, sulfona-
tion, halogenation and Friedel−Crafts reaction of aromatic
compounds (Scheme 1a);1 the other is transition-metal-
Scheme 1. Transformation of Aryl C−H Bonds
Our study began with a typical reaction using 2-
phenoxypyridine and p-toluenesulfonyl chloride as substrates
and [Ru(p-cymene)Cl2]2 as a catalyst. The dual CAr−H bond
functionalization reaction was examined at 120 °C for 24 h in a
sealed tube. As shown in Table 1, the results of the solvent
screening showed the desired product (3aa) could be obtained
in toluene and xylene (Table 1, entries 1 and 2). The major
product isolated from the reaction mixture was the dual CAr−H
bond functionalization product, whose structure was confirmed
by single-crystal X-ray diffraction (Figure 1). Other solvents,
such as acetonitrile, benzene, methanol, 1,4-dioxane, and THF,
were not effective (Table 1, entries 3−7). K2CO3 was not a
suitable base to improve the yield (Table 1, entry 8). Other
ruthenium complexes, such as RuCl3 and Ru(PPh3)3Cl2,
catalyzed aryl C−H bond functionalization. Many ortho-
selective CAr−H bond functionalization reactions catalyzed by
different transition metals have been developed with chelation
assistance of directing groups. These reactions have established
vigorous group of methods to construct C−X bonds in modern
synthetic chemistry (Scheme 1b).2 More recently, break-
throughs have also been made in the direct transformation of
Received: August 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02439
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Letter
a
Table 1. Ru(II)-Catalyzed Dual CAr−H Functionalization
b
entry
catalyst
solvent
xylene
yield (%)
1
[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
RuCl3
83
73
trace
0
2
toluene
acetonitrile
benzene
methanol
1,4-dioxane
THF
3
4
5
0
6
0
7
0
c
8
xylene
82
9
xylene
trace
10
11
12
13
Ru(PPh3)3Cl2
xylene
trace
Ru3(CO)12
xylene
0
0
0
Pd(OAc)2
xylene
−
xylene
Figure 2. Scope of 2-aryloxypyri(mi)dine. 1 (0.2 mmol), 2a (0.6
mmol, 3 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), xylene (1.5 mL), 120
°C, 24 h. Isolated yields based on recovered starting material.
a
The reaction conditions were as follows: 1a (0.2 mmol), 2a (0.6
mmol, 3 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), solvent (1.5 mL),
120 °C, 24 h. Isolated yields based on recovered starting material.
K2CO3 (2 equiv) was added
b
c
Figure 1. Single-crystal X-ray structure of product 3aa.
exhibited poorer catalytic activities (Table 1, entries 9 and 10).
When Ru3(CO)12 or Pd(OAc)2 was used as a catalyst or when
no catalyst was added, no desired product was observed (Table
1, entries 11, 12, and 13).
With the optimized conditions in hand, the scope of the
substrates was examined. As summarized in Figure 2, 2-
phenoxypyridines bearing a methyl group at different positions
of the phenyl ring were employed as coupling partners with p-
toluenesulfonyl chloride. The methyl group at the ortho or para
position of the 2-pyridyloxy directing group did not impede the
reaction (3ba and 3ca). Only trace desired product was
obtained for substrates bearing a methyl group at the meta
position, which presumably resulted from the obvious steric
hindrance. Significant electronic effects of the phenyl
substituents were observed in the process. Electron-donating
substituents (CH3O−) were favorable for the reaction (3da).
In contrast, electron-withdrawing groups deactivated the
reaction. No desired product was obtained when 2-(4-
nitrophenoxy)pyridine was used as a substrate. It is worth
noting that 2-(naphthalen-2-yloxy)pyridine was also a suitable
substrate, and the desired product was obtained in a moderate
yield under the optimized conditions (3ea). The methyl-
substituted 2-pyridyloxy groups and 2-pyrimidyloxy group were
also efficient directing groups in the dual CAr−H bond
functionalization process (3fa, 3ga, and 3ha).
Figure 3. Scope of the arylsulfonyl chlorides. 1a (0.2 mmol), 2 (0.6
mmol, 3 equiv), [Ru(p-cymene)Cl2]2 (5 mol %), xylene (1.5 mL), 120
°C, 24 h. Isolated yields based on recovered starting material.
electron-donating (−OCH3, 3af), and strong electron-with-
drawing (−NO2, 3ag) functional groups and halogens (3ah,
3ai, and 3aj) were well tolerated in the transformation.
Naphthalene-2-sulfonyl chloride was also a good coupling
partner, and the structure of the desired product was confirmed
by single-crystal X-ray diffraction (3ak).
It is important to note that the 2-pyridyl group can be readily
be removed to deliver 2-chloro-5-tosylphenol.10 Therefore, the
new Ru-catalyzed reaction provides a fast-track strategy for the
synthesis of 2-chloro-5-(arylsulfonyl)phenols (Scheme 2).
Moreover, the scope of the arylsulfonyl chlorides was
surveyed under the same conditions as summarized in Figure
3. According to results, alkyl (3ac and 3ad), aryl (3ae),
B
DOI: 10.1021/acs.orglett.7b02439
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Letter
reaction. Furthermore, when complex II in xylene was heated
at 120 °C for 24 h without p-toluenesulfonyl chloride, the
desired product was not obtained (b3). This result shows that
the oxidative addition of complex II with p-toluenesulfonyl
chloride is essential, and the catalytic process involves a Ru(II)/
Ru(IV) cycle, not a Ru(II)/Ru(0) cycle. Third, when the
radical scavenger TEMPO was added into the model reaction,
no desired product was found in the system (c). This indicates
that the reaction involves a radical process, which is consistent
with the mechanism proposed for the ruthenium-catalyzed
meta-sulfonation reaction of arenes.9h Fourth, the reaction
mixture was investigated by GC-MS.12 In addition to the
desired product, 1-(chloromethyl)-methylbenzene and S-p-
tolyl-4-methylbenzenesulfonothioate were observed in the
reaction system (d). This result indicates that the arylsulfonyl
chloride not only was a dual sulfonation and chlorination
reagent but also was an oxidant in the reaction. The observation
of 1-(chloromethyl)-methylbenzene further confirmed that the
dual CAr−H bond functionalization reaction involved a radical
process.
Scheme 2. Removal of the Directing Group
To gain insights into the reaction pathway, a series of
additional experiments were performed as shown in Scheme 3.
Scheme 3. Preliminary Mechanistic Studies
On the basis of the above experimental observations and
related literature,9,13 a plausible catalytic cycle was proposed to
rationalize the ruthenium-catalyzed ortho/meta-selective dual
CAr−H bond functionalization. As shown in Scheme 4, the key
Scheme 4. Proposed Catalytic Cycle
six-membered ruthenacycle A was initially formed from 2-
phenoxypyridine and [Ru(p-cymene)Cl2]2 via an ortho-CAr−H
ruthenation process with chelation assistance from the directing
group. Then, the arylsulfonyl chloride attacked the para
position of the Ru−CAr σ-bond through the strong directing
effect of the Ru−CAr σ-bond to provide the Ru(II) species B.
Furthermore, oxidative addition of the arylsulfonyl chloride on
species B gave the active Ru(IV) complex C, which underwent
reductive elimination to release the final product 2-(2-chloro-5-
(arylsulfonyl)phenoxy)-pyridine and Ru(II) species D. Finally,
C−H bond ruthenation of 2-phenoxypyridine with species D
restarted the catalytic cycle and gave the byproducts S-aryl
arylsulfonothioate and xylene chloride.
In conclusion, we described the discovery of a ruthenium(II)-
catalyzed ortho-chlorination/meta-sulfonation dual CAr−H
bond functionalization of 2-aryloxypyri(mi)dine arenes with
arylsulfonyl chlorides. This reaction provided a fast-track
strategy for synthesis of 2-chloro-5-(arylsulfonyl)phenols after
the removal of the directing group. Novel six-membered
ruthenacycle complexes were identified as the key active
First, the designed compounds were selected as substrates (a).
When using 2-(2,6-dimethylphenoxy)pyridine bearing two
methyl groups to block the two ortho positions of the phenyl
ring, the desired product was not obtained under the standard
conditions (a1), supporting the necessity of ortho-CAr−H
metalation in the reaction process. The desired product was
also given when employing 2-(3-tosylphenoxy)pyridine bearing
a sulfonyl group in the meta position. These results indicate
that sulfonyl and chlorine groups can be introduced into arene
ring in turn. Second, six-membered ruthenacycle complexes I
and II were separately preprepared by mixing 2-phenoxypyr-
idine and 2-(3-tosylphenoxy)pyridine with [Ru(p-cymene)-
Cl2]2 in MeOH at 80 °C for 48 h. It was found that the
preprepared complexes I and II reacted separately with 3 equiv
of p-toluenesulfonyl chloride to give the desired products in
nearly quantitative yields (b1 and b2). These findings indicated
that both preformed complexes I and II might be key active
intermediates in the dual CAr−H bond functionalization
C
DOI: 10.1021/acs.orglett.7b02439
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02439.
■
S
Experimental procedures, characterization data, NMR
spectra of products, and crystal structure (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ligang@aynu.edu.cn.
ORCID
Gang Li: 0000-0002-1609-449X
Author Contributions
§B.Z., X.M., and C.J. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (NSFC, No. 21102005) for financial
support of this work.
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