Rhodium(III)-catalyzed redox-neutral C-H arylation via rearomatization

Article abstract of DOI:10.1021/ol500186j

Rhodium(III)-catalyzed arylation of arenes bearing a chelating group has been realized via a redox-economy process using 4-hydroxycyclohexa-2,5-dienones as the arylating reagents, leading to the synthesis of 3-arylated phenols. This redox-neutral process proceeds via a C-H activation pathway with rearomatization being the driving force.

Full text of DOI:10.1021/ol500186j

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Redox-Neutral C−H Arylation via
Rearomatization
Xueyun Zhang,†,‡ Fen Wang,† Zisong Qi,† Songjie Yu,† and Xingwei Li*,†
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
‡School of Chemistry and Pharmaceutial Engineering, Qilu University of Technology, Ji’nan 250353, China
S
* Supporting Information
ABSTRACT: Rhodium(III)-catalyzed arylation of arenes bearing a
chelating group has been realized via a redox-economy process using
4-hydroxycyclohexa-2,5-dienones as the arylating reagents, leading
to the synthesis of 3-arylated phenols. This redox-neutral process
proceeds via a C−H activation pathway with rearomatization being
the driving force.
Scheme 1. Rhodium(III)-Catalyzed C−C Coupling
ecently, rhodium(III) Cp* complexes have been exten-
Rsively explored as active catalysts for activation of arene
C−H bonds, particularly for C−C and C−N bond formation.1
A large number of new synthetic methods have been developed
by following this Rh(III)-catalyzed C−H activation strategy
under both oxidative and redox-neutral conditions.2 In most
cases, the C−H activation of arenes is facilitated by an ortho
chelating group, and a large variety of coupling partners has
been established, including strained rings,3 alkenes,4 alkynes,2e,5
and a broad scope of activated π bonds such as aldehydes,6
ketones,7 isocyanates,8 isonitrile,9 activated carbenes,10 and
azides.11 Therefore, rhodium(III) catalyzed C−H activation has
been recognized as a powerful strategy for new bond
construction with high functional group compatibility, high
catalytic efficiency, a broad substrate scope, and operational
simplicity. It has been realized as an important complement to
C−H activation catalyzed by other metal systems such as
palladium, ruthenium, and copper.12
Despite the significant progress, it remains necessary to
develop new methods of C−C coupling. In particular, although
biaryls are known as important building blocks in the
pharmaceutical industry and in material studies, only limited
examples of C−H arylation of arenes have been realized by
Rh(III) catalysis.13 These oxidative systems utilized a (hetero)-
arene as the arylating reagent for direct C−H/C−H coupling
(Scheme 1). On the other hand, Li14 and Huang15 have
independently applied Rh(III) catalysts to the redox-neutral
insertion of arene C−H bonds into α,β-unsaturated ketones,16
leading to β-aryl ketone products. Clearly, C−H arylation
under redox-neutral conditions would be highly desirable. To
achieve this redox-economic C−H arylation process, the
oxidizing power needs to be restored into the arylating reagent.
With this hypothesis in mind, we have designed substituted 4-
hydroxycyclohexa-2,5-dienones as the arylating reagent, which
can be regarded as an internal oxidizing coupling partner
because, following insertion of the olefin into the arene C−H
bond, eventual rearomatization should be realized upon
dehydration and tautomerization. This would lead to the
synthesis of 3-arylated phenols as the coupling products, which
are widely present as an important structure motif in natural
products and pharmaceuticals.17 In fact, this rearomatization
strategy has been utilized in coupling reactions.18 However,
challenges remain in this process. This dienone is already a
disubstitituted cyclic olefin with no ring strain. This is made
worse by the γ-branching which further lowers its reactivity
toward migratory insertion of an incipient Rh−C bond. In
addition, the phenol product and the water coproduct may also
exhibit product inhibition.
We initiated our studies with the screening of the conditions
for the coupling of 2-PhPy and 4-hydroxy-4-methylcyclohexa-
2,5-dienone. It was found that while a clean coupling occurred
when [Cp*RhCl2]2(5 mol %)/AgSbF6(20 mol %) was applied
as a catalyst, the desired product 3aa was isolated in only 45%
yield due to low conversion (Table 1). Using a slightly higher
ratio (6:1) of AgSbF6 to the rhodium increased the yield of 3aa
to 51%. However, using a larger ratio caused inhibition. A
screening of solvents revealed that essentially no conversion
was observed in oxygen-containing solvents, and DCE was
Received: January 19, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
ab
,
a
,b
Table 1. Screening of the Reaction Conditions
Scheme 2. Arylation of Arenes: Scope of the Arene
entry
additive (mol %)
AgSbF6 (20)
solvent
DCM
yield
1
2
45
AgSbF6 (30)
DCM
DCM
DCE
51
c
3
none
39
4
AgSbF6 (30)
68
5
AgSbF6 (30)
1,4-dioxane
PhCl
trace
37
6
AgSbF6 (30)
7
AgSbF6 (30)
THF
trace
trace
46
8
AgSbF6 (30)
acetone
DCE
9
AgSbF6 (30)/HOAc (200)
AgSbF6 (30)/PivOH (200)
AgSbF6 (30)/Zn(NTf2)2 (20)
AgSbF6 (30)/Zn(NTf2)2 (40)
AgSbF6 (30)/Zn(OTf)2 (20)
AgSbF6 (30)/Al(OTf)3 (20)
AgSbF6 (30)/In(OTf)3 (20)
AgSbF6 (30)/Cu(OTf)2 (20)
AgSbF6 (30)/Ca(OTf)2 (20)
10
11
12
13
14
15
16
17
DCE
41
DCE
76
DCE
42
DCE
44
DCE
nd
DCE
trace
40
DCE
DCE
65
a
Reactions conditions: 2-phenylpyridine 1a (0.2 mmol), 2a (0.24
mmol), 20 h, [RhCp*Cl2]2 (5 mol %), solvent (2 mL), sealed tube
b
c
under argon. Isolated yield after chromatography. [Cp*Rh-
(MeCN)3](SbF6)2 (10 mol %) was used.
identified as the optimal one. Addition of AcOH or PivOH,
which was often used as an additive to facilitate C−H
activation, failed to give any positive effect. To our delight,
when Zn(NTf2)2 (20 mol %) was introduced as an additional
additive, the yield of 3aa was increased to 76%, while using a
larger amount of Zn(NTf2)2 also caused inhibition. In all cases,
no diarylation was detected. Thus the optimal conditions
constitute the combination of [Cp*RhCl2]2 (5 mol %), AgSbF6
(30 mol %), and Zn(NTf2)2 (30 mol %) in DCE at 100 °C for
20 h. In contrast to the good yield of 3aa using 4-hydroxy-4-
methylcyclohexa-2,5-dienone as a substrate, switching to 4-
methoxy-4-methylcyclohexa-2,5-dienone afforded 3aa in only
42% yield.
With the establishment of the optimal conditions, the scope
and limitation of this coupling system were next explored. The
scope of the arene in the coupling with 2a was examined first
(Scheme 2). Introduction of a variety of electron-donating and
-withdrawing, as well as halogen, substituents into either the
pyridine ring or the phenyl ring of 2-phenylpyridines is well-
tolerated, and the products were isolated in yields ranging from
40% to 81%. Introduction of a relatively bulky substituent
(CH3, Br) into the meta position caused the C−H arylation to
occur at a less hindered ortho position (3ha, 3ja). In line with
this observation, the C−H arylation took place at the less
hindered ortho position for the 2-(2-naphthyl)pyridine
substrate (3ia). In contrast, when a meta OMe group was
installed, a mixture of two regioisomeric products was obtained
in a 1.5:1 ratio (3oa, 3oa′), probably due to the reduced steric
bulk of this group. Instead, the directing effect of the OMe
group might be operational. When the directing group (DG)
was changed to a quinolyl group, a lower yield of the coupled
product (3pa, 3ra) was isolated, likely due to the increased
a
Reactions conditions: arene (0.2 mmol), 2a (0.24 mmol),
[RhCp*Cl2]2 (5 mol %), AgSbF6 (30 mol %), Zn(NTf2)2b (20 mol
%), DCE (2 mL), 100 °C, 20 h, sealed tube under argon. Isolated
yield.
steric hindrance of the DG. The arene ring is not limited to
benzene rings. Indoles and thiophenes also coupled with 2a,
but in moderate or low yield (3sa, 3ta).
The scope of the dienone substrate was next explored in the
coupling with 2-PhPy (Scheme 3). Introduction of a
substituent into the α position of the carbonyl group is
tolerated (3ac, 3ad), and C−H arylation occurred at the less
hindered olefin unit. This observation is also in line with a β-
methyl substituted dienone, where a 3,4,5-trisubstituted phenol
(3ae) was obtained. Variation of the 4- substituent to different
alkyls and to methoxy has been performed (3ab, 3af, 3ag).
Thus 4,4-dimethoxycyclohexa-2,5-dienone coupled with higher
reactivity even at 40 °C, and the product (3ab) was isolated in
60% yield, while the reaction performed under the standard
conditions led to decomposition. To our delight, replacing the
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a
,b
Scheme 3. Arylation of Arenes: Scope of the Dienone
Scheme 5. Proposed Mechanism
a
Reactions conditions: 1a (0.2 mmol), 2a (0.24 mmol), [RhCp*Cl2]2
(5 mol %), AgSbF6 (30 mol %), Zn(NTf2)2 (20 mol %), DCE (2 mL),
100 °C, 20 h, sealed tube under argon. Isolated yield. T = 40 °C.
b
c
methyl group in the dienone substrate with a CF3 increased the
coupling efficiency and product 3ag was isolated in high yield,
likely ascribable to the enhanced electrophilicity of the dienone
substrate induced by the CF3 group. Importantly, the dienone
can be extended to its N-Ts imine derivative, where the
analogous product 3ah was obtained in 50% yield, while 2-(3-
bromophenyl)pyridine coupled to give 3ai with lower
efficiency, indicating that these conditions are not optimal for
the N-Ts imine substrate.
Several experiments have been carried out to probe the
reaction mechanism. Cyclometalated Rh(III) complex 4 was
prepared and was designated as a catalyst precursor (10 mol %)
for the coupling of 2-PhPy and 2a in the presence of AgSbF6
(30 mol %) and Zn(NTf2)2 (20 mol %) (Scheme 4). The fact
cationic rhodium(III) intermediate. Subsequent olefin insertion
into the incipient Rh−C bond generates a Rh(III) alkyl
intermediate, where the olefin insertion is proposed to be
facilitated by Zn(NTf2)2 which enhanced the electrophilicity of
the dienone substrate. Protonolysis of the Rh−alkyl bond or
ligand metathesis/cyclometalation with an incoming 2-PhPy
releases the Rh(III) species, and the alcohol intermediate
undergoes dehydration and tautomerization to furnish the final
product.
In summary, we have realized a Rh(III)-catalyzed C−H
arylation of arenes using cyclohexa-2,5-dienones as an arylating
substrate by taking advantage of rearomatization. This reaction
proceeds via a C−H activation pathway to afford di- and
trisubstituted phenols. A relatively broad spectrum of both
coupling partners has been defined. The current C−H
acrylation method expanded the strategy and applications of
Rh(III)-catalyzed C−H activation/C−C coupling reactions and
may find synthetic utility in the construction of complex
molecules.
Scheme 4. Mechanistic Studies
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, characterization data, and copies of NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
that product 3aa was isolated in comparable yield (70%)
suggests the relevancy of C−H activation, and a cationic
cyclometalated rhodium(III) species is likely involved. To
further probe this C−H activation process, the intermolecular
KIE has been measured using an equimolar mixture of 2-PhPy
and 2-PhPy-d5 in the competitive coupling with 2a at a low
conversion. A KIE value of 2.0 was obtained from H NMR
analysis, and this suggests that the C−H cleavage is probably
involved in the rate-limiting step.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xwli@dicp.ac.cn.
Notes
1
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
A plausible mechanism to account for this catalytic process is
given in Scheme 5 on the basis of our observations and
literature precedent. Cyclometalation of 2-PhPy affords a
■
We thank the Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, and the NSFC for financial support.
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