Mild Rh(III)-catalyzed direct C-H bond arylation of (hetero)arenes with arylsilanes in aqueous media

Article abstract of DOI:10.1021/ol500754h

An efficient rhodium(III)-catalyzed C-H bond activation and further direct arylation of (hetero)arenes with organosilanes in aqueous media was developed. This reaction shows good substrate scope and excellent functional group compatibility and gives the products in good yields with excellent regioselectivity.

Full text of DOI:10.1021/ol500754h

Letter
pubs.acs.org/OrgLett
Mild Rh(III)-Catalyzed Direct C−H Bond Arylation of (Hetero)Arenes
with Arylsilanes in Aqueous Media
Ming-Zhu Lu,† Ping Lu,† Yun-He Xu,*,† and Teck-Peng Loh*,†,‡
†Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: An efficient rhodium(III)-catalyzed C−H bond
activation and further direct arylation of (hetero)arenes with
organosilanes in aqueous media was developed. This reaction
shows good substrate scope and excellent functional group
compatibility and gives the products in good yields with
excellent regioselectivity.
ransition-metal-catalyzed C−H bond activation or func-
tionalization has emerged rapidly as an efficient and
co-workers.8 Shortly after that, our group also developed a
direct arylation of cyclic enamide with arylsilanes using
Pd(OAc)2 as the catalyst.9 Zhang and co-workers also reported
the regioselective C2-arylation of indoles with arylsilanes in
acidic medium by palladium catalyst.10b However, there are still
very few examples on C−H bond direct arylation using
organosilanes as the coupling reagents.10 Very recently, the Shi
group reported an example of direct oxidative coupling with
arylsilanes via rhodium(III)-catalyzed C−C bond cleavage.11
Encouraged by this work and pursuing our continuous interests
in Rh(III)-catalyzed C−H bond functionalization,12 herein, we
report an efficient Rh(III)-catalyzed C−H bond direct arylation
of (hetero)arenes with arylsilanes under mild reaction
conditions.
Indole represents one of the most important structural
scaffolds in bioactive products and medicinal reagents.13
Therefore, we chose indole as the model substrate for this
reaction with trimethoxyphenylsilane 2a in the presence of 2
mol % [Cp*RhCl2]2 and 8 mol % AgSbF6 as the catalyst, 2
equiv of AgF as the activator, 2 equiv of Cu(OAc)2 as the
oxidant, at 130 °C in dioxane for 48 h. Unfortunately, no
desired product was observed. This result prompted us to
evaluate the influence of different substituents on the indole
nitrogen atom. After extensive screenings, we were pleased to
find that the reaction of N-(2-pyrimidyl)indole 1a with
trimethoxyphenylsilane 2a resulted in the formation of the
product in 78% yield (Table 1, entry 1). No desired product
was detected in the absence of [Cp*RhCl2]2 or AgF (Table 1,
entry 2 and 3). Cu(OAc)2 was an efficient oxidant to promote
this reaction as only 21% yield was obtained without this
oxidant (Table 1, entry 4). 80 °C was found to be the optimal
T
straightforward synthetic protocol employed in the synthesis of
complex natural products or functional molecules over the past
decade.1 This strategy obviates prefunctionalization of the
starting materials, thus dramatically improving the overall
efficiency in an atom- and step-economical manner for carbon−
carbon and carbon−heteroatom bond formation. Among many
transition-metal catalysts, palladium catalysts are well-known to
meet this purpose.2 Despite significant advances made in recent
years, there is still a need to design a new system that has high
functional group tolerance and can work for a wide variety of
substrates in high selectivity using low catalyst loading. In this
context, the development of a novel and efficient catalytic
system for C−H bond functionalization is highly desirable.
Recently, increased attention has been focused on Rh(III)-
catalyzed C−H bond activation because of its high selectivity,
broad substrate scope, and excellent functional group
tolerance.3 Many examples of C−H bond direct olefination
using various directing groups have been reported.4 However,
direct arylation to form a biaryl structural motif via rhodium-
(III)-catalyzed C−H bond functionalization has been seldom
explored. Until now, only a few examples under relatively high
temperature were reported.5 Thus, there still remains a major
challenge in achieving an efficient and selective direct arylation
of aromatic or alkenyl C−H bond under mild conditions.
The Hiyama cross-coupling reaction is one of the most useful
and reliable approaches for the formation of C−C bonds and is
well utilized by organic chemists.6,7 Compared with many other
organometallic coupling-partners widely used in conventional
coupling reactions, organosilicon reagents have many unique
advantages, including nontoxicity, high stability, environmental
benignity and ease of introduction into substrates. The
pioneering work of organosilicon reagents in Pd(II)-catalyzed
C−H functionalization reactions was first reported by Shi and
Received: March 13, 2014
Published: April 30, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Table 2. Rh(III)-Catalyzed Direct Arylation of 1a with
a
Various Arylsilanes 2
b
entry
1
fluoride
solvent
temp (°C)
time (h)
yield (%)
AgF
AgF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DMF
130
130
130
130
100
80
48
48
48
48
48
48
48
48
48
48
48
48
48
24
24
24
24
78
0
c
2
3
0
d
4
AgF
AgF
AgF
AgF
CsF
TBAF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
21
84
88
69
<5
<5
92
83
95
85
95
95
65
92
5
6
7
60
8
80
9
80
10
11
12
13
14
80
80
THF
80
DCM
80
THF
80
e
15
THF
80
e
16
e
H2O
80
f
17
THF/H2O
80
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (2
mol %), AgSbF6 (8 mol %), fluoride (2.0 equiv), Cu(OAc)2 (2.0
b
c
d
equiv), solvent (2 mL). Isolated yields. No [Cp*RhCl2]2. No
e
f
Cu(OAc)2. No AgSbF6. THF/H2O (1 mL/1 mL).
temperature, with the yield 88% (Table 1, entry 6). Other
fluoride sources substantially inhibited this transformation
(Table 1, entry 8 and 9). Different solvents were subsequently
investigated, and THF was found to be the best solvent (Table
1, entry 10−13). Interestingly, this reaction could be conducted
in the absence of AgSbF6 in 24 h with the same yield (Table 1,
entry 15). Much to our surprise, this reaction could be
performed in H2O in 65% yield (Table 1, entry 16). To the best
of our knowledge, this is the first example of transition-metal-
catalyzed C−H bond functionalization with organosilicon
reagents in water.14 After many trials, we were delighted to
find that the desired product could be achieved in 92% yield
when carried out in 1:1 mixture of THF and H2O as the
cosolvent (Table 1, entry 17). With our long-standing interests
in developing efficient reactions in aqueous media,15 we
selected this mixture solvent system for this reaction.16
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (2
With the optimized reaction conditions in hand, we next
turned our attention to examine the substrate scope of this
process. Various arylsilanes 2 were surveyed under the
optimized conditions (Table 2). Triethoxyphenylsilane 2b
showed similar efficiency as with trimethoxyphenylsilane 2a
giving the desired product 3aa in excellent yield (Table 2,
entries 1 and 2). Dimethoxydiphenylsilane 2c was also
applicable for this reaction but with a slight decrease in
reactivity than monophenylsilanes (Table 2, entry 3). The
different substituents had a negligible electronic effect on this
transformation, both the phenylsilanes with electron-donating
and electron-withdrawing group on the phenyl ring could
furnish the desired products in high to excellent yields. It was
worth noting that C−Cl on the phenylsilane could be tolerated
under the reaction conditions, enabling further functionaliza-
tion at the chloro substituted position (Table 2, entry 7).
Thienylsilane 2j could also be employed as the coupling partner
mol %), AgF (2.0 equiv), Cu(OAc)2 (2.0 equiv) in THF/H2O (1 mL/
1 mL). Isolated yields.
b
and gave the corresponding product in 67% yield, an attractive
alternative for aryl−heteroaryl bond formation under mild
conditions (Table 2, entry 10). In addition, dimethylphenylsi-
lanol 2k also showed good efficiency in this transformation
under the same reaction conditions and gave the product 3aa in
78% yield (Table 2, entry 11).
The scope of this transformation with respect to arene
substrates was next evaluated under the optimal conditions.
The results are summarized in Scheme 1. Much to our delight,
a broad scope of substrates bearing various groups at 3−7-
positions proved to be favorable in the reaction and gave the
corresponding products in excellent yields. Notably, both
electron-donating and electron-withdrawing groups, including
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Organic Letters
Letter
Scheme 1. Rh(III)-Catalyzed Direct Arylation of Various
Indoles and Pyrroles with Trimethoxyphenylsilane 2a
Scheme 2. Rh(III)-Catalyzed Direct Drylation of
Heteroarenes 5 with Trimethoxyphenylsilane2a
a b
,
Scheme 3. Kinetic Isotope Effect
Scheme 4. Proposed Catalytic Mechanism
a
Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (2
mol %), AgF (2.0 equiv), Cu(OAc)2 (2.0 equiv) in THF/H2O (1 mL/
b
1 mL). Isolated yields.
fluoro (3ja and 3ma), chloro (3ca and 3ga), bromo (3da, 3ka
and 3na), methoxy (3ia), and in particular, cyano (3la) and
ester group (3fa and 4ba), were well tolerated under the
conditions. Moreover, substituents at the 3- and 7-positions of
indole did not cause obvious steric inhibition on this reaction.
In addition, this protocol was not limited to indole substrates.
The pyrrole substrates 4a−4c were also found to react with 2a
smoothly and provided the products in 58, 63, and 88% yields,
respectively.
To explore the utility of this transformation, other N-
containing heterocycles were also examined (Scheme 2).
Benzo[h]quinolone, pyridinyl, pyrazolyl, and pyrimidyl groups
demonstrated good reactivity, and the desired products were
obtained in good to excellent yields (52−77%).17
Preliminary isotope experiments were conducted to obtain
more insights into the mechanism of this process. Intermo-
lecular competition experiments between N-(2-pyrimidyl)-
indole 1a and its deuterated analogue 1a-d exhibited a kinetic
isotopic effect (KIE) of 1.1 (Scheme 3), which suggested that
the C−H cleavage was not the rate-determining step in the
catalytic cycle. On the basis of previous reports,8−11 we
proposed the plausible mechanism to account for this reaction
(Scheme 4). The process is likely to be initiated by the
coordination of the nitrogen atom of 2-pyrimidyl group of 1a to
the rhodium catalyst and subsequent cyclometalation process
via C−H bond cleavage gives the five-membered rhodacycle A.
Next, the intermediate reacts with the pentavalent arylsilicate B
to afford the Rh(III) intermediate C, which is generated in situ
with fluoride. Finally, reductive elimination provides the
product 3a and Rh(I) species, which is reoxidized to Rh(III)
species by AgF or Cu(OAc)2 to complete the catalytic cycle.
In conclusion, we have demonstrated a versatile rhodium-
(III)-catalyzed C−H bond activation and further direct
arylation of (hetero)arenes with organosilicon reagents in
aqueous media. This transformation exhibits excellent reactivity
and broad substrate scopes, which provides the coupling
products in good to excellent yields. Various functional groups
are well tolerated under the mild reaction conditions. Further
investigation to extend this reaction is now ongoing in our
laboratory and will be reported in due course.
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Organic Letters
Letter
Synth. Catal. 2013, 355, 1724. (m) Zhao, P.; Liu, R.; Wang, F.; Han, K.
L.; Li, X. W. Org. Lett. 2012, 14, 4166.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, HRMS). This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(5) (a) Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xyh0709@ustc.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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Am. Chem. Soc. 2009, 131, 14188.
(8) Yang, S. D.; Li, B. J.; Wan, X. B.; Shi, Z. J. J. Am. Chem. Soc. 2007,
129, 6066.
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21372210) and the
Singapore Ministry of Education Academic Research Fund
(MOE2011-T2-1-013, NEA1002111 and MOE2010-T2-2-067)
for the funding of this research.
(9) Zhou, H.; Xu, Y.-H.; Chung, W.-J.; Loh, T.-P. Angew. Chem., Int.
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