Direct Hiyama Cross-Coupling of (Hetero)arylsilanes with C(sp2)-H Bonds Enabled by Cobalt Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c00631

We report a chelation-assisted C-H arylation of various indoles with sterically and electronically diverse (hetero)arylsilanes enabled by cost-effective Cp*-free cobalt catalysis. Key to the success of this strategy is the judicious choice of copper(II) fluoride as a bifunctional sliane activator and catalyst reoxidant. This methodology features a broad substrate scope and good functional group compatibility. The synthetic versatility of this protocol has been highlighted by the gram-scale synthesis and late-stage diversification of biologically active molecules.

Full text of DOI:10.1021/acs.orglett.0c00631

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Letter
Direct Hiyama Cross-Coupling of (Hetero)arylsilanes with C(sp2)−H
Bonds Enabled by Cobalt Catalysis
Ming-Zhu Lu,* Xin Ding, Changdong Shao, Zhengsong Hu, Haiqing Luo, Sanjun Zhi, Huayou Hu,
Yuhe Kan, and Teck-Peng Loh*
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ABSTRACT: We report a chelation-assisted C−H arylation of various indoles with sterically and electronically diverse
(hetero)arylsilanes enabled by cost-effective Cp*-free cobalt catalysis. Key to the success of this strategy is the judicious choice of
copper(II) fluoride as a bifunctional sliane activator and catalyst reoxidant. This methodology features a broad substrate scope and
good functional group compatibility. The synthetic versatility of this protocol has been highlighted by the gram-scale synthesis and
late-stage diversification of biologically active molecules.
irect functionalization of inert C−H bonds represents a
sought-after strategy for forging diverse carbon−carbon
cobalt-catalyzed directed C−H arylation reactions with
arylboronic acids were also realized by the groups of Zhu,7a
Song,7b and Punniyamurthy.7c
D
and carbon−heteroatom bonds, as this strategy could enable
the direct synthesis of functionalized organic molecules in an
atom- and step-economical fashion, markedly reshaping the
logic of organic synthesis.1 Thus, the development of highly
efficient catalytic systems for the selective manipulation of C−
H bonds has attracted considerable attention from the
synthetic community. Despite the significant advances
achieved in the past several decades, a vast majority of the
well-established C−H functionalization reactions rely on the
use of rare and expensive second- or third-row transition-metal
catalysts.2 Undoubtedly, their widespread use substantially
raises concerns about the sustainability and economics of these
strategies. In this context, as a representative of a first-row
transition metal, earth-abundant air-stable cobalt complexes
have recently emerged as robust and versatile catalysts for
addressing these issues and a large variety of C−H
functionalizations have been realized by cobalt catalysis with
comparable efficiency.3 Most notably, the direct C−H
arylation reactions of (hetero)arenes using aryl Grignard
reagents,4a aryl halides,4b−e and phenol derivatives4f as viable
cross-coupling partners were successively established by in situ-
generated low-valent cobalt catalysis. In 2016, You et al.
described the cobalt-catalyzed oxidative cross-coupling reac-
tions of (hetero)arenes via double C−H activation.5 Moreover,
Song and Zhang independently reported the oxidative C−H/
C−H bond arylation of unactivated arenes under cobalt
catalysis through a mixed directing group strategy.6 Recently,
The Hiyama cross-coupling has been widely recongized as a
highly powerful approach for the formation of carbon−carbon
bonds in organic chemistry because of the distinguishing
features of organosilicon reagents such as low toxicity, high
stability, ready availability, controllable reactivity, and excellent
functional group compatibility, which offer remarkable
synthetic advantages over classic organometallic nucleophiles.8
Significant effort has been dedicated to silicon-based cross-
coupling reactions via C−H activation and functionalization
strategy.9 However, these methods largely depend on the use
of precious transition-metal catalysts, such as Pd,10 Rh,11 Ru,12
and Ir.13 In contrast, earth-abundant, environmentally benign
first-row transition-metal-catalyzed C−H bond functionaliza-
tion with readily available organosilicon reagents as coupling
partners has met with very limited success in terms of catalytic
efficiency and substrate scope (Scheme 1).14 Given the
sustainable nature of first-row transition-metal catalysts, studies
of direct C−H Hiyama cross-coupling by employing first-row
Received: February 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00631
© XXXX American Chemical Society
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A

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a
Scheme 1. First-Row Transition-Metal-Catalyzed C−H
Functionalization with Arylsilanes
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
additive
solvent
yield
c
1
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
CoCl2
KF
CsF
AgF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
toluene
PhCl
xylene
toluene
toluene
toluene
toluene
<5
<5
<5
0
11
0
c
2
3
4
5
6
7
8
9
c
d
TBAF
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CuF2
CoBr2
0
Co(acac)2
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
Co(acac)3
−
13
15
21
46
43
43
56
67
79
0
10
11
12
13
14
15
16
17
transition-metal catalysis as a viable alternative are highly
desirable for mitigating industrial costs and environmental
impacts.
e
e
e
e
,
,
,
f
f
f
,
g
g
To exploit the full potential of cost-effective cobalt catalysis,
we report herein the cobalt-catalyzed chelation-assisted C−H
arylation of indoles and pyrroles with sterically and electroni-
cally diverse (hetero)arylsilanes (Scheme 1). This cobalt-based
strategy features a broad substrate scope and excellent
functional group compatibility, which would effectively
complement the precious transition-metal-mediated Hiyama-
type processes and also significantly contribute to improving
the sustainability of organosilicon reagents in the field of C−H
functionalization chemistry.15
Our studies began with screening conditions for direct
C(sp2)−H arylation of readily prepared N-(2-pyrimidyl)indole
1a. After extensive efforts, we found that the treatment of 1a
with 3.0 equiv of trimethoxyphenylsilane 2a in the presence of
20 mol % Co(OAc)2 and 3.0 equiv of CuF2 (in 1,2-DCE at
140 °C under air for 24 h) gave the coupling product 3a in
11% yield (Table 1, entry 5). Other fluorides such as KF, CsF,
AgF, or TBAF were ineffective in activating the C−Si bond
and facilitating the transmetalation from silicon to cobalt
catalyst in this transformation (Table 1, entries 1−4). The
nature of the cobalt catalyst could significantly affect the
efficiency of the reaction, and commercially available Co-
(acac)3 was found to be the best choice, albeit in 15% yield
(Table 1, entry 9). A subsequent evaluation of different
solvents revealed that toluene was the optimal solvent to afford
the product in 46% yield (Table 1, entry 11). Furthermore,
increasing the reaction temperature to 160 °C resulted in the
formation of product 3a in 56% yield (Table 1, entry 14). The
optimal result was achieved when the reaction was conducted
in toluene (0.5 mL) under O2 (1.0 atm), with a 79% isolated
yield (Table 1, entry 16). As expected, a control experiment
demonstrated that reaction of 1a with 2a in the absence of a
cobalt catalyst failed to deliver the desired coupling product
(Table 1, entry 17).
,
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol, 3.0 equiv), Co
catalyst (0.04 mmol, 20 mol %), additive (0.6 mmol, 3.0 equiv),
b
c
solvent (2.0 mL), at 140 °C for 24 h. Isolated yield. Mn(OAc)2·
4H2O (0.6 mmol, 3.0 equiv) was added as the oxidant. TBAF (1.0
mol/L in THF). At 160 °C. Under O2 (1.0 atm). Solvent (0.5 mL).
d
e
f
g
proceeded smoothly to deliver the corresponding products in
yields from 65% to 73% (3m−3p). Moreover, substituents at
the ortho position of the substrates did not affect the efficiency
of this process (3q−3t). Naphthylsilanes proved to be
favorable coupling partners, leading to products 3u and 3v in
68% and 64% yields, respectively. Notably, a broad range of di-
and trisubstituted arylsilanes participated well in this trans-
formation under the optimal conditions (2w−2an), whereas
sterically congested mesityltrimethoxysilane 2ao resulted in a
moderate yield (46%). It is particularly noteworthy that this
cobalt-based strategy is also compatible with various
heteroarylsilanes, enabling the formation of desired products
3ap−3au in synthetically acceptable yields (44−66%).
To further extend this strategy, the scope of this Hiyama-
type C−H arylation with respect to (hetero)arenes was next
investigated (Scheme 3). In general, a broad range of indole
substrates bearing diverse functional groups were well tolerated
with the optimal conditions to deliver the corresponding
products (4b−4ag). Specifically, substrates with substituents at
position 3 reacted smoothly to furnish arylation products 4b−
4e in high yields (71−81%); substituents at position 7 of
indoles diminished the efficiency of the reaction, and the
products were obtained in moderate yields (49−57%). The
arylation reaction tolerates sensitive halide functional handles
such as fluoro (4f and 4v), chloro (4c and 4n), bromo (4h, 4o,
and 4x), and iodo (4p), enabling this methodology orthogonal
to the traditional cross-coupling reactions. In particular,
synthetically useful functional groups such as cyano (4d, 4i,
4u, and 4z) and ester (4e, 4m, 4aa, and 4ad) were well
accommodated with the typical conditions without any
compromise. Disubstituted indoles reacted uneventfully to
produce products 4ae−4ag in 64−70% yields. Additionally,
pyrrole substrates 1ah−1aj also proved to be viable substrates
With the optimized conditions established, the substrate
scope of this cobalt-catalyzed C−H Hiyama cross-coupling was
evaluated.16 As shown in Scheme 2, a variety of arylsilanes
bearing both electron-donating and -withdrawing functional
groups at the para position could successfully give the desired
coupling products (3b−3l) in moderate to good yields (52−
82%). The reaction of meta-substituted arylsilanes with 2a
B
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Scheme 2. Cobalt-Catalyzed C(sp2)−H Arylation of N-(2-
Scheme 3. Cobalt-Catalyzed C(sp2)−H Arylation of Indoles
a,b
a,b
Pyrimidyl)indole 1a with (Hetero)arylsilanes 2
1 with Trimethoxyphenylsilane 2a
a
Unless otherwise noted, the reaction conditions were as follows: 1
(0.2 mmol), 2a (0.6 mmol, 3.0 equiv), Co(acac)3 (0.04 mmol, 20 mol
%), CuF2 (0.6 mmol, 3.0 equiv), toluene (0.5 mL), under O2 (1.0
b
atm), at 160 °C for 24 h. Isolated yields.
reaction was performed on a 5.0 mmol scale (Scheme 4).
Moreover, the pyrimidyl auxiliary could be readily removed by
treatment with NaOEt (3.0 equiv) in DMSO, affording free
(NH) indoles 5a and 5b in 86% and 82% yields, respectively.
Furthermore, late-stage diversification of biologically active
molecules was conducted, and substrates derived from
melatonin 6a, tryptamine 6b, and tryptophan 6c were
smoothly arylated to generate the corresponding products
7a−7c in 52%, 69%, and 74% yields, respectively. Viibryd
(vilazodone hydrochloride) is a novel antidepressant drug
approved for the treatment of major depressive disorder
(MDD).17 We further applied this strategy as the key step of
the synthesis of vilazodone derivative 10 from commercially
available precursor 7. The C−H arylation of intermediate 8
afforded the corresponding product 9 in 76% isolated yield,
which could be readily converted to 2-arylated vilazodone
derivative 10 by the well-established method.18
A series of control experiments were conducted to gain
insights into the mechanism of this process (Scheme 5). First,
a H/D scrambling experiment was carried out in the absence
of coupling partner 2a, and the deuterium incorporation of
recovered 1a revealed that the C−H cobaltation step should be
rapid and reversible in nature. Moreover, an intermolecular
kinetic isotope effect (KIE) study from two parallel experi-
ments using 1a and its deuterated analogue 1a-d revealed a low
kH/kD value of 1.14, which implies that the C−H cleavage
might not be involved in the rate-limiting step. Furthermore,
intermolecular competition experiments between arylsilanes 2d
a
Unless otherwise noted, the reaction conditions were as follows: 1a
(0.2 mmol), 2 (0.6 mmol, 3.0 equiv), Co(acac)3 (0.04 mmol, 20 mol
%), CuF2 (0.6 mmol, 3.0 equiv), toluene (0.5 mL), under O2 (1.0
b
c
atm), at 160 °C for 24 h. Isolated yields. The corresponding
aryltriethoxysilane was used.
for generating the desired products in moderate yields (46−
61%).
To showcase the synthetic practicality of this strategy, we
next carried out a gram-scale C−H Hiyama cross-coupling of
substrate 1a with trimethoxyphenylsilane 2a. The desired
arylation product 3a was isolated in 70% yield when the
C
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Although the detailed mechanism of this cobalt-catalyzed
C−H Hiyama cross-coupling remains uncertain, a plausible
catalytic cycle was tentatively proposed on the basis of
preliminary observations and previous reports (Scheme 6).5−7
Scheme 4. Synthetic Applications
Scheme 6. Plausible Catalytic Cycle
Initially, coordination of the nitrogen chelating group to the
cobalt(III) catalyst facilitates the reversible C−H cobaltation
through a concerted metalation deprotonation (CMD) process
to afford the cobaltacycle species I, which may further proceed
via a one-electron oxidation to deliver the key cobalt(IV)
intermediate II. Subsequent transmetalation with the pentava-
lent silicate III generated in situ by the fluoride ion results in
the formation of cobaltacycle V (path a). Alternatively, the
arylsilicate probably proceeds via a transmetalation reaction to
give the copper−aryl species IV (path b),19 which may render
the following transfer of an aryl group to the cobalt-metal
center more readily. The cobaltacycle intermediate V under-
goes the oxidatively induced reductive elimination step to
afford the desired arylated product and release the Co(II)
species.13 Finally, the Co(II) species is reoxidized to regenerate
the Co(III) catalyst by Cu(II) salt or O2 oxidant,7 thus
sustaining the continuity of the proposed cycle.
Scheme 5. Preliminary Mechanistic Studies
In conclusion, we have developed a chelation-assisted C−H
arylation reaction of diverse indoles and pyrroles with a large
variety of (hetero)arylsilanes by cost-effective Cp*-free cobalt
catalysis. Key to the success of this strategy is the judicious
utilization of copper(II) fluoride as both an efficacious fluoride
source to activate the C−Si bond and the crucial reoxidant in
the catalytic cycle. This protocol features a broad substrate
scope and accommodates various functional groups. We
anticipate that the successful transmetalation from silicon to
cobalt will offer a novel synthetic approach to include a wide
range of readily available substrates and work for a large
number of silicon-based cross-coupling processes to give highly
effective transformations.
and 2k were performed to delineate the electronic preference
of the reaction, and the ratio of the corresponding coupling
products clearly indicated that electron-deficient 4-CF3-
substituted arylsiliane 2k was preferentially converted to the
desired product (1/3.67 3d/3k). Intermolecular competition
experiments between differently substituted indoles with 2a
indicated that, although a more electron-deficient indole 4u
reacts to a greater extent, the difference was negligible. These
observations are consistent with the proposal that the
electrophilic C−H cobaltation is unlikely and indole C−H
activation is not the turnover-limiting step in this reaction.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00631.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, and HRMS) (PDF)
D
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AUTHOR INFORMATION
Corresponding Authors
■
Ming-Zhu Lu − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China; orcid.org/0000-0002-6333-0803; Email: mzlu@
hytc.edu.cn
Teck-Peng Loh − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371;
orcid.org/0000-0002-2936-337X; Email: teckpeng@
ntu.edu.sg
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Authors
Xin Ding − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China
Changdong Shao − Jiangsu Key Laboratory for Chemistry of
Low-Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China
Zhengsong Hu − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China
Haiqing Luo − Department of Chemistry & Chemical
Engineering, Gannan Normal University, Ganzhou 341000,
China
Sanjun Zhi − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China
Huayou Hu − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China; orcid.org/0000-0003-4795-0866
Yuhe Kan − Jiangsu Key Laboratory for Chemistry of Low-
Dimensional Materials, School of Chemistry and Chemical
Engineering, Huaiyin Normal University, Huaian 223300,
China; orcid.org/0000-0002-2082-6796
(k) Gandeepan, P.; Muller, T.; Zell, D.; Cera, G.; Warratz, S.;
̈
Ackermann, L. 3d Transition Metals for C−H Activation. Chem. Rev.
2019, 119, 2192−2452.
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J. Direct Cross-Coupling of C−H Bonds with Grignard Reagents
through Cobalt Catalysis. Angew. Chem., Int. Ed. 2011, 50, 1109−
1113. (b) Gao, K.; Lee, P.-S.; Long, C.; Yoshikai, N. Cobalt-Catalyzed
Ortho-Arylation of Aromatic Imines with Aryl Chlorides. Org. Lett.
2012, 14, 4234−4237. (c) Punji, B.; Song, W.; Shevchenko, G. A.;
Ackermann, L. Cobalt-Catalyzed C−H Bond Functionalizations with
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00631
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledged the generous finanical
support from Jiangsu Province (BK20181066 and
18KJD150002), the National Natural Science Foundation of
China (21762002), and Huaiyin Normal University
JSKLCLDM (JSKC18014).
(5) Tan, G.; He, S.; Huang, X.; Liao, X.; Cheng, Y.; You, J. Cobalt-
Catalyzed Oxidative C−H/C−H Cross-Coupling between Two
Heteroarenes. Angew. Chem., Int. Ed. 2016, 55, 10414−10418.
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Mixed Directing-Group Strategy: Oxidative C−H/C−H Bond
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Zhang, Y. Cobalt-Catalyzed Aerobic Oxidative C−H/C−H Cross-
Coupling of Unactivated Arenes for the Synthesis of Biaryls. Org. Lett.
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