Ruthenium(ii)/acetate catalyzed intermolecular dehydrogenative: Ortho C-H silylation of 2-aryl N-containing heterocycles

Article abstract of DOI:10.1039/c9ob00609e

The first application of a RuHCl(CO)(PPh₃)₃-OAc catalytic system on the selective intermolecular mono C-H silylation of 2-aryl N-heterocycles using HSiEt₃ as the silylating reagent has been described. This protocol features good functional group tolerance and high regioselectivity, and has potential for gram scale-up, which provides a convenient and practical pathway for the synthesis of versatile organosilane compounds. This catalytic system can also be applied to the silylation of challenging sp³ C-H bonds.

Full text of DOI:10.1039/c9ob00609e

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Takeharu Haino et al.
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DOI: 10.1039/C9OB00609E
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Ruthenium(II) / Acetate Catalyzed Intermolecular
Dehydrogenative Ortho C-H Silylation of 2-Aryl N-
Containing Heterocycles
Received 00th January 20xx,
Accepted 00th January 20xx
Shun liu,a Qiao Lin,a Chunshu Liao,a Jing Chen,a Kun Zhang,a Qiang Liu,ab and Bin Li*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
intermolecular C-H ortho-silylation with N-containing heterocycles
as directing groups. Kakiuchi reported the first C-H ortho-silylation
of pyridine derivatives by using Ru3(CO)12 catalyst, but affording
mono silyl-pyridine and di silyl-pyridine products.12 Murata reported
the first [RuCl2(p-cymene)]2 catalyzed ortho C-H silylation but at
200 oC.13 Recently, Mashima14 and Oro15 have succeeded to perform
ortho C-H silylation of pyridine derivatives with good
chemoselective by using (C^C)(C^N)Ir-OAc catalyst or NHC-Ir
catalyst [Ir(H)2(IPr)(py)3][BF4].
The commercial ruthenium(II) complex [RuCl2(p-cymene)]2 with
carboxylate as co-catalyst has shown advantages in Ru(II) catalyzed
C-H bond functionalizations, such as arylation,16 alkenylation,17
annulation18 etc. However, RuHCl(CO)(PPh3)3-carboxylate catalytic
system has never been reported for the direct C-H silylation reaction.
Based on our previous contribution on Ru(II) catalyzed C-H
silylation,19 herein, we report an efficient selective mono C-H
silylation of N-containing heterocycles by using commercially
available RuHCl(CO)(PPh3)3/KOAc catalytic system. (Scheme 1)
The first application of RuHCl(CO)(PPh3)3-OAc catalytic system
on selective intermolecular mono C-H silylation of 2-aryl N-
heterocycles using HSiEt3 as the silylating reagent has been
described. This protocol features good functional group
tolerance, high regioselectivity, gram scale-up ability, which
provides a convenient and practical pathway for the synthesis of
versatile organosilane compounds. This catalytic system can be
also applied to the silylation of challenging sp3 C-H bonds.
Organosilane compounds are important molecules due to their
unique properties of C-Si bonds,1 and they are not only widely
existing in advance materials and pharmaceuticals,2 but also as
valuable key synthetic intermediates for a variety of chemical
transformations in modern organic synthesis.3 Among the most
useful methods for the synthesis of organosilanes, even classical
electrophilic silylation by reagents such as TMSOTf or TMSCl is
well established to be
a simple way to prepare functional
organosilane compounds, the limitations of this method still exist,
such as the low functional group tolerance, waste inorganic salts
production, and a multistep synthetic sequence.4 Recently, the
transition-metal catalyzed direct C-H bond silylation has attracted
much attention as a straightforward method to synthesize functional
organosilane compounds because of their atom- and step-ecconomy.5
Hartwig’s group reported Rh and Ir systems which can efficiently
catalyze the C-H silylation of C=O bond as directing group.6 Choi,7
Huang,8 and Pilarski9 developed the C-H silylation on heteroarenes
using Rh or Ru precatalysts.
N-containing heterocycles are important structural motif as
ligands in material science and drug discoveries,10 Moreover, N-
containing heterocycles including pyridine, oxazoline, quinoline,
thiazole, pyrazole etc are efficient directing groups for ortho C-H
bond functionalization.11 However, only few reports deal with the
synthesis of silyl-functionalized N-containing heterocycles via
a. School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020,
Guangdong Province, P.R. China
b. Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua
University, Beijing, China
E-mail: Dr. Bin Li: andonlee@163.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. Ru(II)-OAc Catalyzed Ortho C-H Activation
J. Name., 2013, 00, 1-3 | 1
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Furthermore, the variety of silanes, such as Et3SiH, Et(Me)2SiH,
(MeO)3SiH, Et2SiH2, (EtO)3SiH, (Me)2PhSiH, (Me)2EtOSiH and
Me(EtO)2SiH, were tested in toluene at 120 oC for 20 h in the
presence of 5 mol% of RuHCl(CO)(PPh3)3, 30 mol% of KOAc, and
4 equiv. of nbe. However, only Et3SiH as coupling reagent could
lead to desired product in good yield, other silanes give the low
yields and seem not favor this ortho C-H silylation. (Table 2)
Optimization of reaction conditions was initiated by
examining the coupling reaction of 2-phenylpyridine (1a) with
triethylsilane (2a) using ruthenium catalysts (Table
product 3a was obtained in 13% GC-yield, in the presence of 5
mol% of [RuCl2( -cymene)]2 as catalyst, equiv. of
1). The
p
4
o
cyclohexene as hydrogen acceptor in toluene at 120 C under
N2 atmosphere (Table 1, entry 1). Upon addition of 20 mol% of
KOAc as co-catalyst, the yield of product 3a increased to 25%
(Table 1, entry 2). When this reaction was performed in DMF
or NMP, no conversion of product 3a was detected (Table1,
entries 3 and 4). The yield of product 3a was slightly improved
Table 2. Ru(II)-Catalyzed ortho C-H Silylation of 2-Phenylpyridine
with different silanes[a]
when using RuCl2(PPh3)3 as catalyst instead of [RuCl2(
cymene)]2 (Table 1, entry 5). It is worthy to mention that the
use of KPF6, AgSbF6, KO Bu, or KBF4, inhibits the formation
p-
t
of the C-H silylation product 3a (Table 1, entries 6-9). When
norbornylene (nbe) was chosen as hydrogen acceptor, the yield
of C-H silylation product 3a increased to 35% (Table 1, entry
10). Fortunately, among the tested ruthenium catalysts, such as
Ru3(CO)12, RuHCl(CO)(PPh3)3, RuH2(CO)(PPh3)3, RuCl2(2,2’-
bipyridyl)3.6H2O and [RuCl2(COD)]n, the best catalyst for this
C-H silylation was found to be RuHCl(CO)(PPh3)3, and the
yield of product 3a reached 82% (Table 1, entries 12-16).
Finally, when the amount of KOAc was increased to 30 mol%,
up to 95% yield of silyl-functionalized pyridine product 3a was
obtained, while only 10% yield of product 3a was observed
with the absence of KOAc. (Table 1, entries 17 and 18) These
results indicated that KOAc plays an important role as the co-
catalyst for the selective C-H silylation.
Entry
Silane
Yield (%)
1
2
3
4
5
6
7
8
Et3SiH
95
12
30
15
26
5
Et(Me)2SiH
(MeO)3SiH
Et2SiH2
(EtO)3SiH
(Me)2PhSiH
(Me)2EtOSiH
Me(EtO)2SiH
20
9
[a]
Reaction conditions: 2-phenylpyridine 1a (0.5 mmol), silane (2.0 mmol),
RuHCl(CO)(PPh3)3 (5 mol%), KOAc (30 mol%), nbe (2.0 mmol), and toluene (1 mL) at
120 oC for 20 h under N2. The product yield was determined by GC-MS.
To evaluate the scope of this catalytic reaction, the optimized
reaction conditions were applied to a range of 2-aryl N-containing
heterocycles 3a-m (Scheme 2). The ortho C-H silylation of 2-aryl
pyridine derivatives (1b-d) occurred on aryl ring bearing Me-, MeO-
and CF3- at the 4-position to afford 3b-d in 84%, 73% and 52%
yields, respectively. These results indicated that the electron-
donating groups provided more reactive substrates for this C-H
silylation than electron-deficient ones (3b-d). The pyridine ring
bearing 3-methyl group or 5-phenyl group were compatible in this
transformation as well (3e-f). Moreover, quinoline derivatives were
also applicable to the catalytic system, and the silylated products 3g-
i were obtained in 75-81% yields. It is noteworthy that the silylation
of 4-chloro-2-phenylquinoline 1h was successfully silylated to
afford the corresponding product 3h without the dehalogenation of
the chloro group. Interestingly, the C-H silylation was located on the
thiophen ring with the reaction of 2-(thiophen-2-yl)pyridine 1j.
Other 2-phenyl N-containing heterocycles, such as thiazole, pyrazole
and oxazoline derivatives, also proceeded smoothly in the C-H
silylation catalytic system, giving the desired silylated products 3k-p
in moderate to good yields. Furthermore, this C-H silylation could
tolerate ester group on the oxazoline aryl ring, and the corresponding
silylated oxazoline product 3q was directly obtained without the
reduction of the carbonyl moiety.
Table 1. Optimization of Ru(II)-Catalyzed ortho C-H Silylation of
2-Phenylpyridine[a]
yield
(%)
entry
1
catalyst
additive
----
alkene
[RuCl2(p-cymene)]2
cyclohexene
13
2
3
4
5
6
7
8
9
10
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
RuCl2(PPh3)3
KOAc
KOAc
KOAc
KOAc
KPF6
AgSbF6
KOtBu
KBF4
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
norbornylene
methyl
25
---b
---c
29
13
---
5
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
RuCl2(PPh3)3
3
35
RuCl2(PPh3)3
KOAc
11
RuCl2(PPh3)3
KOAc
7
acrylate
12
13
14
Ru3(CO)12
RuHCl(CO)(PPh3)3
RuH2(CO)(PPh3)3
RuCl2(2,2’-
bipyridyl)3.6H2O
[RuCl2(COD)]n
KOAc
KOAc
KOAc
norbornylene
norbornylene
norbornylene
30
82
9
15
16
17
18
KOAc
KOAc
KOAc
----
norbornylene
norbornylene
norbornylene
norbornylene
13
48
95d
(85e)
10
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
[a]
Reaction conditions: 2-phenylpyridine 1a (0.5 mmol), triethylsilane (2.0 mmol),
catalyst (5 mol%), additive (20 mol%), alkene (2.0 mmol), and toluene (1 mL) at 120 o
C
for 20 h under N2. The product yield was determined by GC. [b]In DMF. [c]In NMP. [d]30
mol% of KOAc was used. [e]Isolated yield.
2 | J. Name., 2018, 00, 1-3
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Similarly, mixed oxidative O-Si coupling products 4b and double
silylated compound 5b were observed in 72% yield with a ratio of
30:70 (eq 3). These results indicated that both hydrosilation of C=O
bond and oxidative O-Si coupling are more favored than the C-H
silylation process.
The synthetic potential of this C-H silylation was further
demonstrated by a gram-scale synthesis (eq 4). 5 mmol of 2-
phenylpyridine 1a was silylated under the standard conditions to
generate 1.18 g of the desired silylation product 3a (88% yield).
Reaction conditions: 1 (0.5 mmol), triethylsilane (2.0 mmol), RuHCl(CO)(PPh3)3 (5
mol%), KOAc (30 mol%), nbe (2.0 mmol), and toluene (1 mL) at 120 oC for 20 h under
N2.
Scheme 2. Ru(II)-OAc Catalyzed ortho C-H Silylation of 2-Aryl
heterocycles.
Intermolecular sp3 C-H silylation is usually more challenging than
the silylation of sp2 C-H bonds. This catalytic system also displayed
good reactivity for sp3 C-H bond silylation of 8-methylquinoline,
and the corresponding silyl-compound 6 was isolated in 81 %
yield.(eq 5)
Hydrosilanes have been shown to be an excellent reductants for
the reduction of C=O bond. In order to test the reaction rate and the
aldehyde group tolerance, the reaction of 4-(pyridin-2-
yl)benzaldehyde with triethylsilane was performed under similar
conditions (eq 1). Interestingly, only the hydrosilylation product of
aldehyde 4c was produced in 88% isolated yield.20 Under the same
reaction conditions, 68% isolated yield of ortho C-H silylation
product 5c was obtained using silyl ether 4c as the substrate. These
results indicated that: (1) the reaction rate of hydrosilylation of
aldehyde is much faster than the C-H silylation. (2) silyl-group could
be used as a potential hydroxyl protection group in C-H silylation
process.
The easiness and reversibility of the ortho C-H bond cleavage
were studied by H/D exchanges. First, the reaction of 1a in the
presence of KOAc (30 mol%) and D2O (0.2 mL) was carried out
o
under the previous reaction conditions at 120 C for 12 h. 93% of
H/D exchange took place at the ortho C-H bond (Scheme 3). The
same reaction performed without KOAc led to an decreased H/D
exchange at ortho position (68%) at 120 oC for 12 h. However,
o
decreasing the temperature to 80 C and giving lower H/D exchange
under the similar conditions. These results indicated that the KOAc
plays an important role to promote this C-H silylation.
Increasing the quantity of triethylsilane and norbonylene to 6
equivalents under similar conditions, 75% yield of a mixture of silyl-
compounds 4a and 5a with a ratio of 65 : 35 was obtained from the
reaction of 6-(4-(methylthio)phenyl)picolinaldehyde 1p (eq 2).
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First, the Ru-Cl bond of Ru catalyst would be converted to Ru-OAc
bond by the salt metathesis with KOAc. Next, Ru(IV) species B
could be easily generated by the hydrosilylation of triethylsilane, as
it was well demonstrated by Gunanathan20 and Murata13. Then, after
norbornylene insertion, reductive elimination, the active species C
would be formed and release bicyclo[2,2,1]heptane. And the
subsequent acetate promoted C-H bond cleavage gave the
intermediate D, as Ru-OAc catalyst was found the efficiency for C-
H bond activation via C-H bond cleavage as demonstrated by Jutand
and Dixneuf22. Finally, a new Si-C bond was generated to produce
the desired silylated product 3 after reductive elimination of D, and
the active Ru-OAc species would be regenerated by the coordination
of HOAc for the next catalytic cycle.
Scheme 3. H/D Exchange Experiments in 2-Phenylpyridine 1a.
Furthermore, to gather more information, ortho-deuterium labeled
pyridine derivative ([D]-1c) was used to study the kinetic isotopic
effects (KIE) during the C-H silylation. Two separate, parallel
reactions of triethylsilane with pyridine derivative 1c and [D]-1c
were performed to determine the KIE value (Scheme 4), and a
significant KIE value (kH/kD = 2.79) was observed. This result
indicated that C-H bond cleavage step is the rate determining step in
RuHCl(CO)(PPh3)3 catalyzed ortho C-H silylation.
Scheme 6. Proposed Mechanism.
Experimental
1) General Remarks. 1H NMR spectra were recorded in CDCl3 at
ambient temperature on Bruker
AVANCE I 300 or 500
Scheme 4. Isotope Effect of Deuterium-Labeled Substrates.
spectrometers at 300.1 MHz or 500.1 MHz, using the solvent as
internal standard (7.26 ppm). 13C NMR spectra were obtained at 75
or 125 MHz and referenced to the internal solvent signals (central
peak is 77.2 ppm). Chemical shift (δ) and coupling constants (J) are
given in ppm and in Hz, respectively. The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet, and br. for broad. GC analyses were performed with GC-
14C (Shimadzu) equipped with a 30-m capillary column (Supelco,
SPB-5, fused silica capillary column, 30 M*0.25 mm*0.25 mm film
thickness), was used with N2/air as vector gas. GCMS were
measured by GCMS-7890A-5975C (Agilent) with GC-7890A
equipped with a 30-m capillary column (HP-5ms, fused silica
capillary column, 30 M*0.25 mm*0.25 mm film thickness), was
used with helium as vector gas. HRMS were measured by MAT
95XP (Termol) (LCMS-IT-TOF).
Moreover, to test the selectivities of our catalytic system, we
conducted competitive experiments with different subtituted 2-aryl
pyridines 1, which revealed that the electron-rich arenes gave slight
higher reactivity in this RuHCl(CO)(PPh3)3/KOAc catalyzed C-H
silylation, and these results could explain this C-H bond cleavage
process could be an acetate-assisted electrophilic substitution (IES)-
type mechanism19,21 (Scheme 5).
Scheme 5. Competitive C−H Silylation Reaction.
2) General procedure. Ru(PPh3)3(CO)HCl (0.025 mmol, 23.8 mg),
pyridines (0.5 mmol), hydrosilane (2.0 mmol), KOAc (0.15 mmol,
Based on the previous results, a proposed catalytic cycle for the
Ru-OAc catalyzed ortho C-H silylation is illustrated in Scheme 6.
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9. K. Devaraj, C. Sollert, C. Juds, P. J. Gates and L. T. Pilarski, Chem.
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15 mg), norbornylene (2.0 mmol, 197 μL) and toluene (1 mL) were
introduced in a tube under N2, equipped with magnetic stirring bar
and was stirred at 120 C. After 20 h, the conversion of the reaction
was analyzed by gas chromatography. The solvent was then
evaporated under vacuum and the desired product was purified by
using a silica gel chromatography column and a mixture of petrol
ether/ethyl acetate as eluent.
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o
Conclusions
In summary, we have developed a new Ru(II)-OAc catalytic system
and its application in the ortho C-H silylation of 2-aryl heterocycles
using HSiEt3 as the silylating reagent. Many heterocycles such as
pyridine, quinoline, thiazole, pyrazole and oxazoline were converted
into mono-silylated compounds successfully in moderate to good
yields. Moreover, this catalytic system could be applied to the
silylation of more challenging sp3 C-H bonds.
15. L. Rubio-Pérez, M. Iglesias, J. Munárriz, V. Polo, V. Passarelli, J. J.
Pérez-Torrente and L. A. Oro, Chem. Sci. 2017, 8, 4811.
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Conflicts of interest
There are no conflicts to declare.
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B. Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf, Green
Chem. 2011, 13, 3075. (c) R. Manikandan and M. Jeganmohan, Chem.
Commun. 2017, 53, 8931.
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Huang and H.-C. Xu, ACS Catal. 2018, 8, 3820. (c) K. S. Singh, S. G.;
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Acknowledgements
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We thank the Support of the National Natural Science Foundation of
China (No: 21702148), the Foundation of Department of Education
of Guangdong Province.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00609E
Table of contents entry
HSiEt3
Ru-OAc
DG
DG
 up to 88% yield
 high regioselectivity
 gram scale
SiEt3
H
DG
= pyridine, quinoline, thiazole, pyrazole, oxazoline etc
The application of RuHCl(CO)(PPh3)3-OAc catalytic system on selective
intermolecular mono C-H silylation of 2-aryl heterocycles using HSiEt3 as the
silylating reagent has been described for the first time