Ruthenium-Catalyzed Site-Selective Intramolecular Silylation of Primary C-H Bonds for Synthesis of Sila-Heterocycles

Article abstract of DOI:10.1021/jacs.7b06798

Incorporating the silicon element into bioactive organic molecules has received increasing attention in medicinal chemistry. Moreover, organosilanes are valuable synthetic intermediates for fine chemicals and materials. Transition metal-catalyzed C-H silylation has become an important strategy for C-Si bond formations. However, despite the great advances in aromatic C(sp²)-H bond silylations, catalytic methods for aliphatic C(sp³)-H bond silylations are relatively rare. Here we report a pincer ruthenium catalyst for intramolecular silylations of various primary C(sp³)-H bonds adjacent to heteroatoms (O, N, Si, Ge), including the first intramolecular silylations of C-H bonds α to O, N, and Ge. This method provides a general, synthetically efficient approach to novel classes of Si-containing five-membered [1,3]-sila-heterocycles, including oxasilolanes, azasilolanes, disila-heterocycles, and germasilolane. The trend in the reactivity of five classes of C(sp³)-H bonds toward the Ru-catalyzed silylation is elucidated. Mechanistic studies indicate that the rate-determining step is the C-H bond cleavage involving a ruthenium silyl complex as the key intermediate, while a η²-silene ruthenium hydride species is determined to be an off-cycle intermediate.

Full text of DOI:10.1021/jacs.7b06798

Article
pubs.acs.org/JACS
Ruthenium-Catalyzed Site-Selective Intramolecular Silylation of
Primary C−H Bonds for Synthesis of Sila-Heterocycles
Huaquan Fang, Wenjun Hou, Guixia Liu, and Zheng Huang*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Incorporating the silicon element into bioactive
organic molecules has received increasing attention in
medicinal chemistry. Moreover, organosilanes are valuable
synthetic intermediates for fine chemicals and materials.
Transition metal-catalyzed C−H silylation has become an
important strategy for C−Si bond formations. However,
despite the great advances in aromatic C(sp2)−H bond
silylations, catalytic methods for aliphatic C(sp3)−H bond
silylations are relatively rare. Here we report a pincer ruthenium catalyst for intramolecular silylations of various primary C(sp3)−
H bonds adjacent to heteroatoms (O, N, Si, Ge), including the first intramolecular silylations of C−H bonds α to O, N, and Ge.
This method provides a general, synthetically efficient approach to novel classes of Si-containing five-membered [1,3]-sila-
heterocycles, including oxasilolanes, azasilolanes, disila-heterocycles, and germasilolane. The trend in the reactivity of five classes
of C(sp3)−H bonds toward the Ru-catalyzed silylation is elucidated. Mechanistic studies indicate that the rate-determining step is
the C−H bond cleavage involving a ruthenium silyl complex as the key intermediate, while a η2-silene ruthenium hydride species
is determined to be an off-cycle intermediate.
been rather limited, largely because of the lack of synthetic
efficient methods to introduce the silicon atom into hetero-
cycles. For example, the existing methods for the synthesis of
[1,3]-sila-dihydrobenzofurans6 and [1,3]-sila-indolines7 utilize
highly reactive pyrophoric reagents (Na or PhLi) and
commercially unavailable organosilicon reagents.
INTRODUCTION
■
[1,3]-Sila-heterocycles that contain two heteroatoms in the
same cycle, with one of them being a Si-atom, are not naturally
occurring. Seminal works of Tacke and colleagues showed that
the carbon-to-silicon switch in bioactive heterocycles could lead
to sila-congeners with significantly altered properties, partly due
to the different covalent radius and electronegativity of silicon
from carbon.1 Among the notable examples, [1,3]-sila-hetero-
cycles bearing a stable tetraorgano-substituted silicon center,
such as sila-rhubafuran,2 tetrahydrosilaisoquinoline,3 N-Boc-
(R)-silaproline,4 and disila-compound,5 exhibit improved bio-
logical and/or physicochemical properties relative to their
parent carbon compounds (Figure 1). Such attractive features,
in combination with the lack of element-associated toxicity of
silicon, have motivated extensive research on development of
new organosilicon compounds for drug and odorant design.
However, for several decades, the exploration into this field has
These methods suffer from unsatisfactory yields, poor
functional-group tolerance, and formation of waste inorganic
salts. Transition metal-catalyzed dehydrogenative silylation of
C−H bonds has emerged as a powerful tool for C−Si bond
formations,8−10 and the intramolecular reaction offers a useful
route to the synthesis of Si-containing heterocycles. The past
two decades have witnessed significant progress in the
intramolecular silylations of aromatic C−H bonds.11 By
contrast, methods for the intramolecular silylation of aliphatic
C−H bonds are scarce. In 2005, Hartwig reported the first
example of intramolecular C(sp3)−H silylation: a platinum
complex catalyzes the silylation of one n-butyl group of tri(n-
butyl)silane at 200 °C (Figure 2a).11a The same transformation
was achieved using a rhodium catalyst, forming a five-
membered silolane at 180 °C.12 In 2014, Gevorgyan disclosed
a more general, Ir-catalyzed silylation of primary C−H bonds of
silanes bearing a picoline group on Si as the directing group,
furnishing five-membered silolanes at 140 °C.13 Takai found
that a Rh complex of diphosphine ligand is effective for the
silylation of primary C−H bonds in the ortho-alkyl chains.14 By
Figure 1. Examples of C/Si switch in drugs or fragrance leading to
improved biological or physical properties.
Received: June 30, 2017
Published: July 26, 2017
© 2017 American Chemical Society
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To date, catalytic methods of intramolecular silylation of
C(sp3)−H bonds have been established for the preparation of
silolanes and [1,2]-sila-heterocycles, however, the synthesis of
[1,3]-sila-heterocycles via intramolecular silylation of C(sp3)−
H bonds α to heteroatoms is extremely rare. Very recently,
Takai and Murai reported the only example of intramolecular
silylation of C(sp3)−H bonds α to heteroatom (Si): an Ir
catalyst of Me4Phen (Me4Phen = 3,4,7,8-tetramethyl-1,10-
phenanthrene) effects the intramolecular silylation of C(sp3)−
H bonds α to the Si atom.16 Unfortunately, attempted
silylations of C(sp3)−H bonds α to O and N atoms to form
[1,3]-oxasilolanes and [1,3]-azasilolanes were unsuccessful.
Driven by our interest in developing discrete organometallic
catalysts for C(sp3)−H bond functionalizations, recently we
synthesized new pincer Ir and Ru catalysts for alkane
dehydrogenations,17 and developed the first regioselective
alkane silylations to form linear alkylsilanes using an iridium−
iron-catalyzed dehydrogenation−isomerization−hydrosilyla-
tion.18 Here we show that a pincer ruthenium complex is
highly efficient for intramolecular silylations of various primary
C−H bonds, allowing the synthesis of [1,3]-oxasilolanes, [1,3]-
azasilolanes, [1,3]-disila-heterocycles, and [1,3]-germasilolane.
The method enables facile construction of tetraorganosilicons
bearing four different substituents at the Si-atom using simple,
readily accessible starting materials (Figure 2c).
Figure 2. Catalytic methods for intramolecular silylation of C(sp3)−H
bonds.
generating a silyl ether or silyl amine through in situ silylation
of a hydroxyl or amino group, Hartwig developed Ir-catalyzed
silylations of primary and secondary γ C(sp3)−H bonds,
producing [1,2]-sila-heterocycles.11d,15 Jeon employed the same
strategy for the Rh-catalyzed silylation of benzylic primary C−
H bonds (Figure 2b).11s
RESULTS AND DISCUSSION
■
Catalyst Evaluation. Our studies commenced with the
evaluation of catalysts for the intramolecular C(sp3)−H
silylation using (o-OMe-aryl)dimethylsilane 2a as the substrate.
The results are summarized in Table 1. With cis-cyclooctene
a
Table 1. Catalyst Evaluation for the Intramolecular Silylation of (2-Methoxyphenyl)dimethylsilane 2a
b
entry
cat. (mol %)
solvent
H acceptor
yield (%)
1
2
3
4
5
6
1a [2.5]
1b [2.5]
1b [2.5]
1b [2.5]
1b [2.5]
1c [2.5]
1d [2.5]
none
COE
COE
COE
COE
COE
COE
COE
NBE
TBE
96
99
94
96
99
<5
94
23
31
0
none
THF
toluene
hexane
none
c
7
toluene
THF
d
8
e
(Me4Phen)lr [4]
(Segphos)Rh [3]
Ru3(CO)12 [2.5]
(cod)Ru(2-methylallyl)2 [2.5]
[RuCl2(p-cymene)]2 [2.5]
1b [0.1]
9
dioxane
none
10
11
12
13
COE
COE
COE
COE
COE
none
0
none
0
none
96
90
f
14
1b [5]
none
a
b
Reaction conditions: 2a (0.2−4.0 mmol), hydrogen acceptor (1 equiv), and solvent (0.2 mL, unless otherwise noted). Yields were determined by
c
1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard. The precatalyst was activated with NaOtBu (3.75 mol %).
d
Using the same conditions utilized by Hartwig for the silylation of (hydrido)silyl ethers:15b [Ir(cod)OMe]2 (2 mol %), Me4Phen (4.8 mol %) in
e
THF (0.75 mL); Substitution of COE with NBE gave 23% 3a. Using the same conditions utilized by Takai for the silylation of (o-Et-
aryl)dimethylsilanes:14 [Rh(cod)Cl]2 (1.5 mol %), Segphos (4.5 mol %) in 1,4-dioxane (0.25 mL); Substitution of COE with TBE gave 47% 3a. At
f
80 °C for 48 h.
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a
Table 2. Substrate Scope of Ru-Catalyzed Intramolecular Silylation of C(sp3)−H Bonds α to O-Atom
a
Conditions: 2 (0.2−0.5 mmol), COE (1 equiv), 1b (0.1 mol %) at 120 °C for 24 h. Yields shown are of isolated products. Values in the parentheses
b
c
d
e
f
g
are NMR yields. 48 h. 1b (2.5 mol %). 1b (0.5 mol %). COE (2 equiv). 1b (1 mol %). At 150 °C for 60 h.
(COE, 1 equiv) as the hydrogen acceptor, the reaction of 2a
under neat conditions using (POCOP)RuH(NBD) (1a,
POCOP = bis(phosphinite)-based pincer ligand, NBD =
norbornadiene)17d as the precatalyst (2.5 mol %) previously
developed in this group, generated [1,3]-sila-dihydrobenzofur-
an (3a) in 96% yield after 24 h at 120 °C (entry 1). The
bis(phosphine)-based (PCP)RuH(NBD) (1b) was even more
effective than 1a, giving a quantitative yield of 3a under the
same conditions (entry 2). The generation of the silylation
product is accompanied by a concomitant, complete conversion
of COE to cyclooctane (COA). A screening of several
hydrogen acceptor indicated that COE was the optimal choice
(see the Supporting Information, SI). The catalysis with 1b also
occurred efficiently in organic media, such as THF, toluene, and
hexane (entries 3−5, 94−99%). The related pincer Ir catalysts
were also studied for the silylation. While the tBu-substituted
(PCP)Ir precatalyst 1c was ineffective for this reaction (entry
6), the run with the iPr-substituted variant 1d gave the
cyclization product in 94% yield (entry 7). An Ir catalyst15b of
Me4Phen and a Rh catalyst14 of SEGPHOS (SEGPHOS = (R)-
(−)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-
4,4′-bi-1,3-benzodioxole), which proved highly efficient for the
intramolecular C(sp3)−H silylation of (hydrido)silyl ethers and
(o-Et-aryl)dimethylsilanes, respectively, gave 3a in low-to-
moderate yields (entries 8 and 9). Other common Ru(0) and
Ru(II) precatalysts, such as Ru3(CO)12, (cod)Ru(2-methyl-
allyl)2, and [RuCl2(p-cymene)]2, are inactive for the silylation
(entries 10−12). The superior catalytic activity of the pincer Ru
complexes is partly attributed to their high thermal stability.19
The loading of the precatalyst 1b could be reduced to 0.1 mol
% without influencing the conversation significantly (entry
13).20 Performing the reaction at 80 °C with 1b gave the
desired product in high yield, although a 5 mol % catalyst
loading and a longer reaction time (48 h) was required (entry
14).
Substrate Scope. Having identified an effective precatalyst,
1b, for the intramolecular C(sp3)−H silylation, we examined
the scope of this method (Tables 2, 3, and 4). Note that the
starting materials, o-OMe-arylsilanes, o-NMe2-arylsilanes, and o-
SiMe3-arylsilanes, can be readily prepared by one-step arylation
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regardless of the heteroatom adjacent to the C(sp3)−H bond.
The sila-heterocyclic products obtained in this study are
moisture- and air-stable, and can be purified by flash
chromotography and stored on the bench for several months
without decomposition.
Table 3. Substrate Scope of Ru-Catalyzed Intramolecular
a
Silylation of C(sp3)−H Bonds α to N-, Si-, or Ge-Atom
Silylation of C(sp3)−H Bonds α to O Atom. (o-OMe-
aryl)dimethylsilanes bearing electron-donating and -withdraw-
ing groups in all positions of the aryl rings underwent the
intramolecular silylation smoothly (3b−3l) (Table 2). Di-
fluoro-substituted substrates were converted into the desired
cyclization products 3m and 3n in 95% and 91% yield,
respectively. In the presence of 2 equiv of COE, the reaction of
2p resulted in double cyclizations to form the disila-
benzodifuran derivative 3p selectively. The product was
characterized by X-ray diffraction analysis, which revealed a
coplanar three-ring structure. Similarly, the disilylation product
3q with a binaphthyl backbone was obtained in 83% isolated
yield, along with 10% of the monosilylation product.
The substituents at the Si-atom have a large effect on the
reactivity of the silylation. The reaction of (n-heptyl)-
methylsilane 2r proceeded smoothly under the standard
conditions. Introducing a bulky tBu group led to a less reactive
substrate 2s, although the desired product 3s could be formed
in high yield (95%) at elevated temperature (150 °C).
However, under the same conditions, the substrate with two
iPr groups at Si afforded 3t in only 18% yield. Clearly increasing
the size of the substituents at Si reduces the catalytic efficiency
of the silylation.
a
Conditions: 2 (0.2−0.5 mmol), COE (1 equiv), 1b (0.1 mol %) at
b
120 °C for 24 h. Yields shown are of isolated products. 1b (1 mol %).
c
d
e
1b (2.5 mol %). 1b (5 mol %). 1b (10 mol %). The substrate is
synthesized from the reaction of (2-(dimethylsilyl)phenyl)lithium with
chlorotrimethylgermane.
A wide range of diaryl methylsilanes are suitable substrates
for the Ru-catalyzed silylation. Compounds containing two
identical aryl groups underwent desymmetric silylations of
C(sp3)−H bonds. Regardless of the substituents in the aryl
rings, all substrates provided the corresponding cyclization
products in high yields (3u−3ad). In addition, the silylations of
a series of tertiary silanes containing two different aryl
substituents and one Me substituent at Si, were explored. A
variety of functionalities, including ether (3an−3ap), amine
(3ak), fluoro (3al), and thienyl (3am) groups, were found to
be compatible with the reaction conditions. The disilylation
product 3af was obtained in 76% yield using 2.5 mol % of 1b
and 2 equiv of COE. The reaction of 2an containing two ortho-
OMe groups in different aryl rings resulted in the formation of
a mixture of 3an (43%) and 3an′ (47%).
Table 4. Substrate Scope of Ru-Catalyzed Intramolecular
a
Silylation of C(sp3)−H Bonds α to C-Atom
This system is selective for the silylation of primary over
secondary C(sp3)−H bond α to O atom, as demonstrated by
the site-selective silylation of ortho-OMe in one aryl ring, while
the ortho-OEt group in the other ring remained intact (3ao and
3ap). A tertiary C(sp3)−H α to O is hardly active for the
silylation. Attempted cyclization of 2aq containing an ortho-
OiPr gave a trace amount of the cyclization product, but a 42%
yield of a carbosilane dimer 3aq′ resulting from the
intermolecular silylation of one Me substituent at Si from
another molecule.21
a
Silylation of C(sp3)−H Bonds α to N-, Si-, and Ge-
Atom. The catalytic silylation was successfully extended to C−
H bonds α to N-, Si-, and even Ge-atom (Table 3). A range of
(o-NMe2-aryl)methylsilanes with various alkyl or aryl sub-
stituents at Si formed the corresponding sila-methylindolines
4a−4f in high isolated yields. Furthermore, the Ru-catalyzed
intramolecular silylation of C−H bonds α to Si afforded [1,3]-
disila-heterocycles 5a and 5b in 90% and 80% yield,
respectively. To our satisfaction, an unprecedented [1,3]-
Conditions: 2 (0.2−0.5 mmol), COE (1 equiv), 1b (2.5 mol %) at
b
120 °C for 24 h. Yields shown are of isolated products. At 80 °C.
c
d
COE (3 equiv). 1b (1 mol %).
of R2ClSiH (R = Me or iPr), or one-pot, two-step arylation and
arylation/alkylation of MeCl2SiH with the corresponding
Grignard reagents. Most of the silylation reactions were carried
out under neat conditions at 120 °C with low catalyst loadings
(0.1−2.5 mol %), resulting in high isolated yields (>90%)
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germasilolane 6a was obtained in high yield by the silylation of
C−H bond α to Ge, albeit with a high catalyst loading.
Silylation of C(sp3)−H Bonds α C Atom. The pincer Ru
catalyst is also effective for the silylation of primary C−H with
no heteroatom attached (Table 4). For example, the Me groups
of ortho-Et and -iPr moiety were silylated to form Si-containing
heterocycles 7a and 7b in high yields. In addition, the silylation
of primary benzylic C−H bonds could occur to form five-
membered silolanes under relatively mild conditions. Treat-
ment of dimethyl(2-methylbenzyl)silanes with 1 equiv of COE
and 1b (1 mol %) at 80 °C produced silolanes 8a−8d in useful
yields. A unique trisilylation product 8e was obtained when 3
equiv of COE was used. The coplanar four-ring structure was
unambiguously determined by X-ray crystallographic analysis.
Large-Scale Synthesis and Synthetic Utility of [1,3]-
Oxasilolanes. The catalytic silylation process is scalable as
shown by the isolation of 7.6 g of 3a (93% yield) from a 50
mmol scale reaction using a minimum amount of the Ru
catalyst (0.05 mol % 1b), corresponding to a turnover number
(TON) of 1860 (Figure 3a).
Given the high conversions and low catalyst loadings of the
silylation reaction, we envisioned that the crude silylation
silylated product could be suitable to the subsequent cross-
coupling with PhI in one pot without purification. Indeed,
[1,3]-sila-dihydrobenzofuran 3a, derived in situ from the Ru-
catalyzed silylation of 2a, underwent Pd-catalyzed cross-
coupling with PhI to produce 9a in 82% yield (Figure 3c).
Reactivity of Different Types of Primary C−H Bonds.
To our knowledge, while a number of examples of
functionalizations of C−H bonds α to heteroatoms are
known, a comprehensive examination of the reactivity and
selectivity of such C−H bonds toward transition metal-
mediated functionalization has not been conducted. The
examples presented in Tables 2−4 demonstrate the ability of
the Ru complex 1b to catalyze the intramolecular silylation of
various types of primary C−H bonds, including C−H bonds α
to heteroatom (O, N, Si, Ge), benzylic C−H bonds, and C−H
bonds of the ortho-Et group. To assess the relative reactivity of
these primary C−H bonds, we designed six substrates bearing
two different types of primary C−H bonds on two aryl rings for
intramolecular competition studies (Figure 4).
The C−H bond α to N appeared to be more reactive than
that α to O as shown by the selective silylation of the ortho-
NMe2 (12b, 90%) versus the ortho-OMe group (12a, 3%) (eq
1). Given that the NCH2−H and OCH2−H bonds have similar
strength with bond dissociation energies (BDE) of being ca.
Figure 3. Lage-scale synthesis of [1,3]-sila-dihydrobenzofuran and
synthetic utility of [1,3]-oxasilolanes. (a) Gram-scale synthesis of 3a.
(b) Pd-catalyzed Hiyama-Denmark cross-coupling of 3 with Ph-I.
aProduct isolated by distillation. bProduct isolated by silica gel
chromatography. (c) One-pot, two-step Ru-catalyzed silylation and
Pd-catalyzed Hiyama-Denmark cross-couplings.
To demonstrate the synthetic utility of the silylation
products, Pd-catalyzed Hiyama cross-coupling of [1,3]-
oxasilolane 3 with PhI was investigated (Figure 3b). A
combination of Pd(OAc)2 with various phosphine ligands, in
the presence of NaOMe (5 equiv), was effective for the
coupling of 3a and PhI. Unfortunately, most reactions gave a
mixture of C(sp2)−C(sp2) (9a) and C(sp3)−C(sp2) (10a)
coupling products with the former as the major product (see
the SI, for product distributions). Delightfully, the use of X-
Phos (5 mol %) as the ligand proved to be highly selective for
the C(sp2)−C(sp2) coupling. The reactions of 3 and PhI in
diethyl ether at 50 °C for 12 h afforded biaryl products in high
yields. Depending on the purification procedures, either the
products with a silyl ether (9b, 9c) or silanol moiety (11a)
could be isolated (Figure 3b).
Figure 4. Intramolecular competitive silylation of different types of
primary C−H bonds. Reaction conditions: 1b (5 mol %), COE (1
equiv), at 120 °C for 24 h. Yields shown are of isolated products
(unless otherwise noted). aYields were determined by 1H NMR
analysis of the crude reaction mixture using mesitylene as an internal
b
c
standard. 1b (1 mol %). 1b (2.5 mol %).
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91.7 and 92 kcal/mol, respectively,22 the high site-selectivity for
the silylation of NCH2−H is of significance. Even more
intriguingly, the C−H of ortho-SiMe3 was silylated exclusively
(13b, 81%) in the presence of the C−H of ortho-OMe, despite
the fact that the former has much higher BDE than the latter
(98 vs 92 kcal/mol) (eq 2).22a By contrast, the competition
between the ortho-SiMe3 and ortho-NMe2 groups in 14 resulted
in the site-selective silylation of the latter (14a, 57%) (eq 3).
The benzylic C−H has lower BDE than the C−H bond α to O
(90 vs 92 kcal/mol),22b but the latter was effectively silylated
while the benzylic C−H bond remained intact (eq 4). As
expected, the reaction of the substrate containing the ortho-
OMe and ortho-Et groups revealed a specific site-selectivity for
the former (eq 5). Finally, in the presence of both of the
benzylic C−H and C−H bond of ortho-Et, the silylation
occurred exclusively at the position of the former (17, 91%) (eq
6).
The data gained above establish a reactivity order for the Ru-
catalyzed silylation of primary C−H bonds that enables the
formation of Si-containing “five-membered” heterocycles:
ArN(Me)CH2−H > ArSi(Me)2CH2−H > ArOCH2−H >
ArCH2−H > ArCH2CH2−H. The trend cannot be strictly
correlated with the BDE of the primary C−H bonds, implying
that there are both electronic and steric contributions to the
energetics of C−H activations. A Ru(II) silyl complex was
determined to be a key intermediate prior to the rate-limiting
C−H activation step (see below). The corresponding structure
bearing the SiMe3 group probably has the mostly favorable
geometry optimized for the C−H interaction with the Ru
center, while the complex with the NMe2 group is expected to
have a greater steric attraction than that with the OMe group.
With a flexible CH2 linker between Si and the aryl ring bearing
an ortho-Me group in 15, the unhindered rotations around the
C(sp3)−Si and C(sp3)−C(sp2) bonds makes the access of the
benzylic C−H bond to the metal center less likely than the C−
H bond of ortho-OMe located in the other aryl ring.
Mechanistic Analysis. To provide insights into the
mechanism of this silylation reaction, deuterium-labeling
experiments were carried out (Figure 5). The deuterated
substrate 2d-d3 containing an ortho-OCD3 group was submitted
to the standard catalytic conditions. NMR analysis of the
isolated product (3d-d2, 92% yield) revealed 10% D
incorporation (0.58 D) in two methyl groups bonded to Si
and 97% D content in the methene unit, as well as 1% D
content in the 2-position of the aryl ring (eq 7).
To probe the possibility of intermolecular H/D scrambling, a
1:1:2 mixture of 2d-d3, 2i, and COE was submitted to the
catalytic reaction (eq 8, Figure 5). NMR analysis of two isolated
silylation products revealed 8% D incorporation (0.48 D) in the
SiMe2 group of 3d-d2 and ∼1% D incorporation (0.08 D) in the
SiMe2 group of 3i-dx. Note that there is 8% and 1% D content
in the 2- and 5- positions of the aryl ring in 3i-dx, while D was
barely observed in the methene unit of this molecule.
To assess whether the intermolecular D/H exchange
observed in eq 8 involves the Si−H group, the Ru-catalyzed
silylation of 2d-d3 was performed with one equiv of PhSiMe3, in
place of 2i (eq 9, Figure 5). Heating the solution at 120 °C for
24 h resulted in 12% D incorporation (0.71 D) in the SiMe2
group of 3d-d2. Notably, intermolecular D/H scrambling did
not occur with the SiMe3 group of PhSiMe3. The resulting
cyclooctane (COA) contained 0.35 D. Small amounts of
deuterium were also present in the aryl rings of 3d-d2 and
PhSiMe3. These results, together with the phenomena of D
Figure 5. Deuterium-labeling experiments and KIE measurements.
incorporations into the aryl rings observed in 3d-d2 and 3i-dx
(cf. eqs 7 and 8), strongly suggest that an Ru(II) hydride (A)
and deuteride (A-d) species were present in the system, and the
H/D scramblings occurred through the exchange between the
aromatic C−H and the Ru−D of A-d.
Provided the lack of D incorporation in the SiMe3 groups of
PhSiMe3 (cf. eq 9), the H/D scramblings involving the SiMe2
groups of 3d-d2 and 3i-dx most likely occurred via a Ru(II) silyl
intermediate (D), rather than the interaction of the SiMe2
group with the Ru−D of A-d. A plausible H/D exchange
pathway is depicted in Figure 6. A Ru(II) silyl complex (tBu)-
D-d3 derived from the tBu-substituted deuterated substrate 2d-
d3, undergoes β-H elimination of the silyl methyl to form a η2-
silene Ru(II) hydride (tBu)-F-d3. H/D exchange between the
Ru−H bond and the C−D bond of ortho-OCD3 via a σ-bond
metathesis mechanism would generate the η2-silene Ru(II)
deuteride (tBu)-F-d3′. The reinsertion of silene then gives the
intramolecular H/D scrambling product (tBu)-D-d3′. For the
intermolecular H/D crossover reaction, the silene ligand
exchange between (tBu)-F-d3′ and (CF3)-F gives (tBu)-F-d2′
and (CF3)-F-d′. The latter undergoes the silene insertion into
the Ru−D bond, resulting in the D incorporation into the silyl
methyl groups of (CF3)-D-d′. The rate of silene insertion
occurring within (tBu)-D-d3′ would be expected to be greater
than the rate of silene exchange, accounting for the much
higher D incorporation in the SiMe2 group of 3d-d2 compared
to that in 3i-dx. Note that similar ruthenium silene complexes
have been reported by Tilley/Rheingold23 and Berry.24
Finally, measuring the initial rates of the silylations (<20%
conversion) of nondeuterated (2d) and deuterated (2d-d3)
substrates in separated vessels revealed a primary kinetic
isotope effect (KIE value: 3.9) (eq 10, Figure 5), indicating that
the C(sp3)−H cleavage is the rate-determining step.
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Article
Migratory insertion of the hydrogen acceptor, COE, into the
Ru−H bond forms a Ru(II) cyclooctyl B. The intermolecular σ-
bond metathesis between the Ru−C bond of B and the Si−H
bond of 2a affords the Ru(II) silyl intermediate D and COA.
The C−H bond activation via the intramolecular σ-bond
metathesis, which was found to be the rate-determining step,
would form the silylation product 3a and regenerate A. The η2-
silene Ru(II) hydride F is a probable off-cycle intermediate on
the basis of the facile H/D scramblings observed for the SiMe2
group. In addition, the formation of the carbosilane dimer 3aq′
in the reaction 2aq (vide supra) fully accounts for the
occurrence of the silene Ru(II) hydride species (see the
proposed pathway for carbosilane dimer formation in the SI).21
CONCLUSIONS
■
In summary, we demonstrate a highly efficient pincer
ruthenium catalyst for C(sp3)−H silylation to form novel
[1,3]-sila-heterocycle classes, encompassing unprecedented
catalytic intramolecular silylation of C−H bonds α to O, N,
and Ge. This process can be scaled on a commercial synthesis
module using a catalyst loading as low as 0.05 mol %. We also
report a protocol for one-pot, two-step Ru-catalyzed silylation
and Pd-catalyzed Hiyama-coupling of [1,3]-oxasilolane with
aryl iodide. The Ru-mediated cleavage of C(sp3)−H bond is
determined to be the rate-determining step, and the reactivity
order of various types of C(sp3)−H bonds is established. This
silylation method is applicable to the construction of a variety
of tetraorganosilicons containing four nonidentical substituents,
and further studies on catalyst development for the synthesis of
optically active tetraorganosilicons are ongoing in this
laboratory.
Figure 6. Proposed pathways for the intramolecular and intermo-
lecular H/D scrambling.
EXPERIMENTAL SECTION
■
A proposed working mechanism consistent with the
experimental observations is shown in Figure 7. Considering
Materials and Methods. All manipulations were carried out in an
argon-filled glovebox or under an atmosphere of dry argon using
standard Schlenk techniques, unless otherwise stated. n-Hexane was
purified by distillation over CaH2. Toluene, diethyl ether, and
tetrahydrofuran (THF) were freshly distilled from sodium benzophe-
none ketyl prior to use. NMR spectra were recorded on Agilent 400
MHz, Varian Mercury 400 MHz, and Agilent 600 MHz spectrometer.
1H NMR spectra were referenced to residual protio solvent peaks or
tetramethylsilane signal (0 ppm), and 13C NMR spectra were
referenced to the solvent resonance.
General Procedure for Intramolecular C(sp3)−H Silylations.
In an argon-filled glovebox, a 5 mL dried Schlenk tube was charged
with the desired amount of Ru complex 1b, hydrosilane, and cis-
cyclooctene. The tube was sealed tightly with a Teflon plug and the
mixture was stirred at 120 °C for 24 h. After the resulting reaction
mixture was cooled to room temperature, mesitylene (0.5 equiv) was
added as an internal standard and the NMR yield was determined by
1H NMR. The crude mixture was purified by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:150)
or bulb-to-bulb distillation to obtain the silylation product.
General Procedure for Hiyama-Denmark Cross-Coupling of
[1,3]-Sila-dihydrobenzofuran Products. In an argon-filled glove-
box, a 5 mL dried Schlenk tube was charged with Pd(OAc)2 (3.4 mg,
15 μmol, 5 mol %), X-phos (15.8 mg, 33 μmol, 11 mol %), NaOMe
(81 mg, 1.5 mmol) and diethyl ether (1 mL). Then, siladihydro-
benzofuran (0.3 mmol) and PhI (0.6 mmol) was added. The tube was
sealed tightly with a Teflon plug under Ar atmosphere and the mixture
was stirred at room temperature for 1 h, and heated at 50 °C for 12 h.
Then the volatile materials were removed in vacuo. Mesitylene (0.5
equiv) was added as an internal standard and the yield was determined
Figure 7. Proposed reaction mechanism for the intramolecular
C(sp3)−H silylation.
the reluctance of Ru(II) complexes toward two-electron
oxidation,25 the Ru-mediated activations of Si−H and C−H
bonds most likely proceed through a σ-bond metathesis
mechanism. The D incorporations observed in the aryl rings
and COA provide evidence in support of the existence of the
pincer Ru(II) hydride intermediate A during the catalysis.
1
by H NMR, and the crude mixture was purified by flash column
chromatography (silica gel, ethyl acetate/petroleum ether = 1:8) or
bulb-to-bulb distillation.
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Journal of the American Chemical Society
Article
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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/jacs.7b06798.
■
S
General experimental information; synthesis of sub-
strates, ruthenium catayzed intramolecular C(sp3)−H
silylations; crystal structures and crystallographic data for
3p and 8e; Hiyama-Denmark Coupling of [1,3]-sila-
dihydrobenzofuran with PhI; mechanistic studies; addi-
tional references; and NMR spectra (PDF)
Crystallographic data for 3p (CCDC 1544564) (CIF)
Crystallographic data for 8e (CCDC 1544565) (CIF)
AUTHOR INFORMATION
Corresponding Author
*huangzh@sioc.ac.cn.
■
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ORCID
Zheng Huang: 0000-0001-7524-098X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Key R&D Program of China
(2015CB856600, 2016YFA0202900), National Natural Science
Foundation of China (21432011, 21422209, 21421091,
21572255), and Chinese Academy of Sciences
(XDB20000000) is gratefully acknowledged.
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