A Free Radical Cascade Silylarylation of Activated Alkenes: Highly Selective Activation of the Si-H/C-H Bonds

Article abstract of DOI:10.1021/acs.orglett.5b01067

The first example of silylarylation of activated alkenes with silanes is reported via selective activation of the Si-H/C-H bonds, which allows efficient access to silylated oxindoles through a free-radical cascade process. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01067

Letter
pubs.acs.org/OrgLett
A Free Radical Cascade Silylarylation of Activated Alkenes: Highly
Selective Activation of the Si−H/C−H Bonds
Lizhi Zhang, Dong Liu, and Zhong-Quan Liu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou Gansu 730000, P. R. China
S
* Supporting Information
ABSTRACT: The first example of silylarylation of activated alkenes with
silanes is reported via selective activation of the Si−H/C−H bonds, which
allows efficient access to silylated oxindoles through a free-radical cascade
process.
a
Table 1. Modification of the Typical Reaction Conditions
rganosilicon compounds are widely used as powerful
O
building blocks in synthetic organic chemistry.1 The C−
Si bond formation through direct C−H/Si−H bond activation
represents one of the most atom-economical and waste-
minimizing strategies for preparation of organosilicons.2
Although considerable developments in C−Si bond con-
struction via transition-metal-catalyzed Si−H/C−H bond
functionalization have been made in the past decades,3−6
more efficient and versatile methods are still highly desirable.
Of particular interest are the C−H bond activations through
free radical chemistry. We have developed a series of strategies
for C−C bond formation by selective activation of the inert C−
H bond in small molecules during the past years.7 Very
recently, several efficient radical cascade methods for synthesis
of heterocycles via selective functionalization of sp3C−H bonds
have been achieved by us.8 Inspired by these previous studies,
we began to wonder whether the Si−H bond of silane could be
selectively activated by free radical initiation. A silyl radical
would be generated by Si−H bond cleavage, and then it would
undergo a radical addition/cyclization cascade to give a silylated
oxindole (Scheme 1).
b
entry radical initiator (equiv) solvent (mL) silane (equiv) yield (%)
1
DCP (3)
DCP (3)
DCP (3)
DCP (3)
DCP (3)
DTBP (3)
Benzene (3)
ClPh (3)
3
3
3
3
3
3
3
3
3
3
6
10
56 (33)
35
2
3
DCE (3)
18
4
DMSO (3)
DMF (3)
28
5
10
6
Benzene (3)
Benzene (3)
Benzene (3)
Benzene (1)
Benzene (5)
Benzene (3)
Benzene (3)
30
c
7
TBHP (3)
20
d
8
TBHP (3)
18
9
DCP (3)
DCP (3)
DCP (3)
DCP (3)
20 (34)
36 (41)
47 (25)
80 (17)
10
11
12
a
Reaction conditions: N-methyl-N-phenylmethacrylamide (1 equiv,
0.2 mmol), Cu2O (5 mol %, 0.01 mmol), sealed tube, 110 °C, 22 h.
Isolated yields of the desired products and isolated yields of the
methylated products in the parentheses. TBHP (in water). TBHP
Silicon-centered radicals9 play an important role in material
science, polymer science, and organic chemistry.10 A variety of
investigations focusing on generation, transformation, and
application of silyl radicals have been widely studied in the
past century. However, efficient free radical cascade systems
involving silyl radicals through direct Si−H activation remain
challenging in synthetic organic chemistry. Additionally, silane
b
c
d
(in decane).
is used as a tin-free reductant alternative to organotin
compounds in most of these radical systems.11 Herein, we
wish to report the first example of silylarylation of activated
alkenes with silanes through a free-radical cascade process.
On the other hand, as an elegant radical acceptor, N-
arylacrylamide and its derivatives are ready to proceed in radical
cascade reactions resulting in substituted oxindoles.12 Recently,
we reported a free-radical addition/cyclization cascade reaction
of alkanes with activated alkenes to produce a series of alkylated
oxindoles.8a In order to prepare silylated oxindoles via radical
promoted Si−H bond activation, triphenylsilane and N-methyl-
Scheme 1. Free-Radical-Initiated Si−H/C−H Bonds
Activation in Radical Cascade Cyclization
Received: April 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01067
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Letter
a
Table 2. Free-Radical Cascade Silylarylation of N-Arylacrylamide with Silanes
a
Reaction conditions: N-arylacrylamide (1 equiv, 0.2 mmol), DCP (3 equiv, 0.6 mmol), Cu2O (5 mol %, 0.01 mmol), silane (10 equiv, 2 mmol),
b
c
benzene (3 mL) as solvent, sealed tube, 110 °C (measured temperature of the oil bath), 22 h. Isolated yields of the desired products. Isolated
yields of the methylated products in the parentheses. Recovery of starting materials (rsm).
d
N-phenylmethacrylamide were used as the model compounds
to modify the reaction conditions (Table 1). The radical
initiator, solvent, and the equivalent of silane, as shown in Table
1, critically affect the reaction efficiency. As the solvent,
benzene is better than chlorobenzene, 1,2-dichloroethane
(DCE), dimethyl sulfoxide (DMSO), dimethylformamide
(DMF), etc. (entries 1−5). Dicumyl peroxide (DCP), used
as the radical initiator, is more efficient than di-tert-butyl
peroxide (DTBP), tert-butyl hydroperoxide (TBHP), etc.
(entries 6−8). Variation of the solvent volume resulted in
decreasing yield of the desired product but increasing yield of
the methylated oxindoles (entries 9 and 10), which was
B
DOI: 10.1021/acs.orglett.5b01067
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Letter
radical. Additionally, the intermolecular competing kinetic
isotope effect (KIE) experiments through comparison of the
parallel reactions of Ph3SiH/Ph3SiD and N-methyl-N-phenyl
methacrylamide/N-methyl-N-(d5-phenyl)methacrylamide with
the same substrate were carried out (see SI). It was found that
no silylated oxindole was observed in the reaction of N-methyl-
N-phenylmethacrylamide with Ph3SiD. However, reaction of N-
methyl-N-(d5-phenyl)methacrylamide with Ph3SiH gave the
desired product in 81% yield, which resulted in kH′/kD′ = 1.1.
These data indicate that it is not the CAr−H but the Si−H bond
cleavage that should be involved in the rate-determining step of
this reaction.
Scheme 2. Suggested Mechanism
With the experimental data and precedent literature in hand,
we postulated that an electron-catalyzed silyl free-radical
addition/cyclization cascade process would be involved in this
system (Scheme 2).13 An electron is transferred from Cu(I) to
DCP, which generates a Cu(II) species, cumyloxyl anion, and
cumyloxyl radical. Subsequently, the silyl radical A would be
formed through H atom abstraction by the cumyloxyl radical
and/or methyl radical generated from β-cleavage of the
cumyloxyl radical. Since acetophenone and 2-phenylpropan-2-
ol were isolated as byproducts (please see SI), both of the
pathways producing a silyl radical might be involved in this
system. The methylated oxindoles could be formed via methyl
radical addition/cyclization cascade processes. Addition of the
silyl radical A to alkene followed by cyclization to the aromatic
core would give radical intermediate B. Deprotonation of B by
the cumyloxyl anion forms radical anion C, which could be
confirmed by isolation of 1-d-2-phenylpropan-2-ol (see SI). C
releases an electron to the next catalytic cycle and gives the
silylated oxindole.
reported by us very recently.8d Finally, the desired silylated
oxindole and the methylation product were isolated in 80% and
17% yields by using 10 equiv of silane, respectively (entry 12).
As demonstrated in Table 2, a series of silylated oxindoles
can be isolated in moderate to high yields under the typical
reaction conditions. It was found that a wide range of
substituted N-arylacrylamides and silanes are amenable to this
method. The corresponding silylated oxindoles were obtained
in good yields by reaction of triphenylsilane with various
substituted N-arylacrylamides bearing alkyl, phenyl, and
methoxyl groups as well as halogen atoms at the para position
of the aromatic core (entries 1−7). Although only a 30% yield
of the desired product was isolated, the alkynyl group can also
be tolerated in this system (entry 8). In addition, the reaction
occurred smoothly with polysubstituted and ortho-substituted
N-arylacrylamides (entries 9−10). Interestingly, 1-(3,4-dihydro-
quinolin-1(2H)-yl)-2-methylprop-2-en-1-one gave a fused N-
heterocycle in 70% yield (entry 11). Furthermore, substrates
with other functional groups such as ester and amide can also
be survived in this protocol (entries 12 and 13). N-Methyl-N-
(naphthalen-1-yl)methacrylamide led to a high product yield
(entry 14). Additional experiments showed that the N,N-
diphenylmethacrylamide and N-benzyl-N-phenylmethacryl-
amide are effective substrates in this reaction (entries 15−
16). Additionally, other silanes such as methyldiphenylsilane
and dimethyl(phenyl)silane resulted in moderate to high yields
of the corresponding silylated oxindoles (entries 17 and 18).
Compared with triphenylsilane and methyldiphenylsilane, the
dimethyl(phenyl)silane gave a relatively lower yield of the
desired product, which might be due to the stability of the silyl
radical intermediate. Finally, aliphatic silanes such as tert-
butyldimethylsilane and triisopropylsilane were studied, which
were also found to be effective substrates in this system (entries
19 and 20).
In conclusion, an efficient strategy for the synthesis of
silylated oxindoles by a free-radical cascade reaction of N-
arylacrylamides with silanes has been developed. It represents
the first example of radical-initiated silylarylation of activated
alkenes through selective activation of the Si−H/C−H bonds.
Further investigation of C−Si bond formation through radical
Si−H bond activation is underway in this laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data for all
products. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01067.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liuzhq@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This project is supported by the National Science Foundation
of China (Nos. 21272096 and 21472080).
■
A series of experiments were carried out to investigate the
details of the possible mechanism for this reaction. The reaction
was inhibited, and no desired product was found while TEMPO
was added into the system. GC-MS spectra show that it is not
the 2,2,6,6-tetramethyl-1-((triphenylsilyl)oxy)piperidine but
the 1-methoxy-2,2,6,6-tetramethylpiperidine which was formed
(see Supporting Information (SI)). The possible reason may be
that the reaction of the methyl radical with TEMPO occurs far
more quickly than hydrogen abstration of silane by a methyl
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