Copper-Catalyzed Radical Silylarylation of Ynones with Silanes: En Route to Silyl-Functionalized Indenones

Article abstract of DOI:10.1002/adsc.201700926

A copper-catalyzed radical silylarylation of ynones with commercially available silanes using DCP (dicumyl peroxide) as an efficient oxidant has been developed. This approach represents an efficient route to silyl-functionalized indenone derivatives in mo

Full text of DOI:10.1002/adsc.201700926

Title: Copper-Catalyzed Radical Silylarylation of Ynones with Silanes:
En Route to Silyl-Functionalized Indenones
Authors: Jin Xie, Zhongfei Yan, and Chengjian Zhu
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10.1002/adsc.201700926
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Catalyzed Radical Silylarylation of Ynones with
Silanes: En Route to Silyl-Functionalized Indenones
Zhongfei Yan,a Jin Xie,a, * and Chengjian Zhu a, b,
*
a
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
E-mail: xie@nju.edu.cn or cjzhu@nju.edu.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A copper-catalyzed radical silylarylation of
ynones with commercially available silanes using DCP
(dicumyl peroxide) as an efficient oxidant has been
developed. This approach represents an efficient route
to silyl-functionalized indenone derivatives in moderate
to good yield. The resulting silyl-functionalized
structures hold potential for further post-modification to
construct complex target molecules. This protocol is
distinguished by its excellent selectivity, gram scale-up
ability and broad scope as well as readily available
starting materials.
Scheme 1. Strategies accessing silyl-functionalized
indenones.
Keywords: Ynone; Silylarylation; Cascade; Copper
As the indenone motifs are important structural
catalysis
scaffolds in pharmaceuticals, natural products and
material science,[7] a great number of efficient
protocols were developed to construct 2,3-
disubstituted indenone derivatives.[8] However, the
elegant approach to silyl-functionalized indenones[9]
Because of the unique physical and chemical
which hold great promise for post-modifications to
construct complex target molecules, is rather
underdeveloped. Currently, prevalent methods to
access silyl-functionalized indenones are Rh-catalyzed
carbonylative cyclization of silylalkynes with specific
arylboronic acids (Scheme 1, left part).[9] While
powerful, these reactions suffer from the necessity to
prepare both coupling partners from the corresponding
alkynes and aromatic bromides involving handling of
moisture-sensitive butyllithium. Therefore, the
development of alternatives is of great importance to
synthetic chemistry. Herein, we report a copper-
catalyzed radical silylarylation cascade of ynones with
silanes via successive Si-H and C-H bond
functionalization, providing a complementary route to
silyl-functionalized indenones (Scheme 1, right part).
Pleasingly, the ynones are easily prepared by
Sonogashira cross-couling reaction,[10] and all the
other reagents used in this protocol can be directly
obtained from commercial sources.
properties of C-Si bonds, organosilicon compounds
are widely applied in synthetic chemistry,[1a,b]
advanced materials[1c] and drug discovery.[1d] As a
consequence, the development of convenient and
practical methods to incorporate silyl units into
organic molecules is gaining considerable
momentum.[2] The utilization of silanes as silylation
agents[3] inarguably has significant advantages
concerning atom- and step-economy compared to
classical electrophilic silylation reagents such as
TMSCl and TMSOTf.[4] It can avoid either a
prefunctionalization of the reaction partners with
pyrophoric lithium reagents[5], or the use of excess
base to neutralize the acid generated during the
reaction.[6] Recently, the groups of Mizuno,[3a] Liu,[3b,c]
Gao[3d] and Studer[3e] introduced one promising
oxidative radical Si-H bond functionalization strategy,
offering a practical access to valuable organosilicons
from commercially abundant and cheap silanes.
1
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10.1002/adsc.201700926
Advanced Synthesis & Catalysis
Initially, to optimize the reaction conditions, the
reaction of 1,3-diphenyl-2-propyn-1-one (1a) and
triphenylsilane (2a) was chosen as the model system
(Table 1). When CuCl was used as a cheap catalyst in
the presence of 3 equiv DTBP in benzene at 100°C (di-
tert-butyl peroxide), the desired silylarylation product
3a was isolated in 21% yield after 24 h (entry 1).[11]
Subsequently, we screened several cheap and
environmentally benign oxidants. It was found that the
yield could be improved to 78% when DCP (dicumyl
peroxide) was employed instead of DTBP (entries 1-
4). Among the copper salts examined, CuCl gave the
best results (entries 4-8). The control experiments also
demonstrated that CuCl was an essential factor to
obtain a satisfying yield since only a small amount of
3a was produced without CuCl (78% versus 16%; for
more details please see Table S2 and S3 in Supporting
Information). Decreasing the amount of 2a also
lowered the yield (78% versus 61%, entry 4 versus
entry 10).[11] Other solvents tested could not improve
the yields but C6F6 could give a yield of 59% (entries
11-15). Finally, the optimal reaction conditions for this
radical silylarylation cascade were determined to be 10%
CuCl as the catalyst and 3 equiv DCP as oxidant at 100
oC using benzene as solvent.
Table 1: Optimization of the reaction conditions.[a]
Entry Catalyst Oxidant
Solvent
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
DCE
Yield[b] (%)
1
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
DTBP
TBHP[c]
TBHP[d]
DCP
21
2
trace
11
3
4
78
5
DCP
14
6
DCP
6
7
Cu2O
CuCl2
-
DCP
37
8
DCP
10
9
DCP
16
10[e]
11
12
13
14
15
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DCP
61
DCP
24
DCP
PhCl
13
n.d.[f]
DCP
DMSO
C6F6
DCP
59
DCP
MeCN
18
[a] Reaction conditions: 1a (0.2 mmol), 2a (5 equiv), catalyst
o
(10 mol%), oxidant (3 equiv), benzene (2 mL), 100 C, 24
h. DTBP = di-tert-butyl peroxide; TBHP = tert-butyl
hydroperoxide; DCP = dicumyl peroxide. DCE = 1,2-
Scheme 2. The reaction scope. The reaction was carried out
in 0.2 mmol scale under the optimal reaction conditions. The
yields referred to herein are isolated yields after column
chromatography.
[b]
[c]
dichloroethane. Isolated yield. TBHP (70% in water).
[d]
[e]
TBHP (5.5 M in decane). 2a: 4 equiv. [f] n.d. = Not
detected.
2
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10.1002/adsc.201700926
Advanced Synthesis & Catalysis
With the optimized conditions in hand (Table 1,
On the other hand, further transformations of the silyl-
functionalized indenone product 3m to diverse
indenone derivatives 4-7 were investigated, including
palladium catalyzed C-C coupling with iodobenzene
(Scheme 3b), electrophilic bromination and iodination
of the silyl moiety (Scheme 3c and 3d). Notably, the
successful transformation of the silyl group into
halides will provide a powerful platform to synthesize
a set of structurally diverse indenones by the
combination of orthogonal Pd-catalyzed C-C cross-
entry 4), a series of 1,3-diarylpropynones were first
investigated (Scheme 2). Under the standard
conditions, both electron-donating (-Me, -OMe, -Cl
etc.) and electron-withdrawing groups (-CF3 and -CN)
on the phenyl rings of ynones were well tolerated,
giving the desired products in satisfying yields.
Moreover, the incorporation of heteroaryl units into
ynones did not wreck reactivity (3x, 3aa, 3bb).
Unfortunately, 1-phenylhept-2-yn-1-one failed to
deliver the corresponding product (3i). Besides
triphenylsilane, other commercially available silanes,
coupling
techniques
(Scheme
3d).
These
transformations further underlined that the silyl-
functionalized indenones were versatile building
blocks for useful transformations.
i
such as PhMe2SiH, Et3SiH, Pr3SiH and Ph2MeSiH
were examined, and could uniformly afford the silyl-
functionalized indenones 3j-3cc in moderate to good
yields (up to 91%). Interestingly, when an
unsymmetric ynone was employed, the radical
silylarylation cascade reaction exhibited good
regioselectivity (3w:3w’ > 95:5), indicating that the
radical C-H annulation step preferentially occurs at the
electron-rich position of naphthalene.
Scheme 4. Mechanistic experiments.
To gain insight into the mechanism of this novel
transformation, the radical inhibitors TEMPO
(2,2,6,6-tetramethylpiperidinooxy) and BHT (2,6-di-
tert-butyl-4-methylphenol) were added into the model
reaction of 1a and 2a respectively, completely
inhibiting the reaction under the standard conditions
(Scheme 4a).[12] This result indicated that a radical
process might be involved. When deuterated
triphenylsilane Ph3SiD was employed instead of
Ph3SiH under the standard conditions, no 3a was
formed (Scheme 4b). This interesting isotope effect
strongly suggests that the oxidative Si-H cleavage step
to generate a silyl radical would be the rate limiting
step of the silylarylation cascade.
Scheme 3. Synthetic application. Please see Supporting
Information for detailed reaction conditions.
To further demonstrate the practicality of this
protocol, a gram-scale experiment was performed,
furnishing in a slightly lower yield (Scheme 3a);
verifying that our developed protocol is amenable to
construct silylated indenone derivatives in gram scale.
Scheme 5. Proposed mechanism.
3
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10.1002/adsc.201700926
Advanced Synthesis & Catalysis
According to our observation and the previous
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literature,[3b-d] a possible mechanism is illustrated in
Scheme 5. First, Cu(I)-mediated single electron
oxidation with DCP generates the cumyloxyl radical A
and corresponding Cu(II)-complex. Subsequently,
cumyloxyl radical
A undergoes intermolecular
hydrogen atom transfer (HAT) from triphenylsilane 2a
to produce silyl radical B.[13] The resulting silyl radical
B then adds to ynone 1a to give a transient alkenyl
radical C, which undergoes an intramolecular radical
cyclization with the arene. The resulting
cyclohexadienyl radical D undergoes a single electron
transfer (SET) to Cu(II) and subsequent deprotonation
to deliver the desired product 3a (path a). Alternatively,
the direct hydrogen atom abstraction of intermediate D
with radical A is also possible because 16% of 3a can
be obtained in the absence of CuCl (path b).
In summary, we have developed a copper-catalyzed
radical silylation cascade of ynones with silanes using
dicumyl peroxide as an external oxidant. It provides an
important access to silyl-functionalized indenones. A
wide range of ynones and silanes were applied,
delivering the desired indenone derivatives in
moderate to good yields. The commercially abundant
reagents and easily available ynones as well as the
scalability render this protocol very attractive to
construct structurally diverse, silyl-functionalized
indenones. Furthermore, these structures are versatile
building blocks for post-functionalization. The
application of oxidative Si-H functionalization
strategy is undergoing further study in our group.
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Experimental Section
General procedure for silylarylation: In an oven-dried
sealed tube, 1,3-diarylpropynone (1 equiv., 0.2 mmol),
silanes (5 equiv., 1.00 mmol), CuCl (10 mol %, 0.02
mmol), DCP (3 equiv., 0.6 mmol) and benzene (2 mL)
were added into and the resulting mixture was heated
at 100 oC for 24 h. After the reaction was finished, the
solvent was removed under vacuum, and the resulting
residue was purified by column chromatography on
silica gel to afford the desired product with petroleum
ether/ethyl acetate mixture as eluent.
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Acknowledgements
We gratefully acknowledge the National Natural Science
Foundation of China (21732003, 21702098, 21372114 and
21672099). We thank Xuebin Zhu in this group for reproducing the
result for 3a.
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Advanced Synthesis & Catalysis
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[11] It was found that increasing the reaction temperature to
120 oC or changing the amount of silane 2a to 10 equiv.
cannot significantly improve the yield.
[12] The silyl radical adducts with TEMPO and BHT could
not be detected.
[13]The direct hydrogen atom transfer from silanes to
cumyloxyl radical A is more likely herein because no
byproduct acetophenone and methylated indenones were
observed in the reactions. For more discussion about the
formation of acetophenone and methyl radical from
DCP, please see Ref. 3b
5
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10.1002/adsc.201700926
Advanced Synthesis & Catalysis
COMMUNICATION
Copper-Catalyzed Radical Silylarylation of Ynones
with Silanes: En Route to Silyl-Functionalized
Indenones
Adv. Synth. Catal. Year, Volume, Page – Page
Zhongfei Yan, Jin Xie,* and Chengjian Zhu*
6
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