In-situ-generation of alkylsilyl peroxides from alkyl hydroperoxides and their subsequent copper-catalyzed functionalization with organosilicon compounds

Article abstract of DOI:10.1016/j.tetlet.2021.153144

Alkylsilyl peroxides were generated in situ from the corresponding alkyl hydroperoxides using organosilicon compounds of the type Me₃SiX (X = CN, N₃, and halogens) and an amine base. Subsequent in situ copper-catalyzed homolytic cleavage of the alkylsilyl peroxides afforded alkyl radicals, which were then trapped with X (X = CN, N₃, and halogens) to furnish products with new carbon-carbon, carbon-nitrogen, or carbon-halogen bonds in good to high yields.

Full text of DOI:10.1016/j.tetlet.2021.153144

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Tetrahedron Letters 75 (2021) 153144
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Tetrahedron Letters
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In-situ-generation of alkylsilyl peroxides from alkyl hydroperoxides and
their subsequent copper-catalyzed functionalization with organosilicon
compounds
a,
a,b,
Weiping Xu a, Wenfeng Zhong a, Qin Yang a, Terumasa Kato a, , Yan Liu , Keiji Maruoka
⇑
⇑
⇑
a School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
b Laboratory of Organocatalytic Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkylsilyl peroxides were generated in situ from the corresponding alkyl hydroperoxides using
organosilicon compounds of the type Me3SiX (X = CN, N3, and halogens) and an amine base.
Subsequent in situ copper-catalyzed homolytic cleavage of the alkylsilyl peroxides afforded alkyl radicals,
which were then trapped with X (X = CN, N3, and halogens) to furnish products with new carbon-carbon,
carbon-nitrogen, or carbon-halogen bonds in good to high yields.
Received 27 February 2021
Revised 15 April 2021
Accepted 28 April 2021
Available online 30 May 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Copper(I) iodide
Alkylsilyl peroxides
Organosilicon compounds
Radical-based approaches
Cyanation
Introduction
new approach, starting from alkyl hydroperoxide 3, that utilizes
cyanation, azidation, or halogenation reactions.
Chemical reactions that involve alkyl radicals are often power-
ful synthetic tools in organic chemistry [1,2]. The development of
synthetic methods for the generation of alkyl radicals [3] has
gained considerable attention, as the unique properties of reactive
open-shell species enable bond disconnections that are unattain-
able via the use of ionic species [1]. Over several years, we have
developed a Cu-catalyzed method to generate alkyl radicals from
alkylsilyl peroxides (ASPs) 1 [4] under mild reductive conditions
(a reductive b-scission strategy), and we have applied this method
to organic synthesis. ASPs 1 are easily handled and can be readily
synthesized from a variety of alkyl radical precursors using Cu
[5], Fe [6] and Ni [7] catalysis. As part of our continuous studies
on radical-promoted transformations using ASPs 1, we have
recently reported the Cu-catalyzed cyanation and azidation of cyc-
lic ASP 1a with trimethylsilyl cyanide (Me3SiCN) and trimethylsilyl
azide (Me3SiN3), respectively (Scheme 1a) [8]. Based on these
results, we hypothesized that under similar reaction conditions,
it might be possible to generate ASPs 1 in situ from the correspond-
ing alkyl hydroperoxide 3 and a specific Me3SiX reagent (e.g.
X = CN or N3) (Scheme 1b). Herein, we report the realization of this
Results and discussion
The attempted reaction of 3a with Me3SiCN (2 equiv.) in the
presence of 5 mol% each of CuI and the amine ligand 1,10-phenan-
throline (1,10-Phen) was carried out in dimethylformamide (DMF)
at room temperature for 0.5 h to furnish 5-cyano-1-phenylpent-1-
one (2a) in 88% yield (Table 1, entry 1). A two-mmol-scale reaction
of 3a afforded 2a in 80% yield (Entry 1; 76% isolated yield).
Decreasing the quantity of Me3SiCN marginally decreased the yield
of 2a (Entry 2). Increasing the temperature to 60 °C slightly
improved the yield (Entry 3). Switching the solvent from DMF to
MeCN under otherwise similar conditions afforded 2a in 89% yield
(Entry 4). Use of the 2,20-bipyridyl ligand instead of 1,10-Phen low-
ered the yield of 2a (Entry 5). The effect imparted by the amine
additive was found to be critical. Use of 4-dimethylamino-pyridine
(DMAP) as the amine additive decreased the yield of 2a (Entry 6).
Reducing the number of equivalents of DMAP used also reduced
the yield (Entry 7 vs. entry 6). The use of triethylamine, N,N-diiso-
propylethylamine (DIPEA), and 1,4-diazabicycle[2.2.2]-octane
(DABCO) gave unsatisfactory results (Entries 8–12). It should also
be noted that the reaction does not proceed in the absence of the
CuI catalyst. With the optimum conditions for the cyanation
⇑
Corresponding authors.
E-mail addresses: Terumasa.kato.j97@kyoto-u.jp (T. Kato), yanliu@gdut.edu.cn
(Y. Liu), maruoka.keiji.4w@kyoto-u.ac.jp (K. Maruoka).
https://doi.org/10.1016/j.tetlet.2021.153144
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

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W. Xu, W. Zhong, Q. Yang et al.
Tetrahedron Letters 75 (2021) 153144
chlorination of 3a with Me3SiCl (2 equiv.) was undertaken with a
catalytic quantity of CuI and 1,10-Phen (5 mol% each) in DMF at
room temperature, giving coupling product 5a in high yield (Entry
20). The screening of amine bases revealed that a catalytic amount
of triethylamine is also preferrable for the smooth coupling of 3a
with Me3SiCl (Entry 23 vs. entries 21, 25, and 26). Importantly,
the use of 1.2 equiv. of Me3SiCl afforded the chlorination product
5a in an almost quantitative yield (Entry 24).
With the optimized conditions in hand for several different
transformations, we subsequently examined the scope of the CuI-
catalyzed radical functionalization of several cyclic alkyl hydroper-
oxides 3a-f as shown in Table 2. Thus, cyanation of five different
alkyl hydroperoxides 3a-f with Me3SiCN gave the corresponding
cyanation products 2a-f, respectively, in good to high yields
(Entries 1, 6, 11, 16, 21, and 26). In a similar manner, azidation
of 3a-f afforded azidation products 4a-f, respectively, in good to
high yields (Entries 2, 7, 12, 17, 22, and 27). With respect to the
halogenation reactions, not only was the chlorination of alkyl
hydroperoxides 3a-f realized, but the bromination and iodination
of these substrates were also achieved to give the corresponding
halogenation products 5a-f, 6a-f and 7a-f, respectively in good to
excellent yield (Entries 3–5, 8–10, 13–15, 18–20, 23–25, and 28–
30). Alkyl hydroperoxide 3 g was successfully transformed to the
corresponding functionalized methyl ketones 2 g, 4 g, and 5 g in
low to good yields (Entries 31–33).
Scheme 1. Radical-based approaches for the synthesis of functionallized 2.
reaction in hand (Entry 3), the azidation reaction of 3a with Me3-
SiN3 (2 equiv.) in DMF was carried out in the presence of 5 mol%
of both CuI and 1,10-Phen varying the temperature and the reac-
tion time to furnish 5-azido-1-phenylpent-1-one (4a) in high yield
(Entries 14 and 15 vs. entry 13). Several different amine bases were
used with different reaction times and temperatures (Entries 15–
19). The use of a catalytic amount of triethylamine provided 4a
in a similarly high yield (Entry 18). Interestingly, this transforma-
tion is also applicable to the halogenation of 3a. For example, the
Shown in Scheme 2 is our proposed catalytic cycle for the in-
situ-generation of alkylsilyl peroxides from the corresponding alkyl
hydroperoxides, and the subsequent copper-catalyzed homolytic
cleavage of the alkylsilyl peroxides using an organosilicon
Table 1
Optimization of the reaction conditions for the radical functionalization of alkyl hydroperoxides 3a.a
Entry
Me3SiX (equiv.)
Amine (equiv.)
Solvent
Temp (°C), Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Me3SiCN (2)
Me3SiCN (1.2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiN3 (2)
Me3SiN3 (2)
Me3SiN3 (2)
Me3SiN3 (2)
Me3SiN3 (2)
Me3SiN3 (2)
Me3SiN3 (2)
Me3SiCl (2)
Me3SiCl (2)
Me3SiCl (2)
Me3SiCl (2)
Me3SiCl (1.2)
Me3SiCl (2)
Me3SiCl (2)
1,10-Phen (0.05)
1,10-Phen (0.05)
1,10-Phen (0.05)
1,10-Phen (0.05)
2,2-Bipyridyl (0.05)
DMAP (1)
DMAP (0.2)
Et3N (1)
Et3N (0.2)
Et3N (0.2)
DIPEA (1)
DABCO (1)
1,10-Phen (0.05)
1,10-Phen (0.05)
1,10-Phen (0.05)
DMAP (1)
Et3N (0.2)
Et3N (0.2)
DIPEA (1)
1,10-Phen (0.05)
DMAP (1)
Et3N (1)
Et3N (0.2)
Et3N (0.2)
DIPEA (1)
DABCO (1)
DMF
DMF
DMF
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
RT, 0.5
RT, 0.5
60, 0.5
RT, 0.5
RT, 0.5
RT, 6
RT, 12
RT, 6
RT, 12
60, 12
RT, 6
88(80)c
71
90
89
62
50
25
22
39
26
53
<5
28
26
81
5
19
78
13
85
86
90
99
99
87
91
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
RT, 6
RT, 0.5
RT, 12
60, 12
RT, 6
RT, 12
60, 12
RT, 6
RT, 12
RT, 12
RT, 12
RT, 12
RT, 12
RT, 12
RT, 12
a
Unless otherwise noted, the reactions of 3a (0.2 mmol) and Me3SiX (2 equiv.) were carried out in the presence of copper(I) iodide (5 mol%) and an amine additive in the
specified solvent (1 mL) under the indicated reaction conditions.
b
Determined using 1H NMR spectroscopy with CH3NO2 as an internal standard. cTwo-mmol-scale experiment of 3a at RT for 0.5 h.
2

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Tetrahedron Letters 75 (2021) 153144
aUnless otherwise specified, the reactions were carried out as follows: [A] cyanation
of 3 (0.2 mmol) using Me3SiCN (2 equiv.) was performed in the presence of CuI and
1,10-Phen (5 mol% each) in DMF (1 mL) at room temperature for 0.5 h; [B] azidation
of 3 (0.2 mmol) using Me3SiN3 (2 equiv.) was performed in the presence of CuI and
1,10-Phen (5 mol% each) in DMF (1 mL) at 60 °C for 12 h; [C] halogenation of 3 (0.2
mmol) using Me3SiX (X = Cl, Br, I) (1.2 equiv.) was performed in the presence of CuI
(5 mol%) and Et3N (20 mol%) in DMF (1 mL) at room temperature for 12 h. bYield
determined using 1H NMR spectroscopy with CH3NO2 as an internal standard. cYield
in parenthesis refers to the isolated yield. dFor 1 h. eMe3SiN3 (3 equiv.). fUse of 1,10-
Phen (10 mol%) at 60 °C.
Table 2
Scope for the functionalization of alkyl hydroperoxidesa
Scheme 2. Proposed reaction mechanism.
compound of the type Me3SiX (X = CN, N3, and halogen) and an
amine base. In the presence of Me3SiX and the amine base (NR3),
alkyl hydroperoxide 3 transforms into the corresponding alkylsilyl
peroxide 1. The resulting alkylsilyl peroxide 1 decomposes in the
presence of a nitrogen-coordinated copper species, which leads
to the generation of alkoxy radical 8 and copper silanoxide com-
plex 9. Subsequent b-fragmentation of 8 would generate the corre-
sponding alkyl radical 10. After a ligand exchange on the copper
center between an ammonium salt (R3NHX) and a silanoxide, the
coupling of the alkyl radical and the copper-X complex finally
affords the desired product 11.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
This work is dedicated to Professor Stephen F. Martin for his
long-time journal editorship and significant contributions to
organic chemistry. This work was financially supported by the
National Natural Science Foundation of China (No. 21977019,
3

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W. Xu, W. Zhong, Q. Yang et al.
Tetrahedron Letters 75 (2021) 153144
[3] (a) Recent examples of new synthetic methods for generation of alkyl radicals:
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153144.
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