Bis(trialkylsilyl) peroxides as alkylating agents in the copper-catalyzed selective mono-: N -alkylation of primary amides

Article abstract of DOI:10.1039/c7cc02910a

The copper-catalyzed selective mono-N-alkylation of primary amides with bis(trialkylsilyl) peroxides as alkylating agents was reported. The results of a mechanistic study suggest that this reaction should proceed via a free radical process that includes the generation of alkyl radicals from bis(trialkylsilyl) peroxides.

Full text of DOI:10.1039/c7cc02910a

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DOI: 10.1039/C7CC02910A
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Bis(trialkylsilyl) Peroxides as Alkylating Agents in the Copper-
catalyzed Selective Mono-N-alkylation of Primary Amides
Ryu Sakamoto, Shunya Sakurai, and Keiji Maruoka*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The copper-catalyzed selective mono-N-alkylation of primary
amides with bis(trialkylsilyl) peroxides as alkylating agents was
reported. The results of a mechanistic study suggest that this
reaction should proceed via a free radical process that includes the
generation of alkyl radicals from bis(trialkylsilyl) peroxides.
Organic peroxides are highly versatile and can be used as
oxidants, radical initiators, polymerization initiators, cross-
linking agents, and as synthetic building blocks.1 In contrast,
organosilicon peroxides, in which the peroxy group (-O-O-) is
directly bound to at least one silicon atom, have received less
attention.2 Depending on their structures, organosilicon
peroxides can be categorized into three classes, i.e., silyl
hydroperoxides, disilyl peroxides, and alkylsilyl peroxides.
Scheme 1 Examples for the use of disilyl peroxides in organic synthesis.
peroxides as alkylating agents, demonstrated by a copper-
catalyzed selective mono-N-alkylation of primary amides
(Scheme 1b). The corresponding mechanistic study suggested
that the reaction should proceed via a free radical process that
includes the generation of alkyl radicals from disilyl peroxides.
This is, to the best of our knowledge, the first example for the
use of disilyl peroxides as a source of alkyl radicals.
In recent years, dialkyl peroxides such as di-tert-butyl or
dicumyl peroxide, have frequently been used as methylating
agents for e.g. the direct methylation of aryl C-H bonds, the
methylation/cyclization of N-arylacrylamides, and the N-
methylation of amides.8-11 These routes facilitate efficient
methylations through the generation of a methyl radical from
the peroxides. However, the introduction of alkyl groups other
than methyl via a similar radical process has been rarely
reported, most likely due to the limited access to the
corresponding dialkyl peroxides.12 In this context, we became
Among these, disilyl peroxides (R3SiOOSiR3)have found a few
applications in organic synthesis (Scheme 1a).3-7 For example, a
commercially available bis(trimethylsilyl) peroxide has been
employed as an equivalent of the hydroxyl cation in
electrophilic hydroxylations.3 In the Baeyer-Villiger oxidation,
bis(trialkylsilyl) peroxides have been infrequently used as
oxidants,4 while combinations of bis(trimethylsilyl) peroxides
and metal catalysts based on rhenium, zirconium, vanadium, or
chromium have been used for the oxidation of alcohols and for
the functionalization of olefins.5-7 These early studies revealed a
unique reactivity and synthetic utility for disilyl peroxides as
oxidants in organic synthesis. However, applications beyond the
use as oxidants have rarely been investigated. In this context,
we report herein an unprecedented application of disilyl
interested in the potential of bis(trialkylsilyl) peroxides (1),
which can be readily synthesized from the reaction of a
chlorosilane with a hydrogen peroxide-amine complex,13 as an
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo,
Kyoto 606-8502, Japan. E-mail: maruoka@kuchem.kyoto-u.ac.jp;
Fax: +81-75-753-4041; Tel: +81-75-753-4041;
†Electronic Supplementary Information (ESI) available: Experimental Details. See
DOI: 10.1039/x0xx00000x
alternative source of alkyl radicals. As
1 can be substituted on
the silicon atom with various alkyl groups, we envisioned that
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Table 1 Optimization of reaction conditions using ethylbenzene 2a.a
the introduction of alkyl groups other than methyl via a radical
process could be realized if alkyl radicals could be generated
from such bis(trialkylsilyl) peroxides (Scheme 2).
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DOI: 10.1039/C7CC02910A
entry
1
2c
[M]
CuI
Ligand
L1
3a Yield (%)b
2a (%)b
23
60
0
CuI
L1
100
39
3
CuCl
L1
55
41
36
43
0
Scheme 2 Generation of alkyl radicals from disilyl peroxides.
4
Cu(OAc)
Cu(acac)2
Cu(OAc)2
FeCl2
L1
47
5
L1
50
Initially, we examined a metal-catalyzed N-alkylation of
amides as a model reaction.9a,14 When the reaction between
6
L1
51
7
L1
98
benzamide
(2a) and bis(triethylsilyl) peroxide (1a) was
8
Fe(OAc)2
Fe(acac)3
CuI
L1
0
74
conducted at 100 °C in the presence of copper iodide and 2,2'-
bipyrimidine (L1), the desired N-ethylbenzamide (3a) was
obtained in 60% yield (entry 1) under concomitant formation
of triethylsilanol. To rule out silanols as a possible source of the
alkyl radicals, the same reaction was carried out using 2a and
triethylsilanol instead of 1a. However, under otherwise
identical conditions, the formation of 3a was not observed
(entry 2). A screening of several copper catalysts showed that
copper iodide is the most efficient metal source (entries 3-6). In
contrast, the use of several iron salts as catalysts did not afford
the desired products, even though the decomposition of
peroxide 1a was observed (entries 7-9). We then examined the
effect of the ligand on this reaction. A survey of several ligands
9
L1
0
95
10
11d
12e
L2
71
69
81
18
CuI
L2
21
CuI
L2
4
[a] Performed with 2a (0.1 mmol), 1a (2.0 equiv), metal catalyst (10 mol%), and
ligand (10 mol%) in benzene (0.4 M) for 24 h at 100 °C under an atmosphere of
argon. [b] Yields were determined by 1H NMR spectroscopy using DMF as an
internal standard. [c] Triethylsilanol (2.0 equiv) was used instead of 1a. [d] t = 1 h.
[e] 1a (2.0 equiv) was added after stirring for 1 h, and the reaction mixture was
stirred for another hour. L1; 2,2’-Bipyrimidine, L2; 1,10-Phenanthroline
demonstrated that the use of 1,10-phenanthroline
(L2)
improved the yield of 3a (71%; entry 10).15 Moreover, we
discovered that the reaction time can be substantially reduced
(24 h
 1 h) without affecting the product yield (entry 11). A
further improvement of the yield was accomplished by addition
of two further equivalents of 1a after 1 h of stirring (entry 12).
It should be noted that mono-N-alkylated product 3a was
obtained selectively in all cases, while N,N-dialkylation was not
observed. Indeed, the reaction between 3a and 1a in the
presence of a copper catalyst did not furnish any N,N-
diethylamide, and 3a could be recovered.
With optimized reaction conditions in hand, we examined the
scope of silyl peroxides
1 (Scheme 3). The reaction between
benzamide (2a) and bis(trimethylsilyl) peroxide (1b) afforded 3b
in 37% yield, while bis(tributylsilyl) peroxide (1c) furnished 3c in
57% yield. The transfer of secondary alkyl groups was also
possible using appropriate silyl peroxides. When
bis(dimethylisopropylsilyl) peroxide (1d) was used, N-isopropyl
amide 3d was obtained in 63% yield. Similarly, the use of
bis(dimethylcyclohexylsilyl) peroxide (1e) afforded N-cyclohexyl
amide 3e in 61% yield. Subsequently, we attempted the transfer
of tert-butyl groups to the amides. However, the reaction of 2a
with bis(dimethyl-tert-butylsilyl) peroxide (1f) afforded 3f in 9%
yield, together with 3b in 28% yield.14g,16
Scheme 3 Reaction scope with respect to bis(trialkylsilyl) peroxides 1.
a NMR yield.
Reactions using carbamate- or urea-based substrates were also
successful, and furnished 4k and 4l in 47% and 44% yield,
respectively. For the expansion of the substrate scope, we
additionally tested reactions with primary anilines. Although
the reaction between aniline and 1a did not afford any product,
the use of electron-deficient aryl amines such as pyridyl-2-
amine, pyrimidyl-2-amine or pentafluoroaniline furnished
ethylated products 4m-o in low to modest yields.
Then, we examined the reaction scope with respect to
amides (Scheme 4). In the presence of bis(triethylsilyl) peroxide
(
1a) and copper iodide, the N-ethylation of various types of aryl
amides proceeded smoothly to furnish the corresponding
secondary amides 4a in moderate to good yields. The reaction
2
-
h
with alkenyl and alkyl amides afforded the corresponding N-
ethylated amides 4i and 4j in 40% and 51% yield, respectively.
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Scheme 5 Control experiments.
Scheme 4 Reaction scope with respect to amides or arylamines. a NMR yield.
In order to elucidate the underlying reaction mechanism, we
initially tested a radical trapping experiment with the radical
scavenger 2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO).
Addition of TEMPO to the standard reaction between 1a and 2a
inhibited the formation of 3a, while the formation of 1-ethoxy-
2,2,6,6-tetramethylpiperadine
(5) was detected by mass
spectrometry and 1H NMR spectroscopy, suggesting that a free
radical process with the formation of an alkyl radical should be
involved in this reaction (Scheme 5a). Conversely, in the
presence of cyclohexane, the reaction afforded N-cyclohexyl
benzamide (3e) in 42% yield, together with N-ethyl benzamide
Scheme 6 Mechanisms for the generation of alkyl radicals from peroxides.
indicating that the addition of a siloxyl radical to the silicon
center of another peroxide could generate an alkyl radical
under concomitant formation of
In order to reveal a potential involvement of the copper
catalyst in the decomposition of silyl peroxides , we carried out
7 (Scheme 6b).
(3a) in 51% yield (Scheme 5b). Additionally, the amount of
triethylsilanol ( ) that was formed as a side product, increased
6
1
further experiments.20 When 1a was heated to 100 °C in the
presence or absence of catalytic copper iodide, the silyl
peroxide persisted almost quantitatively. In contrast, in the
presence of copper iodide with L1 or amide 2a, decomposition
of the peroxide was observed. These experiments indicate that
a nitrogen-coordinated copper species should be necessary for
the decomposition of 1.
Based on these experiments, we would like to propose a
plausible mechanism for the observed reactions in Figure 1.
compared to the reaction without cyclohexane. This result
suggests the formation of a siloxyl radical, which should abstract
a hydrogen atom from cyclohexane to generate a cyclohexyl
radical and 6
(Scheme 5c).14g
We subsequently examined the mechanism for the
generation of alkyl radicals from silyl peroxides. Previous
research on methylations using di-tert-butyl peroxide (DTBP)
has suggested that methyl radicals should be formed from the
β-scission of tert-butoxy radicals under concomitant formation
of acetone (Scheme 6a).9,10 To the best of our knowledge, there
appears to be no evidence for such a β-scission in trialkylsiloxyl
radicals to afford alkyl radicals and the corresponding
dialkylsilanone (R2Si=O).2d,17 Attempts to trap such silanones by
Initially, nitrogen-coordinated copper species
the silyl peroxide heterolytically, thus affording the
corresponding siloxyl radical ( ) and copper-silanoxide complex
10. Subsequently, should react with another silyl peroxide (1)
8 should cleave
9
9
the
addition
of
methoxytrimethylsilane
or
to furnish alkyl radical 11, while the ligand exchange on the
copper center of 10 between an amide and a silanoxide would
generate intermediate 12 and a silanol. Finally, the reaction
between 12 and alkyl radical 11 should furnish the N-alkylated
hexamethyldisiloxane as trapping agents remained
unsuccessful,18 and the formation of silanone dimers and/or
oligomers was not observed.19 Instead, we detected the
formation of 7 by high-resolution mass spectrometry (HRMS),
amide via intermediate 13
.
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Figure 1 Proposed plausible reaction mechanism.
In conclusion, we have reported the unprecedented use of
bis(trialkylsily) peroxides as a source of alkyl radicals. By using
bis(trialkylsilyl) peroxides, various alkyl radicals can be
generated efficiently, which has been demonstrated in the
context of a copper-catalyzed selective mono-N-alkylation of
primary amides. Our mechanistic studies suggest that the
present reaction proceeds via a free-radical process that
includes the generation of alkyl radicals from bis(trialkylsilyl)
peroxides. Further investigations into the unequivocal
determination of the underlying mechanism and further
applications of these bis(trialkylsilyl) peroxides are currently in
progress in our laboratory.
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12 Only few examples have been reported for ethylations using
bis(1,1-dimethylpropyl)peroxide
or
2-hydroperoxy-2-
methylbutane as ethylating agents; see: ref. 9b, 10b, and 10e.
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This work was partially supported by a Grant-in-Aid for
Scientific Research from the MEXT (Japan).
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