Alkylsilyl Peroxides as Alkylating Agents in the Copper-Catalyzed Selective Mono-N-Alkylation of Primary Amides and Arylamines

Article abstract of DOI:10.1002/chem.201702217

The copper-catalyzed selective mono-N-alkylation of primary amides or arylamines using alkylsilyl peroxides as alkylating agents is reported. The reaction proceeds under mild reaction conditions and exhibits a broad substrate scope with respect to the alkylsilyl peroxides, as well as to the primary amides and arylamines. Mechanistic studies suggest that the present reaction should proceed through a free-radical process that includes alkyl radicals generated from the alkylsilyl peroxides.

Full text of DOI:10.1002/chem.201702217

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Accepted Article
Title: Alkylsilyl Peroxides as Alkylating Agents in the Copper-catalyzed
Selective mono-N-Alkylation of Primary Amides and Arylamines
Authors: Ryu Sakamoto, Shunya Sakurai, and Keiji Maruoka
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Alkylsilyl Peroxides as Alkylating Agents in the Copper-catalyzed
Selective Mono-N-alkylation of Primary Amides and Arylamines
Ryu Sakamoto, Shunya Sakurai, Keiji Maruoka*[a]
Abstract: The copper-catalyzed selective mono-N-alkylation of
primary amides or arylamines using alkylsilyl peroxides as novel
alkylating agents is reported. The reaction proceeds under mild
reaction conditions and exhibits a broad substrate scope with
respect to the alkylsilyl peroxides as well as to the primary amides
and arylamines. Mechanistic studies suggest that the present
reaction should proceed through a free-radical process including
alkyl radicals generated from the alkylsilyl peroxides.
Organic peroxides represent an important structural motif in
organic chemistry, due to their wide range of unique reactivity
and versatile biological activity.[1,2] In academic and industrial
synthesis, organic peroxides have an established track record
as oxidizing agents, radical initiators, polymerization initiators,
cross-linking agents, and as synthetic building blocks. In 2008,
Li and co-workers reported novel applications of dialkyl
peroxides such as di-tert-butyl or dicumyl peroxide as
methylating agents in the direct methylation of aryl C-H bonds.[3a]
Since then, dialkyl peroxides have frequently been used for
various methylation reactions such as the direct methylation of
Scheme 1. Generation of alkyl radicals from (a) dialkyl peroxides and (b)
alkylsilyl peroxides.
aryl C-H bonds, the methylation/cyclization of N-arylacrylamides
and the N-methylation of amides.[3-6] The weak peroxide bond
(O-O bond) in dialkyl peroxides can easily undergo a bond
fission initiated by thermal treatment in the presence/absence of
as alternative alkyl radical sources. A variety of alkylsilyl
metal reagents to give an alkoxy radical. A subsequent β-
became interested in the possibility of using alkylsilyl peroxides
peroxides can be easily synthesized from the corresponding
alcohols, and we expected that a broad variety of alkyl radicals
scission of the alkoxy radical generates a methyl radical under
concomitant formation of
a
ketone (Scheme 1a).[7] This
should thus be accessible, which should allow the transfer of
various alkyl groups other than methyl via a radical process
(Scheme 1b). Herein, we report our initial results on this subject
by demonstrating the selective mono-N-alkylation of primary
amides and arylamines using alkylsilyl peroxides as alkylating
agents. This study reveals that alkylsilyl peroxides rapidly
disintegrate in the presence of a copper catalyst under mild
conditions to generate a variety of alkyl radicals.
approach efficiently generates methyl radicals from dialkyl
peroxides. However, reports on the generation of alkyl radicals
other than methyl via a similar radical process remain rare,
predominantly due to the limited access to the corresponding
dialkyl peroxides.[8] In addition, these approaches often require a
large amount of metal catalyst, as well as prolonged reaction
times and high temperatures, which limit the functional-group
tolerance. Thus, the development of alternative strategies for the
mild and efficient generation of various alkyl radicals from
organic peroxides should be highly desirable.
Initially, we examined the metal-catalyzed N-alkylation of
primary amides using acyclic alkylsilyl peroxides 1 (Table
1).[5a,12] When the reaction between benzamide
2
and
Alkylsilyl peroxides can be regarded as silyl-protected alkyl
hydroperoxides, and represent stable organosilicon peroxides.[9]
These peroxides can be readily synthesized and are easy to
handle on account of their thermal stability.[10] However, in
contrast to organic peroxides, alkylsilyl peroxides have rarely
been used in synthetic organic chemistry.[11] In this context, we
diethylphenyl-substituted peroxide 1a was conducted at 100 °C
in the presence of copper iodide, N-ethyl benzamide (3a) was
obtained in 63% yield (entry 1). Simultaneously, propiophenone
was obtained, which should be generated with an ethyl radical
by β-scission of the corresponding alkoxy radical, in a manner
similar to the formation of methyl radicals from dialkyl peroxides
(Scheme 1a). The addition of 1,10-phenanthroline (L1) as a
ligand afforded 3a quantitatively (entry 2). Subsequently, we
examined the reaction conditions in order to reduce the amount
of reagents required and to decrease the temperature. Lowering
the amount of 1a afforded a similar product yield (entry 3), while
a slightly lower yield was obtained from using 1.2 equiv of 1a
(entry 4). The reaction temperature could be reduced to 60 °C
[a]
R. Sakamoto, S. Sakurai, Prof. K. Maruoka
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo, Kyoto 606-8502, Japan
Fax: (+81) 75-753-4041
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document
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Table 2: Scope of acyclic alkylsilyl peroxides (1).[a,b]
without affecting the product yield (entry 3 vs 5). However, the
cleavage of the peroxide was not observed at 50 °C (entry 6).
The quantities of catalyst and ligand can also be decreased to 5
mol% each without affecting the product yield, provided that the
reaction time is prolonged (2 h; entry 7). The present method
was also applicable to a large-scale reaction (5 mmol) with a
lower catalyst loading (0.5 mol%), which afforded almost the
same product yield of 3 as the reaction on a 0.2 mmol scale
using 5 mol% of catalyst (entry 7 vs 8). In the absence of the
copper catalyst and the ligand, no desired product was obtained
even at high temperature, while peroxide 1a remained intact
(entry 9). The use of FeCl2, AgOTf, or Pd(OAc)2 did not afford
any products (entries 10-12).
Table1: Optimization of the reaction conditions.[a]
Entry
1
1a (equiv)
2.0
[M]/L (mol%)
CuI/- (10)
T (°C)
100
100
100
100
60
3a (%)[b]
63
>99
>99
94
>99
-
2
2.0
CuI/L1 (10)
CuI/L1 (10)
CuI/L1 (10)
CuI/L1 (10)
CuI/L1 (10)
CuI/L1 (5)
3
1.5
4
1.2
[a] Reactions were conducted in the presence of 1 (1.5 equiv), benzamide (0.2
mmol), CuI (5 mol%) and L1 (5 mol%) in benzene under an atmosphere of
argon. [b] Isolated yield. [d] 2.0 equiv of 1b. [e] T = 80 °C; t = 1h. [f] NMR
yield. L1 = 1,10-phenanthroline. THP = tetrahydropyranyl.
5
1.5
6
1.5
50
7[c]
8[e]
9
1.5
60
>99[d]
96[d]
-
1.5
CuI/L1 (0.5)
-
60
Next, the potential suitability of cyclic alkylsilyl peroxides (4)
for this transformation was examined (Table 3). Using the 5-, 6-
and 7-membered cyclic peroxides 4a-c furnished 5a-c in
excellent yields via the ring opening of the cycloalkyl moiety on
the peroxides. When ethyl-substituted cyclopentyl peroxide 4d
was used, the ring opening of the cyclopentyl moiety occurred
selectively to furnish δ-amino ketone 5d in 92% yield, together
with N-ethyl benzamide 3a (4%). The ether moiety in 4e
remained unaffected by the transformation, affording 5e in
moderate yield. In the case of bicyclic peroxide 4f, which is
derived from norcamphor, a diastereomeric mixture of 5f was
obtained via the selective cleavage of the C(1)-C(2) bond of the
norbornane moiety.
1.5
100
60
10[c]
11[c]
12[c]
1.5
FeCl2/L1 (5)
AgOTf/L1 (5)
Pd(OAc)2/L1 (5)
-
1.5
60
-
1.5
60
-
[a] Reactions were conducted in the presence of 1a (1.2~2.0 equiv), 2 (0.2
mmol), catalyst, and 1,10-phenanthroline (L1) in benzene under an
atmosphere of argon; t = 1 h. [b] The yield was determined by 1H NMR
spectroscopy using DMF as an internal standard. [c] t = 2 h. [d] Isolated yield.
[e] The reaction was carried out on a 5 mmol scale; t = 7 h.
Subsequently, other acyclic alkylsilyl peroxides (1) were
examined (Table 2). Although peroxide 1b afforded the
corresponding N-methyl benzamide (3b) in only 24% yield, a
significant improvement of the yield (90%) was accomplished by
replacing one methyl with a phenyl group (1c). In the case of N-
ethylation, triethyl-substituted peroxide 1d afforded a result
similar to that of 1a. Interestingly, peroxide 1e with methyl, ethyl
and phenyl substituents, selectively transferred the ethyl group.
The use of 1f provided N-propyl benzamide (3c) quantitatively.
On the other hand, peroxide 1g with methyl, ethyl and n-propyl
substituents afforded the mixtures of 3a and 3c. The transfers of
secondary alkyl groups such as isopropyl and cyclohexyl and
tetrahydropyranyl moieties from 1h-j were also possible.
However, attempts to transfer a tert-butyl group from 1k were
unsuccessful.
The results on the scope of amides are summarized in
Scheme 2a. In the presence of 1d and a copper catalyst, the N-
ethylation of various aryl, alkenyl and alkyl amides proceeded to
furnish the corresponding products (6a-h) in high yields.
Furthermore, the mono-N-alkylation of primary arylamines was
possible (Scheme 2b). It should be noted that, in contrast to the
mono-N-alkylation of primary amides, the number of reports on
the selective mono-N-alkylation of primary arylamines via a
similar radical process is low.[13] The reaction of aniline and 4-
trifluoromethylaniline with 1a using L1 or 4,7-dimethoxy-1,10-
phenanthroline (L2) as a ligand afforded the corresponding N-
ethyl anilines (7a and 7b) in good yields, while the use of p-
anisidine did not furnish any desired product (7c).[14] The
presence of bromo substituents at the meta- or ortho-positions
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did not affect the reaction. The use of 5-membered cyclic
peroxide 4a with 4-trifluoromethylaniline furnished δ-amino
ketone 7f in 75% yield. The reactions with heterocyclic primary
amines also afforded the corresponding products (7g-i) in
acceptable yields.
benzamide 2 afforded N-methyl benzamide 8 in 21% yield,
together with N-cyclohexyl benzamide 9 (51%) and tert-butyl
alcohol (17%) (Scheme 3a). This result suggests the formation
of an alkoxy radical, which should abstract a hydrogen atom
from cyclohexane under concomitant generation of a cyclohexyl
radical.[12f] When the reaction of benzamide 2 and cyclic
peroxide 4a was carried out under an atmosphere of oxygen,
aldehyde 10 was obtained together with N-alkylated 5a, which
suggests that a terminal alkyl radical should be formed through
the ring opening of the cyclopentyl moiety (Scheme 3b). Such a
radical was successfully trapped using the radical scavenger
2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO).[15] The
notion that alkyl radical intermediates are formed in this reaction
would also be supported by the following results: i) the selectivity
of the transfer of the alkyl substituents from the peroxides was
observed in the order secondary alkyl > primary alkyl > methyl >
phenyl group; ii) peroxide 1g with methyl, ethyl and n-propyl
transferred ethyl and n-propy group in almost same selectivity;
iii) the reaction of 4f derived from norcamphor afforded a
diastereomeric mixture of 5f (d/r = 1/1), whereas the formation of
a single diastereomer would be expected for a reaction that
proceeds via a concerted pathway. To rule out the potential
involvement of alkyl hydroperoxides, which could be formed
from the alkylsilyl peroxide, as a possible source of the alkyl
radicals, the same reaction was carried out using 2 and
hydroperoxide 11 instead of 4a.[16] However, under otherwise
identical conditions, the formation of 5a was not observed
(Scheme 3c). This result indicates the importance of silyl groups
for the cleavage of O-O bond.
Table 3: Scope of cyclic alkylsilyl peroxides (4).[a,b]
[a] Reactions were conducted in the presence of 4 (1.2 equiv), benzamide (0.2
mmol), CuI (5 mol%), and L1 (5 mol%) in benzene under an atmosphere of
argon; T = 50 °C; t = 2 h. [b] Isolated yield. [c] T = 60 °C. [d] 2.0 equiv of 4e; T
= 70 °C.
Scheme 3. Control experiments
Based on these observations, we would like to propose a
plausible mechanism for the present reaction (Figure 1).[17]
Initially, the nitrogen-coordinated copper species 12 should
cleave the alkylsilyl peroxide to afford an alkoxy radical (13) and
a copper-silanoxide complex (14).[18] The β-scission of alkoxy
radical 13 would then generate an alkyl radical (15) and a
ketone, while a ligand exchange on the copper center of 14
between an amide and a silanoxide should afford intermediate
16 and a silanol.[19] A subsequent reaction between 16 and alkyl
radical 15 would then afford the N-alkylated amide.
Scheme 2. Scope of (a) amides and (b) arylamines.
In order to better understand the underlying reaction
mechanism, several experiments were carried out. For example,
in the presence of cyclohexane, the reaction of 1b with
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Figure 1. Proposed plausible reaction mechanism.
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In conclusion, this study reports the unprecedented use of
alkylsilyl peroxides as alkylating reagents in a selective mono-N-
alkylation of primary amides or arylamines. This study also
shows that alkylsilyl peroxides generate a variety of alkyl
radicals under mild conditions. Further investigations regarding
the details of the reaction mechanism and applications of
alkylsilyl peroxides in other reactions are currently ongoing in
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Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific
Research from MEXT (Japan).
Conflict of interest
The authors declare no conflict of interest.
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Keywords: alkylsilyl peroxides • radical •N-alkylation • copper •
synthetic methods
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[19] The formation of silanols derived from the corresponding alkylsilyl
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Entry for the Table of Contents (Please choose one layout)
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Ryu Sakamoto, Shunya Sakurai, Keiji
Maruoka*
Page No. – Page No.
Alkylsilyl Peroxides as Alkylating
Agents in the Copper-catalyzed
Selective
Primary Amides and Arylamines
Mono-N-alkylation
of
Alkylsilyl Peroxides: The copper-catalyzed selective mono-N-alkylations of
primary amides or arylamines using alkylsilyl peroxides as alkylating agents was
described. Mechanistic studies suggest that the present reaction should proceed
through a free-radical process including alkyl radicals generated from the alkylsilyl
peroxides.
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