Copper-Catalyzed Electrophilic Amination of Alkoxyarylsilanes

Article abstract of DOI:10.1002/ejoc.202000562

We report a copper-catalyzed amination reaction between simple alkoxyarylsilanes and N-benzoyloxyamines. Silver fluoride serves as a stoichiometric base as well as an indispensable activator that allows the catalytic process to proceed. Multiply alkoxylated arylsilanes, such as trialkoxyarylsilanes and dialkoxyarylsilanes were transformed into the corresponding tertiary anilines under mild reaction conditions.

Full text of DOI:10.1002/ejoc.202000562

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Copper-catalyzed Electrophilic Amination of Alkoxyarylsilanes
Authors: Qian Zhang, Kenshiro Hitoshio, Hayate Saito, Jun
Shimokawa, and Hideki Yorimitsu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000562
Link to VoR: https://doi.org/10.1002/ejoc.202000562
01/2020

10.1002/ejoc.202000562
European Journal of Organic Chemistry
COMMUNICATION
Copper-catalyzed Electrophilic Amination of Alkoxyarylsilanes
Qian Zhang,[a,b] Kenshiro Hitoshio,[b] Hayate Saito,[b] Jun Shimokawa,*[b] Hideki Yorimitsu*[b]
[a]
[b]
Dr. Qian Zhang
College of Chemistry and Chemical Engineering
Hubei University of Technology
Wuhan 430068, China
Kenshiro Hitoshio, Hayate Saito, Prof. Dr. Jun Shimokawa, Prof. Dr. Hideki Yorimitsu
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo-ku, Kyoto 606-8502, Japan
http://kuchem.kyoto-u.ac.jp/orgchem/
E-mail: shimokawa@kuchem.kyoto-u.ac.jp; yori@kuchem.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: We report a copper-catalyzed amination reaction between
simple alkoxyarylsilanes and N-benzoyloxyamines. Silver fluoride
serves as a stoichiometric base as well as an indispensable activator
that allows the catalytic process to proceed. Multiply alkoxylated
arylsilanes, such as trialkoxyarylsilanes, dialkoxyarylsilanes were
transformed into the corresponding tertiary anilines under mild
reaction conditions.
1b).[14f] Smith also studied a closely related transformation directly
from aryllithium as a one-pot transformation.[14g] The elaborate
silyl group was necessary for these copper-catalyzed aminations
with N-acyloxyamines as a nitrogen source,[14f] leaving simple
alkoxysilanes inapplicable for the reactions. Herein, we describe
electrophilic amination of simple arylalkoxysilanes with N-
benzoyloxyamines and a catalytic amount of (IPr)CuCl in the
presence of AgF as an indispensable stoichiometric base that
serves as an activator for the generation of catalytic species as
well.
Arylamines constitute one of the most fundamental structural
units found broadly in bioactive natural products and important
pharmaceuticals.[1] Among diverse preparative methodologies
known for these molecules, C(sp2)–N bond-forming reactions,
especially the ones using transition metals, represent an
increasingly significant proportion. Continuous pursuits of
amination reaction of aryl halides culminated in the development
of Buchwald–Hartwig amination[2] and the Ullmann-type copper-
catalyzed amination[3] that has broadened the applications of
nitrogen-containing molecules. Besides these established
methodologies, copper-promoted oxidative amination of
arylboronic acids, namely, the Chan–Lam coupling,[4] has also
proven to be a powerful method for C–N bond formation. The
source of the nucleophiles developed for the related Chan–Lam-
type amination were initially arylleads[5] or arylbismuths,[6] and
were later expanded to other arylmetal species,[7] such as
arylmagnesiums,[8] -zincs,[9] -stannanes,[10] -titaniums,[11]
zirconiums,[12] arylaluminums,[13] as well as arylsilanes.[14]
-
Our continuing interest in utilizing silicon functional groups
for efficient transformation inspired us to develop our new
conditions for a new repertoire of Chan–Lam-type amination of
arylsilanes. The pioneering work of this transformation was
reported by Lam et al.[14a] They described trialkoxyarylsilanes are
viable as an alternative to arylboronic acids for the synthesis of
arylamines using a stoichiometric amount of copper(II) acetate
(Scheme 1a). Copper-catalyzed variants under oxygen
atmosphere were later reported by Li[14b] and Cheng.[14c] Recently,
Miura and Hirano reported copper-catalyzed electrophilic
Scheme 1. Copper-mediated Electrophilic Amination of Arylsilanes.
As
amination
a
result of our optimization of copper-catalyzed
of triethoxyphenylsilane (1a) with N-
amination with N-benzoyloxyamines, which in turn required the
14e]
use of HOMSi[14d,
functional group for an efficient
benzoyloxymorpholine (2a), we eventually devised the standard
conditions for the reaction: 2a as the limiting agent (0.1 M), 2.0
transmetalation via a cyclic silanolate intermediate (Scheme
1
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10.1002/ejoc.202000562
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equiv 1a, 4.0 equiv AgF, 5 mol% (IPr)CuCl, toluene, 50 °C, 6 h.
Table 1 shows the results associated with differences based on
the deviations listed. Under the standard conditions (entry 1),
arylamine 3aa was obtained in 67% NMR yield (69% isolated
yield). In the cases of other solvents, lower yields were observed
(entries 2–4). Interestingly, a substantial amount of biphenyl was
observed as an only obsevable byproduct, which would be due to
the formation of arylsilver species followed by the known oxidative
dimerization.[15] Regarding the source of the copper catalyst, a
slightly lower yield (54%) was observed with CuCl(IMes), and the
yield dropped with dppe or with no ligand (entries 5–7). The
choice of AgF as a base was indispensable for this catalytic
reaction.[16] Thus, other bases including other silver salts (entries
8 and 9), CsF (entry 10), Et3N (entry 11), and tBuOK (entry 12)
did not provide any of the desired product. Reducing the amount
of the base resulted in the lowered yield (Table S5). The reaction
was sluggish at room temperature (entry 13) while no significant
change was observed at 70 °C (entry 14). Our attempt to set
triethoxyphenylsilane (1a) as the limiting agent with a slight
excess of 2a gave the product 3aa in substantially lower yield for
an unclear reason (Scheme S1). Therefore, the conditions in entry
1 were confirmed to be optimal.
optimized conditions. Anilines 3 were obtained in moderate yields
when the para position of the aryl group was substituted with an
electron-withdrawing group such as fluoro (3ba) and chloro (3ca)
groups. Pentafluorophenyl (3da) or 2-naphthyl group (3ea) was
also aminated. Electron-donating p-tolyl (3fa) was tolerated, but
3,5-dimethylphenyl (3ga) was not obtained in good yield. p-Anisyl
(3ha), m-anisyl (3ia) aniline products were obtained in moderate
yields. Under the same conditions, ortho-substituted product 3ja
was not obtained. The low reactivity of ortho-substituted
substrates would be ascribed to the steric hindrance exerted by
the substituent. The scope of the copper-catalyzed amination of
1a with respect to different N-benzoyloxyamines 2b–2g were also
investigated. A piperidine unit could be introduced by the current
reaction to give N-phenyl piperidine (3ab) in moderate yield. N-
Boc-4-phenylpiperazine (3ac) and ethoxycarbonyl-substituted
piperidine derivative (3ad) were also installed in moderate yields.
Meanwhile, N-phenylpyrrolidine (3ae) was observed only in a
trace amount, and N-phenylthiomorpholine (3af) and N,N-
dibenzylaniline (3ag) were not obtained at all.
Table 2. Substrate Scope with Respect to Aryl Groups and Amines.[a],[b]
Table 1. Optimization of Amination Conditions.
Entry
Deviation from the standard conditions Yield (%)[a]
3aa
Biphenyl[c]
1
none
67 (69[b]
)
0
2
THF instead of toluene
MeCN instead of toluene
DMF instead of toluene
CuCl(IMes) instead of CuCl(IPr)
CuCl(dppe) instead of CuCl(IPr)
CuCl instead of CuCl(IPr)
AgOAc instead of AgF
Ag2O[d] instead of AgF
CsF instead of AgF
Et3N instead of AgF
tBuOK instead of AgF
rt
47
37
14
54
23
39
0
74
66
99
0
3
4
5
6
0
7
0
8
0
9
0
0
10
11
12
13
14
0
0
0
0
0
0
35
64
0
70 °C
0
[a] Determined by 1H NMR analysis using mesitylene as an internal standard.
[b] Isolated yield. [c] The theoretical maximum yield is 200%. [d] 2.0 equiv was
used.
[a] Isolated yield. [b] Conditions: 2 (0.50 mmol, 0.10 M), 1 (2.0 equiv), AgF (4.0
equiv), CuCl(IPr) (5 mol%), toluene, 50 °C, 4–24 h. [c] Determined by 1H NMR
analysis using mesitylene as an internal standard.
Table 2 shows the scope of the reaction between 1 and 2
with respect to the aryl group and the amine moiety under the
2
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10.1002/ejoc.202000562
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COMMUNICATION
The generality of the current reaction conditions was
examined with variably Si-substituted alkoxyphenylsilanes 4a–
10a (Table 3). In the cases of trialkoxyphenylsilanes, Ph–
Si(OMe)3 (4a) were transformed to 3aa in a competitive yield
(70%), though the conversion of Ph–Si(OiPr)3 (5a) to 3aa was not
efficient probably because of the bulkiness around the silicon
atom to hamper the approach of a fluoride. In the cases of
dialkoxymethylphenylsilanes, Ph–SiMe(OMe)2 (6a) and Ph–
SiMe(OEt)2 (7a) were converted to 3aa in 74% and 68%
respective yields. In turn, Ph–SiMe(OtBu)2 (8a) seemed to be too
bulky for an efficient conversion and gave 3aa only in 4% yield.
In summary, we have developed copper-catalyzed
electrophilic amination between alkoxyarylsilanes 1 and N-
benzoyloxyamines 2 enabled by a stoichiometric amount of AgF
that is not only
a
base but an essential activator.
Triethoxyarylsilanes bearing an electron-withdrawing or -donating
substituent on the aromatic rings could be transformed to tertiary
aniline derivatives 3. Also, various di-, and trialkoxysilyl groups on
arenes were confirmed to be reactive except for the ones bearing
sterically demanding alkoxy substituents. A broad range of
reactivities of silyl groups with regard to the size of the
substituents and the numbers of alkoxy groups are worth further
The reactivity dropped in the case of mono-alkoxydimethylsilanes. investigation. More detailed studies of the use of variably
Thus, Ph–SiMe2(OMe) (9a) gave 3aa in only 10% yield, and Ph–
SiMe2(OtBu) (10a) showed no conversion under the same
conditions. The utility of other reactive silicon functional groups
are the issues to be examined in the following studies.
substituted silyl groups will be reported in due course.
Figure 1. Tentative Mechanism for Amination of Arylsilanes.
Table 3. Substrate Scope with Respect to Silyl Groups.[a],[b],[c]
Acknowledgements
[a] Isolated yield. [b] Conditions: 2a (0.50 mmol, 0.10 M), 1 (2.0 equiv), AgF (4.0
equiv), CuCl(IPr) (5 mol%), toluene, 50 °C, 6 h. [c] Determined by 1H NMR
analysis using mesitylene as an internal standard.
This work was supported by JSPS KAKENHI Grant Numbers
JP18J22838, JP18H04254, JP18H04409, JP19H00895, and
partly by JST CREST Grant Number JPMJCR19R4, Japan. H.S.
acknowledges a JSPS Predoctoral Fellowship. Q.Z. thanks
National Natural Science Foundation of China (NSFC, No.
21702054). J.S. thanks the support by ISHIZUE 2019 of Kyoto
University Research Development Program.
A tentative mechanistic proposal for the copper(I)-catalyzed
amination of 1 with 2 is depicted in Figure 1. Initially, CuCl(IPr)
would be transformed to the corresponding fluoride CuF(IPr) (A)
that would then undergo transmetalation with 1 to give arylcopper
species B with concomitant formation of fluorosilane C as
previously depicted by Ball et al.[17] Oxidative addition of 2 to B
would form copper(III) species D, and the subsequent reductive
elimination would afford the desired arylamine 3 along with copper
benzoate E. The following transmetalation with AgF would give
AgOBz and regenerate A to maintain the catalytic cycle. Because
of the absence of biphenyl byproduct in the case of toluene as a
solvent, the formation of an arylsilver intermediate is not
considered in the current mechanistic sketch. The necessity of the
stoichiometric amount of AgF could be ascribed not only to the
initial formation of CuF(IPr) (A), but to the efficient regeneration of
A from intermediate CuOBz(IPr) (E). A mechanism involving an
SN2 reaction on the nitrogen atom[8b] or a mechanism via radical-
mediated amination[18] could not be denied for this transformation.
Keywords: alkoxysilane • arylamine • copper • catalyst • silver
fluoride
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Entry for the Table of Contents
Key Topic: Amination
A stoichiometric amount of silver fluoride that serves as a base as well as an essential activator enabled a copper-catalyzed C–N-
bond-forming reaction between simple alkoxyarylsilanes and N-benzoyloxyamines. This method allows the amination of simple
arylsilanes bearing two or three alkoxy groups on the silicon atom.
(up to 450 characters)
Institute and/or researcher Twitter usernames: @yorimitsu_lab (laboratory), @jshimok (JS)
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