Production of Quaternary α-Aminonitriles by Means of Indium-Catalyzed Three-Component Reaction of Alkynes, Amines, and Trimethylsilyl Cyanide

Article abstract of DOI:10.1021/acs.orglett.6b00508

A novel synthesis of α-aminonitriles is described via an indium-catalyzed three-component coupling reaction of alkynes, amines, and trimethylsilyl cyanide (Me₃SiCN). Hydroamination of alkynes with a subsequent nucleophilic addition of Me_3<

Full text of DOI:10.1021/acs.orglett.6b00508

Letter
pubs.acs.org/OrgLett
Production of Quaternary α‑Aminonitriles by Means of Indium-
Catalyzed Three-Component Reaction of Alkynes, Amines, and
Trimethylsilyl Cyanide
Yuta Hamachi, Moe Katano, Yohei Ogiwara, and Norio Sakai*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda,
Chiba 278-8510, Japan
S
* Supporting Information
ABSTRACT: A novel synthesis of α-aminonitriles is described via an indium-
catalyzed three-component coupling reaction of alkynes, amines, and
trimethylsilyl cyanide (Me3SiCN). Hydroamination of alkynes with a
subsequent nucleophilic addition of Me3SiCN resulted in a novel approach
to quaternary α-aminonitrile derivatives.
he Strecker reaction, which enables the one-pot synthesis of
α-aminonitriles by a three-component reaction of
Scheme 1. Strecker-Type Reaction of Ketimines Derived from
(a) Ketones and (b,c) Alkynes
T
aldehydes, amines, and cyanides, is the classic method and still
greatly important in organic chemistry.1 The significance of this
reaction is derived from the products, α-aminonitriles, which
constitute versatile precursors for the synthesis of both natural
and non-natural amino acids and other nitrogen-containing
heterocycles.2 A large number of improvements to the original
protocol have been reported over the years, such as the
development of effective catalysts, a broadened scope of the
amines, replacement of toxic cyanide with a safer cyanide source,
and employment of ketones instead of aldehydes. In particular,
the Strecker reaction using ketones has generally proven to be
difficult because ketimine intermediates are less reactive to
cyanide than aldimines. Therefore, although the Strecker
products derived from ketones, quaternary α-aminonitriles, are
important compounds due to their synthetic potential for
asymmetric applications, reliable and efficient procedures for
their structures remain limited (Scheme 1a).3
branched amines from ketimine intermediates via Markovnikov
hydroamination. On the basis of this result, we envisioned that
the addition of “Si−CN” rather than “Si−H” to the ketimines
could achieve a sequential one-pot preparation of α-aminonitriles
including a quaternary carbon center with the indium catalytic
system. Herein, we report a novel and straightforward approach
to quaternary α-aminonitriles by an indium(III)-catalyzed three-
component coupling reaction of alkynes, amines, and Me3SiCN
through intermolecular Markovnikov hydroamination (Scheme
1b).
Hydroamination of alkynes is another efficient approach to
imines,4 and a modified Strecker synthesis using alkynes via
hydroamination, instead of aldehydes or ketones, is considered
to be an alternative synthetic strategy. In particular, Markovnikov
hydroamination is available to give good precursors, ketimines,
for quaternary α-aminonitriles (Scheme 1b). In 2006, Schafer
and co-workers reported the titanium(IV)-catalyzed one-pot
synthesis of α-aminonitriles from terminal alkynes.5 This method
selectively provides only tertiary α-aminonitriles due to the
formation of aldimines via anti-Markovnikov regioselectivity in
the initial hydroamination step and subsequent isomerization
(Scheme 1c). As far as we could ascertain, however, the catalytic
preparation of quaternary α-aminonitriles from alkynes, amines,
and cyanides via ketimine intermediates obtained via inter-
molecular Markovnikov hydroamination remains unexplored
(Scheme 1b).
On the basis of our previous study,6 when phenylacetylene and
p-toluidine were initially treated with 10 mol % of InBr3 in
toluene at 110 °C for 3 h, followed by the addition of 1.5 equiv of
Me3SiCN with further stirring at room temperature for 21 h, the
expected α-aminonitrile 1 was obtained in a 36% yield (Table 1,
entry 1). To promote the addition of Me3SiCN, the reaction
Recently, our research group reported the InBr3-catalyzed
reductive hydroamination of terminal alkynes with amines using
Me2PhSiH as a reducing reagent.6 This reaction provides
Received: February 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00508
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Indium-Catalyzed Three-Component Reaction of
Terminal Alkynes and Aniline Derivatives with Me3SiCN
a
first step
second step
b
entry
catalyst
InBr3
time (h)
temp (°C)
yield (%)
1
2
3
3
3
3
3
3
6
6
6
6
6
6
6
6
rt
36
50
65
27
InBr3
60
80
reflux
80
80
80
80
80
80
80
80
80
80
3
InBr3
4
InBr3
c
5
InBr3
45
d
6
InBr3
55
7
InBr3
85
43
44
85
0
8
InCl3
9
In(OTf)3
InI3
10
11
12
13
14
AlCl3
GaCl3
Zn(OTf)2
none
0
80
0
a
Reaction conditions. First step: alkyne (0.6 mmol), ArNH2 (0.9
mmol), catalyst (0.06 mmol), toluene (1.2 mL), reflux. Second step:
b
c
Me3SiCN (0.9 mmol), 21 h. Isolated yield. InBr3 (5 mol %).
Me3SiCN (2 equiv).
d
a
Reaction conditions. First step: alkyne (0.6 mmol), ArNH2 (0.9
temperature in the second step was examined. Although the
increase in temperature to 80 °C promoted the addition (entries
2 and 3), the reflux condition resulted in a drastic decrease in the
yield of 1 (entry 4). When the reaction was conducted with either
5 mol % of InBr3 or 2 equiv of Me3SiCN at 80 °C, both yields
were slightly reduced (entries 5 and 6). When the reaction time
at the first step was prolonged to 6 h, the yield of 1 was improved
to 85% (entry 7). During the screening of the catalysts (entries
8−13), InI3 and Zn(OTf)2 showed catalytic activity that
compared favorably to InBr3. Also, when the reaction was
conducted in the absence of a catalyst, the first hydroamination
did not occur, and the starting alkyne and amine were completely
recovered (entry 14).
mmol), InBr3 (0.06 mmol), toluene (1.2 mL), reflux, 6 h. Second step:
b
Me3SiCN (0.9 mmol), 80 °C, 21 h. Isolated yields are shown. First
c
step is 24 h. ArNH2 (2 equiv).
first hydroamination did not proceed when employing a sterically
hindered alkyne, 3,3-dimethyl-1-butyne.
Next, the present method was evaluated (Scheme 3) using an
activated alkyne, dimethyl acetylenedicarboxylate (DMAD). The
reaction of DMAD with p-toluidine afforded the desired product
14 in a 44% yield. It is noteworthy that when employing a
a
Scheme 3. Reaction of DMAD and Amines with Me3SiCN
Using the optimal conditions, the scope of both alkynes and
amines was next investigated (Scheme 2). Primary aromatic
amines bearing a chlorine atom on the benzene ring at the 4-, 3-,
or 2-positions were applied to a three-component coupling
reaction with phenylacetylene and Me3SiCN, giving α-amino-
nitriles 2−4 in excellent yields. Anilines containing the other
halogens at the 4-position, bromine and fluorine, were also
converted into the corresponding products 5 and 6 in 88 and
94% isolated yields, respectively. The reactions of anilines with
an electron-withdrawing group, such as 4-trifluoromethyl, 4-
cyano, and 4-nitro, were also applicable to this transformation to
afford 7−9, although the yield of the substrate with a CF3 or NO2
group was remarkably decreased. When the reaction was
conducted with aniline, m-toluidine, or 4-anisidine, the
corresponding α-aminonitriles 10−12 were obtained in 96, 83,
and 76% yields, respectively. When the reaction was performed
with 2-aminopyridine or a secondary N-methylaniline, the
desired products were not obtained under these conditions. An
extension to aliphatic alkynes was then examined. When 1-
hexyne and p-toluidine were employed, the corresponding
product 13 was obtained in a practical yield. Unfortunately, the
a
Reaction conditions. First step: DMAD (0.6 mmol), amine (0.9
mmol), InBr3 (0.06 mmol), toluene (1.2 mL), reflux, 6 h. Second step:
Me3SiCN (0.9 mmol), 80 °C, 20 h. Isolated yields are shown. Second
b
c
1
step is 30 h. Yield of 16 was determined by H NMR analysis as the
mixture with enamine intermediate 16′ due to decomposition of 16.
d
Three days in the second step.
B
DOI: 10.1021/acs.orglett.6b00508
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
secondary amine, N-methylaniline, which is not compatible with
a classic Strecker synthesis, the corresponding α-aminonitrile 15
was obtained. This result implies that the pathway for the
reaction with DMAD is different from that with inactivated
alkynes, as shown in Scheme 2. In addition, the use of piperidine
afforded the corresponding α-aminonitrile 16 in a good yield. In
contrast, when the reaction was carried out with t-butylamine,
the enamine intermediate was obtained in a quantitative yield
without the formation of cyanide addition products. In this case,
it seemed that steric hindrance prevented the intermediate from
undergoing a subsequent cyanosilylation.
Scheme 4. Cyclization and Cyanation of 4-Alkynylamines with
Me3SiCN
a
On the other hand, for other unactivated internal alkynes or
aliphatic amines as a substrate, the desired α-aminonitriles were
not detected at all. Thus, we next attempted to apply this
protocol to intramolecular hydroamination. Recently, Ham-
mond et al. reported the one-pot synthesis of α-CN N-
heterocycles from alkynylamines with Me3SiCN using a
copper(I) or a gold(I) catalyst under microwave conditions.7 It
was assumed that the reaction would proceed via the
intramolecular hydroamination of alkynylamines, followed by
the addition of Me3SiCN to form α-cyanated heterocycles. On
the basis of this example, we anticipated that our indium catalytic
system could also be applied to the reaction of 4-alkynylamines
with Me3SiCN.
a
Reaction conditions: substrate (0.6 mmol), InCl3 (0.06 mmol),
toluene (1.2 mL), rt, 12 h. Isolated yields are shown.
To evaluate the initial intramolecular hydroamination and
subsequent cyanosilylation of 4-alkynylamine 17 with Me3SiCN,
several screenings of the reaction conditions were conducted. On
the basis of the optimal conditions of the three-component
coupling reaction above, when the one-pot stepwise protocol was
initially examined, no desired α-cyanation product 18 was
detected (eq 1). On the other hand, in the presence of Me3SiCN,
second step, though no products were obtained in the absence of
the catalyst, the corresponding α-aminonitrile 12 was obtained in
a 75% yield (eq 4). These results indicate that the indium catalyst
was effective for both hydroamination and cyanation.8
In summary, we have demonstrated a one-pot preparation of
quaternary α-aminonitrile derivatives by an indium-catalyzed
three-component reaction of alkynes, amines, and trimethylsilyl
cyanide. The reaction proceeded via the hydroamination of an
alkyne with a subsequent addition of trimethylsilyl cyanide. Since
the hydroamination approach is considered to be an alternative
route to access the ketimine as a Strecker intermediate, it would
be a potentially powerful synthetic strategy for a variety of
quaternary α-aminonitriles as a complementary tool of a classic
Strecker synthesis. Further substrate scope, asymmetric
application, and other silicon-based nucleophilic versions of
this transformation are now in progress.
a similar one-pot reaction employing the indium catalyst at room
temperature afforded the expected pyrrolidine 18 in a 71% NMR
yield. Also, similar catalytic activity for this procedure was
observed using InCl3, which is more stable under air and is less
expensive than InBr3 (eq 2).
Therefore, we chose InCl3 as the catalyst, and the intra-
molecular hydroamination/cyanosilylation of several 4-alkynyl-
amines with Me3SiCN was examined (Scheme 4). With the
optimal conditions, the α-CN pyrrolidine 18 could be isolated in
a 70% yield. Reactions of secondary alkynylamines bearing
benzylic N-substituents with Me3SiCN afforded the correspond-
ing products 19 and 20 in 47 and 43% yields, respectively. The
substrate containing a phenyl-substituted nitrogen was also
applicable to this reaction, although the yield of product 21 was
slightly decreased to 51%.
To confirm the catalytic effect of the indium catalyst, several
control experiments were then conducted. When phenyl-
acetylene and 4-anisidine were treated with 10 mol % of InBr3
in toluene at 110 °C for 6 h, hydroamination proceeded to
produce imine 22 in an 80% yield (eq 3). Next, when the imine
intermediate 22 was treated with the optimal conditions at the
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00508.
■
S
Experimental procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sakachem@rs.noda.tus.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Scientific
Research (C) (No. 25410120) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan.
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(8) Since the indium salt showed catalytic activity for the cyanation of
ketimine, we envisioned that the indium catalyst could also be
acceptable for the typical Strecker reaction of a ketone. When
acetophenone (0.6 mmol) and aniline (0.9 mmol) were treated with
InBr3 (10 mol %) and Me3SiCN (1.5 equiv) in toluene, as expected, the
corresponding quaternary α-aminonitrile 10 was obtained in a 96%
yield.
D
DOI: 10.1021/acs.orglett.6b00508
Org. Lett. XXXX, XXX, XXX−XXX