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Published on the web December 22, 2012
¢-Amination of Saturated Nitriles through Palladium-catalyzed
Dehydrogenation, 1,4-Addition, and Re-dehydrogenation
Satoshi Ueno,*1 Ryohei Maeda,1 Shohei Yasuoka,1 and Ryoichi Kuwano*1,2
1Department of Chemistry, Graduate School of Sciences, Kyushu University,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581
2International Research Center for Molecular Systems (IRCMS), Kyushu University,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581
(Received October 8, 2012; CL-121033; E-mail: ueno@chem.kyushu-univ.jp, rkuwano@chem.kyushu-univ.jp)
Amination at the ¢-position of 2-arylpropionitriles through
catalytic dehydrogenation occurred by using [PdCl2(PMe3)2]
catalyst and bromobenzene. This is the first catalytic reaction
involving the direct dehydrogenation of saturated nitriles.
Scheme 1. ¢-Amination of saturated nitriles through a cata-
lytic dehydrogenation.
Developments of functionalizations on the alkane moiety of
saturated nitriles would offer a new synthetic route to a variety
of nitriles.1 The saturated nitriles undergo deprotonation at their
¡-position with a base, and the generated (¡-cyano)carbanion
reacts with an electrophile to afford an ¡-substituted nitrile.2
However, no report has been made on the functionalization of
saturated nitriles at the ¢-position. The transition-metal-cata-
lyzed ¢-functionalizations of saturated carbonyl derivatives
through C-H activation using the carbonyl group as a directing
group have been studied widely,3 but the cyano group has never
worked as the directing group for the sp3-hybridized C-H
activation because it does not strongly coordinate to the metal in
a side-on manner. Therefore, it is important to develop a new
method for a ¢-functionalization of saturated nitriles.
In 2009, we reported a catalytic method for a carbon-
nitrogen bond formation of ethyl ketones at the ¢-position.4 The
ethyl ketones undergo dehydrogenation, 1,4-addition, and re-
dehydrogenation to give ¢-amino-¡,¢-unsaturated ketones in
the presence of chlorobenzene and a trimethylphosphine-nickel
catalyst. Recently, Su,5 Clot and Baudoin,6 and Pihko7 also
independently reported ¢-functionalization of some saturated
carbonyl and nitro compounds through dehydrogenation and
addition sequences. Herein we report a ¢-amination of saturated
nitriles through tandem catalytic dehydrogenation, conjugate
addition, and re-dehydrogenation of saturated nitriles, which
are transformed into ¢-aminated ¡,¢-unsaturated nitriles
(Scheme 1).
Table 1. Catalytic ¢-amination of 2-phenylpropionitrile (1a)
with morpholine (2a)a
Yield of Yield of
Entry [M]
X Ligand
3a:4a
3a/%b
4a/%c
1d [Ni(cod)2]
3 PMe3
0
6
0
0
0
0
2
10
22
22
0
®
2
3
4
5
6
7
8
9
[{Pd(©3-allyl)Cl}2] 3 PMe3
[{Pd(©3-allyl)Cl}2] 2 PMe3
[{Pd(©3-allyl)Cl}2] 1 PMe3
[{Pd(©3-allyl)Cl}2] 2 PBu3
[{Pd(©3-allyl)Cl}2] 2 P(2-furyl)3
[{Pd(©3-allyl)Cl}2] 2 PPh3
[{Pd(©3-allyl)Cl}2] 2 PCy3
>99:1
>99:1
>99:1
97:3
85:15
76:24
66:34
>99:1
86
76
61
58
71
42
89
[PdCl2(PMe3)2]
®
aAll reactions were conducted in CPME (1.0 mL). The ratio
of 1a (0.2 mmol)/2a/[M]/Cs2CO3/PhBr was 10:20:1:40:40.
c
bThe GC yield of 3a is average of two runs. The GC yield of
d
4a is average of two runs. Chlorobenzene was used in place
of bromobenzene.
Initially, a mixture of 2-phenylpropionitrile (1a), morpho-
line (2a), cesium carbonate, and chlorobenzene was heated
in the presence of a catalytic amount of trimethylphosphine and
[Ni(cod)2] in cyclopentyl methyl ether (CPME) at 100 °C
(Table 1, Entry 1). Unfortunately, 1a remained intact at 40 h.
Next, palladium was used in place of the nickel catalyst since the
palladium complexes have been used as efficient catalysts for the
dehydrogenation of carbonyl compounds.8,9 In the presence of
[{Pd(©3-allyl)Cl}2] and three equivalents of trimethylphosphine,
the reaction was conducted by using bromobenzene in place
of chlorobenzene,10 the formation of a small amount of ¢-
enaminonitrile 3a was detected by GC analysis at 40 h (Entry 2).
When the amount of trimethylphosphine was decreased to two
equivalents to palladium, 1a completely disappeared at 40 h and
the yield of 3a was dramatically increased to 86% (Entry 3). Use
of equimolar trimethylphosphine to palladium caused a slight
decrease in the yield of 3a, while the 1:1 complex showed higher
catalytic activity (Entry 4).11 In the course of the optimization
with trimethylphosphine, neither ¡-phenylation of 1a (4a)12 nor
N-phenylation of 2a13 was observed by GC analysis.
Next, we investigated the effect of the monodentate
phosphine ligand. When tributylphosphine was used in place
of trimethylphosphine, 3a was produced in 61% yield with the
formation of ¡-phenylated nitrile 4a in 2% yield (Entry 5).12 We
used some phosphines to elucidate the correlation between the
cone angle of the ligands and the product ratio of 3a/4a (Entries
6-8). In these reactions, the ratio of 3a/4a decreased with the
increasing cone angle of the phosphine ligand.14,15 Moreover,
[PdCl2(PMe3)2] was the most effective catalyst, producing 3a in
89% yield (Entry 9).
Chem. Lett. 2013, 42, 40-42
© 2013 The Chemical Society of Japan