Nickel-catalyzed cycloaddition of α,β-unsaturated oximes with alkynes: Synthesis of highly substituted pyridine derivatives

Article abstract of DOI:10.1246/cl.2012.1498

A nickel-catalyzed cycloaddition of α,β-unsaturated oximes with alkynes to afford 2,3,4,6-tetrasubstituted pyridine derivatives has been developed. The reaction involves oxidative addition of the N-O bond of α,β-unsaturated oximes to Ni(0) and subsequent alkyne insertion to an N-Ni bond, followed by intramolecular cyclization. It was also found that β,γ-unsaturated oximes participate in the nickelcatalyzed reaction with alkynes to furnish pyridine derivatives.

Full text of DOI:10.1246/cl.2012.1498

doi:10.1246/cl.2012.1498
1498
Published on the web November 10, 2012
Nickel-catalyzed Cycloaddition of ¡,¢-Unsaturated Oximes with Alkynes:
Synthesis of Highly Substituted Pyridine Derivatives
Yuji Yoshida,1 Takuya Kurahashi,*1,2 and Seijiro Matsubara*1
1Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510
2JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
(Received July 24, 2012; CL-120792; E-mail: kurahashi.takuya.2c@kyoto-u.ac.jp,
matsubara.seijiro.2e@kyoto-u.ac.jp)
Table 1. Nickel-catalyzed cycloaddition of 1 with 2a
A
nickel-catalyzed cycloaddition of ¡,¢-unsaturated
R4
oximes with alkynes to afford 2,3,4,6-tetrasubstituted pyridine
derivatives has been developed. The reaction involves
oxidative addition of the N-O bond of ¡,¢-unsaturated
oximes to Ni(0) and subsequent alkyne insertion to an N-Ni
bond, followed by intramolecular cyclization. It was also
found that ¢,£-unsaturated oximes participate in the nickel-
catalyzed reaction with alkynes to furnish pyridine deriva-
tives.
[Ni(cod)2] (10 mol %)
IPr (10 mol %)
OMe
R3
R2
N
N
R4
R3
+
i-PrOH (5 equiv)
toluene, 130 °C, 3 h
R1
R2
R1
1
2
3
Entry
1
1
2
3
Pr
Yield/%b
OMe
N
N
N
N
Pr
N
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
75
(22)c
Ph
Ph
Me
Ph
Ph
2a
2a
2a
2a
2a
Ph
Ph
Ph
1a
3aa
Pr
Despite the large number of synthetic reactions for the
construction of the pyridine framework, the development of a
new type of reaction that gives direct access to structurally
diverse pyridine derivatives remains an important research topic,
because of the increasing demand for pyridine derivatives that
can function as lead compounds for pharmaceutical drugs and as
potential organic functional materials.1 In this context, we have
developed a nickel-catalyzed intermolecular cycloaddition re-
action to afford structurally diverse pyridines derivatives.
Herein, we report that the cycloaddition of ¡,¢-unsaturated
oximes with alkynes is efficiently catalyzed by Ni(0)/IPr to
afford highly substituted pyridines. The reaction represents the
first example of a nickel-catalyzed formal [4 + 2] cycloaddition
of 1,3-azadienes and alkynes to give pyridines.2,3
Initially, it was found that the reaction of ¡,¢-unsaturated
oxime 1a with 4-octyne (2a) in the presence of a nickel catalyst,
which was prepared in situ from [Ni(cod)2] (10 mol %) and IPr
(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) (10 mol %),
in toluene at 130 °C for 3 h, provided pyridine 3aa in 22%
yield (Table 1, Entry 1, in parentheses). The use of IMes (1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) or phosphine li-
gands such as PPh3, PCy3, Pt-Bu3, and PMe3, in place of IPr
resulted in formation of 3aa in lower yields or trace amounts.
Among various reaction media examined, toluene gave the best
result in providing 3aa. Upon optimization of the reaction
conditions, 3aa was obtained in improved yield (Entry 1):
addition of i-PrOH (5 equiv) was found to be effective in
affording 3aa in 75% yield. With the optimized reaction
conditions in hand, we next examined the substrate scope of this
[4 + 2] cycloaddition. Oximes such as 1b, 1c, and 1d possessing
aliphatic substituents also participated in the reaction to furnish
the corresponding pyridine derivatives (Entries 2-4). Further-
more, it was found that ¡,¢-unsaturated oximes with an aryl
group were generally effective, regardless of electron-donating
or -withdrawing substituents (Entries 5-8). The cycloaddition of
1a with an unsymmetrical alkyne, 4-methyl-2-pentyne (2b), also
gave the pyridine 3ab in 71% yield, consisting of regioisomers
in a 2/1 ratio (Entry 9).
OMe
Pr
N
2
3
4
5
6
71
29
70
85
78
Ph
Me
Me
1b
3ba
Pr
OMe
Pr
N
Me
Ph
1c
3ca
Pr
OMe
Pr
N
t-Bu
t-Bu
Ph
1d
3da
Pr
OMe
N
Pr
Ph
N
4-F-C6H4
Ph
4-F-C6H4
1e
3ea
Pr
OMe
N
Pr
Ph
N
Pr
Pr
Pr
Pr
4-MeO-C6H4
Ph
2a
2a
4-MeO-C6H4
1f
3fa
Pr
OMe
N
Pr
4-F-C6H4
N
7
77
83
Ph
4-F-C6H4
Ph
N
1g
3ga
Pr
OMe
N
Pr
Pr
Pr
8
9
Ph
4-MeO-C6H4
2a
2b
Ph
4-MeO-C6H4
1h
3ha
Me
OMe
N
i-Pr
N
i-Pr
Me
71
(2/1)d
Ph
Ph
Ph
Ph
1a
3ab
aReactions were carried out using [Ni(cod)2] (10 mol %), IPr (10 mol %),
1 (0.3 mmol), and 2 (0.6 mmol) in 1.5 mL of toluene at 130 °C for 3 h in
a sealed tube. bIsolated yields are given. cWithout an addition of i-PrOH.
dRatio of regioisomers.
Chem. Lett. 2012, 41, 1498-1499
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1499
Table 2. Nickel-catalyzed cycloaddition of 4 with 2a
H2
R4
3aa
1a
[Ni(cod)2] (10 mol %)
IPr (10 mol %)
NiH2
Ni(0) / IPr
OMe
R3
N
N
R4
R3
+
Ph
Ph
i-PrOH (5 equiv)
R1
R1
Ph
Ni
H
Ph
toluene, 130 °C, 3 h
OMe
Ni
N
4
2
5
Pr
10
N
Yield/%b
H
Entry
1
4
2
5
6
2a
Pr
Pr
Ph
Ph
Pr
O
OMe
Pr
N
N
80
Ph
Ph
2a
Pr
Pr
Ph
Ph
N
Ph
H
Ni
Pr
N
Ni OMe
Ph
4a
5aa
O
9
7
Ph
Ph
Pr
Pr
Ni
OMe
Pr
Pr
N
N
MeOH
N
Ph
2
3
4
2a
2a
2b
67
4-F-C6H4
i-PrOH
4-F-C6H4
Ph
Ph
Ph
4b
5ba
OMe
8
Pr
Scheme 1. Plausible reaction pathway.
OMe
Pr
N
N
Ph
23
Pr
4-MeO-C6H4
4-MeO-C6H4
Ni(cod)2 (10 mol %)
IPr (10 mol %)
Oi-Pr
Pr
Ph
N
N
4c
5ca
+
Pr
Pr
toluene, 130 °C, 3 h
Ph
Ph
Ph
Ph
Me
OMe
i-Pr
1i
2a
3aa 88% yield
N
N
59
Ph
(5/1)c
Ph
Ph
Scheme 2. Effects of N-substituent on ¡,¢-unsaturated oxime.
Ph
4a
5ab
8 with i-PrOH to afford intermediate 9 is the rate-determining
step in the catalytic process. ¢-Hydride elimination would give
10, and a second ¢-hydride elimination, with aromatization of the
six-membered heterocycle, would provide pyridine 3aa.5
In conclusion, we have demonstrated that ¡,¢-unsaturated
oximes reacted with alkynes in the presence of a nickel catalyst
to furnish 2,3,4,6-tetrasubstituted pyridines. Furthermore, it was
found that the use of ¢,£-unsaturated oximes in place of ¡,¢-
unsaturated oximes also provides 2,3,4,6-tetrasubstituted pyr-
idines.6
aReactions were carried out using [Ni(cod)2] (10 mol %), IPr (10 mol %),
4 (0.3 mmol), and 2 (0.6 mmol) in 1.5 mL of toluene at 130 °C for 3 h in
c
a sealed tube. bIsolated yields are given. Ratio of regioisomers.
As shown in Table 2, the present nickel-catalyzed cyclo-
addition can be applied not only to ¡,¢-unsaturated oximes but
also to ¢,£-unsaturated oximes in the synthesis of pyridines. The
cycloaddition of ¢,£-unsaturated oxime 4a with 4-octyne (2a)
afforded pyridine 5aa in 80% yield under the same reaction
conditions: the reaction was performed by addition of i-PrOH
(5 equiv) in the presence of [Ni(cod)2] (10 mol %) and IPr
(10 mol %) in toluene at 130 °C for 3 h (Entry 1). The reaction of
¢,£-unsaturated oxime 4b bearing an electron-withdrawing
substituent on the phenyl group with 4-octyne (2a) furnished
the correspondingly substituted pyridine 5ba in 67% yield
(Entry 2). However, the cycloaddition of 4c possessing an
electron-donating substituent resulted in formation of 5ca in
lower yield (23%, Entry 3). The reaction of 4a with an
unsymmetrical alkyne, 4-methyl-2-pentyne (2b), furnished the
pyridine 5ab with a regioisomer ratio of 5/1 (Entry 4).
Even though the mechanism of this reaction has not been
elucidated completely, we propose the following reaction path-
way, based on the results that we observed (Scheme 1).4 The
reaction is initiated by the oxidative addition of an oxime N-O
bond to an Ni(0) complex, followed by insertion of an alkyne into
an N-Ni bond to afford intermediate 7. The subsequent intra-
molecular insertion of the olefin affords intermediate 8. The
methoxy ligand on the nickel would then be replaced with i-
PrOH to afford 9. Notably, treatment of 1i with 2a in the presence
of the Ni(0)/IPr catalyst in the absence of i-PrOH furnished
pyridine 3aa in excellent yield (88% yield, Scheme 2). This
result suggests that the ligand-exchange reaction of intermediate
This work was supported by JST, ACT-C and Grants-in-Aid
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. T.K. also acknowledges the Asahi Glass
Foundation, Kansai Research Foundation, and Toyota Physical
and Chemical Research Institute.
References and Notes
1
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Soc. Rev. 2007, 36, 1085. d) P. R. Chopade, J. Louie, Adv. Synth. Catal.
2006, 348, 2307. e) J. A. Varela, C. Saá, Chem. Rev. 2003, 103, 3787.
For nickel-catalyzed dehydrogenative [4 + 2] cycloaddition of 1,3-dienes
with nitriles to provide pyridines, see: M. Ohashi, I. Takeda, M. Ikawa, S.
Ogoshi, J. Am. Chem. Soc. 2011, 133, 18018.
a) P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010, 12, 5688. b) P. C. Too,
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Y. Yoshida, T. Kurahashi, S. Matsubara, Chem. Lett. 2011, 40, 1140.
It is reasonable to consider that the NiH2 reacts with alkynes, which exist in
the reaction mixture in excess, to regenerate the starting Ni(0) complex via
hydrogenation. Indeed, the nickel-catalyzed cycloaddition of 7-tetradecyne
with 1a furnished correspondingly substituted pyridine along with tetradecenes.
Supporting Information is available electronically on the CSJ-Journal Web
site, http://www.csj.jp/journals/chem-lett/index.html.
2
3
4
5
6
Chem. Lett. 2012, 41, 1498-1499
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/