Metal-free synthesis of 2-alkenyl/alkynyl-5-nitropyridines using a three-component ring transformation

Article abstract of DOI:10.1246/cl.150045

A metal-free, facile, and efficient protocol for synthesizing a series of 2-alkenyl/alkynyl-5-nitropyridines was developed by using a three-component ring transformation of 1-methyl-3,5- dinitro-2-pyridone with α,β-unsaturated ketones and ammonium acetate

Full text of DOI:10.1246/cl.150045

CL-150045
Received: January 19, 2015 | Accepted: March 10, 2015 | Web Released: March 14, 2015
Metal-free Synthesis of 2-Alkenyl/Alkynyl-5-nitropyridines
Using a Three-component Ring Transformation
Song Thi Le,1 Haruyasu Asahara,1,2 and Nagatoshi Nishiwaki*1,2
1School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502
2Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502
(E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp)
A metal-free, facile, and efficient protocol for synthesizing a
series of 2-alkenyl/alkynyl-5-nitropyridines was developed by
using a three-component ring transformation of 1-methyl-3,5-
dinitro-2-pyridone with α,β-unsaturated ketones and ammonium
acetate. As 2-alkenyl/alkynyl-5-nitropyridines are not easily
prepared by the Heck or Sonogashira reactions, this method will
be supplementary to these reactions.
methodology for the synthesis of alkenyl/alkynylpyridines is
still challenging.
In our previous work, we developed an efficient preparative
method for arylated nitropyridines 3 by three-component ring
transformation (TCRT) of dinitropyridone 1 with aromatic
ketones 2 in the presence of ammonium acetate as the nitrogen
source (Scheme 1); this can be used as a supplementary method
to the Suzuki reaction.15 These successful experimental results
prompted us to extend the substrate scope for this method to
a series of α,β-unsaturated ketones 4, thus facilitating the
introduction of an alkenyl/alkynyl group into the nitropyridine
framework without using a transition metal.
2-Alkenyl-5-nitropyridines1-3 and 2-alkynyl-5-nitropyri-
dines4 are widely employed as precursors to pharmaceuticals
and biologically active compounds. In addition, alkynylnitro-
pyridines are often found in nonlinear optical materials5 and
organic semiconductors.6 Although the Heck,7 Suzuki,2a,8
Stille,3,9 and Sonogashira10,11 reactions are common protocols
for alkenylation/alkynylation, poisonous and expensive transi-
tion metals are used and a purification step to avoid metal
contamination of the products is necessary. In addition, the
substrates for these reactions, 2-halo-5-nitropyridines, are
commonly prepared by halogenation of 5-nitro-2-pyridone.11,12
2-Alkenyl-5-nitropyridines are also available by condensation
reactions using 5-nitropyridine-2-carbaldehydes13 or 2-methyl-
5-nitropyridines.14 However, troublesome multistep reactions
are necessary for preparing these starting materials. Therefore,
the development of a metal-free, facile, and efficient economical
Dinitropyridone 1 was heated with 4-phenyl-3-buten-2-one
(4a) at 65 °C for 24 h in the presence of 15 equivalents of
ammonium acetate. After removal of the solvent, the residue was
washed with benzene (3 © 10 mL) to remove unreacted ketone
Me
O
NO2
R
N
R
NO2
NH4OAc
Ar
O
EtOH
Ar
N
NO2
24 h, 65 °C
3
2
1
Scheme 1. TCRT of dinitropyridone 1 in the presence of ammonium
acetate.
Table 1. Synthesis of 2-alkenyl-5-nitropyridines 5
Me
O
NO2
R2
NO2
N
NH4OAc
EtOH
R2
R1
O
R1
N
NO2
(1 equiv)
4
1
5
NH4OAc
/equiv
Time
/h
Temp.
/°C
Yield
/%
Recovery
of 1/%
Entry
R1
R2
1
2
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Me
Me
H
a
a
a
a
b
b
c
c
d
d
e
e
f
15
20
30
15
30
15
30
30
30
30
30
15
30
30
24
24
24
4
24
3
24
4
24
2
65
65
65
80
65
80
65
80
65
80
65
80
65
80
21
54
72
82
94
76
63
75
0
68
32
0
trace
0
trace
0
0
0
0
0
0
3
4a
5
p-MeOC6H4
p-MeOC6H4
p-ClC6H4
p-ClC6H4
H
H
Me
Me
6a
7
8a
9
10a
11
12a
13
14a
0
24
2
24
6
18
25
68
79
2,6,6-trimethylcyclohexenyl
2,6,6-trimethylcyclohexenyl
0
0
H
f
aMicrowave heating was used.
776 | Chem. Lett. 2015, 44, 776–778 | doi:10.1246/cl.150045
© 2015 The Chemical Society of Japan

+
R
NH3
R
R
H
4a
OH
NO2
H2N
O2N
O
O2N
O
NO2
O2N
NO2
N
O
2 N
Me
6
O
N
Me
1
R : PhCH=CH
Me
6a
7a
O
O2N
H
Me
NO2
NO2
N
H
NO2
NO2
R
O
Ph
N
N
N
H
R
N
H
Me
5a
8a
9a
Scheme 2. A plausible mechanism for the formation of 2-ethenyl-5-nitropyridine 5a.
Table 2. Synthesis of 2-alkynyl-5-nitropyridines 11
Me
NO2
NO2
N
NH4OAc
EtOH
O
O
N
NO2
R
R
(1 equiv)
10
1
11
NH4OAc
/equiv
Time
/h
Temp.
/°C
Yield
/%
Recovery
of 1/%
Entry
R
1
Ph
Ph
Et
Et
Me3Si
Me3Si
a
20
15
20
15
20
15
24
3
24
3
24
4
65
80
65
80
65
80
83
87
52
80
trace
trace
0
0
0
0
2a
3
a
b
b
c
4a
5
6a
11c 16/11d 35b
11c 24/11d 60b
c
b
aMicrowave heating was used. Desilylated product 11d (R = H) was also obtained.
4a and was purified by column chromatography on silica gel
(eluent: hexane/ethyl acetate = 95/5) to afford 5-nitro-2-(2-
phenylethenyl)pyridine (5a)7 in 21% yield (Table 1, Entry 1).
TCRT is considered to proceed as illustrated in Scheme 2. The
enol form of 4a attacks the 4-position of dinitropyridone 1 to
afford the intermediate 6a, which is then converted to enamine
7a by reaction with ammonium ion.15,16 The amino group of
7a intramolecularly attacks the 6-position, leading to bicyclic
product 8a. After ring opening of 8a, the elimination of
nitroacetamide accompanied by aromatization of intermediate
9a affords alkenylated pyridine 5a.
In this TCRT, the competitive thermal decomposition of
ammonium acetate proceeds, and gaseous ammonia escapes
from the reaction mixture, depleting the nitrogen source. Thus,
when all the ammonium acetate is consumed by TCRT or by
thermal decomposition, the reaction cannot proceed further.
Indeed, the low yield of nitropyridine 5a was improved by
increasing the amount of ammonium acetate; however, this
substantially prolonged the reaction time (Table 1, Entries 2 and
3). Microwave heating was found to be more effective than
conventional heating to increase the yield of 5a within shorter
reaction time (Entry 4).
The application of this TCRT to other vinyl ketones 4b-4f
was also studied. Substituted styryl ketones 4b and 4c underwent
TCRT to afford the corresponding alkenylated pyridines 5b and
5c, respectively (Table 1, Entries 5-7). Among styryl ketones
4a-4c, methoxy-substituted ketone 4b revealed higher reactivity
because electron-rich 4b can easily approach the electron-poor
dinitropyridone 1. When aliphatic ketone 4d was employed, the
reaction was complex and alkenylpyridine 5d was not detected
(Entries 9 and 10). The reaction of mesityl oxide 4e also
afforded a complex mixture, from which alkenylpyridine 5e was
isolated in low yield (Entry 11). Although microwave heating
was somewhat effective for increasing the yield of 5e, the yield
was still low because of side reactions and the instability of the
product (Entry 12). These problems were solved by employing
a bulkier alkyl group to afford alkenylpyridine 5f in high yield
(Entries 13 and 14).
Chem. Lett. 2015, 44, 776–778 | doi:10.1246/cl.150045
© 2015 The Chemical Society of Japan | 777

This TCRT also facilitated alkynylation of the nitropyridine
framework by using alkynyl ketones as substrates. Both
aromatic and aliphatic alkynyl ketones 10a and 10b underwent
TCRT to afford 11a5b,11 and 11b, in good yield, respectively
(Table 2, Entries 1-4). Next, we conducted the ring trans-
formation using trimethylsilylethynyl ketone 10c to prepare the
corresponding pyridine 11c,11 which is regarded as an equivalent
of the unsubstituted ethynylpyridine 11d (R = H).17 As a result,
desilylation also proceeded under the employed reaction
conditions to afford a mixture of 11c and 11d with high total
yield (Entries 5 and 6).
In summary, we have developed a novel method for the
synthesis of alkenylated/alkynylated nitropyridines 5a-5f/11a-
11c through the TCRT of dinitropyridone 1 with unsaturated
ketones 4/10 and ammonium acetate. This method requires
simple manipulations during both the reaction and work-up.
Moreover, this method is metal-free, which enables the omission
of a purification step for removing poisonous transition metal
contamination and reduces the cost of preparation. Hence, this
TCRT is considered supplementary to other methods, including
the Heck and Sonogashira reactions.
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778 | Chem. Lett. 2015, 44, 776–778 | doi:10.1246/cl.150045
© 2015 The Chemical Society of Japan