Synthesis of functionalized 4-nitroanilines by ring transformation of dinitropyridone with enaminones

Article abstract of DOI:10.1016/j.tetlet.2017.11.003

2-Functionalized 4-nitroanilines were readily synthesized by ring transformation using 3,5-dinitro-2-pyridone and enaminones prepared from 1,3-dicarbonyl compounds and amines. Modification of the amino group and the ortho-position could be achieved by sim

Full text of DOI:10.1016/j.tetlet.2017.11.003

Tetrahedron Letters xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of functionalized 4-nitroanilines by ring transformation of
dinitropyridone with enaminones
Saki Naito a, Soichi Yokoyama a,b, Haruyasu Asahara a,b,c, Nagatoshi Nishiwaki a,b,
⇑
a School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
b Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
c Department of Applied Chemistry, Faculty of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Functionalized 4-nitroanilines were readily synthesized by ring transformation using 3,5-dinitro-2-
pyridone and enaminones prepared from 1,3-dicarbonyl compounds and amines. Modification of the
amino group and the ortho-position could be achieved by simply changing the enaminones. Using this
strategy, functional groups such as acetyl, benzoyl, and ethoxycarbonyl groups could be introduced into
the nitroaniline framework.
Received 27 September 2017
Revised 29 October 2017
Accepted 2 November 2017
Available online xxxx
Ó 2017 Published by Elsevier Ltd.
Keywords:
Ring transformation
Nitroaniline
Dinitropyridone
Enaminone
Bicyclic intermediate
Ring transformation is one of the most powerful methods for
constructing versatile ring systems. Besides the Diels-Alder-type1
and degenerate-type2 ring transformations, nucleophilic-type
reactions have recently been recognized as the third type of ring
transformation mechanisms.3 1-Methyl-3,5-dinitro-2-pyridone
(1) can be used as a suitable substrate for this type of reaction
because of its high electrophilicity and the partial structure,
nitroacetamide, which serves as a good leaving group.3 Indeed,
pyridone 1 efficiently reacts with ketones and ammonium acetate
in a three-component ring transformation to afford 4-nitroanilines
20, which possesses alkyl/aryl groups at the 2- and 6-positions, in
moderate to high yields (Scheme 1a).4 It was also possible to mod-
ify the amino group of nitroanilines by using a combination of
amine and acetic acid instead of ammonium acetate (Scheme 1b).4
The presence of both the electron-donating amino group and
the electron-withdrawing nitro group creates a biased electron
density in the molecule, which sometimes shows intramolecular
charge transfer. This electronic property plays an important role
in nonlinear optical materials.5 Therefore, the above ring transfor-
mation is a useful protocol for the construction of a compound
library of diverse nitroaniline derivatives that can be further uti-
lized for the development of new functional materials. However,
only small amounts of the functionalized nitroanilines 30 were
obtained when 1,3-dicarbonyl compounds were used instead of
ketones because of side reactions (Scheme 1c). These results
prompted us to design a new ring transformation using dinitropy-
ridone 1 and enaminones 4 that are readily prepared from 1,3-
dicarbonyl compounds and amines.
When a solution of 1 and 4a in ethanol was heated at 80 °C for
1 day, a trace amount of the ring-transformed products, 2-etha-
noyl-4-nitro-N-propylaniline (3a) and 4-nitro-N-propylaniline
(5a), were detected in the reaction mixture (Table 1, Entry 1). It
was confirmed that the latter product 5a was not formed by the
deacetylation of 3a, as no reaction occurred upon treatment of iso-
lated 3a under the same reaction conditions. Several bases were
used as the additive (Entries 2–10). Addition of propylamine accel-
erated the reaction and increased the yield of 3a (Entry 2). Triethy-
lamine also revealed a similar effect; it was found that the addition
of 1 equiv. of the amine was sufficient and led to completion of the
reaction (Entries 3 and 4). When the reaction time was prolonged
to two days, pyridone 1 was completely consumed and the yield of
3a had increased to 57% (Entries 5 and 6). No positive effect was
observed when the bulkier tributylamine and less nucleophilic
2,6-lutidine were used (Entries 7 and 8). On the other hand, inor-
ganic bases such as potassium carbonate and cesium carbonate
decomposed pyridone 1 without the formation of any detectable
ring-transformed products (Entries 9 and 10).
⇑
Corresponding author at: School of Environmental Science and Engineering,
Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan.
E-mail address: nishiwaki.nagatoshi@kochi-tech.ac.jp (N. Nishiwaki).
https://doi.org/10.1016/j.tetlet.2017.11.003
0040-4039/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Naito S., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.11.003

2
S. Naito et al. / Tetrahedron Letters xxx (2017) xxx–xxx
O
PrNH2
(1.2 equiv.)
NH2
NH4OAc
O
1
(1 equiv.)
R1
R1
R1
R2
O2N
O2N
O2N
Me
Me
Me
N
NE t3 (1 equiv.)
3a
+
5a
(a)
(b)
(c)
O
O
EtOH
51~83%
80 °C, 3 h
EtOH
R1
R2
58%
8%
100 °C, 1 d
NO2
1
NO2
2'
Scheme 2. One-pot synthesis of nitroaniline 3a.
R3
R4
O
N
N
R3
R4
N
H
R2
AcOH
dissolved in ethanol. Then, dinitropyridone 1 and triethylamine
were added, and the solution was heated at 100 °C for 1 day, which
afforded nitroaniline 3a in a comparable yield with the obtained
from the reaction using isolated enaminone 4a.
EtOH
51~99%
O
R1
R2
NO2
NO 2
1
2
This synthetic protocol was also applicable to enaminone 4b,
which was derived from a diketone and a secondary amine.
Although enaminone 4b is not stabilized by an intramolecular
hydrogen bond, it exhibited a higher reactivity than 4a (Table 2).
This reaction was also accelerated by adding diethylamine, and
the yield of 3b increased up to 85% when the reaction was con-
ducted at 80 °C (Entries 1–3). The addition of triethylamine again
revealed an accelerating effect (Entries 4–7). A one-pot reaction
including the preparation of 4b in situ was also possible, although
the yield of 3b decreased to 43%, which is presumably because the
enaminone 4b had not formed in a sufficient amount.
O
NH2
O
NH4OAc
O
R2
N
O
EtOH
0~7%
R1
R2
NO2
1
NO2
3'
Scheme 1. Three component ring transformations affording substituted 4-
nitroanilines.
Under the optimized conditions, the synthesis of other types of
nitroanilines 3 was studied by altering the enaminones 4 prepared
by using other amines and 1,3-dicarbonyl compounds (Table 3).
Bulky alkyl groups such as sec-butyl and tert-butyl and aryl groups
such as phenyl and anisyl were introduced on the amino group of
3 (Entries 1–4). As shown in Table 2, enaminone 4b derived from
This reaction was also influenced to some extent by the choice
of the solvent. The yield of the deacetylated product 5a increased
when the reaction was conducted in methanol (Entry 11).
Although the less nucleophilic 2-propanol and hexafluoro-2-pro-
panol (HFIP) solvents suppressed the side reactions, the yield of
3a also decreased (Entries 12 and 13). A reaction temperature of
100 °C was rather effective in increasing the yield of 3a, however,
competitive decomposition of the substrates occurred at higher
temperature (Entries 14 and 15).
The reaction could be conducted in one-pot without isolating of
enaminone 4a, which simplified the experimental manipulations
(Scheme 2). After heating a mixture of propylamine and acetylace-
tone at 80 °C without a solvent for 3 h, the resultant mixture was
a
secondary amine was also highly reactive. Indeed, the
pyrrolidino-substituted enaminone 4g efficiently reacted with
dinitropyridone 1 to afford the corresponding nitroaniline 3g in a
high yield (Entry 5). The intramolecular hydrogen bond in
enaminones derived from primary amines contributes to
their stabilization, but might also diminish their reactivity for
this reaction.
Table 1
Optimization of reaction conditions for the synthesis of nitroaniline 3a.
Pr
H
H
Pr
N
O
N
H
Pr
O
N
1
+
+
4a
(1 equiv.)
NO2
5a
NO 2
3a
Entry
Additive
Solv.
Temp.
Time
(d)
Yield (%)
(1 equiv.)
(°C)
3a
5a
1
2
3
4
5
6
7
8
None
PrNH2
NEt3
NEt3
PrNH2
NEt3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
HFIPb
EtOH
EtOH
80
80
80
80
80
80
80
80
80
80
80
80
80
100
120
1
1
1
1
2
2
2
2
2
2
1
1
1
1
1
1
2
3
2
1
2
7
7
2
5
1
20
1
1
9
8
22
36
29
52
57
45
5
a
NBu3
2,6-Lutidine
K2CO3
Cs2CO3
NEt3
NEt3
NEt3
9
0
0
10
11
12
13
14
15
40
28
6
63
56
NEt3
NEt3
a
2 equiv.
Hexafluoro-2-propanol.
b
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S. Naito et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
Table 2
O
O
Pr
H
Ring transformation using enaminone 4b.
N
O
O2N
Me
O2N
Me
_
N
N
Et
Et
O
H
Et
Et
4a
N
H
CH2
O
N
NO2
NO2
1
Et
Et
+N
Pr
O
N
6
1
+
+
EtOH
1 d
O
4b
(1 equiv.)
NO2
5b
NO2
3b
_
NO2
NO 2
O2N
Me
O
N
H
O
H
H
Yield (%)a
O
Entry
NEt3
Temp.
N
+
Pr
NO2
H
N
Me
N
Pr
(equiv.)
(°C)
3b
5b
7
8
1
2
3
4
5
6
7
Et2NH (1)
Et2NH (2)
Et2NH (1)
NEt3 (1)
NEt3 (2)
NEt3 (3)
NEt3 (2)
60
60
80
80
80
80
100
50
69
6
4
3
4
10
6
6
H
Pr
NO 2
O
N
85 (80)b
63
O
H
NO 2
H
O
N
+
3a
75
75
68
_
O
O
PrHN
O
N
NO2
10
MeHN
O
Me
Me
9
N
H
Determined by 1H NMR.
Isolated yield.
a
NO 2
b
Scheme 3. A plausible mechanism for formation of 3a.
It was also possible to introduce a benzoyl group at the ortho-
H
H
Pr
H
O
Pr
position of the amino group by using benzoylacetone for prepara-
tion of enaminones 4h and 4i (Entries 6 and 7). Enaminones 4j–n
derived from keto esters were also used as substrates for the ring
transformation (Entries 8–12). Furthermore, it was found that the
reaction was not influenced by the presence of a hydroxy group
on the amino group (Entry 9). In addition, it was not necessary
for the substrate to have an acetyl group, as an alkyl group could
also be introduced at the 6-position of 4-nitroaniline-2-carboxy-
late (Entry 12).
O
N
O
N
EtOH
O
H
H
+
5a
Me
_
O2N
MeHN
N
O
O
NO 2
11
NO2
10
MeHN
O
N
H
NO2
Scheme 4. A plausible mechanism for formation of 5a.
A plausible mechanism for this ring transformation is shown in
Schemes 3 and 4. The reaction is initiated by the attack of enami-
none 4a on the 4-position of dinitropyridone 1 and enamine 7 is
formed via the adduct intermediate 6. The intramolecular attack
of the enamine at the 6-position forms the bicyclic intermediate
8 and the subsequent proton transfer and ring opening reaction
of 9 affords the 1,4-dihydrobenzene intermediate 10, which is con-
sidered to serve a common intermediate for 3a and 5a. Nitroaniline
3a is formed by aromatization of 10, which is accompanied by the
elimination of nitroacetamide. On the other hand, 1,2-dihydroben-
zene 11 is formed when proton transfer occurs before the
Table 3
Scope and limitation of this protocol.
R3
R4
O
O
N
R3
R4
NEt3
(1 equiv.)
O2N
Me
+
R2
O
N
R1
N
R2
R1
EtOH
80 °C
4
NO2
NO2
1
3
Entry
R1
R2
R3
sec-Bu
tert-Bu
Ph
p-MeOC6H4
–(CH2)4–
Pr
Et
R4
Time (d)
Yield (%)
1a
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
H
c
d
e
f
g
h
i
j
k
l
2
2
2
2
2
4
2
1
1
1
1
2
64
39
23
36
87
33
45
61
45
57
31
24
H
Et
H
H
Et
H
H
Ph
OEt
OEt
OEt
OMe
OEt
Pr
CH2CH2OH
Et
H
10
11
12
m
n
Pr
a
At 100 °C.
Please cite this article in press as: Naito S., et al. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.11.003

4
S. Naito et al. / Tetrahedron Letters xxx (2017) xxx–xxx
elimination of nitroacetamide, and it is aromatized to nitroaniline
5a by the elimination of both the acetyl group and nitroacetamide.
When methanol is used as the solvent, its nucleophilic property
might facilitate the deacetylation and lead to the formation of 5a.
The reaction rate acceleration by the addition of amine can be
explained as follows. At first, deprotonation of enaminone 4 by
cleavage of the intramolecular hydrogen bond enhances the nucle-
ophilicity of 4. However, the added amine also plays another role
because the reaction promotion effect was observed when enami-
nones derived from secondary amines were employed. A plausible
secondary role of the amine is that it facilitates the formation of
the enamine intermediate 7 from adduct 6 by deprotonation of
the acetyl group. The amine might assist the ring opening of 8
and the aromatization of 9.
In conclusion, a new ring transformation leading to functional-
ized nitroanilines 3 has been described. The modification of the
nitroaniline framework 3 was easily achieved by altering enami-
nones 4. Although many diverse functionalized nitroanilines are
known, their preparative methods are relatively few. Among these
methods, the amination of 2-halo-5-nitroacetophenone6 and the
derivatization of 4-nitroaniline-2-carboxylic acid7 are the most
commonly employed strategies. However, troublesome multi-step
reactions are necessary for the preparation of the starting materials
in previously reported methods. In contrast, the ring transforma-
tion methods described in this work reduces the number of reac-
tion steps and makes the reaction practically applicable for the
development of new functional materials.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.11.003.
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