Tailor-made synthesis of N,N,2,6-tetrasubstituted 4-nitroanilines by three-component ring transformation of dinitropyridone

Article abstract of DOI:10.1002/ejoc.201403652

The ring transformation of dinitropyridone afforded various kinds of 2,6-disubstituted-4-nitroanilines upon treatment with aliphatic ketones in the presence of ammonium acetate as a nitrogen source, wherein dinitropyridone behaved as the synthetic equival

Full text of DOI:10.1002/ejoc.201403652

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403652
Tailor-Made Synthesis of N,N,2,6-Tetrasubstituted 4-Nitroanilines by
Three-Component Ring Transformation of Dinitropyridone
Song Thi Le,[a] Haruyasu Asahara,[a,b] and Nagatoshi Nishiwaki*[a,b]
Keywords: Nitroheterocycles / Multicomponent reactions / Ring transformation / Ketones / Synthetic methods
The ring transformation of dinitropyridone afforded various
kinds of 2,6-disubstituted-4-nitroanilines upon treatment
with aliphatic ketones in the presence of ammonium acetate
as a nitrogen source, wherein dinitropyridone behaved as the
synthetic equivalent of unstable nitromalonaldehyde. The
benzene ring, as well as the amino group of the nitroaniline
framework, was easily modified by only changing a ketone
and the nitrogen source, which afforded N,N,2,6-tetrasubsti-
tuted 4-nitroanilines in good to excellent yields.
Introduction
Ring transformation reactions provide a unique method
for the synthesis of functionalized heterocyclic compounds,
which are not easily prepared by other methods.[1,2] We have
reported an alternative method for the synthesis of nitro-
pyridines 3 by the three-component ring transformation
(TCRT) of dinitropyridone 1 with aromatic ketones 2 in
the presence of ammonium acetate (Scheme 1),[2] wherein
dinitropyridone 1 serves as the synthetic equivalent of un-
stable nitromalonaldehyde.[3] This reaction is initiated by
the nucleophilic attack of the enol form of 2 followed by
conversion to enamine 4. When the amino group of en-
amine 4 attacks the 6-position (route a), 2-arylated 5-nitro-
Scheme 1. TCRT of dinitropyridone 1 with aromatic ketones 2 in
the presence of ammonium acetate, leading to the formation of 6-
arylated nitropyridines 3.
pyridines
3 are formed via bicyclic intermediates 5
(Scheme 1).[4] However, the β-carbon of enamine 4 cannot
attack the 6-position (route b), because it would form a
sterically strained four-membered ring. On considering this
reaction mechanism, we predicted that another ring trans-
formation would occur when aliphatic ketones 6 having two
α-hydrogen atoms, namely α- and αЈ-, are employed instead
of aromatic ketones 2 (Scheme 2). In this ring transforma-
tion, both the amino group and the β-carbon can attack
the 6-position in the case of enamine 9, which leads to the
formation of nitropyridines 7 (route a) or nitroanilines 8
(route c).
2,6-Disubstituted 4-nitroanilines 8 are useful synthetic
intermediates for functional materials, such as inhibitors of
cholesterol acyl transferase[5] and π-conjugated polymers,[6]
and are key intermediates for the synthesis of compounds
with antimicrobial activities[7] and the β-diketiminate li-
gand.[8] Moreover, the push-pull electronic property is cru-
cial for developing organic materials with potential for ap-
plications in nonlinear optics. Generally, 2,6-disubstituted
4-nitroanilines 8 are prepared from the corresponding anil-
ines by nitration under harsh conditions, wherein protection
and deprotection of the amino group are necessary.[9] How-
ever, the preparation of 2,6-disubstituted anilines is restric-
ted because of the following limitations of the Friedel–
Crafts alkylation:[10] (1) the monoalkylated product un-
dergoes further alkylation to afford polyalkylated products,
(2) it is difficult to introduce two different alkyl groups,
(3) primary alkyl groups longer than the ethyl group cannot
be introduced, (4) phenyl and vinyl groups cannot be intro-
duced, and (5) aminated and nitrated benzenes do not facil-
[a] School of Environment Science and Engineering,
Kochi University of Technology
Tosayamada, Kami, Kochi 782-8502, Japan
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
https://sites.google.com/site/kutnishiwakilab2/nishiwakilab
[b] Research Center for Material Science and Engineering,
Kochi University of Technology
Tosayamada, Kami, Kochi 782-8502, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403652.
Eur. J. Org. Chem. 2015, 1203–1206
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. T. Le, H. Asahara, N. Nishiwaki
SHORT COMMUNICATION
Table 1. Optimization of reaction conditions for the TCRT.
Entry
NH4OAc
[equiv.]
Time
[h]
Yield [%]
8a
7a
1
2
3
4
5
6
5
24
24
24
18
12
6
50
83
86
70
64
55
44
13
13
14
13
13
10
15
10
10
10
work by only changing ketone 6 (entries 3–9). Notably, this
TCRT facilitates the introduction of a propyl or phenyl
group into the benzene ring, which cannot be achieved by
the Friedel–Crafts reaction. As a result, symmetrical and
unsymmetrical nitroanilines 8f–i[11] were easily prepared;
however, the yield of 8i was low, presumably because steric
repulsion by the phenyl groups prevents the formation of
11i (entries 6–9).
Scheme 2. TCRT of dinitropyridone 1 with aliphatic ketones 6 in
the presence of ammonium acetate, affording disubstituted nitro-
pyridines 7 and nitroanilines 8.
itate the alkylation. We believe that our TCRT method will
overcome these disadvantages of the Friedel–Crafts alkyl-
ation and facilitate the synthesis of various 2,6-disubsti-
tuted 4-nitroanilines 8 only by using the appropriate
ketones 6.
Table 2. Application of the TCRT to other aliphatic ketones 6.
Results and Discussion
When dinitropyridone 1 was allowed to react, at 65 °C
for 24 h, with 3-pentanone 6a in the presence of 5 equiv. of
ammonium acetate in ethanol, nitroaniline 8a[11] and nitro-
pyridine 7a[11] were obtained in 50% and 44% yield, respec-
tively, resulting from two kinds of TCRTs (Table 1, entry
1). When 10 equiv. of ammonium acetate were used, the
ratio of 8a to 7a increased considerably without a decrease
in the total yield (entry 2); this indicates the presence of an
equilibrium between 10 and 11, which are kinetically and
thermodynamically controlled intermediates, respectively,
that can interconvert via enamine 9. In the present TCRT,
the competitive thermal decomposition of ammonium acet-
ate to ammonia, which was liberated from the reaction mix-
ture as a gas, also occurred. When all the ammonium acet-
ate was consumed, the TCRT could no longer proceed be-
cause of the lack of a nitrogen source. Thus, increasing the
amount of ammonium acetate prolonged the actual reac-
tion time, resulting in the predominance of nitroaniline 8a.
However, no additional change was observed on using
Entry
Ketone 6
Yield [%]
8[11]
R1
R2
7[11]
7Ј
[11]
1
2
3
4
5
6
7
8
9
Me
H
Et
iPr
Pr
Et
Pr
Me
H
H
H
H
Et
Pr
a
b
c
d
e
f
g
h
i
83
51
66
58
83
67
74
62
8
13
47
10
0
0
0
8
31
6
0
0
13
0
9
24
22
24
81
C6H5 Pr
C6H5 C6H5
As mentioned above, two kinds of TCRTs competitively
larger amounts of ammonium acetate (entry 3). Also, it was occurred to form 5-nitropyridines 7 and 4-nitroanilines 8.
found that heating for 24 h was necessary for the comple- In these reactions, ammonium acetate serves both as a
tion of the TCRT (entries 4–6).
nitrogen source and as an activator of ketone 6. We believe
This TCRT was applied to other ketones 6b–i under the that a combination of amine 12 and acetic acid, used in-
conditions optimized for 6a (Table 2). When acetone 6b was stead of ammonium acetate, can carry out these roles, thus
used as substrate, two kinds of TCRTs occurred, similar to achieving the modification of the benzene ring as well as
6a, to afford nitroaniline 8b[11] and nitropyridine 7b[11] in the amino group of the nitroaniline framework. In this case,
51% and 47% yields, respectively (entry 2). It was possible only nitroanilines 13 will be formed as a TCRT product,
to modify the 2- and 6-positions of the nitroaniline frame- because the aromatization of the intermediate, which is re-
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Eur. J. Org. Chem. 2015, 1203–1206

Tailor-Made Synthesis of N,N,2,6-Tetrasubstituted 4-Nitroanilines
quired for the formation of nitropyridines, is prevented by bination of amine 12 and acetic acid. Consequently, the tai-
the N-substituents (R3 and R4).
lor-made synthesis of N,N,2,6-tetrasubstituted 4-nitroanil-
Propylamine 12A was added to a solution of dinitro- ines 8 and 13 became possible on demand.
pyridone 1, 3-pentanone (6a), and acetic acid in ethanol,
and the resulting solution was heated at 65 °C for 24 h. Af-
ter the usual work-up, 2,6-dimethyl-4-nitro-N-propylaniline
(13Aa) was obtained in 99% yield (Table 3, entry 1). This
Experimental Section
To a solution of the nitropyridone 1 (50 mg, 0.25 mmol) in ethanol
method was applied to the secondary amines, pyrrolidine
12B, and diethylamine 12C, to afford N,N,2,6-tetrasubsti-
tuted 4-nitroanilines 13Ba and 13Ca, respectively, in excel-
lent yields (entries 2 and 3). Methyl ketones 6b–d also
underwent this TCRT by use of a combination of either
propylamine 12A or pyrrolidine 12B with acetic acid to af-
ford the corresponding nitroanilines 13 in moderate to ex-
cellent yields (entries 4–9). Moreover, these reactions could
induce modifications at the 2- and 6-positions by use of
ketones 6e–h, with which a propyl or a phenyl group could
be introduced to the nitroaniline framework (entries 10–15).
(5 mL), were added 3-pentanone (6a, 26 μL, 0.25 mmol) and am-
monium acetate (96.3 mg, 1.25 mmol), and then the resultant mix-
ture was heated at 65 °C for 24 h. After removal of the solvent, the
residue was washed with benzene (3ϫ 10 mL) to remove unreacted
ketone 6a, which affords a mixture of nitropyridine 7a and nitro-
aniline 8a. The separation of products was performed by column
chromatography on silica gel (hexane/ethyl acetate = 95:5) to afford
7a (18.3 mg, 0.11 mmol, 44%) and 8a (20.8 mg, 0.13 mmol, 50%).
The TCRT reaction of the dinitropyridone 1 with other ketones
were performed in a similar way.
Acknowledgments
Table 3. TCRT of dinitropyridone 1 with aliphatic ketones 6 with
a mixture of amine 12 and acetic acid.
We sincerely thank Prof. Satoshi Minakata (Osaka University, Ja-
pan) for his kind assistance. This work was supported by Japan
Society for the Promotion of Science (JSPS) Grants-in-Aid for Sci-
entific Research (KAKENHI) (Grant Number 26410123).
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Entry Ketone 6
Amine 12
Product
Yield
[%]
R1
R2
R3
R4
H
1
2
3
4
Me
Me
Me
Et
Me
Me
Me
H
a
a
a
b
b
c
c
c
d
e
e
f
Pr
–(CH2)4-
Et
Pr
–(CH2)4-
Pr
–(CH2)4-
Et
Pr
Pr
–(CH2)4-
Pr
–(CH2)4-
Pr
A
B
C
A
B
A
B
C
A
A
B
A
B
A
A
13Aa
13Ba
13Ca
13Ab
13Bb
13Ac
13Bc
13Cc
13Ad
13Ae
13Be
13Af
13Bf
13Ag
13Ah
99
98
98
83
68
77
87
51
83
69
68
81
59
80
32
Et
H
5
Et
H
6
Pr
H
H
7
Pr
H
8
Pr
H
Et
H
H
9
iPr
Et
Et
Pr
Pr
H
10
11
12
13
14
15
Et
Et
Pr
Pr
H
f
g
h
C6H5 Pr
C6H5 C6H5
H
H
Pr
Conclusion
In summary, we have developed a new preparative
method for 2,6-disubstituted 4-nitroanilines 8 and 13 by the
TCRT of dinitropyridone 1 with aliphatic ketones 6 in the
presence of ammonium acetates. In this reaction, a number
of ketones 6 can be used as substrates, which facilitate the
modification of the nitroaniline framework. In addition,
this TCRT requires only simple experimental manipulations
and mild reaction conditions, which is advantageous from
the viewpoint of practical use. These features facilitate the
construction of a library of compounds that are not easily
available by other methods. Furthermore, modification of
the amino group was successfully achieved by using a com-
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Eur. J. Org. Chem. 2015, 1203–1206
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. T. Le, H. Asahara, N. Nishiwaki
SHORT COMMUNICATION
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Received: December 19, 2014
Published Online: January 15, 2015
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Eur. J. Org. Chem. 2015, 1203–1206