Mechanistic aspect of ring transformations in the reaction of 5-nitro-4-pyrimidinone with acetophenone derivatives and cycloalkanones depending on the electron density/ring size of the ketone

Article abstract of DOI:10.1016/j.tetlet.2012.12.020

3-Methyl-5-nitro-4-pyrimidinone undergoes two kinds of nucleophilic type ring transformations upon treatment with cycloalkanones in the presence of ammonium acetate, which affords 4,5-disubstituted pyrimidines and 5,6-disubstituted 3-nitro-2-pyridones. In order to improve the synthetic utility of this reaction, it is necessary to control the regioselectivity of these ring transformations. In the present work, we performed DFT calculation to realize the selectivity of two ring transformation products. In cases of adduct intermediates derived from cyclohexanone and cyclooctanone, the 2-attack proceeds preferably to give condensed pyrimidines. On the other hand, the adduct intermediate derived from cycloheptanone undergoes the 4-attack predominantly to afford condensed nitropyridone.

Full text of DOI:10.1016/j.tetlet.2012.12.020

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Tetrahedron Letters 54 (2013) 956–959
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mechanistic aspect of ring transformations in the reaction of
5-nitro-4-pyrimidinone with acetophenone derivatives and cycloalkanones
depending on the electron density/ring size of the ketone
⇑
Nagatoshi Nishiwaki , Ryuichi Sugimoto, Kazuhiko Saigo, Kazuya Kobiro
School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Methyl-5-nitro-4-pyrimidinone undergoes two kinds of nucleophilic type ring transformations upon
treatment with cycloalkanones in the presence of ammonium acetate, which affords 4,5-disubstituted
pyrimidines and 5,6-disubstituted 3-nitro-2-pyridones. In order to improve the synthetic utility of this
reaction, it is necessary to control the regioselectivity of these ring transformations. In the present work,
we performed DFT calculation to realize the selectivity of two ring transformation products. In cases of
adduct intermediates derived from cyclohexanone and cyclooctanone, the 2-attack proceeds preferably
to give condensed pyrimidines. On the other hand, the adduct intermediate derived from cycloheptanone
undergoes the 4-attack predominantly to afford condensed nitropyridone.
Received 3 November 2012
Revised 1 December 2012
Accepted 7 December 2012
Available online 19 December 2012
Keywords:
Bicyclic compound
Cycloalkanone
Nitropyridone
Pyrimidine
Ó 2012 Elsevier Ltd. All rights reserved.
Ring transformation
Ring transformation is one of the valuable methods for synthe-
sizing ring systems which are not easily available by alternative
methods. Although Diels–Alder type1 and degenerated type ring
transformations2 have been widely employed in organic synthesis,
nucleophilic type ring transformation3 still remains being unex-
plored even now. It is demanded to establish the third method as
a synthetic tool for a variety of purposes. Substrates suitable
for the nucleophilic type ring transformation should have high elec-
tron deficiency and have a good leaving group as a partial structure.
From this viewpoint, we have studied ring transformation using
the pyrimidinone 1 as a substrate. Indeed, the pyrimidinone 1
serves as a good substrate to undergo several kinds of nucleophilic
type ring transformations constructing versatile azaheterocyclic
frameworks.4 When the pyrimidinone 1 is allowed to react with
the ketone 2 in the presence of ammonium acetate, two kinds of
three-component ring transformations proceed to afford the
pyrimidine derivative 3 and the 3-nitro-2-pyridone derivative 4
(Table 1). Since both products involve important frameworks for
the research of biologically active compounds and for the develop-
ment of new medicines and agrochemicals, controlling of the selec-
tivity of the reaction path is highly demanded.
considerably influenced by electron density on the benzene ring.
While acetophenone (2b) afforded almost the same amounts of
two products 3b and 4b, the ratio of 4 increased when electron-rich
ketones such as 2a are used. Moreover, the formation of 3 prefera-
bly proceeded in the reactions of 1 with electron-poor ketones such
as 2c together with diminishing total yields.5
A plausible mechanism for these ring transformations is illus-
trated in Scheme 1. Initially, the enamine intermediate 5b is
formed by the addition of the enol 2b0 at the 6-position of 1,
followed by amination by ammonium acetate. The enamine 5b is
considered to serve as a common intermediate for both azahetero-
cyclic compounds, 3b and 4b. When the enamino group of 5b
attacks the 2-position, the pyrimidine 3b is formed via the bicyclic
intermediate (path A). On the other hand, the pyridone 4b is sim-
ilarly formed when the enamino group attacks at the 4-position
(path B). The estimation of partial charges by DFT calculations
using B3LYP/6-31++G⁄⁄ shown in parentheses reveals that the
4-position is more electron deficient than the 2-position. An elec-
tron-rich enamino group can attack both positions to afford the
pyrimidine 3 via more stable intermediate (thermodynamic pro-
cess). In the case of an electron-poor enamino group, only the
4-position is attacked to afford the pyridone 4 (kinetic process).
On the other hand, the ring transformation of the pyrimidinone
1 with cycloalkanones under the same conditions revealed some-
what different selectivities (Scheme 2 and Table 2).5b When the
pyrimidinone 1 was subjected to the reaction with cyclopentanone
(2d) or cyclohexanone (2e), the condensed pyrimidine 3d or 3e
In our previous work, substituted acetophenone derivatives
were employed as reactants to obtain insights useful for controlling
the selectivity. As a result, it was found that the selectivity is
⇑
Corresponding author. Tel.: +81 887 57 2517; fax: +81 887 57 2520.
E-mail address: nishiwaki.nagatoshi@kochi-tech.ac.jp (N. Nishiwaki).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.020

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957
Table 1
Two ring transformations of pyrimidinone 1 with aromatic ketones 2
NH4OAc
(2 equiv.)
O2N
O
NO2
O
N
O
N
+
+
N
MeOH
N
H
N
G
Me
65 °C, 2 d
G
G
1 (1 equiv.)
2 (2equiv.)
3
4
G
Yield (%)
3
4
Me
H
NO2
a
b
c
25
49
27
75
51
15
Ph
O
Ph
path A
path B
path
B
NH2
path
3b
4b
Ph
6
O2N
O
O2N
O
O2N
O
N
N
N
NH4OAc
OH
A
N
2
2b'
N
4
N
Me
Me
Me
5b
(+0.1892 au)
(+0.0385 au)
1
Scheme 1. Divergence of two ring transformations.
NH4OAc
O2N
NO2
N
+
(2 equiv.)
N
(CH2)n
(CH2)n
(CH2)n
+
N
O
MeOH
O
N
H
O
N
Me
65 °C, 2 d
1 (1 equiv.)
2 (2 equiv.)
3
4
Scheme 2. Ring transformations of 1 with cycloalkanones leading to condensed products.
was afforded without the formation of a detectable amount of the
corresponding pyridone 4d or 4e. To the contrary, condensed pyri-
done 4f was predominantly formed in the reaction of 1 with cyclo-
heptanone (2f). Furthermore, cyclooctanone (2g) afforded the
pyrimidine 3g as a major product together with a small amount
of the pyridone 4g. Surprisingly, when acetic acid was employed
as the solvent instead of methanol in the reaction of 1 with 2f,
the selectivity was inverted to afford the pyrimidine 3f exclusively.
Although dramatic change in selectivity was observed, these re-
sults were not reasonably explained by only electron density. Then,
we considered that the selectivity of the ring transformations by
cycloalkanones would depend on activation energies from the
enamine intermediates to the corresponding transition states to
give bicyclic intermediates, because bicyclic compounds were
sometimes isolated in the reactions of nitropyrimidinone or dini-
tropyridone with enolates of 1,3-dicarbonyl compounds,6 which
means that the formation of bicyclic intermediates is a crucial step
in the ring transformation.
Table 2
Ring transformations with cycloalkanones
n
Solv.
Yield (%)
3
4
3
4
5
6
5
d
e
f
g
f
MeOH
MeOH
MeOH
MeOH
AcOH
85
71
11
67
90
0
0
79
17
0
In the reaction with cyclohexanone (2e) as a reactant, the at-
tack of the enamino group in nitro form 5e at the 2-position is
found to be the most advantageous (E1). In the reaction with
cyclooctanone (2g), the attack of the enamino group in the
nitronic acid form 6g at the 2-position shows the lowest activa-
tion energy (E1). Both results reveal that the 2-attack (path A)
occurs more easily to afford the bicyclic intermediate 7 and 8,
from which nitroacetamide is eliminated leading to the pyrimi-
dine derivatives 3e and 3g.
On the other hand, activation energy for the 4-attack (path B)
is the smallest (E3) when cycloheptanone (2f) is employed as a
reactant, although this process is endothermic and energy differ-
ence from the 2-attack (E1) is quite small. The small difference
between E3 and E1 also means that reaction path is readily chan-
DFT calculations were performed using DFT B3LYP/6-31++G⁄⁄
.
Although two tautomeric enamines, the 5-nitro form 5 and the
5-nitronic acid form 6, were employed as starting structures, all
calculations could give no reasonable transition state structures.
This problem was settled by adding one water molecule in the
transition state structures with hydrogen bonds (Fig. 1). Indeed,
the solvent used for ring transformation is not dried, thus an en-
ough amount of water would present in the reaction mixture.
Calculation results are shown in Table 3.

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958
N. Nishiwaki et al. / Tetrahedron Letters 54 (2013) 956–959
O-
N+
O
H
H
N
O-
N+
N
H
O
N
N
H
O
H
O
H
H
Me
H
O
N
N
O
H
Me
H
Figure 1. Transition states between 6f and 8f (left) and between 6f and 10f (right).
Table 3
Energy correlations (kcal molꢀ1) when the enamino group attacks at the 2-position or at the 4-position (water molecule is omitted)
(CH2)n
TS
H
N
NH2
X
E1
E2
X
Y
path
A
Y
N
5 or 6
(CH2)n
O
2
7 or 8
N
O
N
N
H
Me
Me
5 or 6
7 or 8
(CH2)n
TS
X
Y
NH2
E4
path B
X
Y
E3
9 or 10
N
N
5 or 6
(CH2)n
4
N
O
N
N
HO
H
Me
5 or 6
Me
9 or 10
ged when reaction conditions are varied. Indeed, the reaction of
the pyrimidinone 1 with cycloheptanone (2f) in acetic acid
undergoes another ring transformation to afford the pyrimidine
3f exclusively.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.
020.
In summary, the regioselectivity of the ring transformation of
the pyrimidinone 1 with acetophenone derivatives could be real-
ized by considering partial charges of 1. On the other hand, the
regioselectivity depending on the ring size of cycloalkanones
could be realized from the viewpoint of activation energies in
the processes forming bicyclic intermediates. Since the present
reaction includes complex processes, we cannot exclude another
possibility. However, this insight for controlling ring transforma-
tions would be helpful information for designing new ring
transformations.
References and notes
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Delaunay, T.; Genix, P.; Es-Sayed, M.; Vors, J.-P.; Monterio, N.; Balme, G. Org. Lett.
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Org. Lett. 2008, 10, 1923–1926.
2. (a) van der Plas, H. C. J. Heterocycl. Chem. 2000, 37, 427–438; (b) van der Plas, H.
C. In Advances in Heterocyclic Chemistry; Academic Press: London, 1999; Vol. 74,
3. Nishiwaki, N.; Ariga, M. In Topic in Heterocyclic Chemistry; Springer: Berlin, 2007;
Vol. 8, pp 43–72.

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4. (a) Nishiwaki, N.; Nishimoto, T.; Tamura, M.; Ariga, M. Synlett 2006, 1437–1439;
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