Activation of 1-methyl-5-nitro-2-pyrimidinone by dearomatization using a secondary amine

Article abstract of DOI:10.3987/COM-17-S(T)14

Electron-deficient 1-methyl-5-nitro-2-pyrimidinone is easily attacked by methanol or pyrrolidine to afford the corresponding adducts, respectively, by which aromaticity of nitropyrimidinone is lost. Indeed, the amine-adduct exhibited higher reactivity than that of original structure to facilitate the reaction with 1,3-dicarbonyl compound leading to diazabicyclic compound at room temperature. The amine-adduct also underwent the ring opening reaction to furnish nitroenamines with (Z)-configuration.

Full text of DOI:10.3987/COM-17-S(T)14

HETEROCYCLES, Vol. 97, No. 1, 2018, pp. -. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 27th December, 2017, Accepted, 25th January, 2018, Published online, 26th January, 2018
DOI: 10.3987/COM-17-S(T)14
ACTIVATION
OF
1-METHYL-5-NITRO-2-PYRIMIDINONE
BY
DEAROMATIZATION USING A SECONDARY AMINE
Haruyasu Asahara,a,b,c Azusa Yasuoka,a and Nagatoshi Nishiwakia,b*
aSchool of Environmental Science and Engineering, Kochi University of
b
Technology, Tosayamada, Kami, Kochi 782-8502, Japan; Research Center for
Material Science and Engineering, Kochi University of Technology, Tosayamada,
c
Kami, Kochi 782-8502, Japan; Department of Applied Chemistry, School of
Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan.
E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
Abstract – Electron-deficient 1-methyl-5-nitro-2-pyrimidinone is easily attacked
by methanol or pyrrolidine to afford the corresponding adducts, respectively, by
which aromaticity of nitropyrimidinone is lost. Indeed, the amine-adduct
exhibited higher reactivity than that of original structure to facilitate the reaction
with 1,3-dicarbonyl compound leading to diazabicyclic compound at room
temperature. The amine-adduct also underwent the ring opening reaction to
furnish nitroenamines with (Z)-configuration.
INTRODUCTION
Highly electron-deficient heterocyclic compounds are often used in synthesis for polyfunctionalized
compounds because the partial structure serves as a masked form of functionalized building block or its
precursor.1 1-Methyl-5-nitro-2-pyrimidinone (1) is one of such compounds used for the present purpose
that is easily prepared by condensation of N-methylurea and 1,1,3,3-tetramethoxypropane under acidic
conditions followed by nitration.2 The highly electron-deficient property of 1 facilitates the aminolysis to
afford azadienamines (2)3 used as unique bidentate ligands,4 and half hydrolysis of 2 yields
β-formyl-β-nitroenamines (3) which serve as a useful building block for versatile aza-heterocyclic
compounds (Scheme 1).3,5 Nitropyrimidinone (1) also reacts with enolate ions leading to diazabicyclic
compounds (4) or (5) (Scheme 1).2 Although the synthetic utility of 1 has been already revealed, some
extent of aromaticity requires severe reaction conditions, which restricts the further synthetic application.
This paper is dedicated to Prof. Kiyoshi Tomioka’s 70th birthday.

In order to overcome this problem, dearomatization of nitropyrimidinone (1) was studied.
O2N
O2N
RNH2
R
H2O/SiO2
rt, 1 d
N
O
MeOH
60 °C, 3 h
NH
NH
O2N
R
R
N
2
3
N
O
NO2
NO2
NH
O
Me
O
O
ONa
R2
1
R2
R2
HO
R1
NH
or
HO
O
O
N
Me
N
Me
pyridine
or DMF
100 °C, 5 h
R1
R1
4
5
Scheme 1. Chemical conversions of nitropyrimidinone (1)
RESULTS AND DISCUSSION
During the study on the reaction of nitropyrimidinone (1) with nucleophiles in methanol at 150 °C under
microwave irradiation, yellow plates precipitated from the reaction mixture after cooling to room
temperature followed by standing for 1 day. However, the 1H NMR of this crystal showed only signals of
1 although their appearance were obviously different. As a result of X-ray crystallography, the crystalline
product is confirmed to be dihydropyrimidine derivative (6) formed by addition of a methanol to 1, and
elimination of a methanol easily occurs upon dissolving into the organic solvent (Figure 1).
Figure 1. An ORTEP showing the 6-methoxy-1-methyl-5-
nitropyrimidine-2(1H)-one (6) (color labels: gray, carbon; white, hydrogen;
violet, nitrogen; red, oxygen). Thermal ellipsoids are drawn at the 50%
probability level. Deposition number is CCDC-1813483.
This result prompted us to study the reaction of nitropyrimidinone (1) with more nucleophilic amines.
The formed adducts are considered to be enough stable for treating as a synthetic reagent for
polyfunctionalized compounds. When pyrimidinone (1) reacted with pyrrolidine in deuterated chloroform
at room temperature, addition reaction quantitatively occurred to afford two isomeric adducts (7a) and
1
13
(7b) with 1:1 ratio. Although the formation of 7a and 7b was confirmed by H and C NMR spectra,
these products were transformed to pyrimidinone (1) after evaporation. One isomer (7a) showed
correlation between the methyl and pyrrolidino groups, 7a was assigned to 6-adduct. Fortunately, single

crystal could be obtained when deuterated acetonitrile was used as a solvent, the structure of 7a was
confirmed by X-ray crystallography (Scheme 2). Other secondary amines such as piperidine, morphorine
and diethylamine similarly afforded isomeric adducts in quantitative
yields, however easy elimination of amine prevented further analysis.
N
N
O2N
O2N
O2N
N
H
N
NH
NH
(1 equiv.)
+
CDCl3
rt, 5 min
quant.
N
O
N
O
N
O
Me
Me
Me
NOE
1
7b
7a
Scheme 2. Addition of pyrrolidine to nitropyrimidinone (1) and an ORTEP showing the
1-methyl-5-nitro-6-pyrrolidinopyrimidin-2(1H)-one (7a) (color labels: gray, carbon; white, hydrogen; violet,
nitrogen; red, oxygen). Thermal ellipsoids are drawn at the 50% probability level. Deposition number is
CCDC-1813484.
As shown in Scheme 1, when nitropyrimidinone (1) was heated with sodium enolate of diethyl
acetonedicarboxylate in pyridine at 100 °C for 5 h, diazabicyclic compound 5a (R1 = CO2Et, R2 = OEt)
was obtained in 76% yield.2 Since nitropyrimidinone (1) shows aromaticity, severe conditions were
necessary to undergo the reaction. Contrary to this, addition of pyrrolidine furnishes dearomatized
adducts (7a) and (7b) to reveal higher reactivity than 1. Indeed, 7a and 7b generated in situ reacted with
diethyl acetonedicarboxylate even at room temperature, leading to 5a in 87% yield (Scheme 3). In this
reaction, stoichiometric amount pyrrolidine was necessary because formed 5a consumed pyrrolidine by
forming an ammonium salt.
NO2
NH
O
O2N
EtO
HO
O
O
O
N
+
+
O
CHCl3
N
H
EtO
OEt
N
O
N
Me
rt, 1 h
87%
Me
EtO2C
(1 equiv.)
(1 equiv.)
5a
1
(dr = 9:9:1)
Scheme 3. Synthesis of diazabicyclic compound (5a) under mild conditions
N
N
O2N
O2N
NH2
H
(5 equiv.)
N
NH
N
NO2
+
+
N
HN
Me
10 (29%)
O
CHCl3
rt, 7 d
N
O
N
O
O
Me
Me
8 (68%)
9 (41%)
1
7
Scheme 4. Ring opening reaction of adduct (7) leading to nitroenamine (8), N-formylpyrrolidine (9) and
N-methylurea (10). Yields were determined based on pyrimidinone (1).

When adducts (7a) and (7b) were stood in acetonitrile at room temperature for 1 day, the ring opening
reaction also proceeded to afford nitroenamine (8),6 N-formylpyrrolidine (9) and N-methylurea (10) in
17%, 16% and 12% yields, respectively. For this reaction, chloroform was found to be more suitable
solvent, and using excess amounts of pyrrolidine and longer reaction time was effective to increase the
yield of 8 up to 68% (Scheme 4). A plausible mechanism for formation of 8 is shown in Scheme 5.
Adducts (7) is attacked by an additional pyrrolidine to afford tetrahydropyrimidine derivative (11). Each
C–N bond easily cleavages because of the aminal structure, among which the C–N bond at the 6-position
is considered to be more easily cleaved because of the steric repulsion between the methyl and
pyrrolidino groups. After the ring opening reaction, the subsequent C–N bond cleavage yields
nitroenamine (8) by elimination of urea (13), which is hydrolyzed to afford 9 and 10, respectively. During
the second cleavage of intermediate (12), conformer (12a) is more preferable than 12b because of less
steric repulsion between two pyrrolidino groups to afford (Z)-8.
N
N
N
N
N
_
O2N
O2N
O2N
N
N
H
O2N
NH
NH
NH
N
_
+
N
+
N
N
O
N
O
O
HN
O
Me
Me
Me
Me
12
7
11
O2N
N
+
H
H
N
+
N
(Z)-8
(E)-8
8
N
NO2
H
N
_
NO2
_
N
H
N
N
Me NH
O
R
R
N
12a
12b
O
O
13
Scheme 5. A plausible mechanism for the formation of nitroenamine (8)
The generated nitroenamine (8) in situ was easily trapped by cycloaddition. To a solution of adducts (7)
in chloroform, equimolar methyl vinyl ketone was added, and the resultant solution was heated at 60 °C
for 2 days. After concentration of the reaction mixture, the residue was subjected to silica gel column
chromatography to afford 1-nitro-4-pyrrolidinobenzene (14)7 in 28% yield (Scheme 6). In this reaction,
dienamine (15) is generated from methyl vinyl ether and pyrrolidine in situ, which undergoes the
cycloaddition with nitroenamine (8). However, side reactions of 8 also proceeded under heated conditions
to diminish the reaction efficiency. Subsequent aromatization accompanied by elimination of pyrrolidine
and air-oxidation furnishes nitroaniline (14).

N
N
H
O2N
O2N
O2N
O
(1 equiv.)
N
NH
(5 equiv.)
CHCl3
rt
N
O
N
O
N
60 °C, 2 d
Me
Me
1
7
14 (28%)
O2N
N
O2N
7
N
N
8
HN
O2N
air
14
O
N
N
15
Scheme 6. Cycloaddition of nitroenamine (8) and dienamine (15) leading to nitroaniline (14)
In summary, nitropyrimidinone (1) was found to obtain high reactivity upon treatment with pyrrolidine,
which dearomatized adducts (7). Indeed, adducts (7) underwent the reaction with diethyl
acetonedicarboxylate under mild conditions to afford bicyclic compound (5a). Furthermore, ring opening
reaction leads to nitroenamine (8), which is converted to 1-nitro-4-pyrrolidinobenzene (14) in one-pot
reaction. These results will be useful insights for researchers using less reactive aromatic heterocyclic
compounds.
EXPERIMENTAL
Synthesis of amine-adduct (7)
To a solution of nitropyrimidinone (1, 15.5 mg, 0.1 mmol) in deuterated chloroform (0.4 mL), pyrrolidine
1
13
(8 µL, 0.1 mmol) was added. The H and C NMR spectra showed the quantitative formation of adduct
(7) as a mixture of regioisomers with 1:1 ratio, however, elimination of pyrrolidine easily occurred when
the solution was concentrated to afford 1 again. Thus, the following NMR data were analyzed using a
mixture of adducts (7a) and (7b). 1H NMR (400 MHz, CDCl3) 6-adduct (7a): δ 1.77 (br s, 4H), 2.67–2.78
(m, 4H), 3.09 (s, 3H), 5.69 (br s, 1H), 8.00 (br s, 1H); 4-adduct (7b): δ 1.77 (br s, 4H), 2.67–2.78 (m, 4H),
3.30 (s, 3H), 5.70 (br s, 1H), 8.00 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 23.9 (CH2), 24.5 (CH2), 34.4
(CH3), 36.2 (CH3), 46.1 (CH2), 47.3 (CH2), 65.6 (CH), 71.2 (CH), 122.9 (C), 124.5 (C), 134.6 (CH),
139.2 (CH), 152.7 (C), 152.9 (C).
Synthesis of bicyclic compound (5a)
To a solution of nitropyrimidinone (1, 78 mg, 0.5 mmol) in CHCl3 (6.5 mL), were added pyrrolidine (40
µL, 0.5 mmol) and diethyl acetonedicarboxylate (90 µL, 0.5 mmol), and the resultant mixture was stirred

at room temperature for 1 h. After washing with 1 M hydrochloric acid (10 mL × 1), the solvent was
removed under reduced pressure. The residue was extracted with hexane (10 mL × 2), and concentrated to
afford bicyclic compound (5a, 151.9 mg, 0.43 mmol, 86% yield)2 as a white solid. Although formation of
1
three diasteromers was confirmed in the H NMR, these could not be separated and assigned because of
similar property and spectra.
Aminolysis of nitropyrimidinone (1)
To a solution of nitropyrimidinone (1, 31 mg, 0.2 mmol) in CHCl3 (2 mL), pyrrolidine (80 µL, 1.0 mmol)
was added, and the resultant mixture was stood at room temperature for 7 d. After the solvent was
removed under reduced pressure, the residue was subjected to column chromatography on silica gel to
afford nitroenamine (8, 19 mg, 0.136 mmol, 68%, eluted with EtOAc) as a brown solid, and a mixture of
1
N-formylpyrrolidine (9) and N-methylurea (10) (eluted with MeOH, the yields were determined by H
NMR).
Synthesis of nitroaniline (14)
To a solution of nitropyrimidinone (1, 31 mg, 0.2 mmol) in CHCl3 (2 mL), pyrrolidine (80 µL, 1.0 mmol)
was added, and the resultant mixture was heated at 60 °C for 1 d. Then, methyl vinyl ketone (40 µL, 0.4
mmol) was added, and the mixture was heated at 60 °C for 2 d. After the solvent was removed under
reduced pressure, the residue was treated with column chromatography on silica gel to afford nitroaniline
(14, eluted with hexane : EtOAc =1 : 1, 11 mg, 0.056 mmol, 28% yield)7 as a yellow oil.
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