New approach for the synthesis of 1-aryl- and 1-heteroaryl-5-nitrouracil derivatives

Article abstract of DOI:10.1016/j.tet.2007.01.040

1-(2,4-Dinitrophenyl)-5-nitrouracil and its 3-methyl derivatives were synthesized and used as substrates in reaction with aromatic amines and amino pyridines. In the reaction of aniline with 1-(2,4-dinitrophenyl)-5-nitrouracil, only the acyclic adduct was isolated. When 1-(2,4-dinitrophenyl)-3-methyl-5-nitrouracil was treated with aniline and other aromatic amines or amino pyridines, the desired 1-aryl-5-nitrouracil derivatives were obtained in satisfactory yield. The influence of the free H-3 proton present in the uracil ring on the course of the reaction is discussed.

Full text of DOI:10.1016/j.tet.2007.01.040

Tetrahedron 63 (2007) 2859–2864
New approach for the synthesis of 1-aryl- and
1-heteroaryl-5-nitrouracil derivatives
*
Andrzej Gondela and Krzysztof Walczak
Department of Organic Chemistry, Biochemistry and Biotechnology, Silesian University of Technology,
Krzywoustego 4, 44-100 Gliwice, Poland
Received 3 November 2006; revised 5 January 2007; accepted 18 January 2007
Available online 24 January 2007
Abstract—1-(2,4-Dinitrophenyl)-5-nitrouracil and its 3-methyl derivatives were synthesized and used as substrates in reaction with aromatic
amines and amino pyridines. In the reaction of aniline with 1-(2,4-dinitrophenyl)-5-nitrouracil, only the acyclic adduct was isolated. When
1-(2,4-dinitrophenyl)-3-methyl-5-nitrouracil was treated with aniline and other aromatic amines or amino pyridines, the desired 1-aryl-5-
nitrouracil derivatives were obtained in satisfactory yield. The influence of the free H-3 proton present in the uracil ring on the course of
the reaction is discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
treated with different N-centred nucleophiles.6,7 The most
available routes for the synthesis of 1-aryl- or 1-hetero-
aryl-5-substituted uracil derivatives involve condensation
reactions. Thus, 3-methyl-5-nitro-1-(4-nitrophenyl)uracil
was obtained by the condensation of 1-phenylurea with
methyl 3,3-dimethoxypropanoate and subsequent ring
closure under acidic conditions followed by N-3 methylation
and nitration, which occurred on both rings (at C-5 of the
uracil ring and C-4 of the benzene ring).8 A similar pro-
cedure was used for the synthesis of a 1-(2-pyridyl)uracil
derivative.9 In both cases, the final products were obtained
in moderate yield. Other 1-aryluracils have been synthesized
from substituted ureidopropanoic acids or 1-acrylyl-3-aryl-
ureas.10,11 6-Methyl-1,3-oxazine-2,4(3H)-dione was trans-
formed into the appropriate 1-aryl-6-methyluracils when
treated with an excess of arylamines.12 Uracil derivatives,
in reaction with diaryliodonium salts, gave the appropriate
N-mono- and N,N0-diarylation product with high regio-
selectivity.13,14 Attempts at direct N-arylation of uracil
derivatives have also been reported.15–17
Pyrimidines are especially intriguing azine compounds due
to their importance as the constituents of nucleic acids and
useful biological properties. Many N-substituted uracil
derivatives possess biological activity.1,2 N-Glycosides of
substituted uracil are widely used in therapy, mainly as anti-
viral and antineoplastic agents. The most prominent repre-
sentatives are 5-fluorouracil and thymine derivatives.2–4
Uramustine, 5-[N,N0-bis(20-chloroethyl)amino]uracil is used
orally in the treatment of several leukemias5 and stavudine
(D4T) inhibits the replication of HIV. Lamivudine [(ꢀ)-b-
L-(2R,5S)-1,3-oxathiolanylcytosine], a reverse transcriptase
inhibitor, is currently being investigated for therapy of
chronic HBV infection.1
On the other hand, uracil derivatives show interesting
reactivity. The uracil is susceptible to attack by either
electrophiles (nitrogen and oxygen atoms, carbon C-5) or
nucleophiles (carbon C-6, or C-5 in 6-substituted uracil
derivatives), giving different products depending on the ap-
plied reactant. We have paid a special attention to 1-aryl-5-
substituted uracils as useful intermediates in the synthesis of
other uracil derivatives. It has been demonstrated that
3-methyl-1-(4-nitrophenyl)uracil derivatives possessing an
electron-withdrawing group such as nitro, cyano, or carba-
moyl group at the 5-position readily undergo ring transfor-
mation according to the ANRORC type reaction when
2. Results and discussion
In this paper, we describe a simple and effective method for
replacement of the 1-(2,4-dinitrophenyl) substituent by other
substituted benzene or pyridine rings under ANRORC reac-
tion conditions. Formally, this process can be considered
as a transarylation reaction.
The substrates 4 and 6 were obtained by N-1 arylation.17 An
unsubstituted uracil 1 was treated with 1-fluoro-2,4-dinitro-
benzene 2 in the presence of triethylamine as a base. 1-Aryl
derivative 3 was subsequently nitrated using nitrating
Keywords: 1-(2,4-Dinitrophenyl)-5-nitrouracil; 1-Aryl-5-nitrouracil; 3-Methyl-
1-(pyridyl)-5-nitrouracil; ANRORC type reaction; Nucleophilic aromatic sub-
stitution.
* Corresponding author. Tel.: +4832 237 17 92; fax: +4832 237 20 94;
e-mail: krzysztof.walczak@polsl.pl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.040

2860
A. Gondela, K. Walczak / Tetrahedron 63 (2007) 2859–2864
O
O
N
O2N
O2N
NH
NH
F
O
N
O
NO2
O
Et3N
H2SO4, HNO3
NH
O2N
+
DMF, r.t.
62%
-5 °C to r.t.
N
H
O
84%
NO2
2
NO2
1
NO2
3
4
NaH, CH3I
DMF
85%
O
N
O
N
Me
N
O2N
O2N
Me
O
N
H2SO4, HNO3
O
-5 °C to
r.t. 93%
O2N
NO2
NO2
6
5
Scheme 1.
mixture (fuming nitric acid and sulfuric acid (98%) in the
volume ratio 1:2) and gave 4, or methylated at N-3 using
methyl iodide in the presence of sodium hydride, followed
by nitration of 5 using the same nitrating mixture as above,
gave 6 (Scheme 1).
with compounds bearing primary amino group.16,17 In the
course of this reaction, N-1 nitrogen atom connected to
4-nitrophenyl group is replaced by nitrogen atom present
in attacking nucleophile. During this transformation, the
C–N bond in the molecule of nucleophile is retained
and as a second product the 4-nitroaniline is isolated. The
aromatic amines are non-reactive under the applied con-
ditions.18 It can be assumed that introduction of the
2,4-dinitrophenyl group on the N-1 nitrogen atom of 5-nitro-
uracil could accelerate the transformation reaction due to the
better nucleofuge properties of the latter and enable the
reaction with aromatic amines. In primary trials, the nitro de-
rivative 4 was treated with aniline 7. When the solution of 4
was mixed with aniline, the reaction mixture changed colour
and in a couple of minutes yellow precipitation appeared.
After 24 h at room temperature from the post-reaction
mixture, two compounds were isolated: 1-(2,4-dinitro-
phenyl)-3-[(E)-2-nitro-3-phenylamino-acryloyl]urea 8 and
1-(2,4-dinitrophenyl)-3-phenylurea 9 in 78% and 16% yield,
respectively (Scheme 2).
The position of uracil arylation was confirmed on the basis
of NMR spectroscopy. Thus, the 1H NMR spectrum of 3 in-
dicated the presence of two conjugated protons of the uracil
ring at 5.89 and 7.92 ppm, respectively, with a coupling
constant of 8.0 Hz. The protons of the benzene ring were
observed in the following order: the uncovered proton H-30
appears at 8.85 ppm as a doublet (J 2.6 Hz) coupled with
the proton H-50 (dd, 1H, J 2.6 Hz, J 8.7 Hz). The H-50 proton
showed a coupling constant of 8.7 Hz with proton H-60
(8.03 ppm). The signal of the H-3 proton of the uracil ring
was observed at 11.78 ppm as a broad singlet. After the
methylation reaction, this signal was not observed in the
1H NMR spectrum. In compound 6, the proton H-6 of
the uracil ring appeared as a sharp singlet at 9.56 ppm. It
should be mentioned that neither N-3 nor O-arylation prod-
ucts were detected. The signals of two carbonyl groups in the
13C NMR spectrum at 163 and 149 ppm exclude the possi-
bility of O-arylation.
The isolated solid was stable and did not cyclize to the
expected product of ring transformation. It is opposite to
the results obtained in reaction of 4 with amino alcohols
where the product of ring transformation was isolated in
satisfactory yield.17 When instead of compound 4, 1-(2,4-
dinitrophenyl)-3-methyl-5-nitrouracil 6 has been used in
According to reported data, 3-methyl-1-(4-nitrophenyl)-5-
nitrouracil undergoes ring transformation when treated
O
O
O
H
O
O2N
NH
NO2
NH
HN
N
H
HN
N
H
C6H5NH2, (7a)
DMF, r.t.
N
O
O2N
O2N
+
O2N
NO2
NO2
NO2
4
8
9
78%
16%
Scheme 2.

A. Gondela, K. Walczak / Tetrahedron 63 (2007) 2859–2864
2861
O
N
O
O2N
O2N
Me
O
O2N
Me
O
N
NH2
NH2
N
O2N
N
+
+
DMF
r.t., 12-24 h
R1
R2
NO2
R1
7a-f
R2
10a-f
11
NO2
R1
H
N(Et)2
OMe
OMe
OH
R2
H
H
OMe
H
H
Yield [%]
7,10
6
a
b
c
d
e
f
56
45
45
86
68
77
Me
H
Scheme 3.
reaction with aniline, the formation of a yellow adduct was
observed, however after 24 h the TLC indicated the disap-
pearance of the adduct and formation of a new substance.
From the post-reaction mixture, the desired product 10a
was isolated in moderate yield and identified on the basis
of NMR spectra and elemental analysis (Scheme 3). 2,4-Di-
nitroaniline 11, a side product formed in this reaction, was
isolated and identified by comparison with an authentic sam-
When 6 was replaced by unsubstituted uracil derivative 4,
the reaction became more complicated. The TLC indicated
the presence of the acyclic adduct together with several
unidentified compounds. The moderate rate of formation
of the desired product 13e was obtained when the reaction
was conducted in refluxing DMF.
These results suggest that the unsubstituted H-3 proton of the
uracil ring influences somehow the reaction rate in the case
of such weak nucleophiles as aromatic amines. After addi-
tion of the nucleophile (aromatic amine) and ring opening,
the acyclic adduct is stabilized by the formation of hydrogen
bonds (e.g., in forms of B–D, Scheme 5). Several of these
mesomeric structures may be derived from the lactim form
of uracil, which are probably more stable and able to retard
the recyclization. The solvatation effects created by polar
1
ple (mp and H NMR spectroscopy). A similar behaviour
was exhibited by the other investigated anilines 7b–f. This
transformation was next explored using the amino pyridines
12a–d; they react smoothly at room temperature with uracil
derivative 6 giving the appropriate 1-pyridyl substituted
derivatives 13a–d in satisfactory yield (Scheme 4). It is the
first example of direct introduction of a pyridyl moiety at
the N-1 nitrogen atom of the uracil ring.
O
R1
O
NO2
R1
N
NH2
NO2
NH2
N
NO2
O
N
+
+
Z
Y
O
N
NO2
DMF
R2
X
Z
Y
r.t., 24-48 h
NO2
R2
X
12a-d
11
NO2
13a-e
4, 6
12, 13
R1
R2
H
H
H
X
C
C
N
Y
N
Z
C
N
C
Yield [%]
a
b
c
CH3
CH3
CH3
73
62
26
C
C
d
e
CH3 CH3
C
C
C
N
N
C
67
57
H
H
Scheme 4.
O
N
H
H
N
Ar
O
O2N
O2N
H
H
R
H
N
O
O
O
Ar
O
NH
N
O
N
O
NO2
H
Ar
NO2
H
N
H
N
H
O
ArNH2
N
H
N
HN
R
HN
R
O
NO2
B
C
D
A
R = 2,4-dinitrophenyl
Scheme 5.

2862
A. Gondela, K. Walczak / Tetrahedron 63 (2007) 2859–2864
0
0
0
DMF, used as a solvent, can also stabilize the B–D forms but
these effects are difficult to estimate.
H-6), 8.95 (d, 1H, J3 –5 2.4 Hz, H-30), 8.81 (dd, 1H, J3 –5
0
2.4 Hz, J5 –6 8.4 Hz, H-50), 8.16 (d, 1H, J5 –6 8.4 Hz,
H-60). 13C NMR (DMSO-d6) d (ppm) 154.7, 148.7, 148.2,
147.9, 144.9, 134.7, 132.6, 129.6, 126.7, 120.9. Anal. Calcd
for C10H5N5O8 (323.18): %C, 37.17; %H, 1.56; %N, 21.67.
Found: %C, 37.31; %H, 1.72; %N, 21.69.
0
0
0
0
3. Conclusion
In conclusion, an effective method for the regioselective
introduction of a substituted benzene or pyridine ring on
the N-1 nitrogen atom of uracil is described. The hitherto un-
known 1-(2,4-dinitrophenyl)-3-methyl-5-nitrouracil can be
considered as a convenient substrate in nucleophilic substi-
tution reactions of the ANRORC type. The proposed method
establishes a versatile route for the preparation of 1-aryl-
substituted uracil, where the benzene ring contains electron
donating groups.
4.1.3. 1-(2,4-Dinitrophenyl)-3-methyluracil (5). To the
solution of 4 (3.0 g, 10.8 mmol) in anhydrous DMF
(10 mL) at room temperature, sodium hydride (80% immer-
sion in a mineral oil, 0.36 g, 12 mmol) was added in small
portions while stirring. After 30 min methyl iodide (1.7 g,
0.75 mL, 12 mmol) was added dropwise. After decay of sub-
strate (3 h, TLC, 20% MeOH/CHCl3), reaction mixture was
poured into ice-water (50 g/50 g). The formed precipitation
was filtered off, washed with cold water and dried on air.
Crystallization from methanol gives pure compound. Yield
1
4. Experimental
4.1. General
2.68 g (85%), a yellow solid, mp 170–172 ꢁC. H NMR
(DMSO-d6) d (ppm) 8.88 (d, 1H, J3 –5 2.4 Hz, H-30), 8.74
0
0
(dd, 1H, J3 –5 2.4 Hz, J5 –6 9.0 Hz, H-50), 8.03 (d, 1H,
0
0
0
0
J5 –6 9.0 Hz, H-60), 7.96 (d, 1H, J5–6 8.1 Hz, H-6), 6.03
(d, 1H, J5–6 8.1 Hz, H-5), 3.18 (s, 3H, CH3). 13C NMR
(DMSO-d6) d (ppm) 162.1, 150.1, 147.1, 145.1, 142.1,
136.4, 131.7, 129.3, 120.8, 102.2, 27.4. Anal. Calcd for
C11H8N4O6 (292.21): %C, 45.22; %H, 2.76; %N, 19.17.
Found: %C, 45.39; %H, 2.31; %N, 18.98.
0
0
1
NMR spectra were recorded at 300 MHz for H NMR and
75.5 MHz for 13C NMR on a Varian Inova 300 MHz in
DMSO-d6 solution; d-values are in parts per million relative
to tetramethylsilane as an internal standard. Elemental anal-
yses were obtained using a Perkin–Elmer 240C apparatus.
All used reagents were purchased from Lancaster. TLC
60F254 plates and silica gel 60 (0.040–0.063 mm) were
purchased from Merck.
4.1.4. 1-(2,4-Dinitrophenyl)-3-methyl-5-nitrouracil (6).
To a suspension of 5 (2.07 g, 7.1 mmol) in concentrated
sulfuric acid (d¼1.83 g/mL, 6.0 mL) cooled in an ice bath
to 0 ꢁC, fuming nitric acid (d¼1.5 g/mL, 3.0 mL) was added
dropwise at a temperature below 5 ꢁC while stirring. After
addition of nitric acid, the ice bath was removed and stirring
was continued for 4 h at room temperature. Then, the reac-
tion mixture was poured into ice-water (200 g, 1:1). The pre-
cipitated product was filtered off, rinsed with cold water to
pH neutral and then with cold methanol (5 mL). Yield
4.1.1. 1-(2,4-Dinitrophenyl)uracil (3). To a solution of ura-
cil (1.12 g, 10 mmol) in anhydrous DMSO (10 mL) at 50 ꢁC,
triethylamine (1.01 g, 10 mmol) was added dropwise while
stirring. After 10 min, the solution was cooled down to
room temperature and the solution of 1-fluoro-2,4-dinitro-
benzene 2 (1.8 g, 9.7 mmol) in DMSO (1 mL) was added
dropwise. The resulting yellow-reddish solution was stirred
until the substrate had been consumed (approx. 30–60 min
TLC, 10% v/v MeOH/CHCl3) and was then poured into
ice-water (50 g/50 mL). The precipitate formed was filtered
off and after drying in air was crystallized from glacial acetic
acid. Yield 1.75 g (62%), a yellow solid, mp 220–222 ꢁC. 1H
1
2.21 g (93%), a yellow powder, mp 125–127 ꢁC. H NMR
0
(DMSO-d6) d (ppm) 9.56 (s, 1H, H-6), 8.88 (d, 1H, J3 –5
0
2.4 Hz, H-30), 8.74 (dd, 1H, J3 –5 2.4 Hz, J5 –6 8.4 Hz,
0
0
0
0
H-50), 8.14 (d, 1H, J5 –6 8.4 Hz, H-60), 3.26 (s, 3H, CH3).
13C NMR (DMSO-d6) d (ppm) 162.1, 150.1, 147.1, 145.1,
142.1, 136.4, 131.7, 129.3, 120.8, 102.2, 27.4. Anal. Calcd
for C11H7N5O8 (337.21): %C, 39.18; %H, 2.09; %N,
20.77. Found: %C, 39.56; %H, 2.15; %N, 21.03.
0
0
NMR (DMSO-d6) d (ppm) 11.78 (br s, 1H, NH), 8.85 (d, 1H,
0
0
0
0
0
0
0
J3 –5 2.6 Hz, H-3 ), 8.73 (dd, 1H, J3 –5 2.6 Hz, J5 –6 8.7 Hz,
H-50), 8.03 (d, 1H, J5 –6 8.7 Hz, H-60), 7.92 (d, 1H, J5–6
8.0 Hz, H-6), 5.89 (d, 1H, J5–6 8.0 Hz, H-5). 13C NMR
(DMSO-d6) d (ppm) 163.2, 149.6, 147.0, 145.1, 143.7,
136.1, 131.5, 129.2, 120.7, 103.1. Anal. Calcd for
C10H6N4O6 (278.18): %C, 43.18; %H, 2.17; %N, 20.14.
Found: %C, 42.96; %H, 2.21; %N, 19.89.
0
0
4.1.5. 1-(2,4-Dinitrophenyl)-3-[(E)-2-nitro-3-phenyl-
aminoacryloyl]urea (8) and 1-(2,4-dinitrophenyl)-3-phe-
nylurea (9). To the solution of aniline 7 (0.10 g, 1.1 mmol)
in DMF (3 mL) 4 (0.32 g, 1.0 mmol) was added while stir-
ring. After approx. 15 min yellow solid starts precipitating.
The resulting suspension was stirred until the substrate had
been consumed (24 h, TLC, 5% v/v MeOH/CHCl3) and
poured into cold methanol (10 mL). The solid 8 was filtered
off, washed with cold methanol and dried in air. Yield 0.32 g
(78%), a yellow powder. The residue after filtration and
washing was concentrated in vacuum and recrystallized
from methanol. The solid 9 was filtered off, washed with
cold methanol and dried in air. Yield 0.05 g (16%), a yellow
powder.
4.1.2. 1-(2,4-Dinitrophenyl)-5-nitrouracil (4). To a suspen-
sion of 3 (2.13 g, 7.67 mmol) in concentrated sulfuric acid
(d¼1.83 g/mL, 7.0 mL) cooled in an ice bath to 0 ꢁC, fuming
nitric acid (d¼1.5 g/mL, 3.5 mL) was added dropwise at
a temperature below 5 ꢁC while stirring. After addition of
nitric acid, the ice bath was removed and stirring was contin-
ued for 4 h at room temperature. Then, the reaction mixture
was poured into ice-water (200 g, 1:1). The precipitated
product was filtered off, rinsed with cold water to pH neutral
and then with cold methanol (5 mL). Yield 2.03 g (84%),
a yellow powder, mp 267–269 ꢁC (decomp.). 1H NMR
(DMSO-d6) d (ppm) 12.63 (br s, 1H, NH), 9.50 (s, 1H,
4.1.5.1. Compound 8. Mp 210–211 ꢁC. 1H NMR
(DMSO-d6) d (ppm) 12.48 (br s, 1H, NH), 11.83 (br s, 1H,

A. Gondela, K. Walczak / Tetrahedron 63 (2007) 2859–2864
2863
0
0
NH), 11.10 (s, 1H, C]CH), 7.64 (d, 2H, Jo –m 7.8 Hz,
H-2Ar0, H-6Ar0), 8.89 (d, 1H, J3–5 2.7 Hz, H-3Ar), 8.81 (d,
1H, J5–6 9.5 Hz, H-6Ar), 8.70 (br s, 1H, NH), 8.59 (dd,
1H, J3–5 2.7 Hz, J5–6 9.5 Hz, H-5Ar), 7.50 (m, 2H, H-3Ar0,
131.0, 128.3 (2C), 125.4, 114.3 (2C), 55.5, 28.4. Anal. Calcd
for C12H11N3O5 (277.24): %C, 51.99; %H, 4.00; %N, 15.16.
Found: %C, 51.97; %H, 4.02; %N, 5.08.
H-5Ar0), 7.35 (t, 1H, Jm –p 7.4 Hz, H-4Ar0). Anal. Calcd
for C16H12N6O8 (416.31): %C, 46.16; %H, 2.91; %N,
20.19. Found: %C, 46.21; %H, 2.15; %N, 20.13.
4.2.5. 1-(4-Hydroxyphenyl)-3-methyl-5-nitrouracil (10e).
0
0
1
Yield 0.21 g (68%), a brownish solid, mp 286–288 ꢁC. H
NMR (DMSO-d6) d (ppm) 9.91 (s, 1H, OH), 9.03 (s, 1H,
H-6), 7.29 (d, 2H, Jo–p 8.7 Hz, H-20, H-60), 6.86 (d, 2H,
Jo–p 8.7 Hz, H-30, H-50), 3.24 (s, 3H, NCH3). 13C NMR
(DMSO-d6) d (ppm) 158.1, 154.6, 149.7, 148.2, 129.6,
128.2 (2C), 125.3, 115.5 (2C), 28.4. Anal. Calcd for
C11H9N3O5 (263.21): %C, 50.20; %H, 3.45; %N, 15.96.
Found: %C, 50.19; %H, 3.44; %N, 15.74.
1
4.1.5.2. Compound 9. H NMR (DMSO-d6) d (ppm)
10.20 (s, 1H, NH), 10.08 (s, 1H, NH), 8.83 (d, 1H, J3–5
2.7 Hz, H-3Ar), 8.81 (d, 1H, J5–6 9.6 Hz, H-6Ar), 7.51 (d,
2H, Jo –m 8.4 Hz, H-2Ar0, H-6Ar0), 8.49 (dd, 1H, J3–5
0
0
2.7 Hz, J5–6 9.6 Hz, H-5Ar), 7.33 (m, 2H, Hz, H-3Ar0,
H-5Ar0), 7.06 (t, 1H, Jm –p 7.4 Hz, H-4Ar0).
0
0
4.2.6. 1-(4-Methylphenyl)-3-methyl-5-nitrouracil (10f).
1
4.2. Typical preparation procedure of 10a–f
Yield 0.20 g (77%), a yellow solid, mp 193–194 ꢁC. H
NMR (DMSO-d6) d (ppm) 9.08 (s, 1H, H-6), 7.39 (d, 2H,
Jo–p 8.4 Hz, H-20, H-60), 7.34 (d, 2H, Jo–p 8.4 Hz, H-30,
H-50), 3.24 (s, 3H, NCH3), 2.38 (s, 3H, CH3-Ar). 13C
NMR (DMSO-d6) d (ppm) 154.6, 147.9, 139.1, 135.8,
129.6 (2C), 126.8 (2C), 125.5, 28.5, 20.7. Anal. Calcd for
C12H11N3O4 (261.24): %C, 55.17; %H, 4.24; %N, 16.08.
Found: %C, 55.19; %H, 4.25; %N, 16.08.
To the stirred solution of an appropriate aniline 7a–f
(1.1 mmol) in DMF (3 mL) 1-(2,4-dinitrophenyl)-3-methyl-
5-nitrouracil 6 (0.32 g, 1.0 mmol) was added. When the TLC
(AcOEt/n-hexane 1:1 v/v, 12–24 h) indicated the consump-
tion of substrate 6, the solvent was evaporated under reduced
pressure. The residue was dissolved in methanol, decolour-
ized with charcoal and after partial concentration left for
crystallization.
4.3. Preparation of 3-methyl-5-nitro-1-(pyridin-
X-yl)uracils 13a–d
4.2.1. 3-Methyl-5-nitro-1-phenyluracil (10a). Yield 0.14 g
1
(56%), a yellow solid, mp 231–233 ꢁC. H NMR (DMSO-
To stirred solution of X-aminopyridine 12a–d (0.031 g,
0.33 mmol) in DMF (1 mL) 3-methyl-1-(2,4-dinitro-
phenyl)-5-nitrouracil 6 (0.1 g, 0.29 mmol) was added. The
reaction mixture was stirred at room temperature until the
decay of 6 was observed (24–48 h, TLC 3% v/v MeOH/
CHCl3). The solvent was removed under reduced pressure
and the residue was resolved in appropriate solvent (dis-
cussed below are the details of synthesis) and left for crystal-
lization at 0 ꢁC. The precipitated solid was filtered off and
dried in air.
d6) d (ppm) 9.14 (s, 1H, H-6), 7.55–7.50 (m, 5H, Ph), 3.25
(s, 3H, NCH3). 13C NMR (DMSO-d6) d (ppm) 154.6,
149.4, 147.8, 138.2, 129.4, 129.2 (2C), 127.1 (2C), 125.6,
28.4. Anal. Calcd for C11H9N3O4 (247.21): %C, 53.45;
%H, 3.67; %N, 17.00. Found: %C, 53.06; %H, 3.72; %N,
16.66.
4.2.2. 1-(4-Diethylaminophenyl)-3-methyl-5-nitrouracil
(10b). Yield 0.14 g (45%), orange needles, mp 162–
1
163 ꢁC. H NMR (DMSO-d6) d (ppm) 8.99 (s, 1H, H-6),
7.24 (d, 2H, Jo–p 9.0 Hz, H-20, H-60), 6.71 (d, 2H, Jo–p
4.3.1. 3-Methyl-5-nitro-1-(pyridin-3-yl)uracil (13a).
3-Aminopyridine (12a) (0.031 g, 0.33 mmol) was stirred
with 6 (0.1 g, 0.29 mmol) for 48 h; crystallization from the
solution of ethyl acetate and methanol (1:10 v/v). Yield
9.0 Hz, H-30, H-50), 3.38 (q, 4H, J1 –2 6.9 Hz, CH2–CH3),
00
00
00
00
3.24 (s, 3H, NCH3), 1.11 (t, 6H, J1 –2 6.9 Hz, CH2–CH3).
13C NMR (DMSO-d6) d (ppm) 154.6, 149.8, 148.4, 147.7,
127.6 (2C), 125.9, 110.8 (2C), 43.8 (2C), 28.4, 12.3 (2C).
Anal. Calcd for C15H18N4O4 (318.34): %C, 56.60; %H,
5.70; %N, 17.60. Found: %C, 56.58; %H, 5.61; %N, 17.63.
1
0.053 g (73%), a brownish powder, mp 220–222 ꢁC. H
NMR (DMSO-d6) d (ppm) 9.34 (s, 1H, H-6), 8.73–8.68
(m, 2H, H-20, H-60), 7.98 (ddd, 1H, J4 –6 1.5 Hz, J2 –4
0
0
0
0
2.5 Hz, J4 –5 8.2 Hz, H-40), 7.61 (ddd, 1H, J2 –5 0.6 Hz,
0
0
0
0
J5 –6 4.8 Hz, J4 –5 8.2 Hz, H-50), 3.26 (s, 3H, CH3). 13C
NMR (DMSO-d6) d (ppm) 154.6, 150.1, 149.5, 147.9,
147.8, 135.2, 134.9, 126.0, 124.0, 28.5. Anal. Calcd for
C10H8N4O4 (243.17): %C, 48.39; %H, 3.25; %N, 22.57.
Found: %C, 48.41; %H, 3.25; %N, 22.65.
0
0
0
0
4.2.3. 1-(3,4-Dimethoxyphenyl)-3-methyl-5-nitrouracil
(10c). Yield 0.14 g (45%), a dark olive solid, mp 194–
1
195 ꢁC. H NMR (DMSO-d6) d (ppm) 9.08 (s, 1H, H-6),
7.16 (d, 1H, J2 –6 1.8 Hz, H-20), 7.10–7.02 (m, 2H, H-50,
H-60), 3.81 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.25 (s,
3H, NCH3). 13C NMR (DMSO-d6) d (ppm) 154.6, 149.5,
149.3, 148.7, 148.2, 131.0, 125.2 119.3, 111.1, 55.8, 55.7,
28.4. Anal. Calcd for C13H13N3O6 (307.27): %C, 50.82;
%H, 4.26; %N, 13.68. Found: %C, 50.62; %H, 4.21; %N,
13.69.
0
0
4.3.2. 3-Methyl-5-nitro-1-(pyridin-2-yl)uracil (13b). The
reaction was continued for 48 h, after work-up crystalliza-
tion from solution of acetone and methanol (1:1 v/v). Yield
1
0.088 g (62%), brown crystals; mp 204–205 ꢁC. H NMR
(DMSO-d6) d (ppm) 9.41 (s, 1H, H-6), 8.63 (ddd, 1H,
J3 –6 0.7 Hz, J4 –6 1.8 Hz, J5 –6 4.8 Hz, H-60), 8.07 (dt,
0 0 0 0 0 0
1H, J4 –6 1.8 Hz, J4 –3 (5 ) 7.8 Hz, H-40), 7.79 (td, 1H,
4.2.4. 1-(4-Methoxyphenyl)-3-methyl-5-nitrouracil
(10d). Yield 0.24 g (86%), yellow plates, mp 215–217 ꢁC.
1H NMR (DMSO-d6) d (ppm) 9.08 (s, 1H, H-6), 7.43 (d,
2H, Jo–p 9.0 Hz, H-20, H-60), 7.07 (d, 2H, Jo–p 9.0 Hz, H-
30, H-50), 3.81 (s, 3H, OCH3), 3.24 (s, 3H, NCH3). 13C
NMR (DMSO-d6) d (ppm) 159.6, 154.6, 149.6, 148.2,
0
0
0
0
0
J3 –5 (6 ) 0.7 Hz, J4 –3 (5 ) 7.8 Hz, H-30), 7.58 (ddd, 1H, J3 –5
0
0
0
0
0
0
0
0
0.7 Hz, J5 –6 4.8 Hz, J4 –3 (5 ) 7.8 Hz, H-50), 3.27 (s, 3H,
CH3). 13C NMR (DMSO-d6) d (ppm) 154.28, 149.10,
148.94, 148.88, 145.50, 138.90, 126.29, 124.63, 121.36,
0
0
0
0
0

2864
A. Gondela, K. Walczak / Tetrahedron 63 (2007) 2859–2864
28.44. Anal. Calcd for C10H8N4O4 (243.17): %C, 48.39;
%H, 3.25; %N, 22.57. Found: %C, 48.37; %H, 3.29; %N,
22.70.
for C9H6N4O4 (234.17): %C, 46.16; %H, 2.58; %N, 23.93.
Found: %C, 45.94; %H, 2.53; %N, 23.98.
4.3.3. 3-Methyl-5-nitro-1-(pyridin-4-yl)uracil (13c). The
reaction time was 48 h, crystallization from acetone. Yield
0.019 g (26%), a white solid, mp 263–264.5 ꢁC (decomp.).
1H NMR (DMSO-d6) d (ppm) 9.27 (s, 1H, H-6), 8.77 (d,
Acknowledgements
This work was supported by a grant from the Ministry of
Education and Science (No. 3 T09A 07929).
2H, J2 (6 )–3 (5 ) 3.9 Hz, H30, H-50), 7.60 (d, 2H, J2 (6 )–3 (5 )
3.9 Hz, H-20, H-60), 3.26 (s, 3H, CH3). 13C NMR (DMSO-
d6) d (ppm) 154.4, 150.9, 148.8, 147.0 (2C), 145.2, 126.3,
121.8 (2C), 28.4. Anal. Calcd for C10H8N4O4 (243.17):
%C, 48.39; %H, 3.25; %N, 22.57. Found: %C, 48.35; %H,
3.23; %N, 22.61.
0
0
0
0
0
0
0
0
References and notes
1. Block, J. H.; Beale, J. M. Organic Medicinal and Pharmaceu-
tical Chemistry, 11th ed.; Lippincott Williams & Wilkins:
London, 2004; p 375, 406.
2. Jain, K. S.; Chitre, T. S.; Miniyar, P. B.; Kathiravan, M. K.;
Bendre, V. S.; Veer, V. S.; Shahane, S. R.; Shishoo, C.
J. Curr. Sci. 2006, 90, 793.
3. Longley, D. B.; Harkin, D. P.; Johnston, P. G. Nat. Rev. 2003,
3, 330.
4. Hoffmann, Ch.; Rockstroh, J. K.; Kamps, B. S. HIV Medicine
2005; Flying; Steinauser: Paris, 2005; p 620.
4.3.4. 3-Methyl-1-(40-methylpyridin-2-yl)-5-nitrouracil
(13d). The reaction time was 24 h; crystallization from solu-
tion of ethyl acetate. The product precipitated in amounts of
0.036 g; the additional crop of 13d (0.015 g) was obtained
by column chromatography (silica gel, 3% v/v MeOH/
CHCl3). Total yield 0.051 g (67%), a yellow solid, mp
1
198–200 ꢁC. H NMR (DMSO-d6) d (ppm) 9.37 (s, 1H,
H-6), 8.47 (d, 1H, J5 –6 5.1 Hz, H-60), 7.61 (s, 1H, H-30),
5. Baraldi, P. G.; Romagnoli, R.; Guadix, A. E.; Pineda de las
Infantas, M. J. P.; Gallo, M. A.; Espinosa, A.; Martinez, A.;
Bingham, J. P.; Hartley, J. A. J. Med. Chem. 2002, 45, 3630.
0
0
7.41 (d, 1H, J5 –6 5.1 Hz, H-50), 3.26 (s, 3H, CH3), 2.43 (s,
3H, CH3-Py). 13C NMR (DMSO-d6) d (ppm) 154.3, 150.1,
149.2, 148.5, 148.8, 145.6, 126.2, 125.5, 121.6, 28.4,
20.6. Anal. Calcd for C11H10N4O4 (262.23): %C, 50.38;
%H, 3.84; %N, 21.37. Found: %C, 50.35; %H, 3.87; %N,
21.41.
0
0
ꢀ
6. Gondela, A.; Gabanski, R.; Walczak, K. Tetrahedron Lett.
2004, 45, 8007.
7. Gondela, A.; Walczak, K. Tetrahedron: Asymmetry 2005, 16,
2107.
8. Winckelmann, I.; Larsen, E. H. Synthesis 1986, 1041.
9. Wolfbeis, O. S. Liebigs Ann. Chem. 1982, 182.
10. Gabel, N. W.; Binkley, S. B. J. Org. Chem. 1958, 23, 643.
11. Atkinson, M. R.; Shaw, G.; Warrener, R. N. J. Chem. Soc. 1956,
4188.
12. Singh, H.; Singh, P.; Aggarwal, P.; Kumar, S. J. Chem. Soc.,
Perkin Trans. 1 1993, 731.
13. Maruyama, T.; Fujiwara, K.; Fukuhara, M. J. Chem. Soc.,
Perkin Trans. 1 1995, 733.
14. Jacobsen, S. A.; Rødbotten, S.; Benneche, T. J. Chem. Soc.,
Perkin Trans. 1 1999, 3265.
15. Zhou, T.; Li, Ti.-C.; Chen, Z.-Chu. Helv. Chim. Acta 2005,
88, 290.
16. Boga, C.; Bonmartini, A. C.; Fornali, L.; Modarelli, V.; Righi,
L.; Sgarabotto, P. J. Chem. Res., Miniprint 2001, 12, 1217.
17. Gondela, A.; Walczak, K. Tetrahedron Lett. 2006, 47, 4653.
18. Hirota, K.; Kitade, Y.; Sajiki, H.; Maki, Y.; Yogo, M. J. Chem.
Soc., Perkin Trans. 1 1990, 367.
4.3.5. 5-Nitro-1-(pyridin-3-yl)uracil (13e). The solution of
3-aminopyridine (12a) (0.101 g, 1.1 mmol) and 4 (0.323 g,
1.0 mmol) in DMF (5 mL) was refluxed for 1 h, then solvent
was removed in vacuum. The residue was triturated with hot
ethyl acetate to separate the 2,4-dinitroaniline and other side
products. The residual crude product (0.166 g) was dis-
solved in hot 1 M HCl, decolorized with charcoal, neutral-
ized to pHw5 and cooled to room temperature. The
precipitate of 13e was filtered off, washed with water and
dried in air. Yield 0.133 g (57%), a brownish solid, mp
1
241–242 ꢁC. H NMR (DMSO-d6) d (ppm) 12.32 (s, 1H,
NH), 9.28 (s, 1H, H-6), 8.73 (d, 1H, J2 –4 2.5 Hz, H-20),
0
0
8.64 (dd, 1H, J4 –6 1.5 Hz, J5 –6 4.8 Hz, H-60), 8.00 (ddd,
0
0
0
0
1H, J4 –6 1.5 Hz, J2 –4 2.5 Hz, J4 –5 8.2 Hz, H-40), 7.60
0
0
0
0
0
0
(ddd, 1H, J2 –5 0.6 Hz, J5 –6 4.8 Hz, J4 –5 8.2 Hz, H-50).
13C NMR (DMSO-d6) d (ppm) 155.18, 149.97, 149.84,
149.03, 147.92, 135.29, 134.45, 126.25, 123.93. Anal. Calcd
0
0
0
0
0
0