The arylimines of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde: Synthesis and their application in 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1002/jhet.284

(Chemical Equation Presented) A number of aldimines have been obtained in very good yield in reaction of 5-formyl-1,3-dimethyluracil with various substituted anilines in boiling methanol. Selected aldimines were treated with nitrile oxides generated from 4-chlorobenzaldoxime or 4-methylbenzaldoxime forming the appropriate 1,3-cycloadducts in moderate yields.

Full text of DOI:10.1002/jhet.284

1280
The Arylimines of 2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-
carbaldehyde: Synthesis and Their Application in 1,3-Dipolar
Cycloaddition Reaction
Vol 46
Dominika Osyda, Radosław Motyka, and Krzysztof Z. Walczak*
Department of Organic Chemistry, Biochemistry and Biotechnology, Silesian University of
Technology, Krzywoustego 4, 44-100 Gliwice, Poland
*E-mail: krzysztof.walczak@polsl.pl
Received May 18, 2009
DOI 10.1002/jhet.284
Published online 6 November 2009 in Wiley InterScience (www.interscience.wiley.com).
A number of aldimines have been obtained in very good yield in reaction of 5-formyl-1,3-dimethylur-
acil with various substituted anilines in boiling methanol. Selected aldimines were treated with nitrile
oxides generated from 4-chlorobenzaldoxime or 4-methylbenzaldoxime forming the appropriate 1,3-
cycloadducts in moderate yields.
J. Heterocyclic Chem., 46, 1280 (2009).
INTRODUCTION
stituents, we have considered the molecule of 5-formy-
luracil (2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbal-
dehyde) as a suitable reagent for the preparation of
Schiff bases, which could be used further as dipolaro-
philes in 1,3-cycloaddition reaction. The chemical prop-
erties of 5-formyluracil are reported in the literature
mainly in the context of its cytotoxic effect. The
5-formyl-20-deoxyuridine formed by the oxidation of
thymidine induces the damage of DNA [12–16]. Surpris-
ingly, the syntheses involving 5-formyluracil as a rea-
gent are rarely reported. 5-Formyl-1,3-dimethyluracil
reacts with enamines giving 5-(acylvinyl)uracil deriva-
tives. When enamines derived from 1,3-cyclohexane-
dione or ethyl acetate were applied, 5-(9-xanthenyl)ura-
cil and 5-(6-cyclohexadienyl)uracil were obtained [17].
Recently, 5-formyluracil was used for the formation of
nitrones, which treated with allyl alcohol as dipolaro-
phile under harsh conditions to form isoxazolines in
moderate yields [18]. Similarly, several isoxazoles, iso-
xazolines, and isoxazolidines have been synthesized by
1,3-dipolar cycloaddition reactions of nitrile oxides and
nitrones derived from mono- and di-substituted uracil-5-
carbaldehydes and 2,4-dimethoxypyrimidine-5-carbalde-
hyde [19].
The uracil derivatives are broadly known due to their
application in bioorganic and medicinal chemistry. The
5-substituted uracils, mostly in the form of N1-glycosyl
derivatives, possess biological activity, especially
against viruses and neoplastic cells. 5-Fluorouracil and
(E)-5-(2-bromovinyl)-20-deoxyuridine belong to the best
described uracil derivatives [1–3]. Similar to 5-halouri-
dines, their analogues substituted with another heterocy-
clic system at C5 carbon of uracil ring, exhibit interest-
ing biological activities. They form stable complexes
with RNA [4] and inhibit thymidine kinase of HIV-1
virus [5,6]. The introduction of heteroaryl group into
uracil ring can be performed using various methods.
The UV irradiation of persilylated 5-iodo-20-deoxycyti-
dine in the presence of thiophene leads to appropriate 5-
(2-thienyl)-20-deoxycytidine in moderate yield [7]. The
opposite variant of this reaction, when a mixture of 2-
iodothiophene and 2-deoxycytidine was irradiated is also
known [7]. Several 5-heteroaryl-20-deoxyuridines have
been obtained in palladium complexes catalyzed reac-
tion of 5-iodo-20-deoxyuridine with heteroaryltrialkyltin
derivatives [8,9]. Other approaches based on traditional
synthesis of heterocyclic rings involving 5-aminouracil
as a building block in the construction of heterocyclic
system have also been reported [10,11].
The nickel, cobalt, and copper complexes of 5-formy-
luracil thiosemicarbazones were synthesized and their
activity against model leukemia cells was examined
[20]. Schiff bases of 5-formyluracil and chiral amino
As a part of our research interest in the reactivity of
uracil derivatives containing electron-withdrawing sub-
C
V
2009 HeteroCorporation

November 2009 The Arylimines of 2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde: Synthesis
and Their Application in 1,3-Dipolar Cycloaddition Reaction
1281
Scheme 1. Synthesis of aldimines.
performed under similar conditions (excluding time of
reaction), we anticipated the same E configuration for
all the obtained products.
For the primary trials of 1,3-dipolar cycloaddition
reaction four imines 3a–d possessing the substituent on
C4 carbon of benzene ring were selected. The 1,3-dipole
4a was generated in situ from 4-chlobenzaldehyde
oxime using N-chlorosuccinimide and triethylamine as a
base in chloroform solution according to the modified
procedure [24]. The cycloaddition reaction of appropri-
ate aldimine 3a–d with 4-chlorobenzonitrile oxide 4 pro-
ceeded in refluxed CHCl3 (Scheme 2). The products of
reactions: 5-[3-(4-chlorophenyl)-4-(4-aryl)-4,5-dihydro-
1,2,4-oxadiazole-5-yl]-1,3-dimethyl-1H-pyrimidine-2,4-
dione 5a–d were separated by column chromatography
in satisfactory yields (Table 2). A same procedure was
applied when 4-methylbenzonitrile oxide 4b was used as
the 1,3-dipole and cycloaddition reactions were occurred
in 49–51% yields. The structure for all new compounds
5a–h was confirmed by NMR spectroscopy and elemen-
tal analysis. As it was mentioned, the obtained aldimines
have E configuration. The presence of single bond
between C(5) of uracil ring and imine carbon atom
allows for free rotation around this bond. The 1,3-cyclo-
addition reaction of nitrile oxide with double bond is the
suprafacially concerted reaction [25]. However, when
the free rotation is possible, the attack of dipole can
occurs from both sides of imines and results in the for-
mation of racemic mixture.
alcohols undergo highly diastereoselective 1,2- and 1,3-
allylations to form homoallylic amino alcohol appended
uracils [21].
RESULTS AND DISCUSSION
In our trials, which we report herein, 5-formyl-1,3-
dimethyluracil (1) has been used as a carbonyl compo-
nent in the synthesis of imines. For the preparation of 1
uracil was methylated by dimethyl sulfate followed by
the Vilsmeier-Haack formylation using DMF and phos-
phorous trichloride [22]. Overall yield exceeded 60%.
The condensation of 1 with substituted anilines 2a–l
occurs smoothly under mild condition (Scheme 1,
Table 1). The desired aldimines 3a–l were obtained by
refluxing the equimolar amounts of reagents in metha-
nol. The reaction time did not exceed 4 h in the case of
less active anilines. The products 3a–l are well soluble
in hot methanol and, after cooling down to room tem-
perature, they precipitate from the post-reaction solution
in the form of crystalline solids in satisfactory yields
(Table 1). The purity of the obtained imines 3a–d was
sufficient for the further synthesis as it was concluded
from the NMR spectra. Other imines 3e–l were recrys-
tallized from methanol.
CONCLUSION
The structure of the products was assigned on the
bases of NMR data and elemental analysis. The configu-
ration of the double bond in the obtained imines was
assumed as (E), which was confirmed by X-ray analysis
of 3j (Fig. 1) [23]. Because the synthesis of 3a–l was
In summary, we have successfully carried out the
condensation reaction of 1,3-dimethyl-5-formyluracil
with substituted anilines. Reactions proceed under mild
conditions and purity of aldimines in most of the cases
was sufficient for the next step. It should be noticed that
Table 1
Synthesis of imines 3a–l derived from 1,3-dimethyl-5-formyluracil and substituted anilines.
Product 3
R
Yielda (%)
Reaction time (h)
Mp (ꢀC)
a
b
c
d
e
f
g
h
i
H
81
91
93
93
84
61
77
75
79
93
81
75
1.0
1.5
0.5
0.5
1.0
3.0
3.0
3.5
3.0
2.0
2.5
2.5
147–148
155–156
183–185
204–206
282–284
88–90
140–141
143–144
148–149
166–167
197–198
195–197
4-CH3
4-Cl
4-Br
4-NO2
3-CH3
3-Cl
3-Br
3-I
j
k
l
2-CH3
2-Cl
2-Br
a Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1282
D. Osyda, R. Motyka, and K. Z. Walczak
Vol 46
Scheme 2. Synthesis of 1,3-cycloadducts.
MeOH (4 mL) containing 10 mg of p-TSA, appropriate aniline
2a–l (2 mmol) was added and the reaction mixture was refluxed
until the decay of substrates (0.5–3.5 h, Table 1), then cooled
down to 0ꢀC. The precipitate was filtered off, rinsed with cold
methanol (2 mL), and dried in vacuum dessicator over P2O5.
The products were sufficiently pure for the next step. If neces-
sary the crystallization from methanol was applied and the pure
compounds were obtained as light yellow crystals.
Figure 1. Crystal structure of 3j. Displacement ellipsoids are drawn at
the 50% probability level. [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
1,3-Dimethyl-5-(phenyliminomethyl)-1H,3H-pyrimidine-
2,4-dione (3a). 1H NMR (CDCl3): d 3.41 (s, 3H, CH3), 3.51
(s, 3H, CH3), 7.15 (d, 2H, J ¼ 7.5 Hz, arom.), 7.22 (t, 1H, J
¼ 7.5 Hz, arom.), 7.37 (t, 2H, J ¼ 7.5 Hz, arom.), 8.24 (s, 1H,
H-6), 8.58 (s, 1H, imine). 13C NMR (CDCl3): d 28.1., 37.7,
100.2, 109.8, 121.1 (2C), 126.3, 129.3 (2C), 142.9, 151.3,
153.1, 162.5. Anal. Calcd. for C13H13N3O2: C, 64.19; H, 5.39;
N, 17.27. Found: C, 63.89; H, 5.01; N, 16.91.
the presence of neighboring carbonyl group has not
influence on reactivity of 5-formyl group in uracil ring
rather toward weak nucleophiles like aromatic amines.
The obtained Schiff bases were applied as dipolarophiles
in the 1,3-dipolar cycloaddition reactions of 4-chloro-
benzonitrile oxide or 4-methylbenzonitrile oxide to pro-
duce the racemic 5-(4,5-dihydro-1,2,4-oxadiazole-
5-yl)uracil derivatives in satisfactory yields. The attack
of 1,3-dipole on C(5)AC(6)Adouble bond of uracil ring
was not observed [26].
1,3-Dimethyl-5-[(4-methylphenylimino)-methyl]-1H,3H-pyrimi-
1
dine-2,4-dione (3b). H NMR (CDCl3): d 2.36 (s, 3H, CH3, p-
tol), 3.41 (s, 3H, CH3), 3.55 (s, 3H, CH3), 7.10 (d, 2H, J ¼
8.1 Hz, arom.), 7.17 (d, 2H, J ¼ 8.1 Hz, arom.), 8.23 (s, 1H,
H-6), 8.58 (s, 1H, imine). 13C NMR (CDCl3): d 21.1, 28.2,
37.7, 110.0, 121.0 (2C), 129.9 (2C), 136.2, 142.7, 148.7,
151.4, 152.1, 162.5. Anal. Calcd. for C14H15N3O2: C, 65.36;
H, 5.88; N, 16.33. Found: C, 65.63; H, 5.47; N, 15.98.
EXPERIMENTAL
5-[(4-chloro-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
1
dine-2,4-dione (3c). H NMR (CDCl3): d 3.41 (s, 3H, CH3),
NMR spectra were recorded at 300 MHz for 1H NMR and
75.5 MHz for 13C NMR on a Varian Inova 300 MHz in
CDCl3 solution; d values are in parts per million relative to
tetramethylsilane as an internal standard. Elemental analyses
were obtained using a PerkinElmer 240C apparatus. 4-Chloro-
benzaldoxime (mp 107–108ꢀC, lit. mp 107–109ꢀC) and 4-
methylbenzaldoxime (mp 71–73ꢀC, lit. mp 76–78ꢀC) were pre-
pared according to known procedures [27]. The other used
reagents were purchased from Lancaster. TLC 60F254 plates
and silica gel 60 (0.040–0.063 mm) were purchased from
Merck.
3.53 (s, 3H, CH3), 7.10 (d, 2H, J ¼ 8.7 Hz, arom.), 7.33 (d,
2H, J ¼ 8.7 Hz, arom.), 8.24 (s, 1H, H-6), 8.55 (s, 1H, imine).
13C NMR (CDCl3): d 28.2, 37.8, 109.7, 122.4 (2C), 129.4
(2C), 131.9, 143.2, 149.8, 151.3, 153.5, 162.5. Anal. Calcd. for
C13H12ClN3O2: C, 56.23; H, 4.36; N, 15.13. Found: C, 55. 96;
H, 4.02; N, 14.89.
5-[(4-Bromo-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
1
dine-2,4-dione (3d). H NMR (CDCl3): d 3.41 (s, 3H, CH3),
3.53 (s, 3H, CH3), 7.04 (dt, 2H, J ¼ 9.3 Hz, 2.4 Hz, arom.),
7.48 (dt, 2H, J ¼ 9.3 Hz, 2.4 Hz, arom.), 8.24 (s, 1H, H-6),
8.55 (s, 1H, imine). 13C NMR (CDCl3): d 28.2, 37.8, 109.7,
119.7, 122.8 (2C), 132.4 (2C), 143.2, 150.3, 151.3, 153.5,
General procedure for synthesis of imines (3a–l). To the
solution of 1,3-dimethyl-5-formyluracil 1 (0.34 g, 2 mmol) in
Table 2
The products of 1,3-dipolar cycloaddition 5a–h.
Product 5
R
R1
Reaction time (h)
Yielda (%)
Mp (ꢀC)
a
b
c
d
e
f
H
Cl
Cl
Cl
Cl
CH3
CH3
CH3
CH3
1
50
51
44
47
49
51
44
51
114–115
179–180
185–187
212–214
202–203
181–182
180–181
184–185
4-CH3
4-Cl
4-Br
H
2
1
1
2.5
2.5
2.5
2.5
4-CH3
4-Cl
4-Br
g
h
a Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 The Arylimines of 2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde: Synthesis
and Their Application in 1,3-Dipolar Cycloaddition Reaction
1283
162.5. Anal. Calcd. for C13H12BrN3O2: C, 48.47; H, 3.75; N,
13.04. Found C, 48.85; H, 3.68; N, 12.75.
5-[(4-Nitro-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
5-[(2-Bromo-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
1
dine-2,4-dione (3l). H NMR (CDCl3): d 3.13 (s, 3H, CH3),
3.26 (s, 3H, CH3), 6.61 (dd, 1H, J ¼ 7.9 Hz, 1.2 Hz, arom.),
6.77 (dt, 1H, J ¼ 7.9 Hz, 1.2 Hz, arom.), 7.02 (dt, 1H, J ¼ 7.9
Hz, 1.2 Hz, arom.), 7.31 (dd, 1H, J ¼ 7.9 Hz, 1.2 Hz, arom.),
8.03 (s, 1H, H-6), 8.18 (s, 1H, imine). 13C NMR (CDCl3): d
28.2, 37.9, 109.5, 118.5, 120.0, 127.0, 128.6, 133.1, 143.7,
150.2, 151.4, 154.7, 162.4. Anal. Calcd. for C13H12BrN3O2: C,
48.47; H, 3.75; N, 13.04. Found: C, 48.23; H, 3.54; N, 12.85.
General procedure for synthesis of 5-[3-(4-chlorophenyl)-
(4-substituted-phenyl)-4,5-dihydro-1,2,4-oxadiazol-5-yl]-1,3-
dimethyl-1H,3H-pyrimidine-2,4-dione (5a–d). To a solution
of 4-chlorobenzaldoxime (0.12 g, 0.77 mmol) in CHCl3 (4
mL) NCS (0.11 g, 0.85 mmol) was added at room temperature
while stirring. The reaction mixture changed the color from
light yellow, through blue to green. Completion of the reaction
was indicated by the turn the color of reaction mixture to yel-
low (40 min). The solution of 4-chlorobenzohydroximinoyl
chloride was washed with small amounts of cold water (2
mL), dried over anhydrous MgSO4, and immediately used for
the next step. To the solution of 4-chlorobenzohydroximinoyl
chloride the imine 3a–d (0.7 mmol) was added followed by
addition of triethylamine (0.11 mL, 0.77 mmol). The reaction
mixture was refluxed for the time indicated in Table 2, con-
centrated under diminished pressure, and purified on silica gel
packed column using AcOEt:n-hexane (1:1) as an eluent. The
products 5a–d were obtained as solid colorless materials, crys-
tallized if necessarily from methanol.
1
dine-2,4-dione (3e). H NMR (CDCl3): d 3.40 (s, 3H, CH3),
3.54 (s, 3H, CH3), 6.63 (dt, 2H, J ¼ 9.0 Hz, 2.6 Hz, arom.),
8.07 (m, 3H, H-6, arom.), 10.04 (s, 1H, imine). 13C NMR
(CDCl3): d 28.0, 38.2, 69.3, 110.4, 113.5 (2C), 126.5 (2C),
147.7, 151.1, 152.7, 162.1. Anal. Calcd. for C13H12N4O4: C,
54.17; H, 4.20; N, 19.44. Found: C, 53.88; H, 3.87; N, 19.06.
1,3-Dimethyl-5-[(3-methylphenyimino)-methyl]-1H,3H-pyrimi-
1
dine-2,4-dione (3f). H NMR (CDCl3): d 2.37 (s, 3H, CH3, m-
tol), 3.41 (s, 3H, CH3), 3.53 (s, 3H, CH3), 6.97–7.06 (m, 3H,
arom.), 7.26 (t, 1H, J ¼ 8.0 Hz, arom.), 8.32 (s, 1H, H-6),
8.61 (s, 1H, imine). 13C NMR (CDCl3): d 21.5, 28.2, 37.8,
109.8, 118.2, 121.7, 127.3, 129.2, 139.2, 142.6, 147.6, 151.3,
153.0, 162.5. Anal. Calcd. for C14H15N3O2: C, 65.36; H, 5.88;
N, 16.33. Found: C, 64.98; H, 5.55; N, 15.98.
5-[(3-chloro-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
1
dine-2,4-dione (3g). H NMR (CDCl3): d 3.41 (s, 3H, CH3),
3.53 (s, 3H, CH3), 7.02 (d, 1H, J ¼ 8.0 Hz, arom.), 7.14 (m,
1H, arom.), 7.18 (d, 1H, J ¼ 8.0 Hz, arom.), 7.29 (t, 1H, J ¼
8.0 Hz, arom.), 8.24 (s, 1H, H-6), 8.54 (s, 1H, imine). 13C
NMR (CDCl3): d 28.2, 37.8, 109.5, 119.4, 121.4, 126.2, 130.3,
134.9, 143.4, 151.3, 152.7, 154.2, 162.4. Anal. Calcd. for
C13H12ClN3O2: C, 56.23; H, 4.36; N, 15.13. Found: C, 55.92;
H, 3.98; N, 14.87.
5-[(3-Bromo-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
1
dine-2,4-dione (3h). H NMR (CDCl3): d 3.41 (s, 3H, CH3),
3.54 (s, 3H, CH3), 7.07 (dq, 1H, J ¼ 7.5 Hz, 1.3 Hz, arom.),
7.23 (t, 1H, J ¼ 7.5 Hz, arom.), 7.33 (dt, 2H, J ¼ 7.5 Hz, 1.3
Hz, arom.), 8.24 (s, 1H, H-6), 8.54 (s, 1H, imine). 13C NMR
(CDCl3): d 28.2, 37.8, 109.5, 120.0, 123.0, 124.2, 129.1,
130.6, 143.4, 151.3, 152.8, 154.2, 162.4. Anal. Calcd. for
C13H12BrN3O2: C, 48.47; H, 3.75; N, 13.04. Found: C, 48.09;
H, 3.46; N, 12.88.
The same procedure starting from the same molar amounts
of substrates was applied for preparation of 4-methylbenzoni-
trile oxide 4b. The 1,3-dipolar cycloaddition of 4b to aldi-
mines 3a–d was carried out under conditions described earlier.
The products 5e–h were purified by silica gel packed column
using a (1:1) mixture of n-hexane-ethyl acetate as eluent, in
the form of colorless solids.
5-[(3-Iodo-phenylimino)-methyl]-1,3-dimethyl-1H,3H-pyrimi-
1
dine-2,4-dione (3i). H NMR (CDCl3): d 3.41 (s, 3H, CH3),
5-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1,2,4-oxadiazol-5-
(5a). 1H
yl]-1,3-dimethyl-1H,3H-pyrimidine-2,4-dione
3.54 (s, 3H, CH3), 7.03–7.15 (m, 2H, arom.), 7.51–7.56 (m,
2H, arom.), 8.30 (s, 1H, H-6), 8.55 (s, 1H, imine). 13C NMR
(CDCl3): d 28.2, 37.9, 94.6, 109.2, 120.6, 129.9, 130.7, 135.7,
143.7, 151.2, 154.2, 162.3. Anal. Calcd. for C13H12IN3O2: C,
42.30; H, 3.28; N, 11.38. Found: C, 42.05; H, 2.96; N, 11.03.
1,3-Dimethyl-5-[(2-methylphenylmino)-methyl]-1H,3H-pyrimi-
NMR (CDCl3): d 3.39 (s, 3H, CH3), 3.42 (s, 3H, CH3), 6.64
(s, 1H, oxadiaz.), 7.09 (d, 2H, J ¼ 7.7 Hz, arom.), 7.15 (t, 1H,
J ¼ 7.7 Hz, arom.), 7.25 (d, 2H, J ¼ 7.7 Hz, arom.), 7.30 (dt,
2H, J ¼ 8.6 Hz, 1.9 Hz, arom.), 7.52 (s, 1H, H-6), 7.57 (dt,
2H, J ¼ 8.6, 1.9 Hz, arom.). 13C NMR (CDCl3): d 27.9, 37.4,
94.6, 110.5, 123.8, 124.3 (2C), 126.0, 129.1 (2C), 129.3 (2C),
129.3 (2C), 137.0, 142.0, 142.1, 151.4, 154.8, 161.9. Anal.
Calcd. for C20H17ClN4O3: C, 60.53; H, 4.32; N, 14.12. Found:
C, 60.14; H, 3.98; N, 13.88.
1
dine-2,4-dione (3j). H NMR (CDCl3): d 2.31 (s, 3H, CH3, o-
tol), 3.41 (s, 3H, CH3), 3.53 (s, 3H, CH3), 6.89 (d, 1H, J ¼
6.9 Hz, arom.), 7.09–7.21 (m, 3H, arom.), 8.23 (s, 1H, H-6),
8.46 (s, 1H, imine). 13C NMR (CDCl3): d 18.0, 28.1, 37.8,
110.0, 118.1, 126.0, 126.9, 130.4, 131.8, 142.8, 150.6, 151.4,
152.4, 162.6. Anal. Calcd. for C14H15N3O2: C, 65.36; H, 5.88;
N, 16.33. Found: C, 64.97; H, 5.52; N, 15.98.
5-[3-(4-chlorophenyl)-4-(4-methylphenyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl]-1,3-dimethyl-1H,3H-pyrimidine-2,4-dione
1
(5b). H NMR (CDCl3): d 2.28 (s, 3H, CH3, p-tol), 3.38 (s,
3H, CH3), 3.42 (s, 3H, CH3), 6.59 (s, 1H, oxadiaz.), 6.97 (d,
2H, J ¼ 8.4 Hz, arom.), 7.05 (d, 2H, J ¼ 8.4 Hz, arom.), 7.29
(d, 2H, J ¼ 8.6 Hz, arom.), 7.51 (s, 1H, H-6), 7.56 (d, 2H, J
¼ 8.6 Hz, arom.). 13C NMR (CDCl3) d: 21.0, 28.0, 37.6, 94.8,
110.8, 124.0, 124.9 (2C), 129.1 (2C), 129.5 (2C), 130.1 (2C),
136.3, 137.0, 139.4, 142.3, 151.6, 155.1, 162.0. Anal. Calcd.
for C21H19ClN4O3: C, 61.39; H, 4.66; N, 13.64. Found: C,
61.62; H, 4.65; N, 13.29.
5-[(2-chloro-phenylimino)-methyl]-1,3-dimethyl-1H,3H-py-
1
rimidine-2,4-dione (3k). H NMR (CDCl3): d 3.41 (s, 3H,
CH3), 3.54 (s, 3H, CH3), 7.00 (dd, 1H, J ¼ 7.7 Hz, 1.6 Hz,
arom.), 7.13 (dt, 1H, J ¼ 7.7 Hz, 1.6 Hz, arom.), 7.24 (dq,
1H, J ¼ 7.7 Hz, 1.6 Hz, arom.), 7.41 (dd, 1H, J ¼ 7.7 Hz, 1.6
Hz, arom.), 8.32 (s, 1H, H-6), 8.50 (s, 1H, imine). 13C NMR
(CDCl3): d 28.2, 37.8, 109.6, 120.2, 126.8, 127.8, 128.2,
130.0, 143.7, 149.0, 151.4, 155.0, 162.4. Anal. Calcd. for
C13H12ClN3O2: C, 56.23; H, 4.36; N, 15.13. Found: C, 56.56;
H, 4.32; N, 14.91.
5-[3-(3,4-bis-(4-chlorophenyl)-4,5-dihydro-1,2,4-oxadia-
zol-5-yl]-1,3-dimethyl-1H,3H-pyrimidine-2,4-dione
1
(5c). H
NMR (CDCl3): d 3.39 (s, 3H, CH3), 3.42 (s, 3H, CH3), 6.59
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1284
D. Osyda, R. Motyka, and K. Z. Walczak
Vol 46
REFERENCES AND NOTES
(s, 1H, oxadiaz.), 7.10 (dt, 2H, J ¼ 8.9 Hz, 2.4 Hz, arom.),
7.22 (dt, 2H, J ¼ 8.9 Hz, 2.4 Hz, arom.), 7.32 (dt, 2H, J ¼
8.6 Hz, 2.2 Hz, arom.), 7.51 (s, 1H, H-6), 7.55 (dt, 2H, J ¼
8.6 Hz, 2.2 Hz, arom.). 13C NMR (CDCl3): d 28.1, 37.6, 94.8,
110.3, 123.6, 126.0 (2C), 129.4 (2C), 129.5 (2C), 129.6 (2C),
131.9, 137.4, 140.9, 142.3, 151.5, 154.9, 162.1. Anal. Calcd.
for C20H16Cl2N4O3: C, 55.70; H, 3.74; N, 12.99. Found: C,
55.31; H, 3.39; N, 12.67.
5-[3-(4-chlorophenyl)-4-(4-bromo-phenyl)-4,5-dihydro-
1,2,4-oxadiazol-5-yl]-1,3-dimethyl-1H,3H-pyrimidine-2,4-
dione (5d). 1H NMR (CDCl3): d 3.39 (s, 3H, CH3), 3.42 (s,
3H, CH3), 6.59 (s, 1H, oxadiaz.), 7.04 (d, 2H, J ¼ 8.6 Hz,
arom.), 7.32 (d, 2H, J ¼ 8.7 Hz, arom.), 7.37 (d, 2H, J ¼ 8.6
Hz, arom.), 7.50 (s, 1H, H-6), 7.55 (d, 2H, J ¼ 8.7 Hz, arom.).
13C NMR (CDCl3): d 28.1, 37.6, 94.7, 110.3, 119.6, 123.6,
126.2 (2C), 129.4 (2C), 129.5 (2C), 132.6 (2C), 137.4, 141.4,
142.4, 151.5, 154.8, 162.1. Anal. Calcd. for C20H16BrClN4O3:
C, 50.50; H, 3.39; N, 11.78. Found: C, 50.09; H, 2.98; N, 11.39.
[1] Block, J. H.; Beale, J. M. In Organic Medicinal and Phar-
maceutical Chemistry, 11th ed.; Lippincott Williams & Wilkins: Lon-
don, 2004; pp 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] Gutierrez, A. J.; Froehler, B. C. Tetrahedron Lett 1996, 37,
3959.
[5] Herdewijn, P. Antiviral Chem Chemother 1994, 5, 131.
[6] De Winter, H.; Herdewijn, P. J Med Chem 1996, 39, 4727.
[7] Hassan, M. E. Nucleosides Nucleotides Nucleic Acids
1991, 10, 1277.
[8] Wigerinck, P.; Kerremans, L.; Claes, P.; Snoeck, R.;
Maudgal, P.; De Clercq, E.; Herdewijn, P. J Med Chem 1993, 36, 538.
[9] Gutierrez, A. J.; Terhorst, T. J.; Matteucci M. D.; Froehler,
B. C. J Am Chem Soc 1994, 116, 5540.
1,3-Dimethyl-5-[4-phenyl-3-(4-methylphenyl)-4,5-dihydro-
1,2,4-oxadiazol-5-yl]-1H,3H-pyrimidine-2,4-dione
1
(5e). H
[10] Wigerinck, P.; Snoeck, R.; Claes, P.; De Clercq, E.; Herde-
wijn, P. J Med Chem 1991, 34, 1767.
NMR (CDCl3): d 2.34 (s, 3H, CH3, p-tol), 3.39 (s, 3H, CH3),
3.41 (s, 3H, CH3), 6.66 (s, 1H, oxadiaz.), 7.08–7.15 (m, 5H,
arom.), 7.21–7.26 (m, 2H, arom.), 7.53 (m, 3H, H-6, arom.).
13C NMR (CDCl3): d 21.6, 28.0, 37.6, 94.2, 110.9, 122.5,
124.2 (2C), 125.7, 128.1 (2C), 129.3 (2C), 129.6 (2C), 141.5,
142.3, 142.5, 151.6, 155.6, 162.2. Anal. Calcd. for
C21H20N4O3: C, 67.01; H, 5.36; N, 14.88. Found: C, 66.87; H,
4.98; N, 14.49.
[11] Walczak, K.; Pedersen, E. B.; Nielsen, C. Acta Chem Scand
1998, 52, 513.
[12] Privat, E. J.; Sowers, L. C. Mutat Res 1996, 354, 151.
˚
[13] Bjelland, S.; Anensen, H.; Knævelsrud, I.; Seeberg, E.
Mutat Res DNA Repair 2001, 486, 147.
[14] Klungland, A.; Paulsen, R.; Rolseth, V.; Yamada, Y.; Ueno,
Y.; Wiik, P.; Matsuda, A.; Seeberg, E.; Bjelland, S. Toxicol Lett 2001,
119, 71.
1,3-Dimethyl-5-[3,4-di-(4-methylphenyl)-4,5-dihydro-1,2,4-
(5f). 1H
[15] Kamiya, H.; Murata-Kamiya, N.; Karino, N.; Ueno, Y.;
Matsuda, A.; Kasai, H. Mutat Res Genet Toxicol Environ Mutagen
2002, 513, 213.
oxadiazol-5-yl)-1H,3H-pyrimidine-2,4-dione
NMR (CDCl3): 2.27 (s, 3H, CH3, p-tol), 2.33 (s, 3H, CH3, p-
tol), 3.38 (s, 3H, CH3), d 3.41 (s, 3H, CH3), 6.61 (s, 1H, oxa-
diaz.), 6.98 (d, 2H, J ¼ 8.6 Hz, arom.), 7.03 (d, 2H, J ¼ 8.6
Hz, arom.), 7.12 (d, 2H, J ¼ 8.0 Hz, arom.), 7.52 (d, 2H, J ¼
8.0 Hz, arom.) 7.54 (s, 1H, H-6). 13C NMR (CDCl3): d 21.0,
21.60, 28.0, 37.6, 94.2, 111.1, 122.5, 124.5 (2C), 128.2 (2C),
129.5 (2C), 129.9 (2C), 135.8, 139.8, 141.3, 142.2, 151.6,
155.8, 162.2. Anal. Calcd. for C22H22N4O3: C, 67.68; H, 5.68;
N, 14.35. Found: C, 67.28; H, 5.33; N, 14.01.
˚
[16] Anensen, H.; Provan, F.; Lian, A. T.; Reinertsen, H. S.;
Ueno, Y.; Matsuda, A.; Seeberg, E.; Bjelland, S. Mutation Res Fun-
dam Mol Mech Mutagen 2001, 476, 99.
[17] Singh, H.; Dolly, Hundal, M. S.; Hundal, G.; Singh, P.;
Chimni, S. S.; Kumar, S. Tetrahedron 1998, 54, 7563.
[18] Chiacchio, U.; Corsaro, A.; Mates, J.; Merino, P.; Piperno,
A.; Rescifina, A.; Romeo, G.; Romeo, R.; Tejero, T. Tetrahedron
2003, 59, 4733.
[19] Coutouli-Argyropoulou, E.; Lianis, P.; Marigoula Mitakou,
M.; Giannoulis, A.; Nowak, J. Tetrahedron 2006, 62, 1494.
[20] Ferrari, M. B.; Bisceglie, F.; Pelosi, G.; Tarasconi, P.;
Albertini, R.; Bonati, A.; Lunghi, P.; Pinelli, S. J Inorg Biochem 2001,
83, 169.
5-[4-(4-chlorophenyl)-3-(4-methylphenyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl]-1,3-dimethyl-1H,3H-pyrimidine-2,4-dione
(5g). H NMR (CDCl3): d 2.35 (s, 3H, CH3, p-tol), 3.39 (s,
1
3H, CH3), 3.41 (s, 3H, CH3), 6.60 (s, 1H, oxadiaz.), 7.10 (d,
2H, J ¼ 8.9 Hz, arom.), 7.15 (d, 2H, J ¼ 8.1 Hz, arom.), 7.20
(d, 2H, J ¼ 8.9 Hz, arom.), 7.51 (d, 2H, J ¼ 8.1 Hz, arom.)
7.54 (s, 1H, H-6). 13C NMR (CDCl3): d 21.6, 28.1, 37.6, 94.2,
110.5, 122.1, 125.6 (2C), 128.2 (2C), 129.4 (2C), 129.7 (2C),
131.3, 141.3, 141.8, 142.3, 151.6, 155.5, 162.2. Anal. Calcd.
for C21H19ClN4O3: C, 61.39; H, 4.66; N, 13.64. Found: C,
61.02; H, 4.34; N, 13.35.
[21] Kumar, S.; Kumar, V.; Singh, S.; Chimni, S. S. Tetrahedron
Lett 2001, 42, 5073.
[22] Hirota, K.; Kitade, Y.; Shimada, K.; Maki, Y. J Org Chem
1985, 50, 1512.
[23] Crystallographic data for 3j has been deposited in Cam-
bridge Crystallographic Data Centre as supplementary publication
number CCDC 716264. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing data_request@
ccdc.cam.ac.uk, or by contacting. The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44
01223 336033.
5-[4-(4-Bromophenyl)-3-(4-methylphenyl)-4,5-dihydro-1,2,4-
oxadiazol-5-yl]-1,3-dimethyl-1H,3H-pyrimidine-2,4-dione
1
(5h). H NMR (CDCl3): d 2.35 (s, 3H, CH3, p-tol), 3.39 (s,
3H, CH3), 3.41 (s, 3H, CH3), 6.60 (s, 1H, oxadiaz.), 7.04 (d,
2H, J ¼ 8.9 Hz, arom.), 7.15 (d, 2H, J ¼ 8.1 Hz, arom.), 7.35
(d, 2H, J ¼ 8.9 Hz, arom.), 7.51 (d, 2H, J ¼ 8.1 Hz, arom.)
7.53 (s, 1H, H-6). 13C NMR (CDCl3): d 21.6, 28.1, 37.6, 94.1,
110.5, 119.1, 122.1, 125.9 (2C), 128.1 (2C), 129.8 (2C), 132.3
(2C), 141.8, 142.3, 151.6, 155.5, 162.2. Anal. Calcd. for
C21H19BrN4O3: C, 55.40; H, 4.21; N, 12.31. Found: C, 54.99;
H, 3.85; N, 11.98.
[24] Liu, K. Ch.; Shelton, B. R.; Howe, R. K. J Org Chem 1980,
45, 3916.
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863.
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757.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet