Aldimines of 5-aminouracil as reagents in 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1007/s00706-011-0616-1

The condensation of 5-aminouracil with aromatic aldehydes gave the appropriate C-arylimines, which were used in [2+3] cycloaddition with nitrile oxides derived from 4-substituted benzaldoximes. As a result of the dipolar cycloaddition reaction several hit

Full text of DOI:10.1007/s00706-011-0616-1

Monatsh Chem (2011) 142:1155–1161
DOI 10.1007/s00706-011-0616-1
ORIGINAL PAPER
Aldimines of 5-aminouracil as reagents in 1,3-dipolar
cycloaddition reaction
•
Dominika Jakubiec Krzysztof Z. Walczak
Received: 18 August 2010 / Accepted: 5 August 2011 / Published online: 8 September 2011
Ó Springer-Verlag 2011
Abstract The condensation of 5-aminouracil with aro-
matic aldehydes gave the appropriate C-arylimines, which
were used in [2?3] cycloaddition with nitrile oxides
derived from 4-substituted benzaldoximes. As a result
of the dipolar cycloaddition reaction several hitherto
unknown 5-(3,5-diphenyl-1,2,4-oxadiazol-4(5H)-yl)pyrim-
idine-2,4(1H,3H)-diones have been obtained in satisfactory
yields.
the uracil ring as an alternative has been considered
(Fig. 1). The construction of a heterocyclic ring on the C5
carbon atom of the uracil ring was performed using dif-
ferent strategies. Among others, several approaches based
on traditional syntheses of heterocyclic rings using 5-am-
inouracil as a building block have been reported [4–12].
The pyrrole ring was formed by a simple condensation of
5-aminouracil with 2,5-dimethoxytetrahydrofuran (A) [4].
In the reaction of 5-aminouracil with 1,4-dinitroimidazole,
5-(4-nitroimidazol-1-yl)uracil (B) was obtained [5].
Here, the reaction proceeds via an ANRORC degenerated
transformation of the 1,4-dinitroimidazole ring. The intro-
duction of a heteroaryl group into the uracil ring can be
performed using other methods. The UV irradiation of
persilylated 5-iodo-20-deoxycytidine in the presence of
thiophene leads to 5-(2-thienyl)-20-deoxycytidine in mod-
erate yield (C) [6]. The opposite variant of this reaction,
when a mixture of 2-iodothiophene and 2-deoxycytidine is
irradiated, is also known [6].
Several 5-heteroaryl-20-deoxyuridines were obtained in
the reaction of 5-iodo-20-deoxyuridine with hetero-
aryltrialkyltin derivatives catalyzed by palladium
complexes (D) [7, 8]. In recent years many attempts based
on 1,3-dipolar cycloaddition reactions for the construction
of heterocyclic systems on the uracil ring have been
reported [9–12]. Thus E was synthesized in the reaction of
a 5-ethynyluracil derivative with an appropriate nitrile
oxide, generated from dibromoformaldoxime. In turn,
using a nitrile oxide or N-methylnitrone derived from
5-formyluracil, uracil derivatives possessing isoxazoline,
isoxazole, or isoxazolidine rings on the C5 carbon atom
were obtained in satisfactory yields (e.g., F). The latter can
be considered as an analogue of the natural C-nucleoside
pseudouridine, a C-5-linked uridine containing a modified
sugar moiety.
Keywords Cycloadditions ꢀ Chlorination ꢀ Heterocycles ꢀ
Nitrile oxides ꢀ Nucleosides ꢀ Schiff bases
Introduction
Pyrimidine nucleosides as components of nucleic acids and
their important role as anticancer and antiviral agents
inspire further search for new analogues with possible
useful properties. The previous studies resulted in the dis-
covery of several nucleoside analogues with an inhibitory
effect on the growth of cancers and proliferation of viruses
[1–3]. The most prominent representatives are 5-fluoro-
uracil, trifluridine, and acedurid [3]. The modifications
were mainly introduced on the C5 carbon atom of the uracil
ring, since substituents at this location are not involved in
the complementary base-pairing of DNA. Among other
modifications, the introduction of a heterocyclic system to
D. Jakubiec ꢀ K. Z. Walczak (&)
Department of Organic Chemistry,
Bioorganic Chemistry and Biotechnology,
Silesian University of Technology,
Krzywoustego 4, 44-100 Gliwice, Poland
e-mail: krzysztof.walczak@polsl.pl
123

1156
D. Jakubiec, K. Z. Walczak
R
O
N
NH2
O
NO2
N
N
S
O
HN
2, 3
a
b
c
d
e
f
R
H
CH3
Cl
Br
N
O
CHO
HN
NH2
N
HN
HN
O
N
R
O
N
R
+
O
N
H
O
N
H
DMSO, p-TSA
r.t., 24 h
O
N
H
R
2a-2f
N(CH3
OH
)
2
B
C
A
1
3a-3f
O
N
N
O
H3C
Scheme 1
O
O
N
O
Br
S
HN
HN
HN
OBz
aldimines 3a–3f were precipitated from the water slurry.
The analysis of NMR spectra indicated that the applied
procedure of isolation affords sufficiently pure products
ready to be used in the next step without further purifica-
tion. The yields were excellent.
O
N
R
O
N
R
O
N
H
D
E
F
R = 2-Deoxy-ß-D-ribofuranosyl
Fig. 1 Uracil derivatives possessing a 5-heterocyclic substituent
As the obtained imines 3 were poorly soluble in chlo-
roform, the solvent of choice for the preparation of nitrile
oxides, their 4-methoxybenzyl derivatives 5a–5e were
selected due to their enhanced solubility. The imines 3a–3e
were treated with an excess of 4-methoxybenzyl bromide
(4) in the presence of potassium carbonate as a base. The
imine 3f (R=OH) was excluded due to the possible for-
mation of a benzyl ether on the 4-hydroxyl group present in
the phenyl substituent. The benzylation was carried out in
anhydrous DMF at slightly elevated temperature. When the
TLC indicated the total consumption of starting imine 3,
the solution was cooled down to room temperature. The
formed precipitate was filtered off, rinsed with methanol,
and dried in a desiccator under diminished pressure
(Scheme 2; Table 1). The products were used in the next
step without further purification.
As a part of our research interest on the reactivity of
uracil derivatives containing electron-withdrawing substit-
uents, we utilized 5-formyluracil (2,4-dioxo-1,2,3,4-
tetrahydropyrimidine-5-carbaldehyde) as a suitable reagent
for the preparation of Schiff bases, used further as dipol-
arophiles in the 1,3-cycloaddition reactions [13]. Our
recent successful results prompted us to consider a differ-
ent strategy involving 5-aminouracil as a substrate for the
synthesis of imines and a subsequent [2?3] cycloaddition
reaction. It is well known that in the case of imine Diels-
Alder cycloaddition the nitrogen lone pair is exo in the
transition state of the addition as a result of the lowest
repulsion between lone pair and conjugated electrons of the
diene [14]. The same type of interaction may be expected
in the case of imines derived from 5-aminouracil where the
E-geometry should be the most favored as a result of the
electron repulsion of the nitrogen lone pair, the C4 car-
bonyl group, and the C5–C6 double bond of the uracil. The
E-configuration has been observed in crystals of imines
derived from 5-formyluracil and aromatic amines [13].
In the present paper we report our attempts to use
5-aminouracil for the formation of appropriate imines fol-
lowed by their 1,3-dipolar cycloaddition reaction with
nitrile oxides leading to various 5-(3,5-diphenyl-1,2,4-oxa-
diazol-4(5H)-yl)pyrimidine-2,4(1H,3H)-diones.
R
R
3, 5
a
b
c
d
R
H
CH3
Cl
Br
O
O
R1
O
N
N
HN
K2CO3, 4
N
DMF, 50 °C
6-12 h
O
N
H
N
R1
e
N(CH3)2
5a-5e
3a-3e
R1 = CH3OC6H4CH2
4: CH3OC6H4CH2Br
Scheme 2
Results and discussion
Table 1 The protected imines 5a–5e
As starting materials for the formation of imines we chose
monosubstituted benzaldehydes. Thus, 5-aminouracil (1)
was treated with an equimolar amount of the appropriate
aldehyde 2a–2f in a polar aprotic solvent (Scheme 1). The
reactions were carried out in the presence of a catalytic
amount of p-toluenesulfonic acid (p-TSA) at room tem-
perature. After the consumption of starting material, the
reaction mixture was poured onto ice. The obtained
Product 5
R
Time/h
Yielda/%
M.p./°C
a
b
c
H
6
12
8
90
54
88
79
54
127–129
139–140
140–141
142–143
165–166
CH3
Cl
d
e
Br
6
N(CH3)2
12
a
Isolated yields
123

Aldimines of 5-aminouracil as reagents in 1,3-dipolar cycloaddition reaction
1157
Scheme 3
H
C
Cl
C
(a)
C
N
O
N
OH
N
OH
NCS
Et3N
R2
CHCl3, r.t.
CHCl3
R2
R2
8a R2 = Cl
8b R2 = CH3
7a R2 = Cl
7b R2 = CH3
6a R2 = Cl
6b R2 = CH3
R
R
(b)
O
O
O
R1
R1
O
N
8a or 8b
CHCl3
reflux
N
N
N
N
9
a
b
c
d
e
f
R
H
R2
Cl
O
N
R1
N
R1
CH3 Cl
Cl Cl
Br Cl
R2
5a-5d
9a-9h
5
a
b
c
d
R
H
CH3
Cl
Br
R1 = CH3OC6H4CH2
H
CH3
CH3 CH3
Cl
Br
g
h
CH3
CH3
The 1,3-dipole was generated in situ from 4-chloro-
benzaldehyde oxime (6a) using N-chlorosuccinimide and
triethylamine as a base in chloroform solution according to
the modified procedure [15] (Scheme 3a). In the first trials
of 1,3-dipolar cycloaddition, the reactions of the imines
5a–5d with the appropriate nitrile oxide were carried out at
room temperature. After a prolonged time of up to 72 h, the
formation of a cycloadduct was not observed. Finally, the
cycloaddition reactions of imines 5a–5d with 4-chloro-
benzonitrile oxide (8a) proceeded in boiling CHCl3
(Scheme 3b). The products, 1,3-bis(4-methoxybenzyl)-
5-[5-(4-substituted-phenyl)-3-(4-chlorophenyl)-1,2,4-oxa-
diazol-4(5H)-yl]pyrimidine-2,4(1H,3H)-diones 9a–9d, were
isolated in satisfactory yields using column chromatogra-
phy (Table 2). The same procedure was applied when
4-methylbenzonitrile oxide (8b) was used as the 1,3-dipole.
Also in this case, the cycloaddition resulted in satisfactory
yields (cycloadducts 9e–9h). The yields ranged from 25 to
52%. Apart from the desired products, in the post-reaction
mixtures we observed mainly unreacted starting com-
pounds used for the generation of nitrile oxides and also
traces of aldimines. The structures of all newly obtained
compounds 9a–9h were confirmed by NMR spectroscopy
Table 2 The products of 1,3-dipolar cycloaddition 9a–9h
Product 9
R
R2
Time/h
Yielda/%
M.p./°C
a
b
c
d
e
f
H
Cl
5
5
6
6
5
6
5
6
32
52
38
27
25
31
42
26
165–167
146–147
183–185
174–176
90–92
CH3
Cl
Cl
Cl
Br
Cl
H
CH3
CH3
CH3
CH3
CH3
Cl
144–145
167–168
161–162
g
h
a
Br
Isolated yields
atom of the uracil ring and the imine nitrogen atom allows
for a free rotation around this bond, however the steric
hindrance probably impedes free rotation. The 1,3-cyclo-
addition of nitrile oxide to a double bond is a suprafacial
concerted reaction [17], however when the free rotation is
possible, the attack of dipole can occur from both sides
of the double bond. In these studies, we identified the
formation of a single product—a racemate, which was the
result of addition to the imine double bond. The yields
ranging from moderate to satisfactory can be attributed to a
high steric hindrance around the imine double bond in the
stage of the adduct formation.
1
and elemental analysis. The H NMR spectra of the pro-
tected imines 5a–5d in the range of 9.29–9.61 ppm
exhibited a characteristic signal assigned to the proton of
the CH=N group. This signal disappeared in the spectra of
cycloadducts 9. Here, a singlet derived from the proton
present in the 4,5-dihydro-1,2,4-oxadiazole ring between
6.30 and 6.40 ppm was observed [16]. As mentioned in the
‘‘Introduction,’’ the obtained imines derived from 5-am-
inouracil should have (E)-configuration around the C=N
bond. The presence of a single bond between the C5 carbon
Conclusion
5-Aminouracil is a convenient substrate for the synthesis of
appropriate imines in the reaction with aromatic aldehydes.
The condensation occurs under mild conditions in the
123

1158
D. Jakubiec, K. Z. Walczak
3
1H, imine), 7.76 (d, 2H, JH,H = 8.7 Hz, arom.), 7.66 (d,
presence of p-TSA as a catalyst. The obtained imines were
reactive towards 1,3-dipoles, namely nitrile oxides gener-
ated from 4-substituted benzaldoximes in the reaction with
NCS under basic conditions. The expected cycloadducts
were obtained in moderate yields.
3
3H, JH,H = 8.7 Hz, arom., H-6) ppm; 13C NMR (DMSO-
d6): d = 161.3, 156.7, 150.0, 139.0, 136.1, 136.1 (2C),
129.6 (2C), 124.1, 121.7 ppm.
5-[4-(N,N-Dimethylamino)benzylideneamino]pyrimidine-
2,4(1H,3H)-dione (3e, C13H14N4O2)
Yield 86%; m.p.: 322–324°C; 1H NMR (DMSO-d6):
Experimental
3
d = 11.23 (s, 1H, N–H), 10.94 (d, 1H, JH,H = 5.1 Hz,
N–H), 9.03 (s, 1H, imine), 7.60 (d, 2H, JH,H = 8.7 Hz,
3
1
NMR spectra were recorded at 300 MHz for H NMR and
3
arom.), 7.39 (d, 1H, JH,H = 5.1 Hz, H-6), 6.73 (d, 2H,
75.5 MHz for 13C NMR on a Varian Inova 300 MHz in
CDCl3 solution; d values are reported in parts per million
relative to tetramethylsilane as an internal standard.
Elemental analyses were performed using a Perkin-
Elmer 240C apparatus; the results agreed favorably
with calculated values. 4-Chlorobenzaldoxime (6a) and
4-methylbenzaldoxime (6b) were prepared according to
known procedures [18]. The other used reagents were
purchased from Lancaster. TLC 60F254 plates and silica gel
60 (0.040–0.063 mm) were purchased from Merck.
3JH,H = 8.7 Hz, arom.), 2.98 (s, 6H, CH3) ppm; 13C NMR
(DMSO-d6): d = 161.6, 158.8, 152.1, 150.2, 134.8, 129.5
(2C), 124.5, 123.6, 111.5 (2C), 39.52 (2C) ppm.
5-(4-Hydroxybenzylideneamino)pyrimidine-2,4(1H,3H)-
dione (3f, C11H9N3O3)
Yield 88%; m.p.[300°C; 1H NMR (DMSO-d6): d = 11.29
(s, 1H, N–H), 11.03 (d, 1H, JH,H = 4.8 Hz, N–H), 10.00
3
(s, 1H, –OH), 9.15 (s, 1H, imine), 7.64 (d, 2H,
3
3JH,H = 8.7 Hz, arom.), 7.47 (d, 1H, JH,H = 4.8 Hz,
3
H-6), 6.84 (d, 2H, JH,H = 8.7 Hz, arom.) ppm; 13C
NMR (DMSO-d6): d = 161.5, 160.1, 158.5, 150.2, 136.0,
129.8 (2C), 128.2, 123.1, 115.6 (2C) ppm.
General procedure for the synthesis of imines 3a–3f
To a solution of 0.25 g of 5-aminouracil (1, 2 mmol) in
6 cm3 of dry DMSO, the appropriate benzaldehyde 2a–2f
(2 mmol) and 10 mg of p-TSA were added. The reaction
mixture was stirred for 24 h, and then poured onto 60 g of
ice. The precipitated solid was filtered off, rinsed with
2 cm3 of cold methanol, and dried in a vacuum desiccator
over P2O5. The products 3a–3f were obtained in very good
yields as light yellow crystals and used for the next step
without further purification.
General procedure for the benzylation of imines
To a solution of imine 3a–3e (1 mmol) in 6 cm3 of dry
DMF, 0.304 g solid K2CO3 (2.2 mmol) was added, and the
reaction mixture was stirred for 30 min. After that time the
first portion of p-methoxybenzyl bromide (4, 0.603 g,
3 mmol) was added, and the reaction was stirred for 3–4 h
at 50°C. Then, the next portion of p-methoxybenzyl bro-
mide (0.201 g, 1 mmol) was added, and the reaction
mixture was heated for further 2–8 h, and poured onto 60 g
of ice. The waxy residue was extracted by three portions
(20 cm3) of chloroform. The organic layer was dried over
MgSO4 and evaporated. Then 20 cm3 MeOH was added.
The precipitated solid was filtered off, rinsed with 2 cm3
cold methanol, and dried in a vacuum desiccator over
P2O5. The products 5a–5e were obtained in good yields as
light yellow crystals.
5-(Benzylideneamino)pyrimidine-2,4(1H,3H)-dione (3a)
Yield 89%; m.p.: 302–304°C; the NMR spectrum was
found comparable with the one reported in [19].
5-(4-Methylbenzylideneamino)pyrimidine-2,4(1H,3H)-
dione (3b, C12H11N3O2)
Yield 93%; m.p.: 328–330°C; 1H NMR (DMSO-d6):
d = 11.36 (s, 1H, N–H), 11.15 (s, 1H, N–H), 9.31 (s,
3
1H, imine), 7.70 (d, 2H, JH,H = 7.8 Hz, arom.), 7.57 (s,
1H, H-6), 7.28 (d, 2H, 3JH,H = 7.8 Hz, arom.), 2.36 (s, 3H,
–CH3) ppm; 13C NMR (DMSO-d6): d = 161.5, 158.3,
150.2, 140.7, 137.7, 134.3, 129.4 (2C), 127.7 (2C), 122.4,
21.2 ppm.
5-(Benzylideneamino)-1,3-bis(4-methoxybenzyl)-pyrimi-
dine-2,4(1H,3H)-dione (5a, C27H25N3O4)
1H NMR (CDCl3): d = 9.61 (s, 1H, imine), 7.82–7.74 (m,
2H, arom.), 7.52–7.44 (m, 3H, arom., H-6), 7.44–7.38 (m,
3H, arom.), 7.28 (d, 2H, 3JH,H = 8.7 Hz, arom.), 6.89 (d, 2H,
5-(4-Chlorobenzylideneamino)pyrimidine-2,4(1H,3H)-
dione (3c)
3
3JH,H = 8.7 Hz, arom.), 6.85 (d, 2H, JH,H = 8.7 Hz,
Yield 93%; m.p.: 351–353°C (Ref. [20] 345–346°C).
arom.), 5.14 (s, 2H, –CH2–), 4.92 (s, 2H, –CH2–), 3.80 (s,
3H, –CH3), 3.78 (s, 3H, –CH3) ppm; 13C NMR (CDCl3):
d = 160.7, 160.3, 159.9, 159.3, 150.6, 139.6, 137.2, 131.1,
130.8 (2C), 130.0 (2C), 129.1, 128.7 (2C), 128.4 (2C), 127.2,
123.0, 114.6 (2C), 113.9 (2C), 55.4, 55.3, 52.2, 44.5 ppm.
5-(4-Bromobenzylideneamino)pyrimidine-2,4(1H,3H)-
dione (3d, C11H8BrN3O2)
Yield 96%; m.p.: 346–348°C; 1H NMR (DMSO-d6):
d = 11.40 (s, 1H, N–H), 11.23 (s, 1H, N–H), 9.40 (s,
123

Aldimines of 5-aminouracil as reagents in 1,3-dipolar cycloaddition reaction
1159
1,3-Bis(4-methoxybenzyl)-5-(4-methylbenzylideneamino)-
pyrimidine-2,4(1H,3H)-dione (5b, C28H27N3O4)
General procedure for the synthesis of 9a–9h
1H NMR (CDCl3): d = 9.56 (s, 1H, imine), 7.73 (d, 2H,
3JH,H = 7.8 Hz, arom.), 7.60 (s, 1H, H-6), 7.48 (d, 2H,
To a solution of 4-chlorobenzaldoxime (6a, 2.2 equiv.) in
4 cm3 CHCl3, NCS (2.42 equiv.) was added at room tem-
perature while stirring. The reaction mixture changed the
color from light yellow via blue to green. Completion of
the reaction was indicated when the color of the reaction
mixture turned back to yellow. The solution was washed
with small amounts of cold water (2 cm3), dried over
anhydrous MgSO4, and immediately used for the next step.
To this solution the imine 5a–5d (1 equiv.) was added
followed by addition of triethylamine (1.1 equiv.). The
reaction mixture was refluxed for 2–4 h. After that time the
next portion of triethylamine was added (1.1 equiv.), and
reflux was continued for further 2–4 h. After that time, the
solvent was removed under diminished pressure, and the
residual oil was purified on a silica gel packed column
using AcOEt:n-hexane (1:2) as an eluent. The products
9a–9d were obtained in moderate yields as solid pale-
yellow materials crystallized from AcOEt: n-hexane.
The same procedure starting from the same equimolar
amounts of substrates was applied for preparation of
4-methylbenzonitrile oxide (8b). The 1,3-dipolar cycload-
dition of 8b to aldimines 5a–5d was carried out under
conditions described above. The cycloadducts 9e–9h were
obtained in moderate yields as solid pale-yellow materials
crystallized from AcOEt: n-hexane.
3
3JH,H = 8.7 Hz, arom.), 7.28 (d, 2H, JH,H = 8.7 Hz,
3
arom.), 7.22 (d, 2H, JH,H = 7.8 Hz, arom.), 6.89 (d, 2H,
3
3JH,H = 8.7 Hz, arom.), 6.84 (d, 2H, JH,H = 8.7 Hz,
arom.), 5.14 (s, 2H, –CH2–), 4.91 (s, 2H, –CH2–), 3.79
(s, 3H, –CH3), 3.77 (s, 3H, –CH3), 2.38 (s, 3H, CH3) ppm;
13C NMR (CDCl3): d = 159.4, 158.7, 158.4, 157.7, 149.0,
137.7, 129.2 (2C), 128.5 (2C), 128.4, 128.3, 128.2, 128.0
(2C), 127.5, 127.2, 125.7, 113.1 (2C), 112.4 (2C), 53.9,
53.8, 50.8, 43.0, 20.2 ppm.
1,3-Bis(4-methoxybenzyl)-5-(4-chlorobenzylideneamino)-
pyrimidine-2,4(1H,3H)-dione (5c, C27H24ClN3O4)
1H NMR (CDCl3): d = 9.61 (s, 1H, imine), 7.72 (d, 2H,
3JH,H = 8.7 Hz, arom.), 7.52–7.44 (m, 3H, arom., H-6),
3
7.37 (d, 2H, JH,H = 8.7 Hz, arom.), 7.28 (d, 2H,
3
3JH,H = 8.7 Hz, arom.), 6.90 (d, 2H, JH,H = 8.7 Hz,
3
arom.), 6.85 (d, 2H, JH,H = 8.7 Hz, arom.), 5.14 (s, 2H,
–CH2–), 4.92 (s, 2H, –CH2–), 3.80 (s, 3H, –CH3), 3.78 (s,
3H, –CH3) ppm; 13C NMR (CDCl3): d = 160.3, 160.0,
159.3, 159.0, 150.5, 140.3, 136.9, 135.8, 130.8 (2C), 130.0
(2C), 129.5 (2C), 129.0 (2C), 127.1, 122.6, 114.7 (2C),
113.9 (2C), 55.5, 55.4, 52.3, 44.5 ppm.
1,3-Bis(4-methoxybenzyl)-5-(4-bromobenzylideneamino)-
pyrimidine-2,4(1H,3H)-dione (5d, C27H24BrN3O4)
1H NMR (CDCl3): d = 9.61 (s, 1H, imine), 7.65 (d, 2H,
1,3-Bis(4-methoxybenzyl)-5-[3-(4-chlorophenyl)-5-phenyl-
1,2,4-oxadiazol-4(5H)-yl]pyrimidine-2,4(1H,3H)-dione
(9a, C34H29ClN4O5)
3
3JH,H = 8.7 Hz, arom.), 7.53 (d, 2H, JH,H = 8.7 Hz,
1H NMR (CDCl3): d = 7.47 (m, 3H, arom.), 7.44–7.31 (m,
arom.), 7.50–7.44 (m, 3H, arom., H-6), 7.27 (d, 2H,
3
3JH,H = 8.7 Hz, arom.), 6.90 (d, 2H, JH,H = 8.7 Hz,
3
4H, arom.), 7.28 (d, 2H, JH,H = 8.4 Hz, arom.), 6.99 (d,
3
arom.), 6.85 (d, 2H, JH,H = 8.7 Hz, arom.), 5.14 (s, 2H,
3
3
2H, JH,H = 8.7 Hz, arom.), 6.83 (d, 2H, JH,H = 9.0 Hz,
–CH2–), 4.92 (s, 2H, –CH2–), 3.80 (s, 3H, –CH3), 3.78 (s,
3H, –CH3) ppm; 13C NMR (CDCl3): d = 160.2, 160.0,
159.3, 159.1, 150.5, 140.3, 136.2, 132.0 (2C), 130.7 (2C),
130.0 (2C), 129.8 (2C), 129.0, 127.1, 125.4, 122.5, 114.7
(2C), 113.9 (2C), 55.5, 55.4, 52.3, 44.5 ppm.
arom.), 6.81–6.71 (m, 5H, arom., H6), 6.34 (s, 1H,
2
oxadiaz.), 5.01 (d, 1H, JH,H = 13.8 Hz, –CH2–),
2
4.83–4.68 (m, 2H, –CH2–), 4.48 (d, 1H, JH,H = 14.4 Hz,
–CH2–), 3.83 (s, 3H, –CH3), 3.79 (s, 3H, –CH3) ppm; 13C
NMR (CDCl3): d = 160.3, 159.9, 159.3, 156.2, 150.2,
141.8, 137.0, 136.5, 130.2, 130.1 (2C), 129.6 (2C), 129.1
(2C), 129.0 (2C), 128.8 (2C), 128.4, 128.2 (2C), 126.2,
124.1, 114.6 (2C), 113.8 (2C), 113.5, 98.9, 55.5, 55.4, 52.1,
44.2 ppm.
1,3-Bis(4-methoxybenzyl)-5-[4-(N,N-dimethylamino)benz-
ylideneamino]pyrimidine-2,4(1H,3H)-dione
(5e, C29H30N4O4)
1H NMR (CDCl3): d = 9.29 (s, 1H, imine), 7.66 (d, 2H,
3
3JH,H = 8.7 Hz, arom.), 7.49 (d, 2H, JH,H = 8.7 Hz,
1,3-Bis(4-methoxybenzyl)-5-[3-(4-chlorophenyl)-5-(4-
methylphenyl)-1,2,4-oxadiazol-4(5H)-yl]pyrimidine-
2,4(1H,3H)-dione (9b, C35H31ClN4O5)
3
arom.), 7.32 (s, 1H, H-6), 7.26 (d, 2H, JH,H = 8.7 Hz,
3
arom.), 6.88 (d, 2H, JH,H = 8.7 Hz, arom.), 6.84 (d, 2H,
3
3JH,H = 8.7 Hz, arom.), 6.67 (d, 2H, JH,H = 8.7 Hz,
3
1H NMR (CDCl3): d = 7.44 (d, 2H, JH,H = 8.4 Hz,
3
arom.), 7.35 (d, 2H, JH,H = 8.1 Hz, arom.), 7.27 (d, 2H,
arom.), 5.14 (s, 2H, –CH2–), 4.88 (s, 2H, –CH2–), 3.79
(s, 3H, –CH3), 3.77 (s, 3H, –CH3), 3.02 (s, 6H, CH3) ppm;
13C NMR (CDCl3): d = 161.1, 160.6, 159.8, 159.2, 152.4,
150.7, 136.5, 130.7 (2C), 130.1 (2C), 129.9 (2C), 129.3,
127.5, 125.1, 124.5, 114.5 (2C), 113.8 (2C), 111.6 (2C),
55.4, 55.3, 52.1, 44.4, 40.3 (2C) ppm.
3
3JH,H = 8.7 Hz, arom.), 7.15 (d, 2H, JH,H = 7.8 Hz,
3
arom.), 6.99 (d, 2H, JH,H = 8.7 Hz, arom.), 6.87–6.70
(m, 7H, arom., H6), 6.33 (s, 1H, oxadiaz.), 5.01 (d, 1H,
2
2JH,H = 13.5 Hz, –CH2–), 4.76 (d, 1H, JH,H = 13.5 Hz,
2
–CH2–), 4.72 (d, 1H, JH,H = 14.7 Hz, –CH2–), 4.50
123

1160
D. Jakubiec, K. Z. Walczak
(d, 1H, 2JH,H = 14.7 Hz, –CH2–), 3.83 (s, 3H, –CH3), 3.79
(s, 3H, –CH3), 2.39 (s, 3H, –CH3) ppm; 13C NMR (CDCl3):
d = 160.4, 159.9, 159.2, 156.2, 150.2, 141.7, 140.2,
136.5, 133.9, 130.1 (2C), 129.6 (2C), 129.5 (2C), 129.1
(2C), 129.0 (2C), 128.4, 128.2 (2C), 126.3, 124.2, 114.6
(2C), 113.8 (2C), 113.6, 98.8, 55.4, 55.3, 52.1, 44.2,
21.5 ppm.
1,3-Bis(4-methoxybenzyl)-5-[3,5-bis(4-methylphenyl)-
1,2,4-oxadiazol-4(5H)-yl]pyrimidine-2,4(1H,3H)-dione
(9f, C36H34N4O5)
1H NMR (CDCl3): d = 7.42–7.32 (m, 4H, arom.),
7.17–7.02 (m, 6H, arom.), 6.87–6.68 (m, 7H, arom., H6),
6.39 (s, 1H, oxadiaz.), 4.99 (d, 1H, 2JH,H = 13.5 Hz, –CH2–),
2
4.82 (d, 1H, JH,H = 13.5 Hz, –CH2–), 4.68 (d, 1H,
2
2JH,H = 14.7 Hz, –CH2–), 4.51 (d, 1H, JH,H = 14.7 Hz,
5-[3,5-Bis(4-chlorophenyl)-1,2,4-oxadiazol-4(5H)-yl]-1,3-
bis(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione
(9c, C34H28Cl2N4O5)
–CH2–), 3.82 (s, 3H, –CH3), 3.78 (s, 3H, –CH3), 2.38 (s, 6H,
–CH3) ppm; 13C NMR (CDCl3): d = 160.5, 159.8, 159.1,
156.7, 150.4, 141.7, 140.6, 139.9, 134.2, 130.2 (2C), 129.5
(2C), 129.4 (2C), 129.3 (2C), 128.6, 128.1 (2C), 127.8 (2C),
126.5, 122.5, 114.5 (2C), 114.1, 113.7 (2C), 98.3, 55.4,
55.3, 52.1, 44.2, 21.7, 21.5 ppm.
3
1H NMR (CDCl3): d = 7.41 (pseudo-t, 4H, JH,H
=
8.4 Hz, arom.), 7.33–7.25 (m, 4H, arom.), 7.00 (d, 2H,
3JH,H = 8.7 Hz, arom.), 6.88–6.79 (m, 4H, arom.),
6.79–6.72 (m, 3H, arom., H6), 6.32 (s, 1H, oxadiaz.),
2
5.02 (d, 1H, JH,H = 13.8 Hz, –CH2–), 4.84–4.75 (m, 2H,
2
1,3-Bis(4-methoxybenzyl)-5-[5-(4-chlorophenyl)-3-(4-
methylphenyl)-1,2,4-oxadiazol-4(5H)-yl]pyrimidine-
2,4(1H,3H)-dione (9g, C35H31ClN4O5)
–CH2–), 4.48 (d, 1H, JH,H = 14.7 Hz, –CH2–), 3.85 (s,
3H, –CH3), 3.79 (s, 3H, –CH3) ppm; 13C NMR (CDCl3):
d = 160.3, 160.0, 159.3, 156.2, 150.2, 141.5, 136.7, 136.1,
135.5, 130.2 (2C), 129.6 (2C), 129.5 (2C), 129.1 (2C),
129.0 (4C), 128.3, 126.1, 123.8, 114.6 (2C), 113.8 (2C),
113.4, 98.1, 55.5, 55.4, 52.0, 44.3 ppm.
1H NMR (CDCl3): d = 7.44–7.34 (m, 4H, arom.),
7.33–7.24 (m, 2H, arom.), 7.16–7.02 (m, 4H, arom.),
6.89–6.69 (m, 7H, arom., H6), 6.38 (s, 1H, oxadiaz.), 5.01
2
2
(d, 1H, JH,H = 13.8 Hz, –CH2–), 4.83 (d, 1H, JH,H
=
2
13.8 Hz, –CH2–), 4.75 (d, 1H, JH,H = 14.4 Hz, –CH2–),
4.50 (d, 1H, 2JH,H = 14.4 Hz, –CH2–), 3.84 (s, 3H, –CH3),
3.78 (s, 3H, –CH3), 2.38 (s, 3H, –CH3) ppm; 13C NMR
(CDCl3): d = 160.4, 159.9, 159.2, 156.7, 150.4, 141.4,
140.9, 135.8, 130.3 (2C), 129.5 (2C), 129.4 (4C), 129.0
(2C), 128.5, 127.8 (2C), 126.3, 122.1, 114.6 (2C), 113.9,
113.8 (2C), 97.5, 55.5, 55.3, 52.0, 44.3, 21.7 ppm.
1,3-Bis(4-methoxybenzyl)-5-[5-(4-bromophenyl)-3-(4-chlo-
rophenyl)-1,2,4-oxadiazol-4(5H)-yl]pyrimidine-
2,4(1H,3H)-dione (9d, C34H28BrClN4O5)
1H NMR (CDCl3): d = 7.55–7.35 (m, 4H, arom.),
3
7.35–7.20 (m, 4H, arom.), 7.02 (d, 2H, JH,H = 8.4 Hz,
arom.), 6.84 (s, 4H, arom.), 6.80–6.72 (m, 3H, arom., H6),
2
6.31 (s, 1H, oxadiaz.), 5.02 (d, 1H, JH,H = 13.5 Hz,
1,3-Bis(4-methoxybenzyl)-5-[5-(4-bromophenyl)-3-(4-
methylphenyl)-1,2,4-oxadiazol-4(5H)-yl]pyrimidine-
2,4(1H,3H)-dione (9h, C35H31BrN4O5)
–CH2–), 4.85–4.71 (m, 2H, –CH2–), 4.49 (d, 1H,
2JH,H = 14.4 Hz, –CH2–), 3.86 (s, 3H, –CH3), 3.79 (s,
3H, –CH3) ppm; 13C NMR (CDCl3): d = 160.3, 160.1,
159.3, 156.1, 150.2, 141.6, 136.7, 136.0, 132.0 (2C), 130.2
(2C), 129.8 (2C), 129.6 (2C), 129.1 (4C), 128.3, 126.2,
124.4, 123.8, 114.7 (2C), 113.9 (2C), 113.4, 98.1, 55.5,
55.4, 52.1, 44.3 ppm.
1H NMR (CDCl3): d = 7.45 (d, 2H, 3JH,H = 8.4 Hz, arom.),
3
7.36 (pseudo-t, 4H, JH,H = 7.8 Hz, arom.), 7.14–7.02
(pseudo-t, 4H, arom.), 6.88–6.78 (m, 4H, arom.), 6.77–6.71
(m, 3H, arom., H6), 6.37 (s, 1H, oxadiaz.), 5.00 (d, 1H,
2
2JH,H = 13.5 Hz, –CH2–), 4.83 (d, 1H, JH,H = 13.5 Hz,
–CH2–), 4.74 (d, 1H, 2JH,H = 14.4 Hz, –CH2–), 4.50 (d, 1H,
2JH,H = 14.4 Hz, –CH2–), 3.84 (s, 3H, –CH3), 3.78 (s, 3H,
–CH3), 2.38 (s, 3H, –CH3) ppm; 13C NMR (CDCl3):
d = 160.4, 159.9, 159.2, 156.7, 150.4, 141.4, 141.0, 136.4,
131.9 (2C), 130.3 (2C), 129.7 (2C), 129.6 (2C), 129.5 (2C),
128.5, 127.8 (2C), 126.3, 124.2, 122.0, 114.6 (2C), 113.9,
113.8 (2C), 97.6, 55.5, 55.4, 52.1, 44.3, 21.7 ppm.
1,3-Bis(4-methoxybenzyl)-5-[3-(4-methylphenyl)-5-phenyl-
1,2,4-oxadiazol-4(5H)-yl]pyrimidine-2,4(1H,3H)-dione
(9e, C35H32N4O5)
1H NMR (CDCl3): d = 7.51–7.45 (m, 2H, arom.),
3
7.44–7.30 (m, 5H, arom.), 7.11 (d, 2H, JH,H = 7.8 Hz,
3
arom.), 7.06 (d, 2H, JH,H = 8.7 Hz, arom.), 6.83 (d, 2H,
3JH,H = 8.7 Hz, arom.), 6.79–6.68 (m, 5H, arom., H6),
2
6.40 (s, 1H, oxadiaz.), 5.00 (d, 1H, JH,H = 13.5 Hz,
2
–CH2–), 4.82 (d, 1H, JH,H = 13.5 Hz, –CH2–), 4.69 (d,
Acknowledgments The authors thank the National Science Centre
in Poland (grant no. N N204347840) for financial support.
2
1H, JH,H = 14.7 Hz, –CH2–) 4.49 (d, 1H, JH,H
2
=
14.7 Hz, –CH2–), 3.82 (s, 3H, –CH3), 3.78 (s, 3H,
–CH3), 2.38 (s, 3H, –CH3) ppm; 13C NMR (CDCl3):
d = 160.4, 159.8, 159.2, 156.2, 150.4, 141.7, 140.7, 137.3,
130.3 (2C), 130.0, 129.5 (2C), 129.4 (2C), 128.7 (2C),
128.6, 128.1 (2C), 127.8 (2C), 126.4, 122.4, 114.5 (2C),
114.0, 113.8 (2C), 98.3, 55.4, 55.3, 52.1, 44.2, 21.7 ppm.
References
1. Liekens S, Bronckaers A, Balzarini J (2009) Lancet Oncol 10:628
2. Remres WA (2004) In: Block JH, Beale JM (eds), Organic
medicinal and pharmaceutical chemistry, 11th edn. Lippincott
Williams and Wilkins, London
123

Aldimines of 5-aminouracil as reagents in 1,3-dipolar cycloaddition reaction
1161
3. Gumina G, Choi Y, Chu CK (2003) In: Chu CK (ed), Antiviral
nucleosides—chiral synthesis and chemotherapy, Elsevier,
London
4. Wiegerinck P, Snoeck R, Claes P, De Clercq E, Herdewijn P
(1991) J Med Chem 34:1767
5. Walczak K, Pedersen EB, Nielsen C (1998) Acta Chim Scand
52:513
6. Hassan ME (1991) Nucleosides Nucleotides Nucleic Acids
10:1277
7. Wiegerinck P, Kerremans L, Claes P, Snoeck R, Maudgal P, De
Clercq E, Herdewijn P (1993) J Med Chem 36:538
8. Gutierrez AJ, Terhorst TJ, Matteucci MD, Froehler BC (1994) J
Am Chem Soc 116:5540
9. Chacchio U, Corsaro A, Mates J, Merino P, Piperno A, Rescifina
A, Romeo G, Romeo R, Tejero T (2003) Tetrahedron 59:4733
10. Coutouli-Argyropoulou E, Pilanidou P (2003) Tetrahedron Lett
44:3755
11. Coutouli-Argyropoulou E, Tsitabani M, Petrantonakis G, Terzis
A, Raptopoulou C (2003) Org Biomol Chem 1:1382
12. Coutouli-Argyropoulou E, Lianis P, Mitakou M, Giannoulis A,
Nowak J (2006) Tetrahedron 62:1494
13. Osyda D, Motyka R, Walczak KZ (2009) J Heterocycl Chem
46:1280
14. Buonora P, Olsen JC, Oh T (2001) Tetrahedron 57:6099
15. Liu KC, Shelton BR, Howe RK (1980) J Org Chem 45:3916
16. Aitken RA, Raut SV (1996) J Chem Soc Perkin Trans 1:747
17. Gothelf KV, Joergensen KA (1998) Chem Rev 98:863
18. Wiley RH, Wakefield BJ (1960) J Org Chem 25:546
19. Upadhyay KK, Kumar A (2010) Org Biomol Chem 8:4892
20. Shaker RM, Abd EM (2008) Zeitsch Naturforsch B Chem Sci
63:1431
123