A convenient synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)- diones

Article abstract of DOI:10.1016/j.tetlet.2011.10.033

The synthesis of 5-heteroaryl-substituted uracil derivatives is presented. The 1,3-dipolar cycloaddition reaction was applied for the construction of a heterocyclic ring. The nitrile oxides were obtained from the appropriate 4-substituted benzaldoximes us

Full text of DOI:10.1016/j.tetlet.2011.10.033

Tetrahedron Letters 52 (2011) 6890–6891
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A convenient synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-diones
Dominika Jakubiec a, Krzysztof Z. Walczak a,
⇑
a Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4, Gliwice 44-100, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 5-heteroaryl-substituted uracil derivatives is presented. The 1,3-dipolar cycloaddition
reaction was applied for the construction of a heterocyclic ring. The nitrile oxides were obtained from
the appropriate 4-substituted benzaldoximes using N-chlorosuccinimide (NCS) under basic conditions.
[2+3] Cycloaddition of nitrile oxides with 5-cyanouracil as a dipolarophile gave the corresponding 5-
(3-substituited-1,2,4-oxadiazol-5-yl)uracils in satisfactory yields under mild conditions. 5-Substituted
uracils having an additional heterocyclic ring were obtained as a result of the [2+3] cycloaddition of 5-
cyanouracil to nitrile oxides generated from thiophene-2-carbaldehyde and 5-formyluracil derivatives.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 September 2011
Revised 26 September 2011
Accepted 7 October 2011
Available online 14 October 2011
Keywords:
5-Cyanouracil
1,3-Dipolar cycloaddition
Nitrile oxide
Imidoyl chloride
5-Heteroaryluracil
Nucleoside analogues have very well recognized activity against
several types of neoplastic cells. They belong to the group of
antimetabolites which are compounds applied in the anticancer
therapy. The best known are floxuridine, cytarabine and gemcita-
bine.1 The antiviral activity of several modified nucleosides is an-
other area of interest. The most prominent are the drugs available
for the treatment of HIV infections (AZT, ddC, d4T and others) or
HBV infections.1,2 The efficacy of nucleosides depends on their abil-
ity to mimic natural congeners. At present, significant attention has
been paid to nucleoside analogues having a heterocyclic ring as a
substituent.3,4 Modifications are mainly introduced on the C5 car-
bon 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
the uracil ring gives increased anticancer activity.5 The construction
of a heterocyclic ring on the C5 carbon atom of the uracil ring was
performed using different strategies. Among others, several
approaches based on traditional syntheses of heterocyclic rings
using 5-aminouracil as a building block were reported.6,7 A pyrrole
ring was formed by a simple condensation of 5-aminouracil with
2,5-dimethoxytetrahydrofuran.6 In the reaction of 5-aminouracil
with 1,4-dinitroimidazole, 5-(4-nitroimidazol-1-yl)uracil was
obtained.7 Here, the reaction proceeds via ANRORC (addition of
the nucleophile, ring opening, ring closure) degenerate transforma-
tion of the 1,4-dinitro-imidazole ring. The introduction of a hetero-
aryl group onto the uracil ring can be performed using other
methods. UV irradiation of persilylated 5-iodo-20-deoxycytidine in
the presence of thiophene leads to the appropriate 5-(2-thienyl)-
20-deoxycytidine in moderate yield.8 Several 5-heteroaryl-20-
deoxyuridines were obtained by the reaction of 5-iodo-20-deoxyur-
idine with heteroaryltrialkyltin derivatives catalysed by palladium
complexes.9 The palladium-catalysed Suzuki–Miyaura reaction was
also applied for the synthesis of 5-heteroaryl uracils.10,11 In recent
years, many attempts based on [2+3] cycloaddition reactions for
the construction of a heterocyclic system on the uracil ring have
been reported.12–16 Using nitrile oxide or N-methylnitrone derived
from 5-formyluracil, uracil derivatives possessing isoxazoline, isox-
azole or isoxazolidine rings on carbon C5 were obtained in satisfac-
tory yields.15 In most of the modification reactions, uridine or
N-alkylated uracils were used as scaffolds for the construction of
the 5-heteroaryl derivatives.
In our investigations we used as the dipolarophile commercially
available 5-cyanouracil unsubstituted on both nitrogen atoms
(N1 and N3). This approach retained the opportunity for further
modifications of the uracil moiety including coupling with a sugar
molecule. The 1,3-dipoles were obtained according to a previously
described procedure.16 Thus, 4-substituted benzaldehydes were
converted into oximes 1a–f, followed by chlorination using a small
excess of NCS. Reactions were carried out in dry DMF at room tem-
perature (Scheme 1).17 The extent of the reaction was monitored
by TLC (ethyl acetate/n-hexane, 1:1, v/v) and usually after 1 h total
consumption of the starting material was observed. The oximoyl
chlorides 2a–f were used immediately for the next step without
further purification. A solution of oximoyl chloride 2a–f was mixed
with 5-cyanouracil 3 and triethylamine was added dropwise while
stirring. The reaction was run for 24 h at room temperature and the
expected products 4a–f were obtained in moderate yields
(19–51%) (Table 1).18 The presence of an electron-withdrawing
nitro group decreased significantly the yield, and the expected
⇑
Corresponding author. Tel.: +48 32 2371792; fax: +48 32 2372094.
E-mail address: Krzysztof.walczak@polsl.pl (K.Z. Walczak).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.033

D. Jakubiec, K. Z. Walczak / Tetrahedron Letters 52 (2011) 6890–6891
6891
Using the same reaction conditions cycloadducts 4h and 4i were
obtained in 60% and 51% yields, respectively. The performed exper-
iments suggest that the presence of the weakly acidic N1 and N3
hydrogen atoms in unsubstituted 5-cyanouracil does not affect the
dehalogenation of the oximoyl chlorides or the course of the [2+3]
cycloaddition reaction. The amount of base used was equimolar
with respect to the starting aldoxime (in the case of aldoxime
chloride 2h a 100% excess of triethylamine was used). It is notewor-
thy that we did not observe the formation of the corresponding
furoxans. Perhaps the in situ prepared nitrile oxides have consider-
ably lower stability or higher reactivity towards 5-cyanouracil in
comparison with other nitrile oxides.21,22
In conclusion, we have developed a procedure for the easy access
to 5-substituted uracil derivatives, possessing a 1,2,4-oxadiazole
ring on carbon C5 of the uracil ring. The described route opens access
to 5-heteroaryluracils, and may be used for the synthesis of new
analogues of uridine and its congeners.
Acknowledgement
The authors thank the National Science Centre, Poland (Grant
No. N N204347840) for financial support.
Scheme 1. The synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-diones.
References and notes
1. Block, J. H.; Beale, J. M. Organic Medicinal and Pharmaceutical Chemistry, 11th
ed.; Lippincott Williams and Wilkins: New York, 2004.
Table 1
Synthesized 5-(1,2,4-oxadiazol-5-yl)uracils 4a–i
2. Gumina, G.; Song, G. Y.; Chu, Ch. K. FEMS Microbiol. Lett. 2001, 202, 9–15.
3. Lee, Y. S.; Kim, B. H. Bioorg. Med. Chem. Lett. 2002, 12, 1395–1397.
4. Lee, Y. S.; Park, S. M.; Kim, B. H. Bioorg. Med. Chem. Lett. 2009, 19, 1126–1128.
5. Lee, Y. S.; Park, S. M.; Kim, H. M.; Park, S. K.; Lee, K.; Lee, Ch. W.; Kim, B. H.
Bioorg. Med. Chem. Lett. 2009, 19, 4688–4691.
Product
4a
R
Yielda (%)
40
Mp (°C)
204–206
6. Wigerinck, P.; Snoeck, R. S.; Claes, P.; De Clercq, E.; Herdewijn, P. J. Med. Chem.
1991, 34, 1767–1772.
7. Walczak, K.; Pedersen, E. B.; Nielsen, C. Acta Chem. Scand. 1998, 52, 513–515.
8. Hassan, M. E. Nucleosides, Nucleotides Nucleic Acids 1991, 10, 1277–1283.
9. Wigerinck, P.; Kerremans, L.; Claes, P.; Snoeck, R.; Maudgal, P.; De Clercq, E.;
Herdewijn, P. J. Med. Chem. 1993, 36, 538–543.
10. Pomeisl, K.; Holy, A.; Pohl, R. Tetrahedron Lett. 2007, 48, 3061–3067.
11. Pomeisl, K.; Holy, A.; Pohl, R.; Horska, K. Tetrahedron 2009, 65, 8486–8492.
12. Chacchio, U.; Corsaro, A.; Mates, J.; Merino, P.; Piperno, A.; Rescifina, A.; Romeo,
G.; Romeo, R.; Tejero, T. Tetrahedron 2003, 59, 4733–4738.
13. Coutouli-Argyropoulou, E.; Pilanidou, P. Tetrahedron Lett. 2003, 44, 3755–3758.
14. Coutouli-Argyropoulou, E.; Tsitabani, M.; Petrantonakis, G.; Terzis, A.;
Raptopoulou, C. Org. Biomol. Chem 2003, 1, 1382–1388.
4b
4c
4d
4e
51
40
44
19
195–197
170–172
171–173
178–179
H3C
Cl
Br
O2N
4f
51
28
172–174
>190
15. Coutouli-Argyropoulou, E.; Lianis, P.; Mitakou, M.; Giannoulis, A.; Nowak, J.
Tetrahedron 2006, 62, 1494–1501.
MeO
S
16. Osyda, D.; Motyka, R.; Walczak, K. Z. J. Heterocycl. Chem. 2009, 46, 1280–1284.
17. General procedure for the preparation of uracils 4a–i: To a solution of oxime 1a–i
(0.4 mmol) in dry DMF (3 ml), NCS (0.44 mmol, 0.059 g) was added at room
temperature while stirring. Completion of the reaction was indicated by TLC
(EtOAc/n-hexane, 1:1 v/v). The solution of generated oximoyl chloride 2a–i
was immediately used for the next step without purification. 5-Cyanouracil (3)
(0.35 mmol, 0.048 g) was added followed by dropwise addition of Et3N
(0.4 mmol, 0.06 ml). In the case of 1h, 0.8 mmol of Et3N was used. The
reaction mixture was stirred for 24 h at room temperature. After that time the
solvent was removed under reduced pressure and the residue purified on a
silica gel packed column using EtOAc/n-hexane (1:1) as eluent. The products
4a–i were obtained in satisfactory yields.
4g
O
Me
N
4h
60
51
207–209
234–235
O
N
Me
O
N
O
HN
O
4i
18. 5-(3-Phenyl-1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-dione
(4a):
white
OMe
crystals; yield 40%; 1H NMR (300 MHz, DMSO-d6) d 12.53 (s, 1H, NH), 12.33
(s, 1H, NH), 8.77 (s, 1H, H-6), 7.72 (dd, 2H, arom, J = 7.8 Hz, J = 1.5 Hz), 7.54–
7.39 (m, 3H, arom) ppm. 13C NMR (75 MHz, DMSO-d6) d 160.3, 153.5, 147.6,
142.8, 130.6, 130.4, 128.8 (2C), 125.6 (2C), 113.8, 89.7 ppm. Anal. Calcd for
a
Isolated yields.
C
12H8N4O3: C, 56.25; H, 3.15; N, 21.87. Found: C, 56.05; H, 2.98; N, 21.56 MS:
m/z [M+H]+ = 257 (100%); 258 (15.5%).
cycloadduct 4e was obtained in only 19% yield. In another trial the
oxime of thiophene-2-carbaldehyde 2g was used. Using the same
procedure, the [2+3] cycloaddition product 4g was isolated
in 28% yield.19 In two other experiments we used oximes of
1,3-dimethyl-5-formyluracil (1h) and methyl 3-[5-formyl-2,4-di-
oxo-3,4-dihydropyrimidin-1(2H)-yl]propanoate (1i)20 as the nitrile
oxide precursors. These experiments were performed in order to
establish the possibility of constructing 5-(1,2,4-oxadiazol-5-
yl)uracils bearing an additional uracil moiety.
19. 5-[3-(Thien-2-yl)-1,2,4-oxadiazol-5-yl]pyrimidine-2,4(1H,3H)-dione (4g): white
crystals; 1H NMR (300 MHz, DMSO-d6) d 12.37 (s, 1H, NH), 12.34 (s, 1H, NH),
8.81 (s, 1H, H-6), 7.67 (dd, 1H, arom, J = 5.1 Hz, J = 0.9 Hz), 7.50 (dd, 1H, arom,
J = 3.8 Hz, J = 0.9), 7.11 (dd, 1H, arom, J = 5.1 Hz, J = 3.8 Hz) ppm. 13C NMR
(75 MHz, DMSO-d6) d 160.2, 152.9, 147.3, 139.5, 133.7, 129.3, 129.1, 127.7,
113.6, 89.8 ppm. Anal. Calcd for C10H6N4O3S: C, 45.80; H, 2.31; N, 21.36. Found:
C, 45.49; H, 2.08; N, 21.09. MS m/z [M+H]+ = 263 (100%); 264 (14%); 265 (6%).
20. Boncel, S.; Walczak, K. Lett. Org. Chem. 2006, 3, 534–538.
21. Grundmann, C.; Datta, S. K. J. Org. Chem. 1969, 34, 2016–2018.
22. Grundmann, C. Synthesis 1970, 344–359.