Synthesis of 5 ‐ hetaryluracil derivatives via 1,3 ‐ dipolar cycloaddition reaction

1,3 ‐ Dipolar cycloaddition is a convenient method for construction of various heterocyclic systems. We applied this method for the synthesis 5 ‐ hetaryluracil derivatives where substituted uracils played the role of 1,3 ‐ dipoles or dipolarophiles. Treatment of the nitrile oxide derived from 5 ‐ formyluracil and substituted alkenes gave the appropriate 5 ‐ (4,5 ‐ dihydroisoxazol ‐ 3 ‐ yl)pyrimidine ‐ 2,4(1 H ,3 H ) ‐ diones, which by oxidation with N ‐ bromosuccinimide were transformed into appropriate 5 ‐ (isoxazol ‐ 3 ‐ yl)uracils. When 5 ‐ cyanouracil was used as a dipolarophile in the reaction with nitrile oxides, generated from aromatic aldoximes, several


Results and Discussion
The key substrates 5-formyluracils 3 and 6 were obtained in a sequence of reactions (Scheme 1).To avoid interaction of protons present in the uracil molecule 1 with reactants used in the next steps an uracil derivative was primary alkylated either on both ring N atoms or only on N1.Uracil 1 was alkylated with dimethyl sulfate under basic conditions and the resulting 1,3-dimethyl uracil 2 was formylated under Vilsmeier-Haack reaction conditions. 55n a parallel experiment, uracil 1 at first was treated with formaldehyde in the presence of triethylamine and the resulting 5-hydroxymethyluracil 4 was oxidized by ceric ammonium nitrate (CAN) 56 to 5formyluracil 5.In both cases the product was obtained in a satisfactory yield exceeding 70% (Scheme 1).Compound 5 was alkylated by methyl acrylate in the presence of triethylamine as a base and product 6 was achieved in 80% yield. 56Uracil derivatives 3 and 6 were transformed into appropriate oximes 7a, b in the reaction with hydroxylamine hydrochloride and sodium acetate in aqueous ethanol solution (Scheme 2).
The oximes 7a and 7b were obtained as mixtures of geometrical isomers E and Z. Separation of the isomers was performed using column chromatography.The ratio of the isomers strongly depended on the reaction time.After 24 hours only isomer Z of 7a was obtained; when the time of reaction was extended to 6 days the isomer equilibrium settled to a ratio of Z/E = 58:42 as determined by 1 H NMR analysis.In the case of 7b formation of both isomers was observed from the beginning till the end of the reaction: after 24 h the ratio Z/E was 84:16 and after 6 days changed to Z/E = 26:74.Mixtures of stereoisomeric oximes 7a,b were transformed in situ into the corresponding nitrile oxides by a treatment with N-chlorosuccinimide (NCS) and triethylamine, these then were directly used in 1,3-dipolar cycloadditions.
Scheme 4. Aromatization of selected cycloadducts by oxidation with NBS.
For the synthesis of 5-(1,2,4-oxadiazol-3-yl)uracil derivatives we explored a synthetic pathway where uracil derived aldoximes were directly treated, in the presence of cerium ammonium nitrate, with an excess of the appropriate nitrile 12, used as a solvent. 58The procedure is simplified in comparison to that described above for the synthesis of 5-(isoxazol-3-yl)uracils.Nevertheless, also in this case, yields of isolated products were only moderate (Scheme 5).Scheme 5.An alternative approach toward the synthesis of 5-hetaryluracils.
The 1,3-dipolar cycloaddition reaction of nitrile oxides to 5-ethynyl uracils has been described in the chemical literature as a method for the preparation of isoxazoles. 36We decided to use 5-cyanouracil 16, a new commercially available dipolarophile (Scheme 6) for a similar purpose.In this case we generated the nitrile oxide from aromatic aldoximes 14.Application of 5-cyanouracil as a dipolarophile in reactions with aromatic nitrile oxides opened up a new simple route to 5-(1,2,4-oxadiazol-5-yl)uracil derivatives.The cycloaddition reaction was carried out in DMF solution with NCS as the chlorinating agent and triethylamine as a base at room temperature for 24 h.The aldoximes were used in a slight excess in respect to the 5-cyanouracil.Isolation of cycloadducts 17 using column chromatography gave pure products in moderate yields of 44-51%.

Conclusions
We have devised a synthetic pathway for the preparation of various 5-hetaryluracil derivatives using 1,3dipolar cycloaddition reaction.We showed that the studied uracil derivatives could be used either as a source of 1,3-dipoles or dipolarophiles.Nitrile oxides generated in situ from substituted 5-formyluracil oximes treated with alkenes as the dipolarophiles afforded cycloadducts in moderate yields of 40-60%.An oxidation step is necessary to obtain isoxazole derivatives.We also showed that treatment of 5-formyluracil oximes with nitriles in the presence of ceric ammonium nitrate as an oxidizer leads directly to the respective 5-(oxadiazol-3-yl)uracils. 5-Cyanouracil applied as dipolarophile and reacting with aromatic aldoximes gives 5-(oxadiazol-5yl)uracil derivatives in satisfactory yields.In summary we proved that different types of 5-heteroaryluracil derivatives could be synthesized by manipulation of 1,3-dipole and dipolarophile structures.The cycloadducts were obtained in moderate yields regardless of the cycloaddition method applied.Traces of unidentified compounds near to the base line of TLC plates were observed.These are probably the products of nitrile oxide dimerization or isomerisation, like furoxanes or isocyanates etc.In our opinion the moderate yields obtained can be attributed mainly to the crystallization used as a final purification method.