Halogenation and nitration of 1-carboxymethyl-5-methyluracil. Halophilic reaction involving acetic anhydride
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Halogenation and nitration of 1-carboxymethyl-5-methyluracil. Halophilic reaction involving acetic anhydride I. B. Chernikova and М. S. Yunusov Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation. Е-mail: [email protected] 1-Carboxymethyl-5-halo-6-hydroxy-5-methyl-5,6-dihydrouracils and 1-carboxymethyl6-hydroxy-5-methyl-5-nitro-5,6-dihydrouracils were synthesized for the first time by oxidative halogenation and nitration of 1-carboxymethyl-5-methyluracil. Dihydrouracil derivatives bearing a Br atom at position C(5) and a hydroxy group at position C(6) treated with Ac2О undergo deoxyhalogenation. Keywords: thymine, halogenation, nitration, halophilic reaction.
Pyrimidine derivatives are essential components of modern medicines. The high pharmacological activity of pyrimidines is determined by their structural similarity with endogenous biologically active compounds. Antiviral,1,2 antitumor,3 antiinflammatory,4 antibacterial,5 and antioxidant6 properties of uracil derivatives have been widely studied. In order to expand the range of potential biologically active compounds among uracil derivatives, in the present work we synthesized 1-carboxymethyl-5-methyluracil derivatives using oxidative halogenation and electrophilic nitration. The starting compound, 1-carboxymethyl-5-methyluracil (1), was obtained by alkylation of thymine with chloroacetic acid.7 Derivatives 2—4 were synthesized for the first time by halogenation or nitration of compound 1 according to procedures developed earlier8 (Scheme 1). Bromination of compound 1 with KBr in 20% aqueous H2SO4 gave bromohydrin 2 in 78% yield. The use of a mixture of НCl—H2O2 in СН2Cl2 was found to be the best method for the synthesis of chlorohydrin 3. Treatment of compound 1 with a nitrating mixture H2SO4—HNO3 gave product 4. Geometry of compounds 2—4 probably corresponds to the structure of analogous 5-substituted derivatives of 5-fluorouracil, in which the OH group at the C(6) atom occupies an axial position due to the anomeric effect, while the fluorine atom is equatorial.9 The suggested stereochemistry is consistent with the anomeric effect for -substituted saturated N(O,S)-heterocycles, which, as shown in many examples, predominantly leads to the axial orientation of the OH group at -position to the heteroatom in the heterocycle.10 In order to study the possibility of intramolecular lactonization involving the C(6)OH and N(1)CH2COOH groups of compound 2, which will lead to the correspond-
Scheme 1
Hal = Br (2), Cl (3)
Reagents and conditions: i. (for 2) KBr (2 equiv.), 20% aq. H2SO4, 33% aq. H2O2 (3 equiv.), ~20 С, 10 h; ii. (for 3) 34% aq. НCl (3 equiv.), 33% aq. H2O2 (4 equiv.), СН2Cl2, ~20 С, 5 h; iii. 98% H2SO4, 67% aq. HNO3, 0—20 C, 5 h.
ing bicyclic product, compound 2 was treated with 10% aq. H2SO4 at 70 С; however, the cyclization did not take place under these conditions (Table 1, entry 1). Heating compound 2 in 50% aq. H2SO4 at 80 С led to 1-carb
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