Pyrimidines A-oxidation

A process for the preparation of pyrimidine A-oxides from carboxamide oximes has been developed (98T4387). Direct oxidation of pyrimidines is inconvenient for the preparation of nonsymmetric substituted pyrimidines because it gives a mixture of oxidation products ( -N- and 3-A-oxides). Methoxybutenone with carboxamide oximes regioselectively forms A-oxides of pyrimidines 281, which indicates... 

Attempts to establish the structure of the initial adduct by NMR-spectroscopy failed because of the low solubility of 27. This makes it impossible to draw a clear conclusion as to whether the ammonia adds to C-6 (as occurs in the case of the A-methylpyrimidinium salts) or at C-2. Since NMR spectroscopy of a solution of 4,6-diphenylpyrimidine in potassium amide/liquid ammonia strongly supports the formation of an anionic C-2 adduct (75UP1], it is justified to assume that also in the deamination of 27 by liquid ammonia, a C-2 adduct 28 is involved (Scheme III. 16). It is evident that the major part of the deamination (73%) does not involve a ringopening reaction the main deamination reaction occurs by an Sn2 attack of ammonia on the A-amino group in 27. A similar mechanism has also been postulated in the deoxygenation of pyrimidine A-oxides, when they are heated with liquid ammonia (Scheme III.16) [77UP2]. 

This degenerate ring transformation is generally applicable, since with different aryl substituents at positions 1, 4, and 6, aryl-substituted pyrimidine A -oxides are indeed formed. In a very similar reaction, 4,6-... 

A general method for the synthesis of pyrimidine A-oxides from amidoximes is described. The conversion involves treatment of various carboxamide oximes 325 with 1,1,3,3-tetramethoxypropane, 2,4-pentanedione or 3-ethoxy-2-methylpropenal in the presence of CF3COOH to afford pyrimidine 1-oxides 326 (equation 141) . 

Regioselective chlorination at C-5 of 3-pivaloyloxymethylpyrido[4,3- pyrimidine A -oxide 198 with POCI3 (100°C/2h) gave 199 via a Meisenheimer A -oxide rearrangement (Equation 15)<2004TL3737>. 

Second-Order Rate Coefficients for Base-Catalyzed Deuterium-Hydrogen Exchange in 5-Substituted Pyrimidine A/-Oxides"... 

Pyrimidine A-oxides cannot be nitrated unless they possess electron-donating substituents, e.g., 5-nitration of 2,6-diamino-4-ethylaminopyrimidine A-oxide <1979AJC2049>. 

In the ReissertHenze reaction, quinoline A-oxide reacts with benzoyl chloride and potassium cyanide to give 2-cyanoquinoline in good yield (Scheme 42). Pyridine 1-oxides undergo the ReissertHenze reaction readily when the reaction is carried out in nonaqueous medium using PhCOClMe3SiCN (Scheme 43). Pyrimidine A-oxides and pyrazine A-oxides also undergo ReissertHenze reactions. 

Although pyridazine and pyrazine A-oxides can be readily prepared by oxidation of the parent heterocycles, pyrimidine A-oxides are more difficult to obtain in this way, but they can conveniently be prepared by ring... 

A linear relationship exists between log A h6 and n, for the 5-substituted pyrimidine A-oxides in... 

Pyrimidine A -oxides are formed when pyrimidine-2-thiones are heated with ethanolic hydroxylamine in contrast, the corresponding 2-ones give isoxazoles (Scheme 59). ... 

Pyrimidine A-oxides synthesis, structure and chemical properties , Yamanaka, FI., Sakamoto, T., and Niitsuma, S., Heterocycles, 1990, 31, 923. 

The 6-aminouracils 247 or 6-hydroxyaminouracils 248 reacted with triethyl orthoformate and R CH2CN in the presence of acetic anhydride to give pyrido[2,3-(fjpyrimidines 249 or pyrido[2,3-[Pg.34]

It was also reported that the use of quinoxaline A-oxide gives rise to coupling in even a higher yield than the parent indole-pyridine coupling reaction (Scheme 8) [26], The coupling reactions with isoquinoline, phthalazine, and pyrimidine A-oxides proved to proceed smoothly, and their regioselective outcomes were found to be consistent with the parent coupling reaction. 

A number of aza-aromatic A-oxides, such as pyridine, quinoline, and pyrimidine A-oxides, were converted into the corresponding a-imidazolyl-substituted heteroarenes in good yields on treatment with sulfuryl diimidazole in nonpolar solvents at elevated temperatures (Scheme 19) [45]. 

A variety of pyridine, quinoline, isoquinoline, and pyrimidine A-oxides were converted into the corresponding a-A-aryltriflamido-substituted aza-aromatics in good yields on treatment with A-aryltriflimides, both neat and in solution, at a temperature ranging from ambient to 100 °C (Scheme 22) [48]. 

Nucleophilic substitution by halide, cyanide, carbon nucleophiles such as enamines, and acetate (by reaction with acetic anhydride), with concomitant loss of the oxide function, occurs smoothly in all three systems, though the site of introduction of the nucleophile is not always that (a to the A -oxide) predicted by analogy with pyridine chemistry, for example the reaction of pyrimidine A -oxide with acetic anhydride gives 4- not 2-acetoxypyrimidine. ... 

Using this procedure, low yields were however obtained for pyrimidine A -oxides, presumably due to catalyst inhibition resulting from complexation of the palladium species by the heterocycle. To overcome this issue, a variety of additives were investigated and copper cyanide was found to provide a large improvement in the efficiency of the arylation reaction (eq 22). 

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