Pyrimidine protonation reactions

Pyrido[3,4-d]pyrimidine-2,4-dione synthesis, 3, 215 Pyridopyrimidines, 3, 201 iV-alkylations, 3, 206 biological activity, 3, 260-261 1-electron reductions, 3, 207 IR spectra, 3, 204 mass spectra, 3, 204 MO calculations, 3, 204 NMR, 3, 202, 203 nucleophilic substitution, 3, 213 8-nucleosides synthesis, 3, 206 physical properties, 3, 201-205 protonation, 3, 206 radical reactions, 3, 215 reactions with water, 3, 207 reduced... 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

Corsaro and co-workers studied the reaction of pyridazine, pyrimidine, and pyrazine with benzonitrile oxide and utilized H NMR spectral analysis to determine the exact structure of all the cyclized products obtained from these reactions <1996T6421>, the results of which are outlined in Table 1. The structure of the bis-adduct product 21 of reaction of pyridazine with benzonitrile oxide was determined from the chemical shifts of the 4- and 5-isoxazolinic protons at 3.76 and 4.78 ppm and coupled with the azomethine H at 6.85 ppm and with the 5-oxadiazolinic H at 5.07 ppm, respectively. They determined that the bis-adduct possessed /(-stereochemistry as a result of the large vicinal coupling constant (9.1 Hz). Similarly, the relative stereochemistry of the bis-adducts of the pyrimidine products 22-25 and pyrazine products 26, 27 was determined from the vicinal coupling constants. 

Figure 8.29 The initial reactions of glutamine metabolism in kidney, intestine and cells of the immune system. The initial reaction in all these tissues is the same, glutamine conversion to glutamate catalysed by glutaminase the next reactions are different depending on the function of the tissue or organ. In the kidney, glutamate dehydrogenase produces ammonia to buffer protons. In the intestine, the transamination produces alanine for release and then uptake and formation of glucose in the liver. In the immune cells, transamination produces aspartate which is essential for synthesis of pyrimidine nucleotides required for DNA synthesis otherwise it is released into the blood to be removed by the enterocytes in the small intestine or by cells in the liver.

The reaction was found to fail with l-methyl-5-nitrouracil and 5-nitrouracil. This is because both uracils, containing dissociable protons, exist in the basic solution in the anionic forms, which inhibit the addition of the nucleophiles at the C-6 position. Attempts to bring about these pyrimidine-to-pyrimidine ring transformations with cyanoacetamide, ace-toacetamide, and phenylacetamide were not successful. A substituent at C-6 of 5-nitrouracil suppressed the reaction l,3,6-Trimethyl-5-nitrouracil was recovered almost quantitatively. 

As can be seen also with pyridazines and pyrimidines, the protons of pyrazines are relatively acidic <2001T4489>, and the simple pyrazine is lithiated with 4 equiv of LTMP at —75 °C <1995JOC3781>. Since the lithio intermediate, however, is highly unstable, the subsequent substitution with electrophiles should be carried out within a very short reaction period. 

An unusual reaction leading to the formation of 4-thioxopyrazolo[3,4-d]-pyrimidines has been reported. 1-Substituted 4-cyano-5-aminopyrazoles (103, R = H) react with phenyl isothiocyanate in dimethylformamide (DMF) saturated with hydrogen chloride to yield 1-substituted 4(5//)-pyrazolo[3,4-d]-pyrimidinethione (110). A proposed reaction sequence involved an initial nucleophilic addition of phenyl isothiocyanate to the protonated o-amino-nitrile to give an o-aminothioamide (108), followed by formylation by the dimethylformamide-hydrogen chloride mixture affording 109, which then cyclizes to the final product 110 (70MI1). 

Reaction of 2-amino-3-phenylazo-5-methyl-6,7-dihydropyrazolo [ 1,5-a] -pyrimidine-7-one (209) with ACOH/H2SO4 gives the pyrazolo[l,5-a]-pyrimidine derivative 210 (77JHC155). This reaction can be looked at as electrophilic substitution of the arylazo function by the proton. Similarly, 4,5,6,7-tetrahydro-2-phenyl-3-phenylazo-5-oxopyrazolo[l,5-a] pyrimidine gives 4,5,6,7-tetrahydro-2-phenyl-5-oxopyrazolo[l,5-a]pyrimidine 212 by the action of acetic/hydrochloric acid (75T63). 

Evidence for the formation of Meisenheimer-type adducts from a purine system has been obtained by Liotta in two cases.43 The addition of t-BuO to 6-(2-hydroxyethoxy)-9-methoxymethyIpurine in t-BuOH, as monitored by H-NMR spectroscopy, causes an upfield shift of both pyrimidine and imidazole ring protons and the conversion of two absorptions of the methylene protons of the CH2CH2OH group to a broad absorption of the dioxolane ring, in agreement with the formation of the spiro adduct 19. Similarly, adduct 20 was formed from 6-methoxy-9-methoxymethylpurine by slow reaction with MeCT in 7-BuOH. 

All these bases absorb around 260 nm. Thymine and cytosine are most sensitive to irradiation. Two most important types of photochemical reactions that have been observed for these pyrimidine bases are photohydration and photodimerization. In vivo systems, interactions between protons and nucleic acids can also be initiated by radiations of wavelength dlorter than 300 nm. 

The weakly basic portion of thiamin or of its coenzyme forms is protonated at low pH, largely on N-l of the pyrimidine ring. 86 88 The pKa value is 4.9. In basic solution, thiamin reacts in two steps with an opening of the thiazole ring (Eq. 14-15) to give the anion of a thiol form which may be crystallized as the sodium salt.79 84 This reaction, like the competing reaction described in Eq. 7-19, and which leads to a yellow... 

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