Pyrimidines basicity

Salt Formation. As a weaMy basic pyrimidine and a thiazolium cation, thiamine forms both mono- and dipositive salts, eg, the two commercial... 

In the zigzag polymeric chains of compounds [M(p-ox)(H20)(7/7-ade-KA )] 2(9i/-ade) (H20) (M° = Co, Zn), the adenine nucleobase binds to the metal centres through the less basic pyrimidinic N3 atom (Fig. 10) in contrast to what occurs in the previously described purine compounds where the organic ligands are coordinated through the imidazole N9 atom. 

The nucleophilicity of amine nitrogens is also differentiated by their environments. In 2,4,5,6-tetraaminopyrimidine the most basic 3-amino group can be selectively converted to a Schiff base. It is meta to both pyrimidine nitrogens and does not form a tautomeric imine as do the ortho- and /xira-amino groups. This factor is the basis of the commercial synthesis of triamterene. 

Basically, AZT is anabohcaHy phosphorylated to AZT mono-, di-, and tri-phosphates by various enzymes (kinases) of a target ceU (159). AZT-triphosphate competes with other phosphorylated pyrimidine nucleosides for incorporation into HIV DNA by the viral reverse transcriptase. Incorporation of the AZT-triphosphate into reverse transcriptase results in viral DNA chain termination. Reverse transcriptase is essential in the repHcative cycle of HIV. 

The simple pyrimidinamines, e.g. (7 R = H), are bases of moderate strength, pXa 3-6. Thus the rise in basic strength from pyrimidine (pXa 1.31) to pyrimidin-2-amine (pXa 3.54)... 

Alkylation of pyrimidin-2(or 4)-amine on a ring-nitrogen gives an imine, e.g. (8), of quite high basic strength (pjSTa 10.7) because its cation, e.g. (13 R = Me), has typical and effective resonance stabilization indeed, methylation of pyrimidine-2,4-diamine gives a still stronger base (pjSTa> 13) due to an even more resonance-stabilized cation (14). 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Pyrimidin-2-amine, 4-benzyIoxy-6-fluoro-hydrolysis, 3, 92 Pyrimidin-2-amine, 5-bromo-basic pK, 3, 61 Busch reaction, 3, 99 Pyrimidin-2-amine, 4-t-butyl-diazotization, 3, 85... 

Pyrimidin-2-amine, 4-chloro-6-nitroamino-synthesis, 3, 69 Pyrimidin-2-amine, 5-cyano-basic pXj, 3, 61... 

Pyrimidin-2-amine, 4,6-dimethyl-basic pX 3, 61 diazotization, 3, 85 reactions... 

Pyrimidin-2-amine, 4-ethyI-5-(2 -hydroxy-4 -nitrophenyI)-6-methyl-synthesis, 3, 121 Pyrimidin-2-amine, 4-methyl-basic pXj, 3, 61 Pyrimidin-2-amine, N-methyl-hydrolysis, 3, 84 synthesis, 3, 135 Pyrimidin-2-amine, 5-nitro-basic pXj, 3, 61 hydrolysis, 3, 84 Pyrimidin-2-amine, 4-phenyl-synthesis, 3, 109 Pyrimidin-2-amine, 5-phenyl-nitration, 3, 78... 

Pyrimidin-5-amine, 4-methylamino-synthesis, 3, 121 Pyrimidin-5-amine, 4-oxo-purfne synthesis from, 5, 582 Pyrimidinamines acylation, 3, 85 alkylation, 3, 86 basic pXa, 3, 60-61 diazotization, 3, 85 Dimroth rearrangement, 3, 86 electrophilic reactions, 3, 68 Frankland-Kolbe synthesis, 3, 116 hydrolysis, 3, 84 IR spectra, 3, 64 N NMR, 3, 64 nitration, 3, 69 Principal Synthesis, 3, 129 reactivity, 3, 84-88 structure, 3, 67 synthesis, 3, 129 Pyrimidin-2-amines alkylation, 3, 61, 86 basic pK , 3, 60 diazotization, 3, 85 hydrogenation, 3, 75 hydrolysis, 3, 84 mass spectra, 3, 66 Pyrimidin-4-amines acidity, S, 310 alkylation, 3, 61, 86 basic pXa, 3, 61 Schifi base, 3, 85 synthesis, 3, 110, 114 1,3,5-triazines from, 3, 518 Pyrimidin-5-amines basic pXj, 3, 61 hydrogenation, 3, 75 reactions... 

Pyrimidine-4,6-diamine, 2-pfaenyl-synthesis, 3, 107 Pyrimidine-2,4-diamines antimicrobial, 3, 151 azo dyes from, 1, 331 basic p/Ca, 3, 61 Elbs persulfate reaction, 3, 74 =N NMR, 3, 64 synthesis, 3, 111 Pyrimidine-4,5-diamines basic pKa, 3, 61 hydrolysis, 3, 84 oxidation, 3, 87 reactions... 

Pyrimidine-2,4,5-triamine, 6-hydroxy-as cofactor of phenylalanine hydroxylase, 1, 261 Pyrimidine-2,4,5-tri amines basic p/fa, 3, 61 Pyrimidine-2,4,6-triamines synthesis, 3, 115... 

Diaryl-1,3,6-trimethyl-1,2,3,4,5,6,7,8-oetahydropyrido[4,3-reaction between methylamine, formaldehyde, and a l,l-diarylpropan-2-one in the presence of a basic... 

The methods outlined, of course, are readily applicable to a wide variety of substituted heterocycles like the carboxyl, hydroxy and mercapto derivatives of pyridines, pyridine 1-oxides, pyrroles, etc. The application to amines and to diaza compounds such as pyrimidine, where the two centers are basic, is obvious except that now 23 takes the role of the neutral compound, 21 and 22 the roles of the tautomeric first conjugate bases, and 20 the role of the second conjugate base. Extensions to molecules with more than two acidic or basic centers, such as aminonicotinic acid, pyrimidinecarboxylic acids, etc., are obvious although they tend to become algebraically cumbersome, involving (for three centers) three measurable Kg s, four Ay s, and fifteen ideal dissociation constants (A ), a total of twenty-two constants of which seven are independent. 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

To establish a mechanism for the formation of 33, the reaction has been monitored by H-NMR spectroscopy (91CB2013).Tlie basicity of the azine is a rate-determining effect as well as a steric hindrance. Pyridine is more reactive than pyrimidine. 2-Substituted pyridines do not give the corresponding salts. 

Acidic and basic hydrolysis of ethyl 4-oxo-4//-pyrido[l, 2-u]pyrimidin-3-carboxylates gave 3-carboxylic acid derivatives (OlMIPl). Stirring rerr-butyl ( )-3-(2-hydroxy-8-[2-(4-isopropyl-l, 3-thiazol-2-yl)-l-ethenyl]-4-oxo-4//-pyrido[l,2-u]pyrimidin-3-yl)-2-propenoate in CF3CO2H at room temperature yielded ( )-3-substituted 2-propenoic acid. 

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