Imidazole pyrimidines

Compound 642, obtained by condensation of glyoxal with benzotriazole and morpholine undergoes interesting [2+3] cyclocondensation with 2-aminopyridine to give imidazo[l,2- ]pyridine 643 (Equation 15) <2003JOC4935>. Similar derivatives of piperidine and pyrrolidine are also described. 2-Amino- and 6-aminopyrimidines react similarly to give imidazo[l,2- ]- and imidazoll - pyrimidines, respectively. 

The second-order rate constants for the reaction of the anions formed from imidazoles, pyrimidines, and purines with quinone methides and benzhydrylium ions in DMSO and in water have been measured and their N and % values in the log k = Sf N+E) equation determined. As expected, the nucleophiles are more reactive in DMSO than in water and the anions are 10" -10 times more reactive than their neutral counterparts. However, the solvent effects vary markedly with each nucleophile. The % values range from 0.50 to 0.77, whereas the N values for the anionic nucleophiles vary from approximately 15 to 21 in DMSO and from 10 to 12 in water. The Brpnsted basicity is correlated with the nucleophilicity in DMSO but not in water. 

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

The pyrimidine ring system is planar, while the purine system deviates somewhat from planarity in having a slight pucker between its imidazole and pyrimidine portions. Both are relatively insoluble in water, as might be expected from their pronounced aromatic character. 

MO studies (AMI and AMI-SMI) on the tautomerism and protonation of 2-thiopurine have been reported [95THE(334)223]. Heats of formation and relative energies have been calculated for the nine tautomeric forms in the gas phase. Tire proton affinities were determined for the most stable tautomers 8a-8d. Tire pyrimidine ring in the thiones 8a and 8b has shown a greater proton affinity in comparison with the imidazole ring, or with the other tautomers. In solution, the thione tautomers are claimed to be more stabilized by solvent effects than the thiol forms, and the 3H,1H tautomer 8b is the most stable. So far, no additional experimental data or ab initio calculations have been reported to confirm these conclusions. 

Pteridine, pyrimidine, pyrrole, and imidazole derivatives as natural compounds of marine origin influencing larval settlements and metamorphosis of marine sessile organisms 99YZ457. 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

Note that nitrogen atoms have different roles depending on the structure of the molecule. The nitrogen atoms in pyridine and pyrimidine are both in double bonds and contribute only one tt electron to the aromatic sextet, just as a carbon atom in benzene does. The nitrogen atom in pyrrole, however, is not in a double bond and contributes two tt electrons (its lone pair) to the aromatic sextet. In imidazole, both kinds of nitrogen are present in the same molecule— a double-bonded "pyridine-like" nitrogen that contributes one v electron and a pyrrole-like" nitrogen that contributes two. 

Pyrimidine and imidazole rings are particularly important in biological chemistry. Pyrimidine, for instance, is the parent ring system in cytosine, thymine, and uracil, three of the five heterocyclic amine bases found in nucleic acids An aromatic imidazole ring is present in histidine, one of the twenty amino acids found in proteins. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

On the other hand, the fragmentation of pyramine obtained from (2 -l3C)AIRs indicated clearly that C-2, in the ribose part, was the precursor of carbon C-7 of the methyl on C-2 of the pyrimidine ring (Scheme 29). This result was confirmed by an experiment with a sample of AIRs labeled with l4C on C-l, C-2, C-3, on the ribose, and C-5 on the imidazole, with an approximate distribution of 1, 1, 3, 3. This precursor produced pyramine with the methyl group almost as radioactive as C-l or C-2, and much less than C-3 of AIRs. Because of the incorporation of C-5 of imidazole into C-4 of pyramine, and the comparable activities of C-3 and C-5 in the precursor AIRs, the specific activity of pyramine... 

Because sugars are involved in most of the mechanisms established for the synthesis of these heterocycles, the development of carbohydrate chemistry has been most helpful in these researches—especially for the preparation of specifically labeled molecules. Conversely, the contribution of these efforts to carbohydrate chemistry and biochemistry has shown the involvement in biosynthesis of 1 -deoxy-D-f/rreo-pentulose—scarcely before recognized and considered a rare sugar—and of fully functionalized pentuloses of still unknown configuration (or their phosphates). Finally, evidence has been found in prokaryotes for a most extraordinary transformation of 5-amino-l-(P-D-ribofuranosyl)imidazole 5 -phos-phate into a pyrimidine. Surely, this transformation should be explained in terms... 

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