Substituted pyrimidines, pyrimidine ring

The structure of guanine illustrates an important feature of substituted pyrimidines and purines Oxygen substitution on the ring favors the keto form rather than the enol Ammo substitution does not... 

Despite considerable localization of tt-electrons at the nitrogen atoms of pyrimidine, the ring system is still sufficiently aromatic to possess substantial stability. This is a great advantage in the primary synthesis of pyrimidines, in the synthesis of pyrimidines from the breakdown or modification of other heterocyclic systems and in the myriad of metatheses required to synthesize specifically substituted pyrimidines. 

Dimethylisoxazol-5-amine is easily acylated to its formyl derivative (697) which, on catalytic hydrogenation, undergoes ring cleavage and recyclization to yield 5,6-dimethyl-pyrimidin-4(3H)-one (698) other acyl derivatives give analogous 2-substituted pyrimidines... 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

As shown in Eigure 18.17, thiamine is composed of a substituted thiazole ring joined to a substituted pyrimidine by a methylene bridge. It is the precursor of thiamine pyrophosphate (TPP), a coenzyme involved in reactions of carbo-... 

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

A combination of the preceding type of synthesis and of cyclization of 4-amino-5-arylazopyrimidine can be seen in the novel procedure of Richter and Taylor. Proceeding from phenylazomalonamide-amidine hydrochloride (180), they actually close both rings in this synthesis. The pyrimidine ring (183) is closed by formamide, the triazole (181) one by oxidative cyclization in the presence of cupric sulfate. Both possible sequences of cyclization were used. The synthetic possibilities of this procedure follow from the combination of the two parts. The synthesis was used for 7-substituted 2-phenyl-l,2,3-triazolo[4,5-d]-pyrimidines (184, 185). An analogous procedure was employed to prepare the 7-amino derivatives (188) from phenylazomalondiamidine (186). 

The halogen atom in benz-chloro substituted quinazolines is very stable (as in chlorobenzene), whereas the halogen atoms in positions 2 and 4 show the enhanced reactivity observed with halogen atoms on carbon atoms placed a and y to heterocyclic ring nitrogens. The chlorine atom in position 4 is more reactive than in position 2, and this property has been used to introduce two different substituents in the pyrimidine ring. ... 

The usual syntheses of quinazolines make use of an o-disubstituted benzene structure (46) from which the quinazoline skeleton is completed by adding C-2 and N-3 in various ways. Substituents could either be in (a) the pyrimidine ring or (b) the benzene ring or in both rings. The syntheses will be described in this order and the methods used for (a) apply equally well to quinazolines substituted in both rings. 

A. Quinazolines Substituted in the Pyrimidine Ring 1. Alkyl- and Aryl-quinazolines... 

Quinazolines substituted in the pyrimidine ring with fluoro, bromo, or iodo atoms are not known. 

The reaction involves an electrophilic attack into the 5-position of the pyrimidine ring and thus only those pyrimidines that are activated toward electrophilic substitution by the presence of electron-donating substituents at the 2- and 4-positions undergo cyclization. 2,4,6-Triaminopyrimidine, 6-aminouracil, 6-amino-2-thiouracil, 4-amino-2,4 dimercaptopyrimidine, 2,4-diaminopyrimidin-6(l/I)-one, and various 4-amino-vV-alkyl and aryl pyriinidones have all been converted into pyrido[2,3-[Pg.160]

All existing syntheses of pyrido[4,3-d]pyrimidines from pyridines build up the pyrimidine ring from a 3-substituted 4-aminopyridine by methods closely similar to those applied for the other systems (routes i and u). The preparation of suitable 4-aminopyridines presents some... 

A large number of nucleophilic substitution reactions involving interconversions of pyridopyrimidines have been reported, the majority of which involve substituents in the pyrimidine ring. This subject has been reviewed previously in an earlier volume in this series which dealt with the theoretical aspects of nucleophilic re-activiti in azines, and so only a summary of the nucelophilic displacements of the substituent groups will be given here. In general, nucleophilic substitutions occur most readily at the 4-position of pyrido-... 

E. C. Taylor and his co-workers have demonstrated an important principle in the ring-opening of pyridopyrimidines and other fused pyrimidine systems to o-aminonitriles. They have demonstrated that based-catalyzed cleavage of a 4-substituted pyrimidine will occur provided that (a) the anion formed by the attack by the base at the 2-position can be stabilized by appropriate structural features in the remainder of the molecule and (b) that the substituent attached to the 4-position is capable of departure with its bonding pair of electrons in... 

Triazanaphthalene (449) is the most unstable of the pyrido-pyrimidines to ring-degradation at pH 2 or pH 7.7 The 4-oxo derivative was converted into the 4-thioxo compound via nucleophilic displacement of the acyloxy intermediate formed with phosphorus pentasulfide. The 4-carboxymethylthio-pyridopyrimidine underwent some substitution by hydroxide ion but primarily gave the ring-opening reaction, which is facilitated by resonance activation of the 2-position by the 6-aza moiety. 

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... 

X-Ray analyses and solid-state IR spectra were recorded for a number of 1,4-and 1,6-dihydropyrimidines, demonstrating the dependency of the tautomeric composition in the crystal on the substitution in the pyrimidine ring and on the ability of these compounds to form intermolecular hydrogen bonds. Thus,... 

CN/CC replacements were also observed when the pyrimidine ring is part of a bicyclic system. Reaction of quinazoline with active methylene compounds, containing the cyano group (malonitrile, ethyl cyanoacetate, phenylacetonitrile) gave 2-amino-3-R-quinoline (R = CN, C02Et, Ph) (72CPB1544) (Scheme 12). The reaction has to be carried out in the absence of a base. When base is used, no ring transformation was observed only dimer formation and SnH substitution at C-4 was found. 

The reaction is hindered by substitution in the 7-position, as revealed in the formation of 2e. Ynamine attack at the other imino moiety in the pyrimidine ring is even possible, which leads to 1,5-diazocines in an analogous reaction mechanism (cf. Section 1.5.). 

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