Pyrimidine Ring Substitution

When an equimolar mixture of pyrimidine and thiazole was given to Staph, aureus instead of thiamin the nature of the substitution at 5 in the pyrimidine was important. Thus, —CH2 NH2, —CH2 OH and —CH2 NH CSH permitted growth but —CH2 CO -NHa or — CH3 did not. The relative effects of these various substituents at position 5 was interpreted (159) to mean that for use the pyrimidine and thiazole portions were united by Staph, aureus to give the thiazolium compound thiamin itself, and that the two components were not used separately. With pea-roots similar differences are found in the availability of the substitution at 5 these also appear to be related to the ability of the root-cells to form the link with the thiazole. Thus —CH,Br (100%), —CH2-NH-CSH (100%) —CH2 NH2 (95%) and —CH2-OEt (25%) decrease in availability in the order shown, while —H, —CH2 COOH and —CH2 CO NH2 could not be used (30). 

Direct evidence for the synthesis of thiamin by joining the pyrimidine and thiazole components was shown for Phycomyces blakesleeanus by Bonner and Buchman (38). They further showed that after growth the resting mycelium broke down the thiamin, with destruction of the thiazole and liberation of the free pyrimidine. With Staph, aureus Hills (127) found similarly that the destruction of the thiazole was more rapid than that of the pyrimidine. 

Those organisms e.g., Glaucoma piriformis and Phytophthora cinruimomi) which require the intact thiamin molecule and cannot use the two components, evidently cannot link them together as other protozoa. Staph, aureus, Phycomyces blakesleeanus, and pea-roots can when the substitution in the 5 —CH2-group is suitable. 

---

Pyrimidine ring substitution Substituent effects on the pyrimidine ring were examined while retaining the 7,8-dimethoxy substitution pattern in the carbocyclic ring (Figure 9). A methyl group in the 3-position (L) decreased intravenous activity by more than 100-fold. Similarly, introduction of carbethoxyalkyl substituents in position 3 (LI and Lll) resulted in compounds which are inactive or considerably less active than the N-unsubstituted analog (XXXV). 

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. 

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-... 

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.). 

Base-mediated intramolecular cyclization of an amino-substituted triazole onto the chloropyrazole of compound 257 with loss of HG1 generates the central pyrimidine ring of 258 (Equation 70) <2004JCM50, 2004SC151>. 

Condensation of the 3,5-diamino-substituted pyrazole 303 with the dioxopyrrolidine ester 304 leads to formation of the central pyrimidine ring of 305 in good yield (Equation 82) <2002JCCS1051>. 

One example, however, which involves closure of the central pyrimidine ring is the thermally induced intramolecular condensation of the pyrrolidone-substituted aminoquinoline derivative 246 (Equation 73) <1999JHC755>. 

One of the most important reactions of purines is the bromination of guanine or adenine at the C-8 position. It is this site that is the most common point of modification for bioconjugate techniques using purine bases (Figure 1.53). Either an aqueous solution of bromine or the compound N-bromosuccinimide can be used for this reaction. The brominated derivatives then can be used to couple amine-containing compounds to the pyrimidine ring structure by nucleophilic substitution (Chapter 27, Section 2.1). 

Due to the electronegativity of the two nitrogen atoms, pyrimidine is a deactivated, rc-electron-deficient heterocycle. Its chemical behavior is comparable to that of 1,3-dinitrobenzene or 3-nitropyridine. One or more electron-donating substituents on the pyrimidine ring is required for electrophilic substitution to occur. In contrast, nucleophilic displacement takes place on pyrimidine more readily than pyridine. The trend also translates to palladium chemistry 4-chloropyrimidine oxidatively adds to Pd(0) more readily than does 2-chloropyridine. 

Most of these studies relate to derivatives of one ring system triazolo[l,5-tf]pyrimidine. 13C and 1SN chemical shifts of some 5,7-disubstituted [l,2,4]triazolo[l,5- ]pyrimidines substituted in the pyrimidine ring (and also some of their Au(m) chloride complexes) were published by Sztyk et al. <2002MRC529> the data are shown in Table 1. 

---