Pyrimidine rings

A variation of this procedure is used for sulfisomidine because of the different character of the amino group in the 4-position of a pyrimidine ring. Two moles of the sulfonyl chloride are condensed with one mole of 4-amino-2,6-dimethy1pyrimidine in the presence of triethylamine. The resulting bis(acetylsulfanilyl) derivative is readily hydrolyzed to the product. The formation of the bis(acetylsulfanilyl) derivative has also been employed for other heterocycHc amines, eg, for synthesis of sulfathiazole and sulfamoxole (44), but the 1 1 reaction is probably preferable. 

Syntheses of the Pyrimidine Ring from Other Heterocycles... 

The pyrimidine ring is virtually flat. Its corrected bond lengths, as determined by a least-squares analysis of the crystal structure data for a unit cell of four molecules, are shown in formula (2) (60AX80), and the bond angles derived from these data show good agreement with those (3) derived by other means (63JCS5893) for comparison, each bond... 

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

It is possible to prepare pyrimidines from other heteromonocyclic compounds by a variety of processes, or from fused heterobicyclic systems which already contain a pyrimidine ring by preferentially degrading the unwanted second ring. In the latter case, the bicyclic system may best be made from a pyrimidine in the first place, occasionally even from the self-same pyrimidine to which it reverts on degradation. Such syntheses may be of interest but are certainly not of any utility. 

Likewise there are no reports of systematic photochemical studies, but the pyrido[2,3-ii]pyrimidine ring system appears relatively photostable, as photolytic removal of D-ribityl and hydroxyethyl A -substituents was employed in structural confirmation studies (74JCS(P1)1225). Photo adducts of deazafiavins with cyclohexadienes have been studied, however (77ZN(B)434), as have several other aspects of deazafiavin photochemistry. 

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

A reversal of the position of the substituents on the pyrimidine ring is involved in the reductive cyclization of 4-ketoalkyl-5-phenylazopyrimidines to give, e.g. 6-alkylpyrido[3,2- f]pyrimidines (76JHC439). 

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. 

In all types of NMR spectra H, C, N), 2-azidopyrimidine (2) can be distinguished by the symmetry of its pyrimidine ring (chemical equivalence of 4-H and 6-H, C-4 and C-6, N-1 and N-3) from tetrazolo[l,5-a]pyrimidine ( ) because the number of signals is reduced by one. Hence the prediction in Table 30.1 can be made about the number of resonances for the -butyl derivative. 

FIGURE 11.2 (a) The pyrimidine ring system by convention, atoms are numbered as indicated, (b) The purine ring system, atoms numbered as shown. 

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. 

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. 

A relatively small number of quinazolines unsubstituted in the pyrimidine ring are known. Four distinctly different methods are... 

Of greater versatility is an extension of Albert and Royer s acridine synthesis. The first successful use of this in the quinazoline series was for the removal of the chlorine atom in 2-chloro-4-phenylquin-azoline, although it had been used previously to prepare 8-nitro-6-methoxyquinazoline in very poor yield. The 4-chloroquinazoline is converted to its 4-(A -toluene-p-sulfonylhydrazino) quinazoline hydrochloride derivative which is decomposed with alkali in aqueous ethylene glycol at lOO C (Scheme 13). The yields are high (60-70%) when R is Me, Cl, OMe but low when R is NO2, and in the latter case it is preferable to use dilute sodium carbonate as the base. This reaction is unsatisfactory if the unsubstituted pyrimidine ring is unstable towards alkali, as in 1,3,8-triazanaphthalene where the pyrimi-... 

The trioxo formulation (190, R — H) of 2,4,6-trihydroxypteridine is supported by the fact that its ultraviolet spectrum resembles that of the A-methyl derivative (190, R = Me), the pyrimidine ring in the parent compound having been assigned the dioxo configuration by analogy. On the basis of ultraviolet spectral data, the trioxo con-... 

The pyridopyrimidines discussed in this review are derived by the ortho fusion of the pyridine and pyrimidine rings through ring carbon atoms. There are four such compounds for which the nomenclature and numbering of Chemical Abstracts (1-4) will be used. Alternative names used in the literature are 1,3,8-triazanaphthalene (1), 1,3,5-tri-azanaphthalene (2), 1,3,7-triazanaphthalene or copazoline (3), and 1,3,6-triazanaphthalene (4). There has been no previous review of the... 

---