Covalent hydrates, oxidation

Oxidations of pyridopyrimidines are rare, but the covalent hydrates of the parent compounds undergo oxidation with hydrogen peroxide to yield the corresponding pyridopyrimidin-4(3 T)-ones. Dehydrogenation of dihydropyrido[2,3-(i]pyrimidines by means of palladized charcoal, rhodium on alumina, or 2,3-diehloro-5,6-dicyano-p-benzo-quinone (DDQ) to yield the aromatic derivatives have been reported. Thus, 7-amino-5,6-dihydro-1,3-diethylpyrido[2,3-d]-pyri-midine-2,4(lif,3f/)-dione (177) is aromatized (178) when treated with palladized charcoal in refluxing toluene for 24 hours. 

Covalent hydration has been demonstrated in the following families of compounds 1,6-naphthyridines, quinazolines, quinazoline. 3-oxides, four families of l,3,x-triazanapththalenes, both l,4,x-triazanaphthalenes, pteridines and some other tetraazanaphthalenes, and 8-azapurines these compounds are discussed in that order. In general, for any particular compound (e.g. 6-hydroxypteridine) the highest ratio of the hydrated to the anhydrous species follows the order cation > neutral species > anion. In some cases, however, anion formation is possible only when the species are hydrated, e.g. pteridine cf. 21 and N-methyl-hydroxypteridines (Section III, E, 1, d). Table V in ref. 10 should be consulted for the extent of hydration in the substances discussed here. 

At the present time, the greatest importance of covalent hydration in biology seems to lie in the direction of understanding the action of enzymes. In this connection, the enzyme known as xanthine oxidase has been extensively investigated.This enzyme catalyzes the oxidation of aldehydes to acids, purines to hydroxypurines, and pteridines to hydroxypteridines. The only structural feature which these three substituents have in common is a secondary alcoholic group present in the covalently hydrated forms. Therefore it was logical to conceive of this group as the point of attack by the enzyme. 

The situation in the pteridine series is somewhat more complex. Pteridine, 2-, 4-, and 7-hydroxypteridine, and some of the dihydroxy-pteridines are oxidized, stepwise and quantitatively, in the presence of xanthine oxidase to a single substance, 2,4,7-trihydroxypteridine. Notably, 6-hydroxypteridine, which readily forms a covalent hydrate, is not attacked. 

The high activating power of the furoxan ring in nucleophilic addition has also been observed by Bailey et al.2 9 in 7-nitro-l,2,5-oxadiazolo[3,4-c]-pyridine 3-oxide, a nitropyrido[3,4-c]furoxan that easily undergoes covalent addition of water by nucleophilic attack at the position para to the nitro group. The structure of the covalent hydrate is supported by elemental analysis, osmometric molecular weight determination, and H-NMR spectra in DMSO-[Pg.429]

Insertion of a methyl group at the site where nucleophilic attack occurs during hydration considerably hinders the reaction and lowers the percentage of covalently hydrated species at equilibrium. Covalent hydrates are converted by mild oxidation into oxo compounds. 

In the active site of a hydroxylase, an OH group can be transferred from the peroxide to a suitable substrate (Eq. 18-42). Although radical mechanisms are likely to be involved, such hydroxylation reactions can also be viewed as transfer of OH+ to the substrate together with protonation on the inner oxygen atom of the original peroxide to give a 4a - OH adduct. The latter is a covalent hydrate which can be converted to the oxidized flavin by elimination of H20. This hydrate is believed to be the third spectral intermediate identified during the action of p-hydroxybenzoate hydroxylase 286 287 290... 

Pteridine also adds ammonia at low temperature to form 4-amino-3,4-dihydropteridine (42) which is transformed in a slower reaction into 6,7-diamino-5,6,7,8-tetrahydropteridine (43) (Scheme 5). 2-Chloropteridine (36) shows the same behavior, whereas 2-chloro-4-phenylpteridine (37) and 2-methylthiopteridine (38) lead directly to the corresponding 6,7-diamino-5,6,7,8-tetrahydro derivatives (43) (Scheme 5). The 4-amino-3,4-dihydropteridines can easily be oxidized to the 4-aminopteridines <75RTC45>. Covalent hydrations with various 6,7-bis-trifluoromethyl-pteridine derivatives were studied showing that 6,7-bis-trifluoromethylpteridine (40) itself and the cor-... 

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