2.4- Diamino-7,8-dihydropteridines

N -Alkylation of 7,8-dihydropteridines. Direct monoalkylation at N of 2,4-diamino-7,8-dihydropteridines (1) can be accomplished by treatment with 1.1 eq. of n-butyUithium in DMSO (the actual reagent is lithium methylsulfinylmethylide) and then with a slight excess of an alkyl halide. No substitution in... 

Extensive NMR investigation of the formation of adducts between pteri-dine and liquid ammonia has shown that two different species are obtained the covalent 1 1 a-adduct 4-amino-3,4-dihydropteridine, and the thermodynamically more favored 2 1 a-adduct 6,7-diamino-5,6,7,8-tetrahy-dropteridine (Scheme 11.42) (75RTC45 76OMR607). This adduct is also formed in ammonia [71JCS(C)2357]. 

Pteridine adds ammonia at low temperature to form 4-amino-3,4-dihydropteridine (246) which is transformed in a slower reaction into 6,7-diamino-5,6,7,8-tetrahydropteridine (247) (cf. similar adducts with water, 166 and 167). 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

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-... 

The conditions which have been used for the decarboxylation of pteridinecarboxylic acids vary considerably. One method is by thermal decarboxylation, for example thermal decarboxylation of 2,4-diamino-7-oxo-7,8-dihydropteridine-6-carboxylic acid to give 2,4-diaminopteridin-7(8//)-one (l).180 For further examples, see reference 18. 

Hexahydrohomofolic acid (V.36) was synthesized by Nair et al. [221] by condensation of 2,4-diamino-6-chloro-5-nitropyrimidine with the amino ketal (V.37), followed by ketal acidolysis, reductive cyclization to a 7,8-dihydropteridine, aerobic oxidation, ester hydrolysis, A, A -bis(tri-fluoroacetylation), mixed anhydride condensation with diethyl L-glutamate, and cleavage of the ester and amide groups with base. Ketal (V.37) was... 

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