Pteridine, 6-bromo

Regioselective 6-alkoxylation of pteridines has been carried out by reacting 1,3-dimethyllumazine (85) or 2-dimethylamino-4(37/)-oxopteridine (86) with NBS in methanol or ethanol. Some 6-bromo product is also formed but this does not seem to be an intermediate in the reaction since these compounds are stable in refluxing ethanol and a pathway involving an intermediate bromonium ion is proposed (Scheme 29) [95H(41)781]. 

The amino-ketone (292) dimerised when liberated from its salt, giving a dihydropyrazine air-oxidation gave the pyrazine (293), which exhibited characteristic u.v. and c.d. features n — k and tt —> 7t ). ° Some novel fused heterocycles have been obtained by suitable condensations of 3-oxo- and 7-oxo-steroids with nitrogenous compounds cyanoguanidine, for example, affords diamino-pyrimidines (294), and 2,4,5,6-tetra-aminopyrimidine reacts with a 2-bromo-3-oxo-steroid to give a diamino-pteridine. 

The 7t-electron deficiency of pteridine should greatly aid nucleophilic substitution, but complications arise because of the ready nucleophilic covalent addition reactions referred to previously. However, nucleophilic displacement of halo substituents occurs very easily, except in the presence of electron-donating groups such as amino, etc. Increasing the number of such substituents increases the difficulty of carrying out nucleophilic substitutions. The kinetics for the aminolysis of 2,4,6,7-tetrabromopteridine shows that the order of reactivity for bromo substituents is 7 > 6 > 2 > 4.30,19 It is probable that 2,4,6,7-tetrachloropteridine shows the same pattern of reactivity and that generally bromo- and chloropteridines react similarly. 

The introduction of a methoxy or ethoxy group to the 6-position of 2-(dimethylamino)pteridin-4(3//)-one (5) can be carried out using a two-step process requiring iV-bromosuccinimide and the appropriate alcohol. The pathway involves the addition of bromonium ion across the 5,6-bond, then addition of the alcohol and the elimination of hydrogen bromide. The 6-bromo derivative is not an intermediate in the reaction since it is stable to the alcohol under reflux. Some of the 6-bromo derivative is also formed in the reaction but it can be separated chromato-graphically.253... 

Amino-5-bromo-3-cyanopyrazine is an intermediate in the construction of pteridines. Before forming the fused pyrimidine ring, the pyrazine is alkynylated in the 5-position (82) in moderate to good yields (87JOC3997 88JOC35). 

An alternative method of synthesis of (IV.91) from 2,4-diamino-6-bromo-methylpteridine was described in 1980 by Piper and Montgomery [120]. The bromo compound was treated with triphenylphosphine in DMA (60-63 °C, 1.5 h), and the resultant ylide was condensed with diethyl N- 4-formylbenzoyl)-L-glutamate to obtain diester (IV.97) in 78% yield. Catalytic reduction of the 9,10 double bond resulted in partial reduction of the pteridine ring to a 7,8-dihydro derivative. Reoxidation of ring B with HjOj followed by ester hydrolysis with NaOH afforded (IV.91) (62%). 

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