SYNTHESIS OF N-(PURIN-8-YL)ARYLAMINES

Methods for direct synthesis of N-(purin-8-yl)arylamines were investig ated. N-(Purin-8-yl)arylamines are adducts from reaction of electrophi lic metabolites of arylamines with DNA and have not been readily avail able by direct synthesis. Ability to generate significant quantities o f this class of DNA adduct by synthetic means would facilitate basic r esearch in molecular toxicology. Two routes with common thiourea inter mediates were developed for this purpose. In the first route, 6-hydrox y-2,4,5-triaminopyrimidine was caused to react in aqueous medium with dithiocarbamate derivatives of o-, m-, or p- toluidine to form corresp onding 4-diamino-5-(tolylthioureido)aminopyrimidin-6-ones in 60-70% yi elds. The thiourea intermediates were converted to carbodiimides and i solated in 20-25% yields after treatment with HgO in dimethylformamide . The carbodiimides were cyclized at 125-degrees-C in dimethylformamid e under N2 for 45 h to yield N-(guanin-8-yl)(o-, m-, or p-)toluidines in 65-75% yields. In the second route, direct reaction of p-tolyl isot hiocyanate with 6-hydroxy-2,4,5-triaminopyrimidine or with 4,5,6-triam inopyrimidine in dimethylformamide and triethylamine led to the format ion of -diamino-5-(p-tolylthioureido)aminopyrimidin-6-one and 4,6-diam ino-5-(tolylthioureido)aminopyrimidine, respectively, in 77-79% yields . Methylation of the two thiourea derivatives by methyl iodide in dime thylformamide gave the corresponding methylisothiuronium derivatives, which were isolated in 71% and 84% yields (as HI salts), respectively. Conversion of the methylisothiuronium derivatives to N-(guanin-8-yl)- p-toluidine or N-(adenin-8-yl)-p-toluidine was accomplished by heating in dimethylformamide for 5-7 h at 80-90-degrees-C, in 70% and 62% yie lds, respectively. The most efficient synthesis of the thioureas would appear to proceed by coupling the triaminopyrimidine precursor with t he easily prepared dithiocarbamate derivatives of the arylamine follow ed by conversion to a methylisothiuronium and thermal cyclization of t he methylated intermediate. These routes should be directly applicable to polynuclear arylamines and suitably blocked diaminoarenes.