132 AARON BENDICH 



5-acylaminopyrimidines (cf. Cavalieri et al.*^^). A new variation employs 

 ethyl nitrosocyanoacetate (or ethyl hydroxyiminocyanoacetate) which, 

 upon condensation with the proper amidine or urea derivative, yields 5- 

 nitrosopyrimidines directly .^^° 



Although the 4 , 5-diaminopyrimidines also serve routinely as intermedi- 

 ates in the synthesis of pteridines/"* -^^ their use in purine synthesis pre- 

 sents little ambiguity because of the reagents employed and the much 

 greater reactivity of the 5-amino group. Reaction of 4 , 5-diamino-2 , 6-di- 

 hydroxypyrimidine with ethyl chloroformate leads only to the 5-urethan, 

 and the urethan (sodium salt) cyclizes to uric acid upon heating.^^ With 

 formic acid, it appears that only the 5-formyl derivatives are formed from 

 di-, tri-, and tetra-aminopyrimidines.^'''^^'^'"''^^^ When 2,4,5-triamino-6- 

 hydroxypyrimidine is refluxed with formic acid-sodium formate, guanine is 

 formed directly in excellent yield without the necessity of isolating the in- 

 termediate 5-formyl compound .^^ Similarly, a nearly quantitative yield of 

 hypoxanthine is obtained merely by refluxing 4 , 5-diamino-6-hydroxy- 

 pyrimidine (sulfate) with formic acid."° However, other 4-amino-5-formyl- 

 aminopyrimidines show a reluctance to dehydrate to the corresponding 

 purines, and it is necessary to heat the dry compounds or their sodium or 

 potassium salts at elevated temperatures to effect ring closure. Thus, 

 xanthine, 2,6-diaminopurine, 2-mercaptoadenine, 2-mercaptohypoxan- 

 thine, 6-methylpurine, purine, and A^'-alkylxanthines are formed when 

 the dehydrations of the isolated intermediate 5-formyl derivatives are 

 carried out at i52-300°.3o, 36. 113,182,270 ,286 .442 



For this reason, more suitable techniques of purine formation from 

 4 , 5-diaminopyrimidines were sought. In one method, 4 , 5 , 6-triamino- 

 pyrimidine is smoothly converted by treatment with sodium dithiofor- 

 mate into its 5-thioformyl derivative, and, by boiling in water, hydrogen 

 sulfide is eliminated to furnish adenine.'*^^ This procedure, which was em- 

 ployed for the preparation of 1,3-N^Mabeled adenine, yields a mixture 

 of products 65% of which is adenine and the remainder mainly 4,6-di- 

 amino-5-formylaminopyrimidine."' In another method, adenine is formed 

 directly by heating 4,5,6-triaminopyrimidine-2-sulfinic and formic acids 

 to 150-160°.^^^ The sulfinic acid is obtained by alkaline peroxide oxidation 

 of the 2-mercaptopyrimidine. 



A more general method^^^ involves the heating (160°) of the sulfates of a 



«' L. F. Cavalieri, V. E. Blair, and G. B. Brown, /. Am. Chem. Soc. 70, 1240 (1948). 



"0 P. D. Landauer and H. N. Rydon, /. Chem. Soc. 1953, 3721. 



^" M. Gates, Chem. Revs. 41, 63 (1947). 



"« J. H. Speer and A. L. Raymond, /. Am. Chem. Soc. 75, 114 (1953). 



"« M. Hoffer, Jubilee Vol. Dedicated to Emil Christoph Barell, 1946, 428. 



