CHEMISTRY OF PURINES AND PYRIMIDINES 133 



number of 4 , 5-diaminopyrimidines with an equivalent amount of formic 

 acid in excess foiTnamide in a sealed tube. Excellent, and in some cases 

 quantitative, yields of isoguanine, 2,6-diaminopurine, 2-mercapto- and 

 2-carboxymethylmercapto-adenine, and adenine are obtained in this pro- 

 cedure which is useful in isotopic syntheses.^^^-^^^'^^^ With the proper sul- 

 fates, direct formation of adenine, xanthine, guanine, and 2-methylhypo- 

 xan thine occur in excellent yield when only formamide is used/^^'^*^*^^ It is 

 of interest that both formic acid and formamide are required to convert 

 2-hydroxy-4 , 5 , 6-triaminopyrimidine sulfate into isoguanine. '^^ 



By the judicious choice of labeled intennediates such as formic acid, 

 urea, thiourea, formamidine, guanidine, cyanoacetic ester, malononitrile, 

 phenylazomalononitrile, acetamidocyanoacetic ester, etc., isotopes have 

 been introduced in nearly every position of purine molecules when the 

 various methods detailed above have been employed. Since C-8-labeled 

 purines may be made suitably from C'^- or C^^-formic acid in the last step 

 of the synthesis, considerable attention has been drawn to this type of 

 synthesis. It is found that the labeled formyl group of 4,6-diamino-5- 

 formamidopyrimidine sulfate exchanges with nonisotopic formyl groups 

 when the ring closure is carried out in formamide, and a 75 % diluted C-8- 

 labeled adenine results.''^* The report*"*^ of only a 20% dilution when A^- 

 formylmorpholine was substituted for formamide could not be confirmed^^'' 

 since a 50 % dilution was found upon reexamination. No dilution of the 

 resulting C-8-labeled adenine occurs when 4, 5, 6-triaminopyrimidine sul- 

 fate is heated with A^-formyl-C"-morpholine or when the dehydration of 

 4,6-diamino-5-C^*-formamidopyrimidine sulfate is carried out in diethanol- 

 amine at 210°.^^^ The above dilutions were tentatively explained on the 

 basis of a special type of exchange termed "reversible transformylation" 

 in which formylation of both the 4 (or 6)- and 5-amino groups was believed 

 to occur followed by a random deformylation during ring closure. Another 

 explanation lies in the possibility of a lability of carbon 8 in exchange re- 

 actions at elevated temperatures {ca. 200°) with carbon donors such as 

 formamide. An example of such an exchange is seen in the conversion of 

 uric acid into xanthine by means of hot formamide. ^^^ 



Some of the principles that have been discussed are illustrated below in 

 the synthesis of adenine labeled at N-1 and N-3 with N^^, and with C'^ 

 or C^^ at C-4, C-6, and 0-8:438.444 



4" L. F. Cavalieii and G. B. Brown, /. Am. Chem. Soc. 71, 2246 (1949), 



446 H. Bredereck, H.-G. von Schuh, and A. Martini, Chem. Ber. 83, 201 (1950). 

 448 V. M. Clark and H. M. Kalckar, /. Chetn. Soc. 1950, 1029. 



447 R. Abrams and L. Clark, /. Am. Chem. Soc. 73, 4609 (1951). 



