CHEMISTRY OF PURINES AND PYRIMIDINES 125 



weights of picrates. This method'*°^ was used to establish the molecular 

 weight of the aglycone (adenine) of cordycepin.^^^'^^^ Purines and pyrimi- 

 dines can be recovered from their picrates by extracting hj^drochloric acid 

 solutions of these salts with benzene or ether,"" -^"^ by the use of anion-ex- 

 change resins (cf . Davoll and Lowy^^^) or by saturating dry ether or acetone 

 suspensions with HCl gas; in the last procedure, the purines and pyrimidines 

 are often obtained as the crystalline hydrochlorides. 



m. Synthetic Methods 



It is a tribute to the ingenuity of the earlier workers that many of the 

 recent syntheses of pyrimidines and purines employing isotopes have been 

 fashioned from methods (see General References) devised by the earlier 

 workers. There have been a few newer developments, and emphasis shall 

 be given to these in the following sections. 



1. General Methods for Pyrimidines and for the Introduction of 



Isotopes 



Since they are cyclic amidines, pyrimidines have been synthesized by 

 condensing amidines, or substituted amidines such as ureas, thioureas, and 

 guanidines, with the appropriate compound containing at least three 

 carbon atoms in a chain. The latter include esters of malonic, acetoacetic, 

 cyanoacetic, and their substituted acids, or the free acids, /3-diketones, 

 a, /3-unsaturated esters, malononitrile, 1 ,3-dialdehydes, etc. Examples of 

 this type of synthesis were given for the preparation of thymine, uracil, 

 and orotic acid and have been adapted for the introduction of isotopes. ^^^ '^^g 

 Depending upon the choice of reactants, pyrimidines with varying degrees 

 of substitution may be obtained. For instance, guanidine and nitromalonal- 

 dehyde condense in mildly alkaline solution to give 2-amino-5-nitropyrimi- 

 dine which is hydrolyzed to 2-hydroxy-5-nitropyrimidine on boiling with 

 aqueous ammonia; the latter compound is prepared also from urea and 

 nitromalonaldehyde.^°^ 2-AminopyTimidine is formed by reacting guanidine 

 and iS-ethoxyacrolein acetal in ethanolic HCl.'*"^ Convenient sjTitheses of 

 uracil and isocytosine are afforded by the condensation, respectively, of 

 urea and guanidine with formylacetic acid (formed in situ from malic 

 acid) in fuming sulfuric acid.^"^-^'*® Similarly, thymine and 5-methyIisocy- 

 tosine are derived from ^S-methyhnalic acid.^°'' 



"1 K. G. Cunningham, W. Dawson, and F. S. Spring, J. Chem. Soc. 1951, 2305. 



"2 J. K. Parnas, Biochem. Z. 206, 16 (1929). 



«3 W. J. Hale and H. C. Brill, J. Am. Chem. Soc. 34, 82 (1912). 



*o* R. W. Price and A. Moos,"/. Am. Chem. Soc. 67, 207 (1945). 



"5 D. Davidson and O. Baudisch, J. Am. Chem. Soc. 48, 2379 (1926). 



"8 W. T. Caldwell and H. B. Kime, /. Am. Chem. Soc. 62, 2365 (1940). 



"7 H. W. Scherp, J. Am. Chem. Soc. 68, 912 (1946). 



