130 AARON BENDICH 



A^-substituted ureas and other active methylene compounds (malononitrile, 

 acetoacetate, etc.) may also be used in this method. The application of the 

 newer reducing agents, lithium aluminium and boron hydrides, to the 5- 

 carbethoxy or 5-carboxy compounds might prove useful in the preparation 

 of 5-hydroxymethylpyrimidines (cf. Wyatt and Cohen^^'^"). In connection 

 with the free acid forms of XL and XLII, they are both transformed into 

 uraciP^® •■*27 by heating with 20% sulfuric acid at 160-170°, yet uracil-4- 

 carboxylic acid (orotic acid) is not decarboxylated at 200°.^" 



A new reaction of acetylene with nitriles leads to the synthesis of 2,4- 

 disubstituted pyrimidines.^^* For example, 2,4-dimethylpyrimidine results 

 when acetonitrile, potassium, and acetylene are autoclaved at 175-200°. 



2. General Methods for Purines and for the Introduction of 



Isotopes 



a. From Purines 



The syntheses and transformations in the purine series developed by 

 Fischer,^ some of which were discussed above, were based mainly upon 

 2,6,8-trichloropurine. The preparation of this valuable intermediate has 

 been improved considerably by using dimethylaniline in the reaction be- 

 tween uric acid and POCI3 .''^^ When a limited amount of triethylamine is 

 used in place of the dimethylaniline, 8-chloroxanthine is obtained from 

 monopotassium urate, and with an excess of triethylamine, 2,8-dichloro-6- 

 diethylaminopurine is formed.^^" The latter reaction may be of a general 

 nature since the hydroxyls of hypoxanthine and xanthine are all replaced 

 by diethylamino groups upon refluxing with triethylamine and POCI3 . 

 The resulting 6-diethylaminopurine is also prepared from 6-methylmer- 

 captopurine by heating with aqueous diethylamine in a sealed tube.'^° 



Other 6-aminopurines are formed smoothly upon reacting 6-methylmer- 

 captopurine with the appropriate amines, but, unlike the mercaptopyrimi- 

 dines, 6-mercaptopurine does not react satisfactorily. As with pyrimi- 

 dines,^'^'^'* 6-mercaptopurine is prepared by heating hypoxanthine with 

 P2S5 in tetralin.^^" Another synthesis that has a counterpart in the pyrimi- 

 dine series'*'^ is the direct formation of 6-mercaptopurine from 6-chloropu- 

 rine by boiling with alcoholic thiourea.^^® 6-Chloropurine (formed by react- 

 ing hypoxanthine with POCI3 in the presence of dimethylaniline) and 

 6-mercaptopurine are reduced to purine, respectively, upon catalytic hy- 



«6 C. W. Whitehead, /. Am. Chem. Soc. 74, 4267 (1952) ; 75, 671 (1953). 



«7 H. L. Wheeler and C. O. Johns, A7n. Chem. J. 38, 594 (1907). 



«8 T. L. Cairns, J. C. Sauer, and W. K. Wilkinson, /. Am. Chem. Soc. 74, 3989 (1952). 



«9 J. Davoll and B. A. Lowy, J. Am. Chem. Soc. 73, 2936 (1951). 



«« R. K. Robins and B. E. Christensen, /. Am. Chem. Soc. 74, 3624 (1952). 



