CHEMISTRY OF PURINES AND PYRIMIDINES 127 



been developed, and some of these have been mentioned above. A wide 

 variety of 2,4- and 6-hydroxypyrimidines including uracil, 5-nitro-, and 

 4-methyluracil, barbituric acid, 6-amino-4-hydroxy-2-methylthiopyrimi- 

 dine, etc. are converted by means of POCI3 into the corresponding chloro 

 derivatives. (A considerable improvement in the chlorination procedure 

 involves the addition of dimethylaniline to the reaction mixtures.^^^'^^^'^''^-^'*) 

 Any or all of the chloro atoms of these compounds are often readily replaced 

 by hydrogen or by amino, mercapto, alkoxy groups, etc. (cf. Johnson and 

 Hahn'^). For example, 2,6(or 4)-dichloropyrimidine and benzenesulfon- 

 hydrazide condense smoothly and the resulting hydrazino derivative is 

 converted to pyrimidine upon alkaline hydrolysis.'*'^ Dechlorination may 

 also be effected by catalytic hydrogenation, or reduction with phosphonium 

 iodide or zinc and water, thus making available many new pyrimidines.'^"'- 



286,312,317,415 



Amination of chloropyrimidines usually proceeds smoothly, and, in the 

 cases of 5-nitro-2,6-dichloropyrimidine and its 4-methyl homologue, re- 

 placement of only the 6-chloro atom by an amino group may be 

 effected.i'^'286 However, amination of other 2 ,6(or 4)-dichloro- or -diethoxy- 

 pyrimidines leads to mixtures of monoamino isomers'^ and a method utiliz- 

 ing mercapto derivatives has been developed which obviates this difficulty. 



The mercapto derivatives have been prepared by total synthesis involving 

 thiourea or substituted thioureas in the type of condensation discussed 

 above, and through the replacement of chloro atoms by alkali hydrosul- 

 fides.'^'*'''^^* A new method, bypassing the halogenated pyrimidines, de- 

 pends upon the direct thiation of uracils by heating with phosphorus penta- 

 sulfide in an inert medium such as xylene or tetrahn.^'^'^'* The resulting 

 2,6-pyrimidinedithiols usually lead to 6-amino-2-pyrimidinethiols exclu- 

 sively upon reaction with ammonia or amines.^" Thus, the dithiol com- 

 pounds derived from uracil and thjmine give excellent yields of 2-cytosine- 

 thiol and 5-methyl-2-cytosine-thiol, respectively.^'^ •'*'* These compounds, 

 in turn, are converted to cytosine and 5-methylcytosine^'^ '^'^ by an appli- 

 cation of the Wheeler-Liddle desulfurization technique. ^'^^ The reactions are 

 illustrated : 



«* J. Baddiley and A. Topham, J. Chem. Soc. 1944, 678. 



«5 M. P. V. Boarland, J. F. W. McOmie, and R. N. Timms. J. Chem. Soc. 1952, 4691. 



«« G. B. Elion and G. H. Hitchings, J. Am. Chem. Soc. 69, 2138 (1947). 



*" P. B. Russell, G. B. Elion, E. A. Falco, and G. H. Hitchings, /. Am. Chem. Soc. 71, 



2279 (1949). 

 «8 D. J. Brown, J. Soc. Chem. Ind. (London) 69, 353 (1950). 

 "9 G. H. Hitchings, G. B. Elion, E. A. Falco, and P. B. Russell, /. Biol. Chem. 177, 



357 (1949). 



