CHEMISTRY OF PURINES AND PYRIMIDINES 129 



h. Newer Methods 



A convenient method for the preparation of a variety of pyrimidines has 

 been developed by Whitehead.^^^ Urea, ethjd orthoformate, and ethyl 

 cyanoacetate condense when heated together to give ethyl ureidomethyl- 

 enecyanoacetate (XXXIX), in 69 % yield, and this in turn, by refluxing in 

 ethanol-sodium ethoxide, isomerizes quantitatively to 5-carbethoxycytosine 

 (XL). (Cf. Wheeler and Johns^-^ for a synthesis of XL by an indirect 

 method.) If ethyl malonate is used instead, diethyl ureidomethylenemalo- 

 nate (XLI) is formed; it can also be obtained by permitting urea and 

 ethoxymethylenemalonic ester to react at room temperature in ethanol- 

 sodium, ethoxide, luit the \deld is smaller. ^-^ XLI cyclizes to 5-carbethoxy- 

 uracil (XLII). 



CN 



H-CH-COOEt 

 + 

 NHj OEt CN 



C + CH 



NHo 

 NH."^CHCOOEt ''h?ft' N^^^°^' 



XJ 



//\ /\ (69%) = r PH '^^%) 



NHj EtO OEt ^ ^N^ "^ '"^ 



Urea Ethyl cyanoacetate + XXXIX XL 



Ethyl orthoformate Ethyl ureido- S-Carbethoxycytosine 



methylenecjanoacetate 



COOEt 

 I 

 H-CH-COOEt 

 + 

 NHj OEt 



I I 



C + CH 



// \ / \ 



NH2 EtO OEt 



Ethyl malonate + 

 Ethyl orthoformate 



OH 



(40%) \^ COOEt 



NH2 "^CHCOOEt "hTat" N 



NaOEt, L ^COOEt 



72%) 



XJ 



0-C^ ^CH ' ° HO N 



N 



XLI XLII 



Diethyl ureido- 5-Carbethoxyuracil 



methvlenemalonate 



NaOEt /rooni temp. 

 (22%) 



COOEt 



NHj ^C-COOEt 



I II 



C + CH 

 //\ I 



NH2 OEt 



Ethoxymethylene- 

 malonic ester 



