126 AARON BENDICH 



An interesting synthesis of thymine, shown below, was developed by 

 Bergmann and Johnson /°* Urea and methylcyanoacetic acid are heated 

 with acetic anhydride to give methylcyanoacetylurea (XXXVIII), which, 

 as expected, rearranges under the influence of aqueous alkali to yield 4- 

 aminothymine. However, XXXVIII absorbs one mole of hydrogen in the 

 presence of a platinum catalyst to give anunonia and thymine: 



O 



OH II OH 



CH3 H C CH3 I CH3 



\ / \ / 



N CH "= . N 



N 



NaOH 



Pt 



+ NH3 



/\N/\ C CN /^N' 



HO NH2 /' \ HO 



O NH2 



XXXVIII 

 4-Aminothymine Methylcyanoacetylurea Thymine 



This reaction is based upon a similar conversion of cyanoacetylurea to 

 uracil and ammonia^'^^ under reducing conditions (H2 and a nickel catalyst) . 

 It was believed^"^ that the cyano group was first reduced to an imino group, 

 which in turn was hydrolyzed to ammonia and an aldehydo group prior to 

 cyclization. Although this explanation is plausible, it does not receive sup- 

 port from the catalytic reduction of 4-aminouracil to uracil.^^° Cyanoacetyl- 

 urea is prepared by the action of phosphorus oxychloride upon urea and 

 cyanoacetic acid'^ and undergoes a base-catalyzed ring closure to 4-amino- 

 uracil. The latter is also made by refluxing urea and cyanoacetic ester in 

 ethanol containing sodium ethoxide/" 



Urea (N'^) and cyanoacetal [(C2H60)2CHCH2CN] condense in boihng 

 butanol in the presence of sodium butoxide to give an intermediate ureide 

 which cyclizes to 1,3-labeled cytosine upon acidification. *^2 j^ a similar 

 manner, guanidine (N'^) affords isotopically labeled 2,4(or 6)-diamino- 

 pyrimidine.'*^' Other examples of this type of synthesis are given below in 

 the section on purines. 



a. Transformations; the Value of Halogen and Mercapto Derivatives 



Because certain pyrimidines are difficult to prepare by more direct means, 

 a number of transformations of more easily accessible compounds have 



"8 W. Bergmann and T. B. Johnson, J. Am. Chem. Soc. 55, 1733 (1933). 



"9 H. Rupe, A. Metzger, and H. Vogler, Helv. Chim. Acta 8, 848 (1925). 



*!" J. C. Ambelang and T. B. Johnson, /. Am. Chem. Soc. 63, 1934 (1941). 



«i M. Conrad, Ann. 340, 310 (1905). 



*i2 A. Bendich, H. Getler, and G. B. Brown, /. Biol. Chem. 177, 565 (1949). 



^'3 A. Bendich, W. D. Geren, and G. B. Brown, /. Biol. Chem. 185, 435 (1950). 



