92 AARON BENDICH 



acid. Since no direct method has been developed for the preparation of substitution 

 derivatives ( — OH, — NH2 , etc.) of the 5-methyl group of pyrimidines,'" recourse has 

 been made to indirect methods*^"'" such as the Curtius technique. When this reaction 

 was applied to ethyl-2-ethylmercapto-6-hydroxypyrimidine-5-acetate, the 5-carbeth- 

 oxymethyl group was converted to the ethyl ester of the methylurethan ( — CH2- 

 COOC2H5 -> — CH2NHCOOC2H5) and the urethan was hydrolyzed with liberation of 

 ethyl mercaptan to yield S-aminomethj'luracil (or "thyminylamine," XXI). ^'-^^ This 

 compound (XXI) was converted to 5-hydroxymethyluracil (or "thyminyl alcohol," 

 XXII) by hydrolysis or nitrous acid deamination. ("Thyminyl alcohol," which should 

 prove to be identical with the deamination product of 5-hydroxymethylcytosine of 

 Wyatt and Cohen, ^* could not be prepared'' by the action of formaldehyde upon uracil.) 

 Both the 5-hydroxymethyl- and the 5-aminomethyluracils were unstable to treatment 

 with hot water, and in the case of the latter compound (XXI) a carbon-carbon cleavage 

 resulted with the formation of uracil, ammonia, and formaldehyde. The extreme in- 

 stability of these substances explains the difficulty '^ in preparing "absolutely pure" 

 specimens. A similar instability towards hydrolysis of substituted 5-aminomethylura- 

 cils is manifested by the cleavage of these compounds to uracil, formaldehyde, and a 

 substituted ammonia.'" The chloromethylation'^ of l,4-dimeth3'luracil with formalde- 

 hyde and HCl gives rise to l,4-dimethyl-5-chloromethyluracil which is also unstable 

 towards hot water and (presumably via a conversion to 5-hydroxymethyl) decomposes 

 into formaldehyde and an insoluble dimethyluracil condensation product.'^ A similar 

 behavior is described'^' *■* for 4-methyl-5-chloromethyluracil from which the unstable 

 5-hydroxymethylpyrimidine (XIX) has been prepared.*'' 



It will be pointed out in greater detail later that many analogies exist in the chemis- 

 try of pyrimidines and pyridines. For example, the 3 and 5 (or /3) positions of pyridine 

 and the chemistry of certain j8-substituted pyridines are often akin to those of carbon 

 5 of pyrimidines. However, the hydroxy or aminomethyl groups of pyridoxine (XVII) 

 and pyridoxamine (XVIIa) survive severe hydrolytic conditions with strong mineral 

 acid.9«-'8 



As to the stability of thiamine (XVI), most of the available data generally deal 

 with the integrity of the intact vitamin, rather than the stability of the carbon-carbon 

 linkage between C-5 of the pyrimidine and its side chain, but it might be mentioned 

 that thiamine can be heated to 120°C at pH 3.5 without any decomposition.'' The 

 reader is referred to excellent discussions of the chemistry of the vitamin. i""-'"' As for 



'« D. Riehl and T. B. Johnson, Rec. trav. chivi. 59, 87 (1940). 



'1 T. B. Johnson and A. Litzinger, /. Am. Chem. Soc. 57, 1139 (1935). 



'2 A. Litzinger and T. B. Johnson, /. Am. Chem. Soc. 58, 1936 (1936). 



'3 T. B. Johnson and A. Litzinger, J. Am. Chem.. Soc. 58, 1940 (1936). 



'^ R. C. Fuson and C. H. McKeever, in "Organic Reactions" (Adams, ed.). Vol. 1, 

 p. 63. Wiley, New York, 1942. 



'^K. Schmedes, Ann. 441, 192 (1925). 



'6 M. Hochberg, D. Melnick, and B. L. Oser, J. Biol. Chem. 155, 129 (1944). 



'^ E. Cunningham and E. E. Snell, J. Biol. Chem. 158, 491 (1945). 



'8 D. Melnick, M. Hochberg, H. W. Himes, and B. L. Oser, /. Biol. Chem. 160, 1 (1945). 



"Ref. 101, p. 104. 

 lo" R. R. Williams and T. D. Spies, "Vitamin Bi (Thiamin), and Its Use in Medicine." 



Macmillan, New York, 1938. 

 '"^ H. R. Rosenberg, "Chemistry and Physiology of the Vitamins." Interscience, New 



York, 1942. 

 '"* F. A. Robinson, "The Vitamin B Complex." Wiley, New York, 1951. 



