III. INDUSTRIAL PREPARATION 421 



Amines of any kind react with aqueous or alcoholic solutions of dithio- 



RNHo + HCSSK = RNH— CHS + KSH 



formates under very mild conditions. In the case of aniline or aminoquino- 

 line the \neld is quantitative; no yields are given for 2-methyl-4-amino-5- 

 aminomethylpyrimidine, but b,y analogy it must be assumed that the 

 yield is good. As sodium dithioformate is technically easily available with 

 good yields, this process offers a minimum of inconvenience for part 3 of 

 the synthesis of thiamine. The bad odor of unwanted sulfur compounds in 

 the reaction can be overcome by suitable engineering (closed reaction 

 vessels, centrifuges, and good ventilation of the working rooms). 



6. C + D, Ring Closure to the Thiazole Ring 



The ring closure between this formamide and the halogenated ketones 

 takes place easily (e.g., mixing the two components in the presence of a 

 small amount of alcohol and keeping the mixture for three days at room 

 temperature), but the yields were not too good at the beginning. Buchman 

 got 50 % 4-methyl-5-|S-hydroxyethyl thiazole,*^ about the same yield as 

 Clarke and Gurin" obtained for the 5-/3-ethoxy ethyl compounds. Using the 

 pure "ether" instead of the alcohol, Stevens and Stein^i could increase the 

 yield to 70 %. It can be assumed that the condensation of 7-chloro-7- 

 acetopropylacetate with thioformamide gives still better results. 



There w^as no lack of experiments to replace the thioformamide by raw 

 materials of easier accessibility. Ammonium dithiocarbaminate (from am- 

 monia and carbon dilsufide) condenses with the halogenated ketone to 

 2-mercapto-4-methyl-5-jS-acetoxyethyl thiazole (excllent yields are 

 claimed, but no figures are given); Spiegelberg*^ has shown that the mer- 

 captol group can be replaced by hydrogen when it is oxidized with 30% 

 hydrogen peroxide in acid solution to the sulfinic acid. Sulfur dioxide is 

 split off and oxidized by more hydrogen peroxide to sulfuric acid. The yield 

 is more than 75%; in the case of 2-morcapto-4-mothyl-5-/3-chloroethyl 

 thiazole it is 87%. Even with the relatively high price of the 30% hydro- 

 gen peroxide, the process seems promising for technical use. 



7. Linking the Two Ring Systems, Quaternization of the 

 Thiazole to Thiazolium 



Linking the two ring systems together (the final step of the thiamine 

 synthesis) offers little difficulty, especially when the pyrimidine compound 

 with bromine in the 7 position is used. 



*' J. R. Stevens and CJ. A. Htein, J. Am. Chcin.. Sor. 62, 101(1 (1940). 

 "H. Spiegelberg, British Pat. 492,637 (September 23, 1938); U. S. Pat. 2,179,984 

 (November 14, 1939). 



