414 THIAMINE 



sodium and ethyl formate to sodioformylethoxypropionate, using the crude 



CH2=CH— COOEt ^ EtO— GH2— CH2— COOEt 



+ HCOOEt + Na -^ EtO— CHo— C: (CHONa)COOEt 



sodium salt for the ring closure. In the form given by these authors the 

 method is not satisfactory, as formylation and ring closure (see under c) 

 give very poor yields. 



Todd and Bergel'^ formylate cyanoacetic ester in acetic anhydride with 

 ethyl orthoformate to ethoxymethylene cyanoacetic ester.-^ No yield is 



CN— C: (CHOEt)COOEt 



given, but from the abimdant work of Claisen it can be assumed that the 

 reaction goes well. 



An alternative route of the same authors is slightly longer but offers 

 certain advantages at the ring closure. Here ethyl malonate is condensed 

 with ethyl orthoformate in the presence of zinc chloride with a yield of 

 about 60 %, as shown by Claisen." 



EtOOC—C: (CHOEt) COOEt 



In the method of Andersag and WestphaP^ one more carbon atom is 

 added by starting from ethyl succinate to formyl ethyl succinate. The 

 yield of this formylation (60 to 70%) is satisfactory (Wislicenus et al}^). 



EtOOC— CHo— CH(CHO)COOEt 



b. Direct Introduction of the Amino Group in the 4 Position 



The more reactive the methylene group in this series, the better the 

 yield at the formylation. Grewe^'' formylated malonitrile with orthoformic 

 ester in acetic anhydride to ethoxymethylene malonitrile 



HC(0Et)3 + CN— CH2— CN = CN— C:(CHOEt)CN + 2EtOH 



As Diels et al^^ have shown, a yield of 75 % of ethoxymethylene malonitrile 

 can easily be obtained. 



Starting material for malonitrile is chloroacetic acid w liich is converted 

 to ethyl cyanoacetate with 77 to 80 %}'' The next step, cyanoacetamide, 

 gives a yield of 86 to 88 %,•*'* and the conversion of the amide to the nitrile 



26 G. de Bollemont, Compt. rend. 128, 1340 (1899); Bull soc. chim. de Paris 25. 20 



(1901). 

 " L. Claisen, Arm. 297, 76 (1S97). 



28 H. Andersag and K. Westphal, Her. 70, 20;«, 2036 (1937). 



29 W. Wislicenus, E. Boklen, and F. ReuMie, A,,,,. 363, 317 (190S). 



30 R. Grewe, Z. physiol. Chem. 242, 89 (1936). 



=" O. Diels, II. Gartner, and R. Kaack, Her. 35, 3141 (1922). 



32 Organic Syntheses Vol. 1, p. 254. John Wiley ;uul Sons, New York, 1941. 



33 Organic Syntheses, Vol. 1, p. 179, John Wiley and Sons, New York, 1941. 



