Aniline, reaction with ethyl orthoformate

Aminomethylene derivatives of ketones and 1,3-dicarbonyls are used in order to incorporate a formyl group into CH-acidic heterocycles via initial reaction with ethyl orthoformate and aniline followed by hydrolytic cleavage, as is shown e.g. with barbituric acid301 (equation 224). 

The uncatalyzed reactions between anilines, ethyl orthoformate, and diethyl malonate afforded ethyl arylaminomethylenemalonamates (252) in 67-85% yields (87SC549). However, if the malonate was first reacted with ethyl orthoformate and acetic anhydride in the presence of a catalytic amount of ZnCl2 at boiling temperature for 5 hr and aniline was then added to the reaction mixture, reflux being maintained for 0.5 hr, arylaminomethylenemalonates (253) were obtained in 52-85% yields. 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

Reaction with primary arylamines. Investigations of Wichelhaus and of Claisen of the reaction of aniline with triethyl orthoformate were later clarified by Roberts and Vogt, who showed that by adjustment of the catalyst and the experimental conditions it is possible to produce in good yield any one of three products from the two reactants. The initial product in each use is ethyl N-phenylformimidate (1). 

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