Recently, we developed a rapid procedure for the synthesis of various benzylformamides. We also investigated acetamide as an alternative solvent for the reaction. Interestingly, in the reaction conducted on 4-chlorobenzaldehyde, N-(4-chlorobenzyl)formamide was produced only as a minor product. The use of acetamide resulted in a substantial shift towards N,N-di-(4-chlorobenzyl)formamide and N,N,N-tri-(4-chlorobenzyl)amine that were produced with the isolated yields of 33.5% and 12.4%. N,N-di-(4-chlorobenzyl)formamide appeared to be the main product of the reaction. We hypothesized that the successful formation of the dibenzyl and tribenzyl products should correlate with electron density on the nitrogen atom of the respective benzylformamides. Therefore, the reaction conducted on benzaldehydes with electron-withdrawing substituents should result in a less pronounced shift towards dibenzyl and tribenzyl products. In this work, this hypothesis was tested on 2,4-dichlorobenzaldehyde. The reaction was conducted on 10 mmol scale at 198⁰C. Column chromatography was used for the isolation of the products of the reaction. NMR-spectroscopy and elemental analysis were used to determine the structure of the products. The reaction was fully completed in 1 minute. It produced N,N-di-(2,4-dichlorobenzyl)formamide and N,N,N-tri-(2,4-dichlorobenzyl)amine with the yields of 22.6% and 5.6%, respectively. N,N-(2,4-dichlorobenzylidene)-bis-acetamide appeared to be the major product of the reaction with the yield of 36.1%. As expected, electron-withdrawing substituents reduced the shift towards the dibenzyl and tribenzyl products. Research reported in this publication was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103442.

Acetamide as a solvent in the rapid synthesis of N-(2,4-dichlorobenzyl)formamide

249th National Meeting (2015)

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