Rapid Synthesis of N-[1-(4-iodophenyl)ethyl]formamide

Background: Earlier, we developed a rapid procedure for the Leuckart reaction and successfully applied it for the synthesis of substituted N-(1-phenylethyl)formamides. Specifically, the reaction between 4-bromoacetophenone and unsubstituted formamide was completed in 15 minutes and produced N-[1-(4-bromophenyl)ethyl]formamide with an isolated yield of 75%. The new procedure appeared to be much faster than the traditional Leuckart reaction that is usually completed within 3 to 6 hours. Hypothesis: Bromine is a moderately electron-withdrawing group. It reduces the electron density on the carbonyl and makes it more reactive towards formamide in the Leuckart reaction. Replacing bromine with iodine, a less electron-withdrawing group, will make the carbonyl slightly less reactive and slow down the Leuckart reaction. In this work, the hypothesis was tested in the reaction between 4-iodoacetophenone and formamide. Methods: The reaction was conducted on a 5 mmol scale at 180ºC - 202ºC. Extraction and column chromatography were used for the isolation of the products of the reaction. NMR-spectroscopy and elemental analysis were used to determine the structures of the products. Result: The reaction was completed in 10 minutes and produced N-[1-(4-iodophenyl)ethyl]formamide in good yield. Conclusion: The reaction with 4-iodoacetophenone was completed even faster than the reaction with 4-bromoacetophenone because of the higher boiling temperature of the reaction mixture. N-[1-(4-iodophenyl)ethyl]formamide is a new compound. Support: Research presented in this presentation was supported by NIH grant 8 P20 GM103442-12 from the National Institute of General Medical Sciences and by the National Science Foundation under NSF EPSCoR Track-1 Cooperative Agreement OIA #1946202