Rapid Synthesis of N-[1-(4-bromophenyl)ethyl]-N-methylformamide

Background: Recently, 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-chloroacetophenone and N-methylformamide was completed in 50 minutes and produced N-[1-(4-chlorophenyl)ethyl]-N-methylformamide with an isolated yield of 88%. The new procedure appeared to be much faster than the traditional Leuckart reaction that is usually completed within 3 to 6 hours. Hypothesis: Chlorine 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 chorine with bromine, 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-bromoacetophenone and N-methylformamide. Methods: The reaction was conducted on a 10 mmol scale at 180ºC - 184ºC. Extraction and column chromatography were used for the isolation of the product of the reaction. NMR-spectroscopy and elemental analysis were used to determine the structure of the product. Result: The reaction was completed in 75 minutes. The isolated yield of N-[1-(4-bromophenyl)ethyl]-N-methylformamide was 90%. Conclusion: The results of the reaction support the initial hypothesis that replacing chorine with bromine will slow down the Leuckart reaction. N-[1-(4-bromophenyl)ethyl]-N-methylformamide 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.