Rapid Synthesis of N-[1-(5-bromo-3-pyridyl)ethyl]formamide

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-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: Replacing acetophenone with acetylpyridine will introduce a more electronegative atom into the aromatic ring. It will reduce the electron density on the carbonyl and make it more reactive towards formamide in the Leuckart reaction, resulting in a shorter reaction time. In this work, the hypothesis was tested in the reaction between 3-acetyl-5-bromopyridine and formamide. Methods: The reaction was conducted on a 5 mmol scale at 180ºC - 199ºC. 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-(5-bromo-3-pyridyl)ethyl]formamide in good yield. Conclusion: The results of the reaction support the initial hypothesis that replacing acetophenone with acetylpyridine will accelerate the Leuckart reaction. The reaction provides a new method for the synthesis of N-[1-(5-bromo-3-pyridyl)ethyl]formamide. 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