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

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-iodoacetophenone and formamide was completed in 10 minutes and produced N-[1-(4-iodophenyl)ethyl]formamide in good yield. The new procedure appeared to be much faster than the traditional Leuckart reaction that is usually completed within 3 to 6 hours. Later, we also conducted the reaction between 4-iodoacetophenone and N-methylformamide. The reaction appeared to be much slower and was completed only in 30 minutes. The results indicated that the size of the substituent attached to the nitrogen atom of formamide plays the major role in determining the rate of the reaction. Hypothesis: Since the ethyl group in N-ethylformamide is larger than the methyl group in N-methylformamide, the reaction between 4-iodoacetophenone and N-ethylformamide will proceed even slower than the reaction between 4-iodoacetophenone and N-methylformamide. Methods: The reaction was conducted on a 5 mmol scale at 180-200 centigrades. 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 40 minutes and produced N-[1-(4-iodophenyl)ethyl]-N-ethylformamide in good yield. Conclusion: The results of the reaction support the initial hypothesis. 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.