Background: Recently, we developed a rapid procedure for the Leuckart reaction and successfully applied it for the synthesis of substituted N-benzyl-N-methylformamides. Interestingly, in the reaction conducted on 3-chlorobenzaldehyde, a large amount of a by-product, N,N-di-(3-chlorobenzyl)-N-methylamine was produced with an isolated yield of 32.6%. N-(3-chlorobenzyl)-N-methylformamide was produced with an isolated yield of 41.8%. The ratio of the yield of the dibenzyl product to the yield of the monobenzyl product was 1:1.28. Hypothesis: Based on the higher electronegativity of the fluoro group, the reaction with 3-fluorobenzaldehyde may produce a lower yield of the respective N,N-dibenzyl-N-methylamine and a higher yield of the respective N-benzyl-N-methylformamide. Methods: The reaction was conducted on 10 mmol scale at 188°C. Column chromatography was used for the isolation of the products of the reaction. NMR-spectroscopy and elemental analysis were used to determine the structures of the products. Results: The reaction was completed in 10 minutes. The isolated yield of N,N-di-(3-fluorobenzyl)-N-methylamine (32.2%) appeared to be very close to the yield of N,N-di-(3-chlorobenzyl)-N-methylamine in the previous reaction. However, the isolated yield of N-(3-fluorobenzyl)-N-methylformamide (62.5%) was approximately 20% higher than the yield of N-(3-chlorobenzyl)-N-methylformamide. The ratio of the yield of the dibenzyl product to the yield of the monobenzyl product was 1:1.94. Conclusions: The results of the reaction support the initial hypothesis. The reaction provides a new method for the synthesis of N-(3-fluorobenzyl)-N-methylformamide and N,N-di-(3-fluorobenzyl)-N-methylamine. Both products of the reaction are new compounds. Support: The project was supported by NIH grant 8 P20 GM103442-12 from the National Institute of General Medical Sciences.

Rapid Synthesis of N-(3-fluorobenzyl)-N-methylformamide

255th National Meeting (2018)

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