N-Methylacetamide → N-[(4-Fluorophenyl)methyl]-N-methylacetamide

Participants

Reaction Steps

Slowly add a solution of 375 g (5.13 mol, 112 equiv) of N-methylacetamide in THF (1.76 L) to 224 g (5.55 mol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil) as a slurry in THF (8.75 L). After 30 minutes when 25% of the solution has been added, add 875 g (4.63 mole, 1 equiv) of 4-fluorobenzylbromide and the remaining N-methylacetamide and 4-fluorobenzylbromide solutions concurrently over the next 3 h. Use a water bath to maintain the temperature below 40° C. Stir the resulting mixture overnight and pour into a mixture of 20% NH4Cl (2.5 L), water (6.5 L), and ethyl acetate (9 L). Separate the layers and back-extract the aqueous layer with ethyl acetate (4.5 L, then 2 L). Combine the organic layers and wash with water (4 L) and then brine (7 L). Dry the organic layer (Na2SO4) and remove the solvent to afford a residue. Dissolve the residue in acetonitrile (7 L) and heptane (1.75 L). Separate the layers and wash the acetonitrile layer again with heptane (1.75 L). Combine the heptane layers and back-extract with acetonitrile (0.5 L). Combine the acetonitrile layers and evaporate to afford 0.814 kg of N-methyl-N-(4-fluorobenzyl)acetamide.

Provenance & Evidence