Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines

Although there are many synthetic
methods to produce fluorinated
and trifluoromethylated organic structures, the construction of difluoromethylated
compounds remains a synthetic challenge. We have discovered that unactivated
imines will react with difluoroenolates under exceedingly mild conditions
when using magnesium salts and organic bases. We have applied this
approach to the iminoaldol reaction to produce difluoromethylene groups
as α,α-difluoro-β-amino-carbonyl groups. This method
provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones
without the need of protecting groups or the use of activated imines.
Moreover, we have applied this strategy to create analogues of the
dual orexin receptor antagonist, almorexant, in only two synthetic
steps.