Substituted fluoropyrrolidines are a popular motif in multiple medicinal chemistry programs.  Fluorine substituted pyrrolidines have advantages over their non-fluorinated comparators due to their modulated basicity, similar lipophilicity, similar size and increased stability.  These properties positively impact the biological performance of the compounds in which they are incorporated.  For these reasons, efficient and scalable synthesis of fluoropyrrolidines benefit drug discovery programs.Here, we report accessing novel 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide.  There are numerous examples of generating pyrrolidines by reacting an electron deficient alkene with azomethine ylides.  There are only a few examples in the literature of using this reaction to generate fluoropyrrolidines despite the fact that vinyl fluorides should be reasonable substrates for the dipolar cycloaddition.  We demonstrate that vinyl fluorides within a,�-unsaturated, styrenyl and even enolether systems can participate in the cycloaddition reaction.  The vinyl fluorides are relatively easy to make through a variety of methods and, therefore, the 3-fluoropyrrolidines are  very accessible.

Accessing novel 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with azomethine ylide precursor N-Benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine

248th National Meeting (2014)

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