Substituted pyrrolidines are common motifs in biologically active compounds. In medicinal chemistry programs, fluorinated pyrrolidines are increasingly being utilized in drug design due to their modulated basicity, lipophilicity and stability. These properties positively impact the biological performance of the compounds in which they are incorporated. For these reasons, efficient incorporation of fluorine and scalable synthesis of fluoropyrrolidines would impact many drug discovery programs.<br/><br/>To access these unique fluoropyrrolidines, we heavily utilize the [3+2] azomethine ylide cycloaddition reaction. In our programs, gamma and beta fluorinated pyrrolidines can be made from fluorinated olefins which are commercially available or easily prepared. We can also introduce fluorine in these positions post cycloaddition. Currently, there are few known reports of gem-difluoroolefins which participate in this [3+2] cycloaddition. Herein, we evaluated the conditions and scope of gem-difluoro olefins with a simple azomethine ylide to afford these unique fluorinated heterocycles.

[3+2] Cycloaddition reactions with a simple azomethine ylide to access unique fluorinated pyrrolidines

252nd National Meeting (2016)

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