Pd-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Unactivated Olefins by a Heck Reaction/Enolate Cyclization Cascade

We disclose a Pd-catalyzed reaction
protocol that regioselectively
difunctionalizes unactivated olefins with aryl iodides and tethered
enolates. The current method allows the rapid synthesis of a variety
of 1,3,4-trisubstituted pyrrolidinones from simple and readily available
amides. We further demonstrate this new method’s application
by postsynthetically modifying the arylacetic acid side chains of
two commercial nonsteroidal anti-inflammatory drugs, indomethacin
and tolmetin, to highly decorated 4-benzylpyrrolidinone frameworks.
Mechanistic studies reveal that the reaction proceeds via a Heck reaction/enolate
cyclization cascade, a process that exploits β-H elimination
in a constructive mode for regioselective 1,2-difunctionalization
of unactivated olefins.