Modular Synthesis of Medium-Sized Fluorinated and Nonfluorinated Heterocyclic Lactones by Sequential CN-Bond-Cleaving Ring Expansion under Pd Catalysis

Fluoro-functionalized
heterocycles and medium-sized heterocycles
are both attractive skeletons in medicinal chemistry. However, the
construction of medium-sized fluoro-functionalized heterocycles remains
unexplored. Their synthesis represents a formidable challenge due
to the unfavorable entropic and enthalpic factors that arise from
medium-sized rings and the unexpected properties induced by fluorinated
groups. Here, we describe an efficient method for the preparation
of highly functionalized gem-difluoromethylene N-heterocyclic lactones with 9- to 11-membered rings in
a sequential CN-bond-cleaving ring-expansion process using difluoro-oxindoles,
various zwitterion precursors, and a Pd catalyst. This sequential
CN-cleaving expansion process was extended to synthesize nonfluorinated,
medium-sized heterocycles with an α-keto-lactone moiety using
isatin derivatives. Additionally, monofluorinated and nonfluorinated
oxindoles were transformed into the corresponding medium-sized heterocyclic
lactones using this protocol. The key for this transformation is the
cleavage of the unreactive amide CN bond, which is smartly activated
by the incorporation of two neighboring electron-withdrawing groups
assisted with the nucleophilic attack of a Pd-coordinated zwitterion.
The site-selective functionalization of a series of heterocyclic products
was demonstrated to show their synthetic utility. Mechanistic details
of the sequential cleavage/expansion process were proposed based on
liquid chromatography–mass spectrometry (LC–MS) analyses.