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

• Published in: ACS catalysis 2020-12, Vol.10 (23), p.14117-14126
• Main Authors: Uno, Hiroto, Kawai, Koki, Shiro, Motoo, Shibata, Norio
• Format: Article
• Language: English
• ISSN: 2155-5435; 2155-5435
• DOI: 10.1021/acscatal.0c03927

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.