gem-Difluorination of Methylenecyclopropanes (MCPs) Featuring a Wagner–Meerwein Rearrangement: Synthesis of 2-Arylsubstituted gem-Difluorocyclobutanes

Abstract

The geminal difluorocyclobutane core is a valuable structural element in medicinal chemistry. Strategies for gemdifluorocyclobutanes, especially the 2-substituted cases, are limiting and often suffer from harsh reaction conditions. Reported herein is a migratory gem-difluorination of aryl-substituted methylenecycloproanes (MCPs) for the synthesis of 2-arylsubstituted gemdifluorocyclobutanes. Commercially available Selectfluor (F-TEDA-BF 4 ) and Py•HF were used as the fluorine sources. The protocol proceeds via a Wagner−Meerwein rearrangement with mild reaction conditions, good functional group tolerance, and moderate to good yields. The product could be readily transformed to gem-difluorocyclobutane-containing carboxylic acid, amine, and alcohol, all of which are useful building blocks for biologically active molecule synthesis.Letter pubs.acs.org/OrgLett

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

“…Very recently, Li and co‐workers described a Selectfluor – HF⋅py‐mediated Wagner−Meerwein‐type rearrangement of methylenecyclopropanes 344 leading to β,β‐difluorinated arylcyclobutanes 345 (Scheme 95). [264] Apart from various functionalized aromatic derivatives, the method was also used to obtain building blocks 312 , 315 , and 318 (n=1) via Ru‐catalyzed oxidation of the phenyl moiety. This reaction sequence was much shorter than that reported previously by our group [247] …”

Integrating I(I)/I(III) catalysis in reaction cascade design enables the synthesis of gem-difluorinated tetralins from cyclobutanols

“…In addition to the well-documented involvement of cyclopropylcarbinyl/bicyclobutonium cations 27 – 29 , direct fluorination of the proposed cyclobutonium species I would also account for the generation of homoallylic fluoride III . It is pertinent to note that Li and co-workers observed disparate reactivity when exposing aryl-substituted methylene cyclopropanes to Selectfluor® and HF: this triggered a Wagner-Meerwein rearrangement to generate difluorocyclobutanes 30 . In our postulated reaction sequence, the process of in situ substrate formation forges a 1,1-disubstituted alkene: this can then engage in an I(I)/I(III) catalysis cycle 31 , enabling a regioselective 1,1-difluorination 32 – 39 to occur via a precedented phenonium ion rearrangement 40 .…”

Fluorination of alkylidenecyclopropanes and alkylidenecyclobutanes: divergent synthesis of fluorinated cyclopropanes and cyclobutanes

“…10 A ring expansion of ACPs with selectfluor and Py·HF via a Wager–Meerwein rearrangement to afford gem -difluorocyclobutanes was achieved by Li's group (Scheme 1b). 11 Huang and co-workers realized the fluorohydroxylation of ACPs with NFS ( N -fluorosuccinimide) (Scheme 1c). Although the cyclopropane motif was retained in the reaction, several limitations still existed such as long reaction times (48 or 60 h), narrow substrate scope (only three examples) and moderate yields of the target products.…”