Rhodium‐Catalyzed Regio‐ and Diastereoselective [3+2] Cycloaddition of gem‐Difluorinated Cyclopropanes with Internal Olefins

Abstract

Direct synthesis of gem‐difluorinated carbocyclic molecules represents a longstanding challenge in organic chemistry. Herein, a Rh‐catalyzed [3+2] cycloaddition reaction between readily available gem‐difluorinated cyclopropanes (gem‐DFCPs) and internal olefins has been developed, enabling the efficient synthesis of gem‐difluorinated cyclopentanes with good functional group compatibility, excellent regioselectivity and good diastereoselectivity. The resulting gem‐difluorinated products can undergo downstream transformations to access various mono‐fluorinated cyclopentenes and cyclopentanes. This reaction demonstrates the use of gem‐DFCPs as a type of “CF2” C3 synthon for cycloaddition under transition metal catalysis, which provides potential strategy for synthesizing other gem‐difluorinated carbocyclic molecules.

Ligand-controlled regioselective cascade C–C/C–F cleavage/annulation of gem-DFCPs: a divergent synthesis of pyrroles

“…Based on the experimental results and previous reports, 7–9 a plausible mechanism was proposed for this reaction (Scheme 3). Initially, the strained gem -DFCP reacted with Pd 0 by oxidative addition to give palladium complex A , which would undergo a β-F elimination to afford the allyl-Pd II intermediate B .…”

“…5 Inspired by Fu's pioneering work, gem -DFCPs have emerged as reliable fluoroallyl precursors to construct monofluorinated alkenes with various nucleophiles (such as organoboronic acids, terminal alkynes, β-naphthols/indoles, arylsulfinates, simple arenes and in situ generated borylalkyl/-alkenyl species). 6 As one of the most important breakthroughs, 7 Li and Lv completely switched the regioselectivity to give branch-enriched fluorinated alkenes with the assistance of bulky N-heterocyclic carbene (NHC) ligands. 8 Intriguingly, Li and Lv observed an unexpected cyclization product when a less steric NHC ligand was used in the palladium catalyzed ring-opening reaction of gem -DFCPs with ketones.…”

Selectivity in Rh-catalysis with gem-difluorinated cyclopropanes

“…Consequently, we disclosed an Rh-catalyzed [3+2] cycloaddition reaction of gem -DFCPs with internal alkenes, resulting in a wide array of highly substituted gem -difluorinated cyclopentanes with three continuous stereocenters in a regio- and diastereoselective fashion (Scheme 12). 37 This reaction represents the first example with CF 2 remaining in gem -DFCPs under transition-metal catalysis with perfect atom economy. Notably, this new route allows the use of a wide range of internal alkenes with good functional group compatibility, even toward the trisubstituted ones.…”

CO2 and palladium enabled highly chemoselective hydroxylation of gem-difluorocyclopropanes

“…In this context, we considered gem -difluorocyclopropane electrophiles, 32–34 because these are known to readily react with potent nucleophiles under transition metal palladium catalysis. 35–55 However, selectively producing hydroxylated products without further reactions constitutes a considerable challenge. We thus designed a method for the hydroxylation of gem -difluorocyclopropanes, which is enabled by CO 2 and Pd(0)-catalysis, affording a large series of important fluorinated cinnamyl alcohols 56–69 from water.…”