Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes

Abstract

Cross-electrophile coupling reactions involving direct C−O bond activation of unactivated alkyl sulfonates or C−F bond activation of allylic gem-difluorides remain challenging. Herein, we report a nickelcatalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic gem-difluorides to synthesize enantioenriched vinyl fluoridesubstituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry. Density functional theory (DFT) calculations demonstrate that there are two competing pathways for this reaction, both of which initiate by coordination of the electron-deficient olefin to the low-valent nickel catalyst. Subsequently, the reaction can proceed by oxidative addition of the C−F bond of the allylic gem-difluoride moiety or by directed polar oxidative addition of the alkyl mesylate C−O bond.

Nickel-catalysed chelation-assisted reductive defluorinative sulfenylation of trifluoropropionic acid derivatives

“…On the basis of the experimental results aforementioned and the previous reports, 1,2,6–14 we proposed a mechanism (Scheme 5). Initially, Ni 0 complex is formed under reductive reaction conditions, 1,2 followed by coordination and oxidative addition to a C–F bond of trifluoropropan esters 1 to form intermediate I .…”

“…Due to the strong chemical bond energy inherent in C(alkyl)–F bond, there have been fewer reported instances of C(alkyl)–F bond activation. 8 Several examples exist where Lewis acids or bases are employed to effectuate the cleavage of C(alkyl)–F bond. 9 Additionally, electrochemistry 10 and photochemistry 11 methodologies have been applied successfully to activate C(alkyl)–F bond through the generation of carbon radicals.…”

Nickel-Catalyzed Stereoselective Coupling Reactions of Benzylic and Alkyl Alcohol Derivatives

“…Upon subjection to the reaction conditions, we were pleased to see that mesylate 56 underwent nickel-catalyzed transformation to the desired fluorinated vinylcyclopropane 58 (Scheme 16). 36 During reaction optimization, we recognized that this transformation was significantly different than the XEC of 1,3dimesylates. For example, in the presence of zinc as the reducing agent, the nickel catalyst was still required.…”

Enantioselective Csp3-Csp3 formation by nickel-catalyzed enantioconvergent cross-electrophile alkyl-alkyl coupling of unactivated alkyl halides

“…Major challenges for the reaction are attributed to highly competitive homocoupling and protonation reactions of each alkyl electrophiles and the stereochemical control of the desired alkyl-alkyl cross-electrophile reaction ( 42 , 43 ). Inspired by the work on the racemic and intramolecular stereospecific cross-electrophile couplings between two alkyl electrophiles ( 27 , 31 , 44 – 47 ) , we herein report the enantioconvergent cross-electrophile coupling of two alkyl halides to furnish saturated tertiary carbon centers. The reductive conditions allow for the chemoselective cross-coupling of two different alkyl halides to build saturated alkylated tertiary carbon centers in high levels of enantioselectivity, representing a reaction mode for enantioselective alkyl-alkyl bond formation ( 48 , 49 ).…”