Sterically Controlled Cu-Catalyzed or Transition-Metal-Free Cross-Coupling of gem-Difluoroalkenes with Tertiary, Secondary, and Primary Alkyl Grignard Reagents

Abstract

A robust copper-catalyzed or transition-metal-free cross-coupling of gem-difluoroalkenes with tertiary, secondary, and primary alkyl Grignard reagents has been developed. Remarkably, the tertiary and secondary alkylation of gem-difluoroalkenes proceeded very smoothly in the presence of 25 mol % of CuCN or under transition-metal-free conditions, affording the tertiary and secondary alkyl-substituted fluoroalkenes in good to excellent yields with excellent Z stereoselectivity.

Palladium-Catalyzed Cross-Coupling of Gem-Bromofluoroalkenes with Alkylboronic Acids for the Synthesis of Alkylated Monofluoroalkenes

“…Further examination revealed that a decrease in the reaction temperature reduces the reaction efficiency (entries [11][12]. Common ligands of palladium were tested (entries [13][14][15][16][17], and bidentate bisphosphines and, above all, those with large P-Pd-P bite angles appeared to be essentials [37]. Under some conditions, (E)-isomer reacts faster than the corresponding (Z)-isomers in Pd-catalyzed coupling reactions (entries 3, 5, 16).…”

“…Pioneering studies to obtain alkyl-substituted monofluoroalkenes were focused on classical olefination (Wittig, Horner-Wadsworth-Emmons or Julia Kocienski reaction) [11,12], electrophilic fluorination or fluorination of alkynes [13][14][15][16]. More recently, transition metal-catalyzed defluorinative alkylation of gem-difluoroalkenes [17][18][19][20][21] or gem-difluorocyclopropanes [22][23][24] with various carbon nucleophiles has proven to be efficient strategies to access alkylated monofluoroalkenes. In the meantime, photoredox monofluoroalkenylation of gem-difluoroalkenes has also been successfully applied for their syntheses [25][26][27][28].…”

Synthesis of Monofluoroalkenes: A Leap Forward

“…In 2016, the Cao group synthesized (Z)-monofluoroalkenes using Grignard reagents and gem-difluoroalkenes (Scheme 97). 113 In the case of tertiary ( 3 R) and secondary ( 2 R) alkyl Grignard reagents, the reaction gave similar yields in the presence or absence of a catalytic amount of CuCN. For primary ( 1 R) alkyl Grignard reagents, it was important to omit the copper catalyst as double addition was observed; otherwise, no stereoselectivity was observed for primary alkyl Grignard reagents.…”

“…In 2016, the Cao group developed a system for the addition-elimination of Grignard reagents to polyfluoroalkenes in the presence of a copper salt (Scheme 237). 113 When (1,2,2-trifluorovinyloxy)arenes were used as the starting material, dialkylation occurred to afford 2-fluorovinyl ethers in high yields with exclusive formation of the E isomer.…”

Rhodium‐Catalyzed Defluorinative Vinylation of gem‐Difluoroalkenes for the Synthesis of 2‐Fluoro‐1,3‐dienes

“…In this regard, gem ‐difluoroalkene represents a useful reaction component as that is easily available from aldehydes, ketones, alkyl halides, trifluoromethyl allyl/propargyl/alkenyl carbonates and diazo compounds. Such fluorinated alkene has been employed as a versatile building block, with which a large variety of mono‐fluoroalkenes featuring synthetically important functionalities, including aryl, alkyl, alkynyl, cyano, trifluoromethyl, as well as heteroatoms, have been successfully prepared through transition‐metal‐catalyzed or radical‐engaged functionalization of the classically considered inert C—F bond. Among the established protocols, C—H activation coupled C—F bond functionalization is of particular interest because of the outstanding efficiency and broad substrate scope.…”