Recent Advances in Transition Metal‐Catalyzed Functionalization of gem‐Difluoroalkenes

Abstract

gem-Difluorinated alkenes are readily accessible building blocks that can undergo functionalization to provide a broad spectrum of fluorinated and non-fluorinated products. Herein, we review recent (since 2017) transition metalcatalyzed transformations of these specialized alkenes and summarize general reactivity patterns of these reactions. Many transition metal-catalyzed reactions undergo net CÀ F bond functionalization reactions to deliver monofluorinated products. These reactions typically proceed through β-fluoroalkylmetal intermediates that readily eliminate a βfluoride to deliver monofluoroalkene products. A second series of reactions exploit coinage metal fluorides to add F À to the gem-difluorinated alkene, and further functionalization delivers trifluoromethyl-containing products. In stark contrast, few transition metal-catalyzed reactions proceed in net "fluorine-retentive processes" to deliver difluoromethylenebased products. Reactions Proceeding via β-Fluoride Eliminationgem-Difluoroalkenes react with a variety of transition metalbased catalyst systems (e. g. Cu, Co, Mn, Pd, Ni, Ru, Rh) in net CÀ F functionalization reactions. These reactions typically proceed through a β-fluoroalkylmetal intermediate that readily undergoes β-fluoride elimination to form a new alkene based product (Scheme 1). At first, reaction of a substrate-ligated complex (1) to the gem-difluoroalkene 2, proceeds through a four-membered transition state 3 to generate the intermediate 4. This process involves the matching of the anionic ligand (Y) with the cationic α,α-difluorinated position of the alkene, which generates an intermediate metalalkyl bearnig two βfluoride atoms. Subsequent β-fluoride elimination generates [a] S.Scheme 3. Plausible mechanism for defluoroborylation of aliphatic gem-difluoroalkenes. Scheme 4. CÀ F Bond borylation of gem-difluoroalkenes. Scheme 5. Copper-catalyzed trans-selective monodefluoroborylation of various gem-difluoroalkenes. Scheme 6. CÀ F Bond borylation of gem-difluoroalkenes. Scheme 7. Copper-catalyzed tunable multi-borylation reactions of gem-difluoroalkenes. In parentheses the ratio of 22, 23 and 24 is reported. Scheme 8. Stereoselective defluorinative borylation and silylation of gem-difluoroalkenes. Scheme 9. a) Synthesis of fluorinated vinylsilanes from gem-difluoro/ polyfluoroalkenes. b) Cross-coupling reaction of 29 b and iodobenzene. Scheme 10. Nickel-catalyzed fluoroalkenylation of unactivated alkylbromides. rr = The regioisomeric ratio of the benzylic fluoroÀ alkenylation product to the other regioisomers. DMA = N,N-Dimethylacetamide. Scheme 14. Iron-catalyzed defluorinative cross-coupling of donor alkenes with gem-difluoroalkenes. Dibm = diisobutyrylmethane. Scheme 15. Nickel-catalyzed reductive aryl monofluoroalkenylation of alkenes. Scheme 16. Plausible mechanism for reductive aryl monofluoroalkenylation of gem-difluoroalkenes. Scheme 17. Nickel-catalyzed hydroalkenylation of alkynes through oxidative cyclization and β-fluoride elimination. Scheme 28. Ruthenium-catalyzed fluoroal...

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes

“…Despite the large body of literature of reactions that proceed through organo-transition-metal intermediates 239 that undergo -fluoride elimination to generate monofluorinated alkenes, [1][2][3] Pd-based catalyst systems can preferentially eliminate an alternate tethered group, such as an acetate, a hydride, or a halide (Cl, Br, I), as predicted by previous computational experiments (Scheme 38). 85…”

“…For example, S N 2′ reactions of gem-difluoroalkenes bearing allylic leaving groups circumvented -fluoro anionic intermediates, thus avoiding the potential for fluoride elimination (Scheme 3). 23,24 Scheme 1 Overview of gem-difluoroalkene reactivity β-Fluoride Elimination R 1 F F R 2…”

“…One potentially useful building block for accessing difluoromethylenes are gem-difluoroalkenes 1 that can be readily accessed by many strate-gies, such as Wittig-type difluoromethylenation, Julia-type and Horner-Wadsworth-Emmons-type difluoroolefination, -elimination of functionalized difluoromethyl compounds, -fluoride elimination from trifluoromethyl compounds, and transition-metal-catalyzed cross-coupling. [1][2][3] Additionally, gem-difluoroalkenes react with high selectivity for a broad-spectrum of functionalization reactions, and in these reactions, the fluorine atoms differentially polarize the termini of the alkene, which in turn enables selective functionalization reactions using many strategies (Scheme 1). First, the -carbon is electron-rich and nucleophilic, which is readily explained by negative hyperconjugative resonance effects.…”

“…First, the -carbon is electron-rich and nucleophilic, which is readily explained by negative hyperconjugative resonance effects. 1,2,4,5 Thus, gem-difluoroalkenes can react with electrophiles typically at the difluorinated position to generate resonance-stabilized cationic intermediates 2 or cationic halonium or thiiranium intermediates 3 that can undergo subsequent reactions with nucleophiles to deliver difunctionalized products (Scheme 1A). Second, gem-difluoroalkenes, bearing two inductively electron-withdrawing fluorine atoms, are intrinsically electrophilic at the difluorinated position, and thus typically react with anionic nucleophiles and nucleophilic radicals with high regioselectivity at the difluorinated carbon.…”

“…One potentially useful building block for accessing difluoromethylenes are gem-difluoroalkenes 1 that can be readily accessed by many strate-gies, such as Wittig-type difluoromethylenation, Julia-type and Horner-Wadsworth-Emmons-type difluoroolefination, -elimination of functionalized difluoromethyl compounds, -fluoride elimination from trifluoromethyl compounds, and transition-metal-catalyzed cross-coupling. [1][2][3] Additionally, gem-difluoroalkenes react with high selectivity for a broad-spectrum of functionalization reactions, and Jacob Sorrentino is a graduate student in the Altman group pursuing a Ph.D. in medicinal chemistry from The University of Kansas (KU). Jacob earned his B.Sc.…”