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 metal-catalyzed transformations of these specialized alkenes and summarize general reactivity patterns of these reactions. Many transition metal-catalyzed reactions undergo net C–F bond functionalization reactions to deliver monofluorinated products. These reactions typically proceed through β-fluoro alkylmetal intermediates that readily eliminate a β-fluoride to deliver monofluoroalkene products. A second series of reactions exploit coinage metal fluorides to add F⁻ 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 difluoromethylene-based products.

1. Introduction

gem-Difluoroalkenes are valuable fluorinated substructures and can be applied for the preparation of pharmaceuticals, agrochemicals, and materials.¹ In addition, this substructure can serve as a bioisostere for the carbonyl group,² and can be found in some biologically active compounds.³ For multiple decades, gem-difluoroalkenes have served as irreversible electrophilic warheads for inhibiting various enzymes.⁴ In both biological and synthetic systems, this reactivity derives from the two sigma-withdrawing fluorine atoms that activate the alkene at the alpha position for attack by nucleophiles. This fundamental reactivity enables the gem-difluoroalkenes to serve as intermediates for a broad spectrum of synthetic transformations (e.g. coupling reaction, condensation, addition-elimination, polymerization, hydrodefluorination) that deliver diverse functional groups, including fluorinated alkene, indole, ester, carboxylic acid,⁵ methylene, cyclopropane, and methyl groups.⁶ gem-Difluoroalkenes also serve as synthetic precursors for the preparation of polymers.⁷ In the last couple of decades, several reviews summarize syntheses of gem-difluoroalkenes,^6,8 whereas only three previous reviews summarize reactions of gem-difluoroalkenes.⁹ Of these reviews, the most recent one presented both the synthesis as well as C–F functionalization reactions of gem-difluoroalkenes.^9c However, the last three years have witnessed many advancements in transition metal-catalyzed functionalization of gem-difluoroalkenes to generate many substructures. As such, we herein summarize the transition metal-catalyzed reactions of gem-difluoroalkenes that functionalize the difluoroalkene group after 2017.^9c This review further excludes reactions of gem-difluoroalkenes that either (i) bear an enolate substructure that perturbs the electronic character of the difluoroalkene,¹⁰ and that (ii) do not directly convert the gem-difluoroalkene to another functional group (e.g. the reaction occurs at a different functional group in the molecule).¹¹ Generally, these transition metal-catalyzed reactions of gem-difluoroalkenes typically participate in defluorination reactions that involve a facile β-fluoride elimination step. In a second series of reactions, AgF and CuF promote the addition of fluoride in a net difunctionalization reaction to generate secondary trifluoromethane-derived products. In contrast, few reactions involve fluorine-retentive processes to deliver products bearing the difluoromethylene groups.

2. Reactions Proceeding via β-fluoride Elimination

gem-Difluoroalkenes react with a variety of transition metal-based catalyst systems (e.g. Cu, Co, Mn, Pd, Ni, Ru, Rh) in net C–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 β-fluoride atoms. Subsequent β-fluoride elimination generates monofluoro-substituted alkene product 5. In these reactions, the generation of a strong M–F bond thermodynamically drives the reactions, and the syn-elimination of M–F typically occurs from an intermediate that minimizes steric clashes to generate a Z-fluoroalkene with a thermodynamically preferred trans arrangement between the vicinal non-fluorinated substituents.

Scheme 1.

Overview of reactions proceeding through β-fluoride elimination pathways.

2.1. Borylation and Silylation

Several Cu-based catalyst systems promote defluorinative borylation reactions of gem-difluoroalkenes. For example, aliphatic gem-difluoroalkenes (6) undergo defluoroborylation by a Cu^I catalyst and Xantphos ligand in presence of (Bpin)₂ as a borylating reagent and KO^tBu as a base (Scheme 2).¹² These reactions generate α-boryl-α-fluoroalkenes (7) in high stereoselectivity for the Z-stereoisomer, and the products were isolated after conversion to the corresponding trifluoroborates (8).

Scheme 2.

Copper-catalyzed defluoroborylation of aliphatic gem-difluoroalkenes.

Initially, CuCl, ligand and KO^tBu formed Cu^I alkoxide 9, which subsequently reacted with diboron compound to form boryl-Cu^I intermediate 10. Then, a four-centered reaction of boryl-Cu^I and gem-difluoroalkene generated the alkyl-Cu^I complex 11, which underwent a β-fluoride elimination to deliver defluoroborylated product (Z)-7 and Cu^I fluoride 12. In the final step, Cu^I fluoride 12 reacted with diboron and KO^tBu to regenerate the transmetallated active boryl-Cu^I complex 10 (Scheme 3).

Scheme 3.

Plausible mechanism for defluoroborylation of aliphatic gem-difluoroalkenes.

In another report a CuOAc-catalyzed stereoselective borylation of gem-difluoroalkenes yielded numerous (Z)-fluorinated alkenyl pinacol boronate esters at room temperature (Scheme 4).¹³ This reaction functioned similarly to that previously discussed (Scheme 3), but instead of aliphatic gem-difluoroalkenes aromatic congeners were used.

Scheme 4.

C–F Bond Borylation of gem-difluoroalkenes.

A Cu^I-catalyzed defluoroborylation of gem-difluoroalkenes delivered various fluoroalkenyl molecules (Scheme 5).¹⁴ Depending upon the electronic character of the gem-difluoroalkene, two distinct boron-based reagents were used. Borylation of gem-difluoroalkenes (15) bearing an electron-deficient aryl groups occurred using (Bpin)₂, while gem-difluoroalkenes with an electron-rich aryl groups occurred using (Bnep)₂. Moreover, the (fluoroalkenyl)-boronic ester products (16 or 16’) were further derivatized to afford the corresponding potassium trifluoroborate salts (17) by reacting with KHF₂ in MeOH. These reactions followed the same reaction mechanism previously discussed (Scheme 3).

Scheme 5.

Copper-catalyzed trans-selective monodefluoroborylation of various gem-difluoroalkenes.

gem-Difluoroalkenes reacted with CO₂ in the presence of alkenylboronic acid pinacol esters using a Cu^I-based catalyst system and Xantphos as a ligand to afford a variety of valuable α-fluoroacrylic acids and α-fluoroacrylates (20, Scheme 6).¹⁵ This one-pot formal ipso monocarboxylation of the C–F bond occured with high (Z)-selectivity and probably involved fluorinated boronate esters (19) as the key intermediate.

Scheme 6.

C–F Bond Borylation of gem-difluoroalkenes.

Cu^I-based catalyst systems also promote chemoselective poly-borylation of gem-difluoroalkenes through a dual C–F bond activation process (Scheme 7).¹⁶ These reactions were tuned to selectively deliver 1,2-alkyldiboronates (22), 1,1,2-alkyltriboronates (23) and 1,1,1,2-alkyltetraboronates (24) by optimizing Cu-based salts, additives, solvents and temperatures. Interestingly, Xantphos was used as a ligand in all three optimized conditions. The multi-borylated products generated after these reactions, were further functionalized to provide other useful building blocks.

Scheme 7.

Copper-catalyzed tunable multi-borylation reactions of gem-difluoroalkenes. In parentheses the ratio of 22, 23 and 24 is reported.

Defluorinative borylation and silylation of gem-difluoroalkenes also occur the using Cu-based catalyst systems with different oxidation states and using a spectrum of ligands and additives (Scheme 8).¹⁷ A CuCl₂ and DPEphos derived system facilitate the borylation reaction, whereas a CuCl and PCy₃ derived system favored the silylation. Of note, the defluorinative silylation did not function with the aliphatic gem-difluoroalkene to give the silylated product (26i), whereas borylation worked on the aliphatic system to afford product 27i in 50% yield. The mechanisms for these reactions likely match the aforementioned Scheme 3 that involved a regioselective olefin insertion followed by a syn-coplanar β-fluoride elimination.

Scheme 8.

Stereoselective defluorinative borylation and silylation of gem-difluoroalkenes.

gem-Difluoroalkenes, tetrafluoroethylene and other polyfluoroalkenes underwent a Cu-catalyzed C–F bond defluorosilylation reaction to produce a number of (Z)-selective vinylsilanes (29, Scheme 9a).¹⁸ The generated (trifluorovinyl)phenyldimethylsilanes (29b) could be further used as a partner in a cross-coupling reaction with iodobenzene to afford α,β,β-trifluorostyrene (31, Scheme 9b).

Scheme 9.

a) Synthesis of fluorinated vinylsilanes from gem-difluoro/polyfluoroalkenes. b) Cross-coupling reaction of 29b and iodobenzene.

2.2. Alkylation and Alkenylation

A regio- and stereoselective convenient nickel-catalyzed reductive coupling reaction of unactivated alkyl bromides with gem-difluoroalkenes generates α-benzyl fluoroalkenes (Scheme 10).¹⁹ This reaction delivered diversely functionalized monofluoroalkenyl derivatives (40) through a distinctive catalytic cycle that combined alkyl-Ni chain-walking with defluorinative coupling.

Scheme 10.

Nickel-catalyzed fluoroalkenylation of unactivated alkylbromides. rr = The regioisomeric ratio of the benzylic fluoro-alkenylation product to the other regioisomers. DMA = Dimethylacetamide.

The reaction initiated through oxidative addition of the C–Br bond to Ni⁰ complex 35 to form Ni^II complex 36. Next, single-electron reduction of complex 36 by Mn⁰ and subsequent chain-walking furnished Ni^I complex 39 bearing a Ni–C bond at the stabilized benzylic position. Subsequent coordination of gem-difluoroalkene 32 generated Ni^I intermediate 40, which underwent regioselective migratory insertion to form alkyl–Ni^I adduct 41 bearing two β-fluorine atoms. In the final step, β-fluoride elimination formed monofluoroalkene 34 and Ni^I−F complex 42, and finally reduction of 42 by another molecule of Mn⁰ regenerated the catalytically active Ni⁰ catalyst (35, Scheme 11).

Scheme 11.

Plausible mechanism for migratory functionalization of unactivated alkylbromides.

Nickel-catalyzed C(sp²)−C(sp³) defluorinative reductive cross-coupling of sterically hindered secondary and tertiary alkyl halides with gem-difluoroalkenes generated monofluoroalkenylated product through selective C–F bond cleavage under mild conditions (Scheme 12).²⁰ The reaction exhibited good functional group tolerance and delivered products with excellent Z-selectivity.

Scheme 12.

Nickel-catalyzed defluorinative reductive cross-coupling of gem-difluoroalkenes. DMA = Dimethylacetamide.

Initially, Ni(COD)₂ converted to the active Ni^I−L_n complex 46. Borylation of 46 generated L_nNi^I−Bpin complex 47, and subsequent single electron transfer (SET) to alkyl halide 44 afforded the caged alkyl radical/Ni^II intermediate 48. Next, regioselective radical addition of 48 to gem-difluoroalkene 43 at the difluorinated position produced the cage 49, which underwent a second SET to form the Ni^III intermediate 50. Finally, β-fluoride elimination from intermediate 50 yielded Z-monofluoroalkene product 45 and Ni^III complex 51, which further reduced to generate active Ni^I catalyst 46. The excellent Z-selectivity was attributed to the minimization of steric clashes during the β-fluoride elimination step from intermediate 50 (Scheme 13).

Scheme 13.

Proposed mechanism of defluorinative reductive cross-coupling of gem-difluoroalkenes.

An Fe-based catalyst system can also trigger cross-coupling reaction of gem-difluoroalkenes with various unactivated and heteroatom substituted olefins through a hydrogen atom transfer (HAT) strategy. This strategy has delivered a small library of alkylated monofluoroalkenes with excellent Z selectivity (Scheme 14).²¹ Mechanistically, HAT from the catalytically active L_nFe^IIIH to the alkene, generated alkyl radical 55. Then, radical addition to the gem-difluoroalkene (53) produced benzyl radical 56, which underwent a single electron reduction by the L_n Fe^II to yield anion 57. In the last step, anion 57 underwent a β-fluoride elimination to form the monofluoroalkene 54.

Scheme 14.

Iron-catalyzed defluorinative cross-coupling of donor alkenes with gem-difluoroalkenes. Didm = diisobutyrylmethane.

A number of substituted oxindoles have been synthesized through Ni-catalyzed enantioselective reductive monofluoroalkenylation of appropriately ortho-substituted arylbromides and gem-difluoroalkenes (Scheme 15).²² The reaction was performed at room temperature and under base-free reaction conditions, and chelating Pfaltz-type ligands were used to control the enantioselective process.

Scheme 15.

Nickel-catalyzed reductive aryl monofluoroalkenylation of alkenes.

The reaction initiated by in situ reduction of NiBr₂ to catalytically active Ni⁰, followed by oxidative addition of arylbromide 58 to afford Ni^II complex 62. Next, migratory insertion into the double bond generated alkyl-Ni^II complex 63, and SET reduction by stoichiometric Mn⁰ formed alkyl-Ni^I complex 64. Subsequent migratory insertion into gem-difluoroalkene 59 occurred in the presence of MgCl_2, which might activate the gem-difluoroalkene 59 through coordination, to produce alkyl-Ni^I adduct 65 bearing two β-fluoride atoms (Scheme 16, pathway A). β-Fluoride elimination from intermediate 65 furnished monofluoroalkene 60 and Ni^I−F complex 66, which further reduced to regenerate the catalytically active Ni⁰ catalyst. An alternative pathway might also involve coupling of gem-difluoroalkene 59 and σ-alkyl-Ni^I intermediate 64 to form σ-alkyl-Ni^III−F complex 67 through a C–F bond oxidative addition to form 67 and a subsequent reductive elimination to produce 60 (Scheme 16, pathway B).

Scheme 16.

Plausible mechanism for reductive aryl monofluoroalkenylation of gem-difluoroalkenes.

2-Fluoro-1,3-dienes 70 can be synthesized through a Ni-catalyzed hydroalkenylation of gem-difluoroalkenes 68 and alkynes 69 (Scheme 17).²³ The optimized conditions used mixture of Ni(cod)₂, and PCy₃, BEt₃, LiOⁱPr, and ZrF₄ to provide high yields of products. The mixture of BEt₃ and LiOⁱPr served as a source of hydride, whereas ZrF₄ improved yields of the products by acting as a co-catalyst.

Scheme 17.

Nickel-catalyzed hydroalkenylation of alkynes through oxidative cyclization and β-fluoride elimination.

Mechanistically, Ni⁰-mediated oxidative cyclization of gem-difluoroalkene 68 and alkyne 69 generated intermediate β,β-difluorinated nickelacyclopentene 72 in a regioselective fashion with the new metal-carbon bond placed at the β-position relative to fluorine, as seen in previously discussed migratory insertion steps. From intermediate 72, β-fluoride elimination formed vinylnickel fluoride 73 bearing a Z-fluoroalkene. Then, reaction of 73 with a combination of Et₃B and ⁱPrOLi generated vinylnickel hydride 74, which underwent a reductive elimination to afford 1,3-diene 70 and regenerated Ni⁰ (Scheme 18).

Scheme 18.

Proposed mechanism for nickel-catalyzed hydroalkenylation of gem-difluoroalkenes.

Organozinc reagents reacted with gem-difluoroalkenes via a Ni-catalyzed cross-coupling pathway to generate a number of alkylated monofluoroalkenes (Scheme 19).²⁴ This lithium chloride-promoted reaction required only mild reaction conditions to selectively form Z-monofluoroalkenes in moderate to good yields.

Scheme 19.

Reaction of difluoroalkenes with organozinc reagents.

2.3. Hydrodefluorination

gem-Difluoroalkenes undergo hydrodefluorination (HDF) in the presence of Cu-based catalyst systems and an protic solvent to produce monofluoroalkenes (Scheme 20). In the presence of a Cu^I salt and the promoter (Y), gem-difluoroalkene (78) produced cis-addition intermediate 79 bearing two β-fluorine atoms to the transition metal that can undergo β-fluoride elimination to form monofluoroalkene 82. In the catalytic cycle, formation of the new transition metal-fluoride bond bond drives the forward reaction. Moreover, the β-fluoride elimination from intermediate 79 drives the Z-stereoselectivity of the product. Subsequent transmetalation of 80 followed by protonolysis furnished hydrodefluorinated product 82. The resulting terminal fluoro-olefin group is useful in materials and in chemical biological probes, and especially in the design of mechanism-based enzyme inhibitors.⁴

Scheme 20.

General schematic representation of hydrodefluorination.

A stereoselective Cu-catalyzed regioselective HDF reaction enabled the conversion of gem-difluoroalkenes to di- or tri-substituted Z-fluoroalkenes using water as the proton source (Scheme 21).²⁵ A variety of substrates e.g. aliphatic, aromatic, α,β-unsaturated and substituted gem-difluoroalkenes were well-tolerated in this selective hydrodefluorination reaction. Further, gem-difluoroalkenes derived from natural products also underwent smooth hydrodefluorination by this process.

Scheme 21.

HDF of gem-difluoroalkenes. ^a(Bnep)₂ was used instead of (Bpin)₂.

In this reaction, precatalytic CuTC reacted with LiO^tBu to form CuO^tBu complex 85, which underwent transmetalation with (Bpin)₂ or (Bnep)₂ to furnish Cu-boronate ester 86. Reaction of 86 with gem-difluoroalkene 83 through a four centered reaction generated alkyl–Cu complex 87. Rotation along the C–C bond aligned the Cu and F substituents and enabled a syn β-fluoride elimination. This process proceeded through stable conformer 88 to form the vinylboronate ester intermediate 89 and Cu–F complex 90. The observed stereoselectivity was rationalized through minimization of the steric clash between the R substituent from gem-difluoroalkene and the bulky boryl group (88 vs. 88’; Scheme 22). LiO^tBu mediated transmetalation of intermediate 89 with Cu–F complex 90 stereoselectively generated a vinyl vinyl-Cu complex 91. Subsequent quenching of vinyl-Cu complex 91 by H₂O delivered the fluoroalkene 84.

Scheme 22.

Plausible mechanism of HDF of gem-difluoroalkenes.

A related stereodivergent hydrodefluorination of gem-difluoroalkenes 92 generated monofluoroalkenes 93 (Scheme 23).²⁶

Scheme 23.

Copper-catalyzed selective defluorination of gem-difluoroalkenes.

This reaction afforded both (Z)- and (E)-terminal monofluoroalkenes from the same starting material with high stereoselectivities. The use of a bulky diboron reagent that increased the steric clash near the transition state selectively furnished the (Z)-terminal monofluoroalkenes, whereas the use of hydrosilanes generated (E)-terminal monofluoroalkenes through an electronic effect.

2.4. Ortho-Directed C–H/C–F Functionalization

Using appropriate directing groups, gem-difluoroalkenes undergo transition metal-catalyzed C–H/C–F functionalization reactions (Scheme 24). In these reactions, N-based groups, typically pyridine derivatives, direct the metal to the ortho position, and a number of different transition metals can be employed.

Scheme 24.

General schematic representation for ortho-directed C–H/C–F Functionalization.

A number of gem-difluoroalkenes 98 coupled with substituted indoles 97 through a Co-catalyzed C–F/C–H functionalization reaction. In this reaction, the N-2-pyridyl group directed C–H functionalization to the C-2 position of the indole, and a syn Co–F elimination delivered the Z-fluoroalkene 99 in high diastereoselectivity (Scheme 25).²⁷ This Co-catalyzed alkenylation reaction occurred at room temperature in a protic solvent (2,2,2-trifluoroethanol) and involved K₂CO₃ as base.

Scheme 25.

Cobalt-catalyzed C–F/C–H functionalization of gem-difluoroalkenes. TFE = 2,2,2-Trifluoroethanol.

In another report, a Mn-catalyzed C–F/C–H functionalization of gem-difluoroalkenes and perfluoroalkenes generated both monofluorionated and polyfluorinated products, respectively. This reaction exploited a 2-pyridyl group to direct the C–F/C–H functionalization (Scheme 26).²⁸ The (per)fluoroalkenylations reactions proceeded with high chemo-, positional- and diastereo-selectivity. The directing (pyridyl) group was removed from the product using MeOTf and NaSPh to reveal free NH-indoles (103).

Scheme 26.

C–F/C–H alkenylation with difluoroalkenes/perfluoroalkenes.

Ruthenium based catalyst systems promoted the C2-selective coupling of gem-difluoroalkenes with indoles (Scheme 27).²⁹ This redox-neutral reaction involved both a C–H bond activation and C–F bond cleavage to afford a broad range of 1,2-diarylsubstituted monofluoroalkenes with high regio- and stereo-selectivities with a preference for generating Z-monofluoroalkenes. The 2-pyridyl and 2-pyrimidnyl groups promoted excellent selectivity for this α-fluoroalkenylation.

Scheme 27.

α-Fluoroalkenylation of indoles via C–H activation. TFE = 2,2,2-Trifluoroethanol.

Mechanistically, cyclometalation of N-pyrimidinylindole (104) with Ru^II produced the five-membered metallacyclic intermediate 107. Subsequent coordination of gem-difluoroalkene (105) afforded a Ru–C(alkyl) complex 108, which underwent a regioselective migratory insertion to form the seven membered metal complex 109. This migratory insertion was controlled by the electronic structure of the gem-difluoroalkene, with the nucleophilic aryl group adding to the electrophilic fluorinated position. This insertion placed Ru at the beta position relative to the fluorine atom. Intermediate 109 subsequently underwent a selective β−F elimination via a syn-coplanar transition state to afford the product 106, along with a Ru^II fluoride. Subsequent anion exchange with a chloride regenerated the active Ru^II complex (Scheme 28).

Scheme 28.

Ruthenium-catalyzed fluoroalkenylation of arenes via C–H activation.

In addition to Ru, Co-based catalyst system also couple gem-difluoroalkenes 111 in C–H bond functionalization reactions of 6-arylpurines 110. These reactions exploit a single-component catalyst [Cp*Co(CH₃CN)₃](SbF₆)₂ and deliver Z-substituted monofluoroalkenes 112 (Scheme 29).³⁰ In these reactions, both the N1 and N7 atoms might contribute to the excellent ortho regioselectivity of the reactions.

Scheme 29.

Synthesis of monofluoroalkenes via cobalt-catalyzed C–H/C–F bond cleavage. TFE = 2,2,2-Trifluoroethanol.

Regio- and stereoselective Rh^III-catalyzed α-fluoroalkenylation of N-nitrosoanilines 113 with 2,2-difluorovinyl tosylates 114 generated ortho substituted products under basic conditions. As seen with previous examples, the sequence involving C–H bond activation, migratory insertion, β-fluoride elimination afforded a series of Z-monofluoroalkenes 115 in good to excellent yields (Scheme 30).³¹ Though the nitrosoaniline directing group differed from the aforementioned N-based heterocycles, it still provided delivered ortho substituted products in high selectivity. Of note, several reactions in this section exploit Ca²⁺-based additives, though authors do not comment on the potential role of this cation. Possibly, the high affinity of Ca²⁺ for fluoride serves to remove the latter anion from reaction mixture, and facilitate regeneration of the active catalyst.

Scheme 30.

Rhodium-catalyzed C–C coupling of N-nitrosoanilines with 2,2-difluorovinyl tosylates. HFIP = Hexafluoroisopropanol.

Rhodium can also serve as a catalyst for the benzylic α-fluoroalkenylation of 8-methylquinolines 116 with gem-difluoroalkenes 117 under basic conditions (Scheme 31).³² Mechanistically, this reaction proceeded similarly to the methods previously discussed in this section, and also delivered Z-monofluoroalkenes 118 in high stereoselevctivity.

Scheme 31.

Rhodium-catalyzed benzylic α-fluoroalkenylation of gem-difluoroalkenes. TFE = 2,2,2-Trifluoroethanol.

gem-Difluoroalkenes also react with Mn-based catalyst systems in C–H activation/C–F cleavage reactions (Scheme 32).³³ In contrast to the previously discussed reactionms, Mn-based system afforded thermodynamically unfavorable E-monofluoroalkenes 121 without using any external oxidants. The E-configuration likely arose from the selective β-defluorination from the key intermediate, though the specific controlling feature was not suggested. However, reactions of imidazole protected indoles afforded Z-monofluoroalkenes instead of E-monofluoroalkenes (example 121g, Scheme 32). The same Z-selective trend was observed in case of sterically hindered gem-difluoroalkenes (examples 121h–i, Scheme 32).

Scheme 32.

Stereoselective synthesis of E-monofluoroarylalkenes via manganese-catalyzed C–H bond activation.

Rh-based catalyst systems can also promote the generation of E-monofluoroalkenes. Specifically the [RhCp*(CH₃CN)₃](SbF₆)₂-catalyzed reactions of 1-arylpyrazoles 122 with methyl trifluoroacrylate 123 afforded a series of E-fluoroalkenes 124 without involving any external oxidant (Scheme 33).³⁴

Scheme 33.

Rhodium-catalyzed C–H bond activation functionalization of 1-arylpyrazoles with methyl trifluoroacrylate.

Rhodium catalyzed alkylation of N-pyrimidylindoles and related compounds with α,α-difluorovinyl tosylate generated various C2 alkylated indoles (Scheme 34).³⁵ In this reaction, the tosyl difluorinated enol ether served as an unusual surrogate for an acetate building block.

Scheme 34.

C–H bond alkylation of indoles.

Mechanistically, selective C–H activation of the indole at the C2 position by the cationic Rh^III catalyst formed the five membered intermediate 128. Subsequent, addition of gem-difluoroalkene 126 to the Rh^III complex 128 generated the 7-membered intermediate 129.Then, 129 underwent an α-elimination of the OTs group to produce the Rh^V–carbenoid complex 130, and intramolecular migration of the indolyl group formed difluorocyclopropane intermediate 131. Subsequent, nucleophilic attack of methanol to the strained intermediate 131, might deliver Rh^III-intermediate 132 (Path A). In the final step, alcoholysis of intermediate 132, furnished product 127 along with the regeneration of the active Rh^III catalyst. In another pathway (Path B), alcoholysis of intermediate 131 might deliver a gem-difluoroalkene intermediate (133), which might further convert to ester 127 (Scheme 35).

Scheme 35.

Proposed mechanism for alkylation of indoles.

3. Annulation Reactions

3.1. Synthesis of Heterocycles

gem-Difluoroalkenes can also serve as building blocks for the preparation of heterocycles, using transition metal-based catalyst systems. In these reactions, one or more of the fluorine atoms typically undergoes substitution to generate one or more new C–C or C–heteroatom bonds. In some cases, the C–F bond is functionalized under base-mediated conditions, though in other cases, the transition metal catalyst generates bonds at alternate, non-fluorinated positions.

A number of dibenz[b,d]-oxepines 137 have been prepared by a base-mediated reaction of 1-bromo-2-(2,2-difluorovinyl)benzene 134 with phenols 135 and subsequent oxidative C–C coupling. Initially, double olefinic C–F bond substitution generated diaryl ketene acetal 136, which subsequently underwent an intramolecular Pd-catalyzed C–H arylation to cyclize the heterocycle and deliver the dibenz[b,d]oxepines (Scheme 36).³⁶

Scheme 36.

One-pot synthesis of dibenzo[b,d]oxepines. DMA = Dimethylacetamide.

In addition to reactions of phenols, 4-hydroxypyridine also served as competent nucleophile for this type of transformation. Reaction of 4-hydroxypyridine 138 with 1-bromo-2-(2,2-difluorovinyl)benzene 134a using K₂CO₃ followed by subjection to a Pd-based catalyzed reaction cyclized product 140 via N-vinylic-4-pyridone 139 as the likely key intermediate (Scheme 37).

Scheme 37.

Formation of heterocycles via reaction of 4-hydroxypyridine with 2-bromophenyl-gem-difluoroalkene. DMA = Dimethylacetamide.

In another report, reaction of primary arylamines 142 with 1-halo-2-(2,2-difluorovinyl)benzene (halo = Br or Cl) 141 delivered a variety of N-substituted-2-fluoroindoles (Scheme 38).³⁷ The first step of this reaction involved a Pd-catalyzed Buchwald-Hartwig coupling that would generated 2-amino-(2,2-difluorovinyl)benzene 143. gem-Difluoroalkene 143 underwent a base-promoted 5-endo-trig intramolecular nucleophilic attack by N and subsequent β-fluoride elimination to generate a diverse array of 2-fluoroindoles 144.

Scheme 38.

Synthesis of N-substituted-2-fluoroindole derivatives. Isolated yields of coupling product 143. Yield of the cyclized product 144 is reported in parentheses.

Rh-based catalyst systems also react with gem-difluoroalkenes to deliver more complex heterocycles. Specifically, a Rh^III-based catalyst system promoted the coupling of β-carboxymethyl α,α-difluoroalkene 145 with 2-phenylpyridine 146 to deliver benzoindolizines 147 through a process that removed three fluorine atoms (Scheme 39).³⁴ The reaction also performed on natural product-based substrates, including a purine derivative and estrone derivative to deliver products 147g and 147h in 51% and 80% yield, respectively.

Scheme 39.

Rhodium-catalyzed C–H bond activation functionalization with methyl trifluoroacrylate. DCE = 1,2-Dichloroethane.

To identify the source of the oxygen in the product’s newly generated carbonyl group, an ¹⁸O isotopic labeling experiment suggested that H₂O was the ultimate source of O in the carbonyl (Scheme 40).

Scheme 40.

The oxygen in the newly generated carbonyl group comes from H₂O. DCE = 1,2-dichloroethane.

A Rh^III-catalyzed [4+1] annulation reaction between the acrylamide 148 and gem-difluoroacrylate 149 delivered 5-methylene-1H-pyrrol-2(5H)-one 150 derivatives with the difluoroalkene serving as the C1 component (Scheme 41).³⁸ In this reaction, both C–F bonds cleaved under mild conditions. The stereospecific transformation resembled a formal dehydrogenative alkylidene carbene insertion reaction.

Scheme 41.

Rhodium-catalyzed oxidant-free [4+1] annulation for the synthesis of 5-methylene-1H-pyrrol-2(5H)-one. DCE = 1,2-dichloroethane.

To probe the key intermediate of this transformation, one control experiment was conducted (Scheme 42). Reaction of 148i and 149a in presence of a different Rh catalyst, [RhCp*(MeCN)₃](SbF₆)₂, and NaOAc, generated the expected annulated product 150i along with acyclic monofluoroacrylate (150i’) as the major product. Subsequent heating of the mixture to 80 °C converted acyclic 150i’ into annulation product 150i, which supported the intermediacy of 150i’. Thus, the reaction seemed to follow a stepwise quasinucleophilic displacement route.

Scheme 42.

Investigation of possible reaction intermediates.

A related heteroannulation reaction was also reported via a dual catalytic system of Rh^III/Ag^I relay catalysis.³⁹ In this case, an –OTs group was used in place of the –CO₂R group, which enabled further synthetic elaboration through cross-coupling reactions.

In another report, a photocatalytic reaction of dihydroisoquinoline acetic acids (151) and α-trifluoromethyl alkenes (152) formed a variety of benzo[a]quinolizidines (154) (Scheme 43).⁴⁰

Scheme 43.

Visible light-induced substitution of two fluorine atoms from a CF₃ group.

By the action of visible light and a Ir^III photocatalyst, dihydroisoquinoline acetic acids (151) underwent oxidative decarboxylation process to form α-amino radical 155, which reacted with trifluoromethyl alkenes (152) to form α-CF₃ radical intermediate 156. Reduction of 156 by Ir^III produced α-CF₃ anion 157, which in turn eliminated one F⁻ and formed the gem-difluoroalkene intermediate 153. The gem-difluoroalkene (153) was again oxidized by *Ir^III and formed amine radical cation 158. Subsequent loss of a proton produced C-centred radical 159, which might form the product through one of two pathways. In Path A, 6-endo-trig radical cyclization would form benzyl radical intermediate 160. Reduction of 160, followed by a β-fluoride elimination step would afford the benzo[a]quinolizidine product (154). In contrast, in Path B, reduction of difluoroalkene radical 159 and subsequent loss of F⁻ would generate the di-radical 162. In the last step, intermolecular radical radical coupling would furnish product 154 (Scheme 44).

Scheme 44.

Plausible mechanism for visible light-induced decarboxylative coupling of vinyl trifluoromethanes.

2,2-Difluorovinyl tosylate (164) can serve as a potential building block for the preparation of a variety of fluorinated heterocycles via Rh^III-catalyzed C–H activation of arenes/alkenes (163, Scheme 45).⁴¹ In this reaction, N-substituted benzamides (163) coupled with 2,2-difluorovinyl tosylate (164) to form various fluorinated quinolin-1(2H)-ones. Notably, the substitution on the N atom of the benzamide, enabled access to different products. Reaction of N-OPiv benzamides in the presence of an alcohol produced gem-difluorinated dihydroisoquinolin-1(2H)-ones (166). In contrast, reactions of N-OMe benzamides, generated acyclic monofluorinated alkenes (167), which in the presence of a Brønsted acid (H₂SO₄), cyclized to form the 4-fluoroisoquinolin-1(2H)-ones (168). Both the process involved a common 7-membered rhodacycle (165) as the key intermediate.

Scheme 45.

Rhodium-catalyzed coupling of benzamides with 2,2-difluorovinyl tosylate. HFIP = Hexafluoroisopropanol.

3.2. Synthesis of Carbocycles

gem-Difluoroalkenes also provide an entry point for the preparation of fluorinated polycyclic aromatic hydrocarbons. In one example, a series of difluorinated three to five-member fused polycyclic aromatic hydrocarbons (PAHs) 170 was fabricated by a Pd^II-catalyzed electrophilic Friedel–Crafts-type cyclization of 1,1,2-trifluoro-1-alkenes or 1,1-difluoro-1-alkenes 169 through a process that removed one fluorine atom (Scheme 46).⁴²

Scheme 46.

Synthesis of vic-difluorophenacenes by electrophilic cyclization of 1,1,2-trifluoro-1-alkenes.

The reaction initiated by conversion of PdCl₂ to a cationic halogen-free complex, followed by coordination of trifluoroalkene 169 to form π-complex 171. Subsequently, an electrophilic Friedel-Crafts-type carbopalladation followed by rearomatization delivered cyclic alkyl-Pd^II intermediate 172. Finally, intermediate 172 underwent a BF₃-assisted β-fluoride elimination to afford vic-difluorinatedphenacenes 170, and regenerated the active cationic Pd^II catalyst (Scheme 47).

Scheme 47.

Plausible mechanism for cyclization of trifluoroalkenes.

Densely substituted 1-(trifluoromethyl)-1H-indene derivatives 175 were accessed via a palladium-catalyzed [3 + 2] annulation of (2,2-difluorovinyl)-2-iodoarenes 173 and internal alkynes 174 through a reaction pathway, initiated by nucleophilic addition of fluoride (Scheme 48).⁴³ This method generated products from symmetrically di-substituted alkynes in high yields, and reactions of unsymmetrical alkynes delivered products bearing the activating substituent (e.g. Ar or ester) at the C-2 position. In this reaction, AgF delivered F^– to the α-position of the gem-difluoroalkene, which is a common reactivity pattern that will be addressed later.⁴⁴

Scheme 48.

F⁻ Nucleophilic-addition-induced synthesis of CF₃ substituted indenes.

Two plausible ionic reaction pathways might deliver the CF₃ substituted indenes. In pathway A, oxidative insertion of (2,2-difluorovinyl)-2-iodoarene 173 with Pd⁰ generated the aryl-Pd intermediate 176 and subsequent coordination of internal alkynes 174 generated intermediate 177. Next, alkyne bound-Pd intermediate 177 underwent a migratory insertion into the alkyne to afford vinyl-Pd intermediate 178, while simultaneously, nucleophilic addition of fluoride generated Ag–Bn intermediate 179. In contrast, pathway B initiated by nucleophilic fluoride addition to (2,2-difluorovinyl)-2-iodoarene 173 to generate the α,α,α-trifluoroethylsilver intermediate 176’ and subsequent oxidative addition of Pd⁰ catalyst and insertion of the alkyne generated common intermediate 179. Finally, intramolecular transmetalation provided six-membered palladacycle 180, which underwent reductive elimination to furnish product 175 and regenerate the active catalyst Pd⁰ (Scheme 49).

Scheme 49.

Proposed mechanism for the synthesis of CF₃ substituted indenes.

In a single example, subjection of an enyne containing a gem-difluoroolfinic site to a Ru-catalyzed hydrogenation reaction delivered a non-fluorinated cyclopentane (Scheme 50).⁴⁵ The hydrogenation of 181 initially generated a Ru-carbene, and coordination of the methoxy-substituent provided Ru-alkyl complex 182, which was set up for an unexpected ring-closing metathesis. From 182, a four-centered reaction delivered metallocycloruthenium complex 183, and elimination from 183 delivered cyclopentane 184.

Scheme 50.

Ruthenium-catalyzed hydrogenative cyclization. DCE = 1,2-dichloroethane.

4. Radical Reactions of gem-Difluoroalkenes in Non-photocatalytic Conditions

gem-Difluoroalkenes also react through a variety of one-electron C–F functionalization processes to deliver monofluoro/polyfluorinated products. The initiation of radicals can occur either photocatalytically (Section 5) or using chemical promoters (Section 4).

A broad range of monofluoroalkenes 187 were generated by a zinc-mediated decarboxylative defluoroalkylation of gem-difluoroalkenes 185. These reactions exploited alkyl N-hydroxyphthalimide (NHP) esters 186 as the radical precursors activated in the presence of Zn⁰. The reactions scaled well and afforded products with excellent Z-stereoselectivity (Scheme 51).⁴⁶

Scheme 51.

Defluoroalkylation of gem-difluoroalkenes. DMA = Dimethylacetamide.

Initially, SET from Zn⁰ to the NHP ester 186 afforded radical anion 188, which fragmented to generate a stabilized NHP anion and an O-based carboxyl radical. The radical decarboxylated to furnish the thermodynamically preferred alkyl radical (R•), and subsequent attack of R• to the gem-difluoroalkene 185 afforded difluorinated radical intermediate 189. A second SET reduction by Zn⁺ generated β-difluorinated anion 190. Finally, β-F elimination via a conformationally favorable anti-coplanar pathway delivered the Z-monofluoroalkene 187 (Scheme 52).

Scheme 52.

Plausible mechanism for decarboxylative alkylation of gem-difluoroalkenes.

5. Photocatalytic Reductive C–F Bond Functionalization

C–F bond activation of gem-difluoroalkenes can readily occur under photoredoxcatalytic conditions. In the presence of a photoredox catalyst, irradiation of gem-difluoroalkenes 191 forms radical 192 via a SET process, which quenches by a second radical to form 193 or 194. This second radical can be generated by the oxidized photoredox catalyst or from transition metal-based co-catalyst (Scheme 53).⁴⁷ Moreover, metallated complex 194 can be converted to the several useful motifs through coupling with organic electrophiles.

Scheme 53.

General schematic representation for photocatalytic reductive C–F bond functionalization.

A visible light-mediated photocatalytic decarboxylative reaction of N-protected α-amino acids (196) with gem-difluoroalkenes (195) generated the corresponding α-amino monofluoroalkenes (197) at room temperature (Scheme 54).⁴⁸ In this reaction, reduction of the gem-difluoroalkene generated an active radical intermediate, which coupled with the α-amino radical (generated by the oxidative decarboxylation of the amino acid) to afford the final monofluoroalkenylated product.

Scheme 54.

Photocatalytic decarboxylative monofluoroalkenylation of α-amino acids and gem-difluoroalkenes.

The reaction initiated by irradiation of the photocatalyst Ir^III to generate an excited *Ir^III. Being a strong oxidizing agent, the excited *Ir^III catalyst removed an electron from the deprotonated N-Boc proline 196a and subsequent decarboxylation produce a transient α-aminoalkyl radical 198 and Ir^II. Next, Ir^II reduced the gem-difluoroalkene 195 to generate the radical anion, which decomposed to the monofluoroalkenyl radical 199 through loss of F⁻, thus regenerating the Ir^III photocatalyst through a SET process. In the last step, radical 198 and 199 cross-coupled with each other to afford product 197 (Scheme 55).

Scheme 55.

Proposed mechanism for the decarboxylative monofluoroalkenylation of N-protected α-amino acids.

Defluorinative monofluoroalkenylation can also occur through cooperative photoredox and hydrogen-atom-transfer (HAT) catalysis.⁴⁹ This strategy regioselectively coupled a variety of amines, ethers, and thioethers to generate monofluoroalkenes bearing various α-heteroatom substituents (Scheme 56).

Scheme 56.

Monofluoroalkenylation of amines, ethers, and thioethers.

At first, irradiation of photocatalyst 203 with a blue LED formed the redox active excited Ir^III* 204, which oxidized quinuclidine (205) to generate radical 207 and Ir^II complex 206. In the next step, reduced catalyst 206 delivered one electron to gem-difluoroalkene 201, and subsequent loss of F⁻ formed the radical 210, and regenerated photocatalyst 203. On the other hand, oxidized quinuclidine radical cation 207 participated in a hydrogen-atom-transfer (HAT) reaction with amine 200, which generated α-aminoalkyl radical 209. Finally, the heterodimerization of radicals 209 and 210 formed the product 202 (Scheme 57).

Scheme 57.

Proposed mechanism for the monofluoroalkenylation of unreactive C–H bonds by cooperative photoredox and HAT catalysis.

A dual catalytic system involving Ir- and Pd-based catalysts enabled selective C–F bond carboxylation of gem-difluoroalkenes.⁵⁰ In this metallaphotoredox C–F functionalization reaction, substituted gem-difluoroalkenes (211) efficiently coupled with the inert electrophile CO₂ to afford a wide range of α-fluoroacrylic acids (212), which readily underwent esterification to generate corresponding methyl esters (Scheme 58).

Scheme 58.

Iridium/palladium co-catalyzed C–F carboxylation of gem-difluoroalkenes.

Irradiation of the photocatalyst (PC) by blue LED generated the excited PC*, which underwent reductive quenching by ⁱPr₂NEt to afford PC⁻¹. SET from PC⁻¹ to the gem-difluoroalkene, geneated fluoroalkenyl radical 213, and reaction of Pd⁰ 214 with fluoroalkenyl radical 213 produced Pd^I intermediate 215. Carboxylation of this intermediate though CO₂ coordination and migratory insertion afforded carboxyl- Pd^I complex 217, and finally, SET between PC⁻¹ and 217 furnished the carboxylated Z-monofluoroalkene (212) and regenerated Pd⁰ (Scheme 59). In this reaction, the observed stereoselectivity was attributed to the reversibility of the addition of Pd⁰ 214 to the fluorovinyl radical.

Scheme 59.

Mechanism of photoredox/palladium dual catalytic C–F carboxylation.

6. Generation of Trifluoromethanes

A number of transition metal-catalyzed reactions convert gem-difluoroalkenes into trifluoromethane-containing products. These reactions require the use of stoichiometric CuF or AgF to nucleophilically add F⁻ to the α-position of the fluorinated alkene while simultaneously generating a β-Cu or β-Ag-trifluoromethanes 219 (Scheme 60). As previously mentioned, many transition metals readily undergo β-fluoride elimination; however, Cu and Ag are unique in their ability to sufficiently stabilize the α-CF₃ groups to enable further functionalization of the Ag–C or Cu–C bonds. Further a potential β-fluoride elimination from compound 219 or related α-CF₃ metal intermediates, would simply regenerate the substrate (218). As such, these reactions might benefit from an equilibrium between the difluoroalkene and the trifluromethyl complex.

Scheme 60.

gem-Difluoroalkenes react with CuF and AgF to form metal heptafluoroisopropyl complexes 219.

The stability of α-CF₃–Ag and α-CF₃–Cu complexes was easily observed though study of reactions of AgF and CuF with hexafluoropropene. The reaction of these metal fluorides generates coinage-metal heptafluoroisopropyl (L_nM-hfip) complexes in presence of 2,2,6,6-tetramethylpiperidine or triphenylpsophine ligands.⁵¹ More specifically, reaction of hexafluoropropene (HFP) with AgF and 2,2,6,6-tetramethylpiperidine (HTMP) delivered silver heptafluoroisopropyl complex 219a (Scheme 61). In this reaction, the anionic F ligand added to the cationic carbon of the gem-difluoroalkene and the cationic metal added to the vicinal position.

Scheme 61.

Formation of silver heptafluoroisopropyl complex.

In contrast, the related Cu complex (219b) was instable, though the use of a phosphine ligand enabled isolation and characterization of the analogous stable Cu-fluoroalkyl complex (219b) (Scheme 62). Of note, though the Ag-fluoroalkyl complexes do not effectively transfer the fluoroalkyl ligand to another substrate, the (phen)(PPh₃)Cu-fluoroalkyl complexes readily, delivered the fluorinated ligand to various substrates.

Scheme 62.

Formation of copper heptafluoroisopropyl complex.

6.1. Synthesis of Trifluoromethyl Derivatives

A Pd-catalyzed fluoroarylation reaction of gem-difluoroalkenes (220) with aryl halides (221) delivered numerous non-symmetric α,α-diaryl, alkylaryl, and alkenylaryl trifluoroethane derivatives (222) (Scheme 63).⁵² This reaction required the use of AgF as the fluorinating agent, which as previously mentioned, generated a stable α-trifluoromethyl metallated intermediate for further functionalization. Of note, among all halides, aryl iodides worked as the best coupling partners for this reaction.

Scheme 63.

Strategies for the construction of 1,1,1-trifluoro-2-arylalkanes.

This reaction proceed by oxidative addition of L_nPd⁰ to the aryl halide to produce the aryl-Pd complex 223. Simultaneously, nucleophilic addition of AgF to the gem-difluoroalkene generated the Bn–Ag intermediate 224, which in turn underwent a conventional polar two-electron transmetallation with aryl-Pd 223 to afford Pd^II intermediate 225. Subsequently, reductive elimination furnished the desired product 222 and regenerated the active Pd-catalyst (Scheme 64).

Scheme 64.

Proposed reaction mechanism for palladium-catalyzed fluoroarylation of gem-difluoroalkenes.

In the presence of CsF, a Cu^I-based catalyst and iodoarenes, tetrafluoroethylene (227) was converted to various pentafluoroethylated products (229) in a simple two-chamber system (Scheme 65).⁵³ In this reaction, (trifluoromethyl)trimethylsilane (TMSCF₃) served as a source for the in situ generation of tetrafluoroethylene. Difluorocarbene, generated from TMSCF₃ and a catalytic amount of NaI, dimerized to produce 1,1,2,2-tetrafluoroethylene. Further, heteroatom nucleophiles also could react with tetrafluoroethylene to produce a number of 1,1,2,2-tetrafluoroethylated compounds (231) in good to excellent yield.

Scheme 65.

Fluoroalkylation with TMSCF₃ via tetrafluoroethylene.

A unique intramolecular fluoride shift was observed in Pd-catalyzed alkylation reactions of 2,3,3-trifluoroallylic carbonates 232 with indoles 233 to afford 3-substituted α-trifluoromethyl indoles 234 (Scheme 66).⁵⁴ A variety of 2,3,3-trifluoroallylic carbonates and substituted indoles were well tolerated under the optimized conditions, and the reaction generally delivered products bearing thermodynamically preferred E-trifluoromethylalkenes. Subjection of pyrrole to the reaction conditions generated a mixture of 2- and 3-substituted products (234c and 234c’).

Scheme 66.

Palladium-catalyzed alkylation of trifluoroallylic carbonates with indoles.

The reaction initiated by oxidative addition of trifluoroallylic carbonate 232 to Pd⁰ to generate trifluoro-π-allyl-Pd complex 235. Subsequent attack of the nucleophilic C-3 position of the indole 233 to the C-2 position of the allylic moiety afforded strained palladacyclobutane 236, and subsequent reaction with ⁻O^tBu rearomatized the indole and formed palladacyclic complex 237. Through participation of indole, intramolecular fluorine atom shift from the tertiary position facilitated the reductive elimination to form palladate 238, and subsequent release of Pd⁰ rearomatized the indole and produced the desired product 234 (Scheme 67).

Scheme 67.

Possible reaction mechanism for alkylation of trifluoroallylic carbonates with indoles.

This reactivity pattern also functions in reactions of other nucleophiles, and these reactions presumably proceed through related trifluoro palladacyclobutane intermediates. For example, O-based nucleophiles 240 coupled with 2,3,3-trifluoroallylic carbonates 239 to afford trifluoromethyl vinyl ethers (241). In these reactions, [Pd(C₃H₅)Cl]₂ and dppf served as a pre-catalytic system and AgBF₄ activated the system (Scheme 68).⁵⁵ A number of aliphatic alcohols and phenols participated in the reaction to produce a diverse array of trifluoromethyl substituted enol ethers.

Scheme 68.

Intramolecular construction of α-trifluoromethyl vinyl ethers by palladium-catalyzed reaction of 2,3,3-trifluoroallylic carbonates and O-based nucleophiles.

Pd-based catalyst systems also promoted alkoxycarbonylations reactions to construct a series of α-difluoromethylated esters in high yields and excellent regioselectivities (Scheme 69).⁵⁶ The use of aromatic gem-difluoroalkenes (242) afforded benzylic α-difluoromethylated esters (244), whereas the use of aliphatic gem-difluoroalkenes promoted a remote olefin functionalization through a cascade involving alkene isomerization to deliver distal-substituted esters 244’ in high yield and selectivity.

Scheme 69.

Synthesis of difluoromethylated esters by Palladium-catalyzed selective carbonylation of gem-difluoroalkenes.

An array of α-trifluoromethyl alcohols have been constructed via Pd-catalyzed selective hydroxyfluorination of gem-difluoroalkenes using N-fluorobenzenesulfonimide (NFSI) as an effective source of fluorine (Scheme 70).⁵⁷ In this reaction, CF₃COOH served as an additive that facilitated the ligand exchange required to form the C–O bond.

Scheme 70.

Palladium-catalyzed hydroxylfluorination of gem-difluoroalkenes.

The first step of the reaction involved the oxidation of Pd⁰ by NFSI to generate Pd^II-fluoride complex 247. Next fluoropalladation of gem-difluoroalkene 245 afforded Pd^II-alkyl intermediate 248, which could follow either of two possible pathways to produce the high-valent Pd^IV intermediate 251. In path A, ligand exchange between complex 248 and CF₃CO₂H would yield intermediate 249, and oxidation by NFSI would generate Pd^Iv intermediate 251. In contrast, path B involved initial oxidation of the Pd^II-alkyl intermediate 248 by NFSI to form Pd^Iv intermediate 250, which would exchange a ligand with CF₃CO₂H to yield high-valent Pd intermediate 251. Finally, reductive elimination from 251 would furnish trifluoroacetyl ester 252, which underwent hydrolysis to furnish α-hydroxytrifluoromethane 246 (Scheme 71).

Scheme 71.

Possible mechanism for the palladium catalyzed synthesis of α-trifluoromethyl alcohols.

6.2. Oxidative Photocatalytic Reactions of gem-Difluoroalkenes

gem-Difluoroalkenes also react through a variety of one-electron C–F functionalization processes to deliver monofluoro/polyfluorinated products.

The initiation of radicals can occur either photocatalytically or using chemical promoters. In one case, an Ir-based catalyst system and Et₃N•3HF promoted the fluorinative allylic alkylation of gem-difluoroalkenes 253 to constructing secondary trifluoromethanes 255 (Scheme 72).⁵⁸

Scheme 72.

Construction of CF₃-substituted tertiary carbon centers. PC = [Ir(dF(CF₃)ppy)₂(5,5’-dCF₃bpy)](PF₆).

In this reaction, visible light irradiation of the Ir^III photocatalyst generated excited state Ir^III*, which transferred a single electron oxidation of gem-difluoroalkene 253 to generate the radical cationic intermediate 256 along with Ir^II. Then, nucleophilic addition of the fluoride ion to intermediate 256 generated benzyl radical 257, which attacked phenylsulfonyl acrylate 254 to generate radical intermediate 258. Subsequent β-fragmentation of intermediate 258 furnished desired product 255, and released the benzenesulfonyl radical. This radical facilitated reoxidation of Ir^II to regenerate the Ir^III active catalyst (Scheme 73).

Scheme 73.

Proposed mechanism for CF₃ substituted tertiary carbon centers formation.

gem-Difluoroalkenes also reacted with fluoroalkyl radicals under photocatalytic conditions to deliver multifluorinated products. These reactions involved a C–F bond functionalization process that ultimately delivered vinyltrifluoromethanes 261.

This reaction exploited CF₃SO₂Na as an efficient source of •CF₃ and Ir^III as a photocatalyst for generating CF₃-containing multifluorinated molecules in moderate to good yields with high stereoselectivity (Scheme 74).⁵⁹

Scheme 74.

Functionalization of multifluorinated compounds via C–F bond cleavage. PC = [Ir(dF(CF₃)ppy)₂(5,5’-d(CF₃)bpy)](PF₆).

Irradiation by visible light sensitized Ir^III to its excited state *Ir^III, which subsequently oxidized NaSO₂CF₃ via a SET and generated •CF₃. Subsequent addition of •CF₃ to gem-difluoroalkene 260 generated transient α-trifluoromethyl radical 262. Next, single electron reduction of 262 by Ir^II, delivered α-trifluoromethyl anion 263 and regenerated the photocatalyst. Finally, β-fluoride elimination from 263 afforded α-vinyl-α-trifluoromethyl product 261 (Scheme 75).

Scheme 75.

Proposed mechanism for photoredox-catalyzed trifluoromethylation of fluorinated alkenes.

Ir^III-mediated visible-light-catalyzed defluorinative cross-coupling of gem-difluoroalkenes with different types of thiols, can regioseletively generate various monofluoroalkenes (Scheme 76).⁶⁰ Of note, reactions of monosubstituted gem-difluoroalkenes worked better in toluene, whereas disubstituted gem-difluoroalkenes, performed better using acetonitrile as a solvent. This reaction functioned not only with aryl and simple alkyl thiols, but also in late-stage modification reactions of natural product-linked thiols (Scheme 76b).

Scheme 76.

Visible-light-mediated defluorinative cross-coupling of gem-difluoroalkenes with thiols.

7. Synthesis of Difluoromethyl Derivatives

In contrast to many reactions of gem-difluoroalkenes that either subtract or add an F-atom and afford monofluorinated or trifluorinated products, respectively, a subset of catalyst systems also promote fluorine-retentive reactions. These reactions generally involve a metal-templated oxidative cyclization of the fluorinated alkene with an unsaturated substrate, which places the fluorinated carbon alpha to the metal center. In this configuration, the α-fluorometal cannot promote a facile β-F elimination.

In one example, a Ni⁰-catalyzed crosstetramerization reaction of tetrafluoroethylene with alkynes, ethylene, and/or styrenes delivered a range of 1,3-diene derivatives with a 3,3,4,4-tetrafluorobutyl chain (Schemes 77 and 78).⁶¹

Scheme 77.

Nickel-catalyzed cross-tetramerization of tetrafluoroethylene with ethylene and alkynes.

Scheme 78.

Nickel catalyzed cross-tetramerization of tetrafluoroethylene, ethylene, alkynes and styrenes.

The reaction initiated by the oxidative cyclization of TFE and ethylene with Ni⁰ followed by a cotrimerization to form a five-membered nickelacycle 272. Then, migratory insertion of an alkyne into the Ni–CH₂ bond delivered seven-membered nickelacycle 273 through cross-tetramerization. The inability of 273 to undergo β-hydride elimination enabled insertion of another molecule of ethylene to generate nine-membered nickelacycle 274, which bears two β-hydrogen atoms. From this intermediate, β-hydride elimination yielded an open chain nickel hydride (275), which after reductive elimination afforded tetrafluoroethyl product 270 and regenerated the Ni⁰ catalyst (Scheme 79).

Scheme 79.

Mechanism of nickel-catalyzed cross-tetramerization.

Ni⁰ also catalyzed three-component coupling reaction of tetrafluoroethylene 276, N-sulfonyl-substituted imines 277, and silanes to deliver diverse fluorine containing amines 278 (Scheme 80).⁶²

Scheme 80.

Nickel-catalyzed three-component coupling reaction of tetrafluoroethylene, N-sulfonyl-substituted imine and Et₂SiH₂.

In this reaction, coordination of L_nNi⁰ with tetrafluoroethylene and N-sulfonyl-substituted imines generated η²:η² Ni complex 279, and an oxidative cyclization afforded the aza-nickelacycle monomer 280 and/or the respective dimer (syn-281 or anti-281). Intermediates 280 and 281 were stabilized by the coordination of the N-sulfonyl group to Ni⁰. Subsequent transmetalation with the silane furnished nickel hydride 282, which reductively eliminated to afford silylated amine 283 and regenerate the L_nNi⁰ catalyst. In the final step, removal of silane from 283 occurred during workup by subjection to mild acid, which furnished the desired fluorinated sulfonamide product (278, (Scheme 81).

Scheme 81.

Plausible mechanism nickel catalyzed three-component coupling reaction of tetrafluoroethylene, N-sulfonyl-substituted imine and Et₂SiH₂.

The synthesis of (difluoromethyl)naphthalenes was accomplished through an intramolecular insertion of 1,1-difluoroallenes at the central carbon (Scheme 82).⁶³ Treatment of o-bromophenyls bearing tethered 1,1-difluoroallenes (284) with a Pd⁰ catalyst system generated an array of (difluoromethyl)naphthalenes (285) via regioselective C–C bond formation at the β-position relative to the fluorine substituents. Notably, this reaction generated products bearing two fluorine atoms and did not involve a defluorination event.

Scheme 82.

Palladium-catalyzed synthesis of (difluoromethyl)naphthalenes.

In this reaction, oxidative addition of bromoallenes (284) to Pd⁰, afforded aryl-Pd^II bromide 286, which underwent regioselective insertion into the β-position of the difluoroalkene to generate π-allyl-Pd^II intermediate 287. Of note, neither the η¹ nor η³ coordination modes of this intermediate bear a β-relationship between the metal and a fluorine atom, thus a β-fluoride elimination step cannot occur. Instead β-hydride elimination from σ-allyl-Pd^II intermediate 288 furnished the cyclic 1,1-difluoro-1,3-dienes (289), and finally, isomerization of 289 provided the desired (difluoromethyl)naphthalene product (285). In this reaction, ethanol might stabilize the reactive Pd⁰·L complex via coordination (Scheme 83).

Scheme 83.

Plausible mechanism of palladium-catalyzed intramolecular synthesis of (difluoromethyl)naphthalenes.

This reaction serve as the first example of generating terminally fluorinated π-allyl-Pd^II intermediates through insertion as opposed to previously reported reactions that involve oxidative addition.^54,64 To establish the intermediacy of π-allyl-Pd^II complex 287, a reaction was performed in presence of NaCHCO₂Et, and as expected, 287 underwent a Tsuji–Trost reaction to afford the corresponding alkylation product (290, Scheme 84).

Scheme 84.

The Tsuji–Trost reaction of the difluorinated π-allyl-Pd^II intermediate.

8. Summary and Outlook

In this review, we summarized the recent transition metal-catalyzed reactions of gem-difluoroalkenes that directly transform the gem-difluoroalknene group. As seen throughout the many examples, gem-difluoroalkenes serve as useful building blocks for generating more elaborate substructures, many of which are found in biologically active compounds and materials. gem-Difluoroalkenes can undergo various types of reactions, including coupling reactions, condensation, addition-elimination, polymerization, hydrodefluorination, etc. in presence of transition metal catalyst systems. Many of these reactions proceed through metal-alkyl intermediates that bear β-fluorine atoms that readily undergo β-fluoride elimination and ultimately deliver monofluorinated products. In a second common reactivity pattern, coinage metal fluorides deliver fluorine to the difluorinated position in net difunctionalization reactions that ultimately deliver secondary trifluoromethane products. In most cases, the reactions perform well on β-aryl-α,α-difluoroalkenes, and the reactions of the corresponding β-alkyl-α,α-difluoroalkenes either (a) remain unclear, or (b) provide distinct products. Although other types of reactions are also known, few reactions deliver products bearing two fluorine atoms, and new synthetic strategies might be required to more broadly deliver difluorinated products.

Biography

Suvajit Koley is a Post-doctoral Research Associate in the Altman’s group at The University of Kansas. He received his B.Sc. degree from the University of Calcutta in India (2009). After obtaining his M.Sc. (2011) and Ph.D (2017) degrees in organic chemistry with Prof. Maya Shankar Singh from Banaras Hindu University, India, he joined Prof. Ganesh Pandey’s research group as a National Post-doctoral Fellow in the Center of Biomedical Research, India (2017–2018). His current research interests include cross-coupling reactions, C–H functionalization reactions, and reactions of fluorinated alkenes.

Ryan A. Altman received a BSc in chemistry from Creighton University in 2003 and a PhD in organic chemistry from the Massachusetts Institute of Technology (MIT) in 2008, studying as a Pfizer and National Institutes of Health predoctoral fellow in the laboratory of Professor Stephen L. Buchwald. From 2008–2011, he trained as a National Institutes of Health postdoctoral fellow under the guidance of Professor Larry E. Overman at the University of California, Irvine, after which he accepted a position in the Department of Medicinal Chemistry at The University of Kansas. The Altman research group works at the interface of synthetic organic and medicinal chemistries, with emphases in the areas of organometallic and organofluorine transformations and unique chemical reactivities enabled by fluorinated substructures. The group’s collaborative medicinal interests span a range of disease states, including pain, oncology, and aging.