Pd-Catalyzed Mizoroki-Heck Reactions Using Fluorine-Containing Agents as the Cross-Coupling Partners

The Mizoroki-Heck reaction represents one of the most convenient methods for carbon-carbon double bond formation in the synthesis of small organic molecules, natural products, pharmaceuticals, agrochemicals, and functional materials. Fluorine-containing organic compounds have found wide applications in the research areas of materials and life sciences over the past several decades. The incorporation of fluorine-containing segments into the target molecules by the Mizoroki-Heck reactions is highly attractive, as these reactions efficiently construct carbon-carbon double bonds bearing fluorinated functional groups by simple procedures. This review summarizes the palladium-catalyzed Mizoroki-Heck reactions using various fluorine-containing reagents as the cross-coupling partners. The first part of the review describes the Pd-catalyzed Mizoroki-Heck reactions of aryl halides or pseudo-halides with the fluorinated alkenes, and the second part discusses the Pd-catalyzed Mizoroki-Heck reactions of the fluorinated halides or pseudo-halides with alkenes. Variants of the Pd-catalyzed Mizoroki-Heck reactions with fluorine-containing reagents are also briefly depicted. This work supplies an overview, as well as a guide, to both younger and more established researchers in order to attract more attention and contributions in the realm of Mizoroki-Heck reactions with fluorine-containing participants.


Introduction
The palladium-catalyzed carbon-carbon cross-coupling of an aryl or vinyl halide and an alkene in the presence of a base is referred as the "Mizoroki-Heck reaction" [1][2][3][4][5][6].The reaction was discovered independently by Heck and Mizoroki more than 45 years ago.Heck first reported the Li 2 PdCl 4 -mediated reactions of organomercury compounds with olefins in acetonitrile or methanol at room temperature [7].Then, Mizoroki and co-workers disclosed the first cross-couplings of aryl iodide with alkenes catalyzed by PdCl 2 in methanol in the presence of potassium acetate at 120 • C [8].In 1972, Heck and co-worker proposed a possible mechanism for the reactions of aryl, benzyl, or styryl halides (R-X) with alkenes and a catalytic amount of Pd(OAc) 2 under milder conditions (Scheme 1) [9].In these conversions, an oxidative addition occurs between Pd(0) (formed in situ from reduction of Pd(OAc) 2 by olefin) and R-X (1), presumably generating a very reactive solvated organopalladium(II) halide ([R-Pd-X], 2), which is probably the same intermediate produced previously in the exchange reactions between palladium halides and organomercury compounds [7].[R-Pd-X] undergoes an addition reaction with olefin (3) to yield a palladium adduct (4), regenerates the Pd(0) species, maintaining the catalytic cycle.Formally speaking, the vinylic hydrogen atom of alkene is substituted by the organic residue (R) of R-X in the reactions (Scheme 1).Scheme 1.A possible mechanism for the Mizoroki-Heck reactions.
On the other hand, fluorine is a very intriguing atom for its unique properties.Introduction of fluorine atom(s) into organic molecules usually brings about a dramatic impact on the physicochemical and biological properties of the molecules [36][37][38].Fluorine-containing organic compounds have found wide application in the areas of chemistry, biology, and materials science over the past several decades [39][40][41][42][43][44][45].There have been as many as 25% of pharmaceuticals and 30-40% of agrochemicals on the market containing at least a single fluorine atom [41].Because only a few naturally-occurring organofluorides have been discovered, most of the fluorinated organic compounds have to be manually synthesized [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51].It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51].In general, the fluorinated compounds can be synthesized by direct fluorination or fluoroalkylation, or through reactions with the fluorine-containing building blocks [39][40][41][42][43][44][45][46][47][48][49][50][51].The incorporation of fluorinecontaining fragments into organic frameworks by Pd-catalyzed Mizoroki-Heck reactions has proved to be the simplest and most convenient pathway to build diverse alkenes bearing fluorinated functionalities.This strategy includes the Pd-catalyzed cross-couplings of fluorinated alkenes with aryl halides or pseudo halides, and Pd-catalyzed reactions of alkenes with the fluorinated aryl or alkyl halides or pseudo halides.Fluorine-containing alkenes are versatile building blocks in the synthesis of bioactive molecules for drug discovery and advanced materials for specific applications (see .The concise, straightforward, selective, and highly efficient preparation of the fluorinated alkenes by the Mizoroki-Heck reactions has made these compounds easy to access and diversify.
To our knowledge, there has been no review article systematically summarizing the Pdcatalyzed Mizoroki-Heck reactions using fluorine-containing agents as the cross-coupling partners.
On the other hand, fluorine is a very intriguing atom for its unique properties.Introduction of fluorine atom(s) into organic molecules usually brings about a dramatic impact on the physicochemical and biological properties of the molecules [36][37][38].Fluorine-containing organic compounds have found wide application in the areas of chemistry, biology, and materials science over the past several decades [39][40][41][42][43][44][45].There have been as many as 25% of pharmaceuticals and 30-40% of agrochemicals on the market containing at least a single fluorine atom [41].Because only a few naturally-occurring organofluorides have been discovered, most of the fluorinated organic compounds have to be manually synthesized [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51].It is undoubted that the development of efficient methods to construct fluorine-containing molecules is of great importance [46][47][48][49][50][51].In general, the fluorinated compounds can be synthesized by direct fluorination or fluoroalkylation, or through reactions with the fluorine-containing building blocks [39][40][41][42][43][44][45][46][47][48][49][50][51].The incorporation of fluorine-containing fragments into organic frameworks by Pd-catalyzed Mizoroki-Heck reactions has proved to be the simplest and most convenient pathway to build diverse alkenes bearing fluorinated functionalities.This strategy includes the Pd-catalyzed cross-couplings of fluorinated alkenes with aryl halides or pseudo halides, and Pd-catalyzed reactions of alkenes with the fluorinated aryl or alkyl halides or pseudo halides.Fluorine-containing alkenes are versatile building blocks in the synthesis of bioactive molecules for drug discovery and advanced materials for specific applications (see .The concise, straightforward, selective, and highly efficient preparation of the fluorinated alkenes by the Mizoroki-Heck reactions has made these compounds easy to access and diversify.
To our knowledge, there has been no review article systematically summarizing the Pd-catalyzed Mizoroki-Heck reactions using fluorine-containing agents as the cross-coupling partners.To fill the gap in this area, we present an overview of the recent advances in the Pd-catalyzed Mizoroki-Heck reactions with the fluorinated cross-coupling participants including the fluorinated alkenes and/or the fluorinated aryl or alkyl halides.This review offers as a guide to both younger and more established researchers, and is intended to attract more attention to and contributions in the development of the Mizoroki-Heck reactions with fluorine-containing cross-coupling reagents.

Fluoroalkenes as Cross-Coupling Participants
The Mizoroki-Heck reaction provides a convenient method for the arylation of olefins [1][2][3][4][5][6].In most cases, the vinylic hydrogen atom is formally substituted by the organic residue of an organic halide under the Heck-type reaction conditions.High regioselectivities of the arylation at the less substituted site of the carbon-carbon double bond of the unsymmetrically substituted olefins are usually observed, which may be attributed to the steric factors [1][2][3][4][5][6].One of the key steps of the reaction is β-hydride elimination.However, when aryl bromide or iodide (7) reacted with vinylidene difluoride (8) in the presence of Pd(OAc) 2 , the expected β-H elimination product, β,β-difluorostyrene (9), was formed only in a very small amount (Scheme 2) [45,52].The major product of the reaction was α-fluorostyrene (10).Moreover, the reaction of vinyl fluoride (11) with 7a gave styrene (12) and stilbene (13), the ratio of which strongly depended on the reaction conditions.Treatment of 7a with trifluoroethylene ( 14) produced an isomeric mixture of 15, 16 and 17 (45%), with 15 being predominant (86% by GC).Unexpectedly, 15 again was the product when chlorotrifluoroethylene (18) was treated with 7a.These results suggested the substitution of a vinylic fluorine atom in all cases, which were distinct from the known Heck-type reactions with non-fluorinated olefins [1][2][3][4][5][6].The transformations represented the first examples of charge-controlled Heck-type reaction, which was only significant in the presence of fluoroolefins [52].
Mizoroki-Heck reactions with the fluorinated cross-coupling participants including the fluorinated alkenes and/or the fluorinated aryl or alkyl halides.This review offers as a guide to both younger and more established researchers, and is intended to attract more attention to and contributions in the development of the Mizoroki-Heck reactions with fluorine-containing cross-coupling reagents.

Fluoroalkenes as Cross-Coupling Participants
The Mizoroki-Heck reaction provides a convenient method for the arylation of olefins [1][2][3][4][5][6].In most cases, the vinylic hydrogen atom is formally substituted by the organic residue of an organic halide under the Heck-type reaction conditions.High regioselectivities of the arylation at the less substituted site of the carbon-carbon double bond of the unsymmetrically substituted olefins are usually observed, which may be attributed to the steric factors [1][2][3][4][5][6].One of the key steps of the reaction is β-hydride elimination.However, when aryl bromide or iodide (7) reacted with vinylidene difluoride (8) in the presence of Pd(OAc)2, the expected β-H elimination product, β,β-difluorostyrene (9), was formed only in a very small amount (Scheme 2) [45,52].The major product of the reaction was α-fluorostyrene (10).Moreover, the reaction of vinyl fluoride (11) with 7a gave styrene (12) and stilbene (13), the ratio of which strongly depended on the reaction conditions.Treatment of 7a with trifluoroethylene ( 14) produced an isomeric mixture of 15, 16 and 17 (45%), with 15 being predominant (86% by GC).Unexpectedly, 15 again was the product when chlorotrifluoroethylene (18) was treated with 7a.These results suggested the substitution of a vinylic fluorine atom in all cases, which were distinct from the known Heck-type reactions with non-fluorinated olefins [1][2][3][4][5][6].The transformations represented the first examples of charge-controlled Heck-type reaction, which was only significant in the presence of fluoroolefins [52].Mechanistically, the reaction starts with the formation of a palladium adduct (19) by the oxidative addition of the in situ generated Pd(0) species with 7a, which undergoes olefin coordination to produce complex 20 (Scheme 2) [52].Then, the phenyl group in 20 transfers from the Pd center to the CF 2 site of 8, affording 21.A β-fluorine elimination of 21 yields α-fluorostyrene (10a) as the final product.Compound 23 would be an intermediate, if the steric aspects were relevant, and a subsequent β-hydride elimination of 23 could form 9a.However, the formation of 23 must be of low probability, as only trace amounts of 9a were detected.The favorable formation of 21 in the reaction of 8 could be explained by the charge-controlled mechanism, which was verified by the MNDO-calculations [52].Furthermore, the reactions of 7a with 11 and 14 obeyed a mechanism similar to that of 7a with 8, and the reaction of 7a with 18 underwent both the olefinic fluorine substitution and the C-Cl bond reduction.The β-fluorine elimination seemed to be the preferred type of elimination, even though the competitive β-hydride elimination was a possible pathway [45,52].This procedure constituted a convenient method for the preparation of α-fluorostyrenes.
More than fifteen years later, Patrick and co-workers found that 3-fluoro-3-buten-2-one (26) reacted smoothly with aryl iodides (25) under the Heck-type cross-coupling conditions to give 3-fluorobenzalacetones (27) in good yields with only Z-stereoselectivity (Scheme 3) [53].The reaction used Pd(OAc) 2 as a catalyst, triphenylphosphine as a ligand, and triethylamine as a base in DMF.The conjugate addition products and the fluoride elimination products were not observed.The preferable trans relationship between the aryl and acyl groups during the reaction was maintained in the configuration of the final product (27).The required syn-elimination of HPdL 2 in intermediate 28 sustained very small steric repulsion between the aryl group and the fluorine atom.Mechanistically, the reaction starts with the formation of a palladium adduct (19) by the oxidative addition of the in situ generated Pd(0) species with 7a, which undergoes olefin coordination to produce complex 20 (Scheme 2) [52].Then, the phenyl group in 20 transfers from the Pd center to the CF2 site of 8, affording 21.A β-fluorine elimination of 21 yields α-fluorostyrene (10a) as the final product.Compound 23 would be an intermediate, if the steric aspects were relevant, and a subsequent β-hydride elimination of 23 could form 9a.However, the formation of 23 must be of low probability, as only trace amounts of 9a were detected.The favorable formation of 21 in the reaction of 8 could be explained by the charge-controlled mechanism, which was verified by the MNDOcalculations [52].Furthermore, the reactions of 7a with 11 and 14 obeyed a mechanism similar to that of 7a with 8, and the reaction of 7a with 18 underwent both the olefinic fluorine substitution and the C-Cl bond reduction.The β-fluorine elimination seemed to be the preferred type of elimination, even though the competitive β-hydride elimination was a possible pathway [45,52].This procedure constituted a convenient method for the preparation of α-fluorostyrenes.
More than fifteen years later, Patrick and co-workers found that 3-fluoro-3-buten-2-one (26) reacted smoothly with aryl iodides (25) under the Heck-type cross-coupling conditions to give 3fluorobenzalacetones (27) in good yields with only Z-stereoselectivity (Scheme 3) [53].The reaction used Pd(OAc)2 as a catalyst, triphenylphosphine as a ligand, and triethylamine as a base in DMF.The conjugate addition products and the fluoride elimination products were not observed.The preferable trans relationship between the aryl and acyl groups during the reaction was maintained in the configuration of the final product (27).The required syn-elimination of HPdL2 in intermediate 28 sustained very small steric repulsion between the aryl group and the fluorine atom.In 2016, Couve-Bonnaire and co-workers reported the ligand-free palladium-catalyzed Mizoroki-Heck reactions of methyl α-fluoroacrylate (30) with aryl or heteroaryl iodides (29), leading to a cheap, efficient, and stereoselective synthesis of fluoroacrylate derivatives (31) in good to quantitative yields (Scheme 4) [54].The transformation had good functional group tolerance and could be extended to more steric hindered trisubstituted alkenes, which were previously the reluctant substrates in the Mizoroki-Heck reactions.The reactions of trisubstituted (E)-3-alkyl-2-fluoroacrylate (32) with 29 under the standard conditions gave the corresponding tetrasubstituted fluoroacrylates (33) in fair to good yields [54].These results constituted the first examples for the synthesis of tetrasubstituted alkenes by using the Mizoroki-Heck reaction.This methodology was also applicable to the preparation of a fluorinated analogue of a therapeutic agent against inflammation and cancers.In 2016, Couve-Bonnaire and co-workers reported the ligand-free palladium-catalyzed Mizoroki-Heck reactions of methyl α-fluoroacrylate (30) with aryl or heteroaryl iodides (29), leading to a cheap, efficient, and stereoselective synthesis of fluoroacrylate derivatives (31) in good to quantitative yields (Scheme 4) [54].The transformation had good functional group tolerance and could be extended to more steric hindered trisubstituted alkenes, which were previously the reluctant substrates in the Mizoroki-Heck reactions.The reactions of trisubstituted (E)-3-alkyl-2-fluoroacrylate (32) with 29 under the standard conditions gave the corresponding tetrasubstituted fluoroacrylates (33) in fair to good yields [54].These results constituted the first examples for the synthesis of tetrasubstituted alkenes by using the Mizoroki-Heck reaction.This methodology was also applicable to the preparation of a fluorinated analogue of a therapeutic agent against inflammation and cancers.
Similarly, Hanamoto and co-worker disclosed the Mizoroki-Heck reactions of (1fluorovinyl)methyldiphenylsilane (35) with aryl iodides (34) catalyzed by Pd(OAc)2 (5 mol%) in the presence of Ag2CO3 (3 equiv) and 4 Å MS in 1,4-dioxane (Scheme 5) [55].The reactions supplied a series of (E)-β-aryl-(α-fluorovinyl)methyldiphenylsilanes (36) in good yields with excellent stereoselectivity.Desilylation/protonation of the product gave the corresponding (E)-β-fluorostyrene derivative with complete retention of the configuration of the double bond, which illustrated the synthetic scope of this method.Moreover, the Mizoroki-Heck reaction of ethyl (Z)-3-fluoropropenoate (Z-37) or ethyl (E)-3fluoropropenoate (E-37) with iodobenzene in the presence of Pd(OAc)2 (5 mol%) produced ethyl 3fluoropropenoate (Z-39) as a sole product (Scheme 6) [56].The reaction proceeded smoothly at the βposition with specific stereoselectivity.The stereochemistry of E-37 was completely inverted and only Z-39 was produced.Meanwhile, compound 40 was formed as a side product via loss of a fluorine atom.It was possible that the catalyst system caused the isomerization.However, the exact mechanism for the high stereoselectivity of the reaction remained unclear.Moreover, the Mizoroki-Heck reaction of ethyl (Z)-3-fluoropropenoate (Z-37) or ethyl (E)-3-fluoropropenoate (E-37) with iodobenzene in the presence of Pd(OAc) 2 (5 mol%) produced ethyl 3-fluoropropenoate (Z-39) as a sole product (Scheme 6) [56].The reaction proceeded smoothly at the β-position with specific stereoselectivity.The stereochemistry of E-37 was completely inverted and only Z-39 was produced.Meanwhile, compound 40 was formed as a side product via loss of a fluorine atom.It was possible that the catalyst system caused the isomerization.However, the exact mechanism for the high stereoselectivity of the reaction remained unclear.

Fluorine-Containing Vinyl Sulfur Compounds as the Cross-Coupling Participants
Ethenesulfonyl fluoride (ESF) is a highly reactive and versatile reagent in the synthesis of a wide variety of organosulfur compounds, which behaves as a strong Michael acceptor or a Diels-Alder dienophile to conveniently introduce an SO2F group [59].In 2016, Wu and Sharpless described a Pdcatalyzed Heck-Matsuda process for the synthesis of the otherwise difficult to access βarylethenesulfonyl fluorides (Scheme 8) [60].In this reaction, ethenesulfonyl fluoride (51) underwent β-arylation with the stable and readily prepared arenediazonium tetrafluoroborates (50) in the presence of catalytic palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride (52) in 43-97% yield.The products 52 proved to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group could be exclusively attacked by nucleophiles under defined conditions, making these simple cores attractive for covalent drug discovery [60].

Fluorine-Containing Vinyl Sulfur Compounds as the Cross-Coupling Participants
Ethenesulfonyl fluoride (ESF) is a highly reactive and versatile reagent in the synthesis of a wide variety of organosulfur compounds, which behaves as a strong Michael acceptor or a Diels-Alder dienophile to conveniently introduce an SO 2 F group [59].In 2016, Wu and Sharpless described a Pd-catalyzed Heck-Matsuda process for the synthesis of the otherwise difficult to access β-arylethenesulfonyl fluorides (Scheme 8) [60].In this reaction, ethenesulfonyl fluoride (51) underwent β-arylation with the stable and readily prepared arenediazonium tetrafluoroborates (50) in the presence of catalytic palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride (52) in 43-97% yield.The products 52 proved to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group could be exclusively attacked by nucleophiles under defined conditions, making these simple cores attractive for covalent drug discovery [60].46) by the Mizoroki-Heck reactions of the polarized carbon-carbon double bonds of the 1,1-difluoro-1-alkene moieties was accomplished (Scheme 7) [45,57,58].In the first step of the reactions, an arylpalladium or aminopalladium intermediate (42 or 47) bearing a 2,2difluorovinyl group is formed from 41 or 46, respectively.Then, intermediate 42 or 47 undergoes a 5endo-trig alkene insertion and subsequent β-fluorine elimination to afford ring-fluorinated indene (45) or 3H-pyrroles (49).In both cases, the CF2 unit was very essential for the cyclization as the corresponding monofluoroalkene, fluorine-free alkene, dichloroalkene, and dibromoalkene didn't give the cyclized products under the same reaction conditions [57,58].

Fluorine-Containing Vinyl Sulfur Compounds as the Cross-Coupling Participants
Ethenesulfonyl fluoride (ESF) is a highly reactive and versatile reagent in the synthesis of a wide variety of organosulfur compounds, which behaves as a strong Michael acceptor or a Diels-Alder dienophile to conveniently introduce an SO2F group [59].In 2016, Wu and Sharpless described a Pdcatalyzed Heck-Matsuda process for the synthesis of the otherwise difficult to access βarylethenesulfonyl fluorides (Scheme 8) [60].In this reaction, ethenesulfonyl fluoride (51) underwent β-arylation with the stable and readily prepared arenediazonium tetrafluoroborates (50) in the presence of catalytic palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride (52) in 43-97% yield.The products 52 proved to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group could be exclusively attacked by nucleophiles under defined conditions, making these simple cores attractive for covalent drug discovery [60].Later, Qin and Sharpless employed a similar strategy for the synthesis of 2-(hetero)arylethenesulfonylfluorides (54) and 1,3-dienylsulfonyl fluorides (56) (Scheme 9) [61].They found that a combination of catalytic Pd(OAc) 2 with a stoichiometric amount of silver(I) trifluoroacetate enabled the coupling process between either an (hetero)aryl or alkenyl iodide (53 or 55) and ethenesulfonyl fluoride (ESF, 51).The reaction was demonstrated in the successful synthesis of eighty-eight compounds in up to 99% yields, including the unprecedented 2-heteroarylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides [61].These substituted ethenesulfonyl fluorides are useful building blocks for consequent synthetic transformations [61].Furthermore, the oxidative Heck cross-coupling reactions have become attractive for modern organic synthesis due to advantages such as efficiency, mild reaction conditions, good functional group tolerance, and widespread applications [62][63][64].In 2017, Arvidsson and co-workers reported an operationally simple method for ligand-and additive-free oxidative Heck couplings of aryl boronic acids (57) with ESF (51) (Scheme 10) [65].The reactions proceeded at room temperature with good chemoselectivity and E-selectivity and offered facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides (58) from the commercially available boronic acids (57).The products (58) have a "dual warhead" with two electrophilic sites that have been used as covalent enzyme inhibitors and as synthetic reagents [65].The authors also demonstrated that aryl-substituted β-sultams could be prepared through a one-pot procedure in which an excess of primary amine was added to the reaction mixture before workup [65].Furthermore, the oxidative Heck cross-coupling reactions have become attractive for modern organic synthesis due to advantages such as efficiency, mild reaction conditions, good functional group tolerance, and widespread applications [62][63][64].In 2017, Arvidsson and co-workers reported an operationally simple method for ligand-and additive-free oxidative Heck couplings of aryl boronic acids (57) with ESF (51) (Scheme 10) [65].The reactions proceeded at room temperature with good chemoselectivity and E-selectivity and offered facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides (58) from the commercially available boronic acids (57).The products (58) have a "dual warhead" with two electrophilic sites that have been used as covalent enzyme inhibitors and as synthetic reagents [65].The authors also demonstrated that aryl-substituted β-sultams could be prepared through a one-pot procedure in which an excess of primary amine was added to the reaction mixture before workup [65].Furthermore, the oxidative Heck cross-coupling reactions have become attractive for modern organic synthesis due to advantages such as efficiency, mild reaction conditions, good functional group tolerance, and widespread applications [62][63][64].In 2017, Arvidsson and co-workers reported an operationally simple method for ligand-and additive-free oxidative Heck couplings of aryl boronic acids (57) with ESF (51) (Scheme 10) [65].The reactions proceeded at room temperature with good chemoselectivity and E-selectivity and offered facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides (58) from the commercially available boronic acids (57).The products (58) have a "dual warhead" with two electrophilic sites that have been used as covalent enzyme inhibitors and as synthetic reagents [65].The authors also demonstrated that aryl-substituted β-sultams could be prepared through a one-pot procedure in which an excess of primary amine was added to the reaction mixture before workup [65].Likewise, Qin and co-workers disclosed the base-free palladium-catalyzed fluorosulfonylvinylation of (hetero)arylboronic acids (60) with ESF (51) under oxidative conditions (Scheme 11) [66].Aryl-and heteroaryl-boronic acids (60) reacted with ESF in the presence of a catalytic amount of Pd(OAc) 2 and excess 2,3-dichloro-5,6-dicyano-p-benzoqui-none (DDQ) or AgNO 3 in AcOH to stereoselectively afford the corresponding E-isomer of β-arylethenesulfonyl fluoride products (61) in up to 99% yield.The utility of the reactions was exemplified by an expanded scope of 47 examples including N-, O-, and S-containing heteroaromatics, demonstrating chemoselectivity over aryl iodides [66]. of eighty-eight compounds in up to 99% yields, including the unprecedented 2heteroarylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides [61].These substituted ethenesulfonyl fluorides are useful building blocks for consequent synthetic transformations [61].Furthermore, the oxidative Heck cross-coupling reactions have become attractive for modern organic synthesis due to advantages such as efficiency, mild reaction conditions, good functional group tolerance, and widespread applications [62][63][64].In 2017, Arvidsson and co-workers reported an operationally simple method for ligand-and additive-free oxidative Heck couplings of aryl boronic acids (57) with ESF (51) (Scheme 10) [65].The reactions proceeded at room temperature with good chemoselectivity and E-selectivity and offered facile access to a wide range of β-aryl/heteroaryl ethenesulfonyl fluorides (58) from the commercially available boronic acids (57).The products (58) have a "dual warhead" with two electrophilic sites that have been used as covalent enzyme inhibitors and as synthetic reagents [65].The authors also demonstrated that aryl-substituted β-sultams could be prepared through a one-pot procedure in which an excess of primary amine was added to the reaction mixture before workup [65].It should be noted that the sulfur-containing olefins (e.g., vinyl sulfides, sulfoxides) are the least investigated substrates in the Mizoroki-Heck reactions, as these substrates may poison the Pd-catalysts to form stable metal-sulfur complexes [67].To date, only a handful of successful Heck cross-coupling reactions based on sulfoxides have been reported, even though these moieties have potential for many synthetic applications.Among this type of molecule, perfluoroalkyl vinyl sulfoxides possess a strongly polarized double bond and is highly reactive, which makes them interesting for investigation.In 2015, Sokolenko and co-workers explored the Heck-type reactions of trifluoromethyl or tridecafluorohexyl vinyl sulfoxides (62) with aryl iodides (63) (Scheme 12) [67].Palladium(II) acetate was found to be the most suitable catalyst for the reactions.By this method, a series of E-1-aryl-2-perfluoroalkylsulfinylethylenes (64) were synthesized.Styrenes (65) without a perfluoroalkylsulfinyl group were also formed (as byproducts) in these cases.The perfluoroalkyl vinyl sulfoxides (62) may undergo both terminal and internal additions of the aryl group (Scheme 12).In the former case, β-elimination of the palladium species and hydride from 67 yields 64.In the latter case, β-elimination of the palladium species and perfluoroalkylsulfinyl group from 68 leads to 65.The formation of stable Pd-S bonds might facilitate the latter process.It should be noted that the sulfur-containing olefins (e.g., vinyl sulfides, sulfoxides) are the least investigated substrates in the Mizoroki-Heck reactions, as these substrates may poison the Pdcatalysts to form stable metal-sulfur complexes [67].To date, only a handful of successful Heck crosscoupling reactions based on sulfoxides have been reported, even though these moieties have potential for many synthetic applications.Among this type of molecule, perfluoroalkyl vinyl sulfoxides possess a strongly polarized double bond and is highly reactive, which makes them interesting for investigation.In 2015, Sokolenko and co-workers explored the Heck-type reactions of trifluoromethyl or tridecafluorohexyl vinyl sulfoxides (62) with aryl iodides (63) (Scheme 12) [67].Palladium(II) acetate was found to be the most suitable catalyst for the reactions.By this method, a series of E-1-aryl-2-perfluoroalkylsulfinylethylenes (64) were synthesized.Styrenes (65) without a perfluoroalkylsulfinyl group were also formed (as byproducts) in these cases.The perfluoroalkyl vinyl sulfoxides (62) may undergo both terminal and internal additions of the aryl group (Scheme 12).In the former case, β-elimination of the palladium species and hydride from 67 yields 64.In the latter case, β-elimination of the palladium species and perfluoroalkylsulfinyl group from 68 leads to 65.The formation of stable Pd-S bonds might facilitate the latter process.

Fluoroalkylated Alkenes as the Cross-Coupling Partners
Perfluoroalkylated alkenes are important feedstocks for the synthesis of useful fluorinecontaining molecules.In 1981, Ojima and co-workers reported the Pd-catalyzed Mizoroki-Heck reactions of 3,3,3-trifluoropropene or pentafluorostyrene (70) with aromatic halides (71) (Scheme 13) [68].The cross-couplings proceeded smoothly by simply heating the mixtures of aryl iodides or bromides, trifluoropropene or pentafluorostyrene, a Pd-catalyst (1 mol%), and a base (such as Et3N or KOAc), which gave a variety of trans-β-trifluoromethylstyrenes or trans-βpentafluorophenylstyrenes (72) in good to high yields via a one-step procedure.The arylation was not sensitive to the electronic nature of the substituents on the aryl halides but was rather sensitive to the steric hindrance.However, aryl chlorides such as chlorobenzene and chlorotoluene were unreactive under the same reaction conditions.Scheme 12.The Mizoroki-Heck reactions of perfluoroalkyl vinyl sulfoxides with aryl iodides.The cross-couplings proceeded smoothly by simply heating the mixtures of aryl iodides or bromides, trifluoropropene or pentafluorostyrene, a Pd-catalyst (1 mol%), and a base (such as Et 3 N or KOAc), which gave a variety of trans-β-trifluoromethylstyrenes or trans-β-pentafluorophenylstyrenes (72) in good to high yields via a one-step procedure.The arylation was not sensitive to the electronic nature of the substituents on the aryl halides but was rather sensitive to the steric hindrance.However, aryl chlorides such as chlorobenzene and chlorotoluene were unreactive under the same reaction conditions.Scheme 13.The Heck-type reactions of aryl halides with 3,3,3-trifluoropropene or pentafluorostyrene.

Fluoroalkylated Alkenes as the
In 2001, Xiao and co-workers found that Pd-catalyzed olefination of aryl halides ( 73) with 1H,1H,2H-perfluoro-1-alkenes (74) provided trans-fluorous ponytail-substituted aryl compounds (75) in good to excellent yields (Scheme 14) [69].Typically, the reactions of 73 with 74 in the presence of NaOAc and the Herrmann-Beller palladacycle catalyst (0.5-1 mol%) in DMF supplied the trans olefins 75 in more than 90% isolated yields in most cases without optimization.Purification of 75 by flash chromatography allowed easy reduction of the C=C double bonds of 75 under the standard Pd/C-or Rh/C-catalyzed hydrogenation conditions [69].This method was successfully applied to the synthesis of binaphathols bearing fluorinated ponytails, which are potential ligands for catalysis in scCO2 and fluorous solvents [69,70].The application of these ligands in the ruthenium-catalyzed hydrogenation of dimethyl itaconate revealed that the fluorous ponytails on the ligands imposed significant effects on the hydrogenation activity, but not on the enantioselectivity [70].
Later, Cai and co-worker developed a PCP Pincer-Pd catalyst (77), which was favorably used in Mizoroki-Heck cross-couplings between perfluoroalkyl alkenes (74) and aryl halides (78) for the preparation of perfluoroalkenylated aryl compounds (79) (Scheme 15) [71].Due to the unique tridentate coordination architecture, the Pincer complex was stable, selective, and highly reactive, and it permitted low catalyst loadings and gave the possibility of fine-tuning the catalytic properties of the metal center.Catalyst 77 showed high catalytic activity in this reaction and the corresponding arylated products were obtained in moderate to excellent yields.Moreover, 77 could be easily separated by F-SPE (Fluorous solid phase extraction) technique and reused three times without significant loss of activity.
In 2001, Xiao and co-workers found that Pd-catalyzed olefination of aryl halides ( 73) with 1H,1H,2H-perfluoro-1-alkenes (74) provided trans-fluorous ponytail-substituted aryl compounds (75) in good to excellent yields (Scheme 14) [69].Typically, the reactions of 73 with 74 in the presence of NaOAc and the Herrmann-Beller palladacycle catalyst (0.5-1 mol%) in DMF supplied the trans olefins 75 in more than 90% isolated yields in most cases without optimization.Purification of 75 by flash chromatography allowed easy reduction of the C=C double bonds of 75 under the standard Pd/C-or Rh/C-catalyzed hydrogenation conditions [69].This method was successfully applied to the synthesis of binaphathols bearing fluorinated ponytails, which are potential ligands for catalysis in scCO 2 and fluorous solvents [69,70].The application of these ligands in the ruthenium-catalyzed hydrogenation of dimethyl itaconate revealed that the fluorous ponytails on the ligands imposed significant effects on the hydrogenation activity, but not on the enantioselectivity [70].In 2001, Xiao and co-workers found that Pd-catalyzed olefination of aryl halides ( 73) with 1H,1H,2H-perfluoro-1-alkenes (74) provided trans-fluorous ponytail-substituted aryl compounds (75) in good to excellent yields (Scheme 14) [69].Typically, the reactions of 73 with 74 in the presence of NaOAc and the Herrmann-Beller palladacycle catalyst (0.5-1 mol%) in DMF supplied the trans olefins 75 in more than 90% isolated yields in most cases without optimization.Purification of 75 by flash chromatography allowed easy reduction of the C=C double bonds of 75 under the standard Pd/C-or Rh/C-catalyzed hydrogenation conditions [69].This method was successfully applied to the synthesis of binaphathols bearing fluorinated ponytails, which are potential ligands for catalysis in scCO2 and fluorous solvents [69,70].The application of these ligands in the ruthenium-catalyzed hydrogenation of dimethyl itaconate revealed that the fluorous ponytails on the ligands imposed significant effects on the hydrogenation activity, but not on the enantioselectivity [70].
Later, Cai and co-worker developed a PCP Pincer-Pd catalyst (77), which was favorably used in Mizoroki-Heck cross-couplings between perfluoroalkyl alkenes (74) and aryl halides (78) for the preparation of perfluoroalkenylated aryl compounds (79) (Scheme 15) [71].Due to the unique tridentate coordination architecture, the Pincer complex was stable, selective, and highly reactive, and it permitted low catalyst loadings and gave the possibility of fine-tuning the catalytic properties of the metal center.Catalyst 77 showed high catalytic activity in this reaction and the corresponding arylated products were obtained in moderate to excellent yields.Moreover, 77 could be easily separated by F-SPE (Fluorous solid phase extraction) technique and reused three times without significant loss of activity.Later, Cai and co-worker developed a PCP Pincer-Pd catalyst (77), which was favorably used in Mizoroki-Heck cross-couplings between perfluoroalkyl alkenes (74) and aryl halides (78) for the preparation of perfluoroalkenylated aryl compounds (79) (Scheme 15) [71].Due to the unique tridentate coordination architecture, the Pincer complex was stable, selective, and highly reactive, and it permitted low catalyst loadings and gave the possibility of fine-tuning the catalytic properties of the metal center.Catalyst 77 showed high catalytic activity in this reaction and the corresponding arylated products were obtained in moderate to excellent yields.Moreover, 77 could be easily separated by F-SPE (Fluorous solid phase extraction) technique and reused three times without significant loss of activity.In 2001, Xiao and co-workers found that Pd-catalyzed olefination of aryl halides ( 73) with 1H,1H,2H-perfluoro-1-alkenes (74) provided trans-fluorous ponytail-substituted aryl compounds (75) in good to excellent yields (Scheme 14) [69].Typically, the reactions of 73 with 74 in the presence of NaOAc and the Herrmann-Beller palladacycle catalyst (0.5-1 mol%) in DMF supplied the trans olefins 75 in more than 90% isolated yields in most cases without optimization.Purification of 75 by flash chromatography allowed easy reduction of the C=C double bonds of 75 under the standard Pd/C-or Rh/C-catalyzed hydrogenation conditions [69].This method was successfully applied to the synthesis of binaphathols bearing fluorinated ponytails, which are potential ligands for catalysis in scCO2 and fluorous solvents [69,70].The application of these ligands in the ruthenium-catalyzed hydrogenation of dimethyl itaconate revealed that the fluorous ponytails on the ligands imposed significant effects on the hydrogenation activity, but not on the enantioselectivity [70].Scheme 14.The Mizoroki-Heck reactions between perfluoroalkyl alkenes and aryl halides.
Genêt and co-workers described the palladium-catalyzed Mizoroki-Heck reactions between aryldiazonium salts (91) and perfluoroalkyl alkenes (92) (Scheme 18) [74].The reactions carried out in methanol at 40 °C in the presence of 0.5 mol% of Pd(OAc)2 afforded a series of long-chain perfluoroalkyl-substituted aromatic compounds (93) in good to excellent yields.However, coupling of 4-iodotoluene (91f) under the same reaction conditions failed to give the desired product (93bb; R = CH3, Rfn = C8F17).Coupling of aryl iodide in the presence of Pd(PPh3)4 and triethylamine in toluene didn't form the expected product neither.Interestingly, under Jeffery's conditions (Pd(OAc)2, DMF, NaHCO3, n-Bu4NHSO4), the reaction of 4-iodotoluene (91f) with 92b (Rfn = C8F17) afforded 93bb in 80% yield, but 4-bromotoluene (91g) remained much less reactive.Thanks to the difference in the reactivity of these functionalities, the Heck-type reaction of 92b with 4-bromobenzenediazonium tetrafluoroborate (91c) produced 93cb (R = Br, Rfn = C8F17) exclusively, showing good chemoselectivity.Hydrogenation of the carbon-carbon double bond of 93 afforded the fluorous aromatic compounds.Perfluoroalkyl-substituted aryl bromides and anilines were also accessed by this method.This protocol represented one of the most efficient methods to install a perfluoroalkyl chain onto an aromatic ring.The simple purification and the high purities of products allowed an easy scale up of this procedure.
In addition, a family of diazonium-functionalized oligo(phenylene vinylene)s (OPVs) tetramers were synthesized by alternating the Mizoroki-Heck cross-coupling and the Horner-Wadswoth-Emmons (HWE) reaction using fluorous mixture synthesis (FMS) technology (Scheme 17) [73].The FMS technology was found to be superior to the solid-phase organic synthesis (SPOS) techniques.The Mizoroki-Heck couplings of bromide 83 with 1H,1H,2H-perfluoroalkenes (84) employed a palladacycle catalyst which proved to be a better catalyst than Pd(OAc) 2 .Hydrogenation of the coupled alkenes (85) followed by removal of the Boc groups gave secondary amines as fluorous tags for diazonium-substituted aryl iodides (87).The final stage of OPV tetramer growth was a Heck-type reaction with an end-capping styrene derivative (89).At the end, the tagged products were detagged by cleaving the triazene linkage and generating a series of aryl diazonium compounds.The fluorous tags could be reused.The aryl diazonium functionalities in the products allowed them to be used as surface-grafting moieties in hybrid silicon/molecule assemblies [73].
Genêt and co-workers described the palladium-catalyzed Mizoroki-Heck reactions between aryldiazonium salts (91) and perfluoroalkyl alkenes (92) (Scheme 18) [74].The reactions carried out in methanol at 40 • C in the presence of 0.5 mol% of Pd(OAc) 2 afforded a series of long-chain perfluoroalkyl-substituted aromatic compounds (93) in good to excellent yields.However, coupling of 4-iodotoluene (91f) under the same reaction conditions failed to give the desired product (93bb; R = CH 3 , R fn = C 8 F 17 ).Coupling of aryl iodide in the presence of Pd(PPh 3 ) 4 and triethylamine in toluene didn't form the expected product neither.Interestingly, under Jeffery's conditions (Pd(OAc) 2 , DMF, NaHCO 3 , n-Bu 4 NHSO 4 ), the reaction of 4-iodotoluene (91f) with 92b (R fn = C 8 F 17 ) afforded 93bb in 80% yield, but 4-bromotoluene (91g) remained much less reactive.Thanks to the difference in the reactivity of these functionalities, the Heck-type reaction of 92b with 4-bromobenzenediazonium tetrafluoroborate (91c) produced 93cb (R = Br, R fn = C 8 F 17 ) exclusively, showing good chemoselectivity.Hydrogenation of the carbon-carbon double bond of 93 afforded the fluorous aromatic compounds.Perfluoroalkyl-substituted aryl bromides and anilines were also accessed by this method.This protocol represented one of the most efficient methods to install a perfluoroalkyl chain onto an aromatic ring.The simple purification and the high purities of products allowed an easy scale up of this procedure.
In 2015, Matsugi and co-workers synthesized f-Fmoc reagents (97) bearing C3F7, C4F9, or C6F13 chains by the Pd(OAc)2-catalyzed Mizoroki-Heck reaction of 94 with 95a, 95b, or 95c, followed by hydroxymethylation and introduction of the N-hydroxysuccinimide group (Scheme 19) [75].The method applied on a multi-gram scale after eight steps gave the desired products 97a, 97b, and 97c with overall yields of 73%, 60%, and 90%, respectively.The Pd-catalyzed doubly tagging Heck reaction of 94 with a mixture of the fluorous alkenes (95) was also studied, leading to an encoded mixture synthesis of f-Fmoc reagents.Addition of 95 in an order of 95c, 95b, 95a to the reaction mixture was found to be an effective condition in the mixed tagging Heck reaction.The target f-Fmoc reagents with C3F7, C4F9, and C6F13 groups could be separated owing to the different fluorine content of the molecules.This method provided a reasonable solution to obtain various f-Fmoc reagents in a one-pot procedure.These f-Fmoc reagents would be useful protecting groups for the effective synthesis of peptide isomer libraries.In 2015, Matsugi and co-workers synthesized f-Fmoc reagents (97) bearing C3F7, C4F9, or C6F13 chains by the Pd(OAc)2-catalyzed Mizoroki-Heck reaction of 94 with 95a, 95b, or 95c, followed by hydroxymethylation and introduction of the N-hydroxysuccinimide group (Scheme 19) [75].The method applied on a multi-gram scale after eight steps gave the desired products 97a, 97b, and 97c with overall yields of 73%, 60%, and 90%, respectively.The Pd-catalyzed doubly tagging Heck reaction of 94 with a mixture of the fluorous alkenes (95) was also studied, leading to an encoded mixture synthesis of f-Fmoc reagents.Addition of 95 in an order of 95c, 95b, 95a to the reaction mixture was found to be an effective condition in the mixed tagging Heck reaction.The target f-Fmoc reagents with C3F7, C4F9, and C6F13 groups could be separated owing to the different fluorine content of the molecules.This method provided a reasonable solution to obtain various f-Fmoc reagents in a one-pot procedure.These f-Fmoc reagents would be useful protecting groups for the effective synthesis of peptide isomer libraries.In 2015, Matsugi and co-workers synthesized f-Fmoc reagents (97) bearing C 3 F 7 , C 4 F 9 , or C 6 F 13 chains by the Pd(OAc) 2 -catalyzed Mizoroki-Heck reaction of 94 with 95a, 95b, or 95c, followed by hydroxymethylation and introduction of the N-hydroxysuccinimide group (Scheme 19) [75].The method applied on a multi-gram scale after eight steps gave the desired products 97a, 97b, and 97c with overall yields of 73%, 60%, and 90%, respectively.The Pd-catalyzed doubly tagging Heck reaction of 94 with a mixture of the fluorous alkenes (95) was also studied, leading to an encoded mixture synthesis of f-Fmoc reagents.Addition of 95 in an order of 95c, 95b, 95a to the reaction mixture was found to be an effective condition in the mixed tagging Heck reaction.The target f-Fmoc reagents with C 3 F 7 , C 4 F 9 , and C 6 F 13 groups could be separated owing to the different fluorine content of the molecules.This method provided a reasonable solution to obtain various f-Fmoc reagents in a one-pot procedure.These f-Fmoc reagents would be useful protecting groups for the effective synthesis of peptide isomer libraries.
In 2017, Konno and co-workers investigated the Pd-catalyzed Mizoroki-Heck reactions of aryldiazonium tetrafluoroborates with different types of CF2CF2-containing alkenes (Scheme 20) [76].A survey of the optimized reaction conditions revealed that the reactions of 4-bromo-3,3,4,4tetrafluoro-1-butene (98) with aryldiazonium salts (99) in the presence of 0.5 mol% Pd(OAc)2 in MeOH at 40 °C for 1 h gave the best yields of the products.The E-configured products (100) were exclusively obtained, and no Z-isomers were detected.In the cases of 4-bromo-3,3,4,4-tetrafluoro-1aryl-1-butenes (101), a bulky P(o-tolyl)3-coordinated palladium catalyst was found to be a good catalytic system, leading to an increased yield of the product (102).High stereoselectivity of the reaction was achieved if 102 containing an electron-deficient aromatic ring, whereas a slight decrease in the stereoselectivity was observed if 102 bearing an electron-donating substituent on the aromatic ring.In the reactions of 4-bromo-3,3,4,4-tetrafluoro-2-aryl-1-butenes (103) with 99, the geometry of the major isomers of 104 was determined as E-configuration on the basis of a proposed reaction mechanism [76].This protocol provided a convenient and highly stereoselective method for the preparation of multi-substituted alkenes (100, 102, and 104) bearing a tetrafluoroethylene fragment, which are promising building blocks for the synthesis of novel CF2CF2-containing organic molecules [76].
In a similar manner, Konno and co-workers examined the palladium-catalyzed Heck reactions of (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one (105a) with the readily available aryldiazonium salts (106) (Scheme 21) [77].The reactions allowed for easy and regio-and stereoselective access to a variety In 2017, Konno and co-workers investigated the Pd-catalyzed Mizoroki-Heck reactions of aryldiazonium tetrafluoroborates with different types of CF 2 CF 2 -containing alkenes (Scheme 20) [76].A survey of the optimized reaction conditions revealed that the reactions of 4-bromo-3,3,4,4-tetrafluoro-1-butene (98) with aryldiazonium salts (99) in the presence of 0.5 mol% Pd(OAc) 2 in MeOH at 40 • C for 1 h gave the best yields of the products.The E-configured products (100) were exclusively obtained, and no Z-isomers were detected.In the cases of 4-bromo-3,3,4,4-tetrafluoro-1-aryl-1-butenes (101), a bulky P(o-tolyl) 3 -coordinated palladium catalyst was found to be a good catalytic system, leading to an increased yield of the product (102).High stereoselectivity of the reaction was achieved if 102 containing an electron-deficient aromatic ring, whereas a slight decrease in the stereoselectivity was observed if 102 bearing an electron-donating substituent on the aromatic ring.In the reactions of 4-bromo-3,3,4,4-tetrafluoro-2-aryl-1-butenes (103) with 99, the geometry of the major isomers of 104 was determined as E-configuration on the basis of a proposed reaction mechanism [76].This protocol provided a convenient and highly stereoselective method for the preparation of multi-substituted alkenes (100, 102, and 104) bearing a tetrafluoroethylene fragment, which are promising building blocks for the synthesis of novel CF 2 CF 2 -containing organic molecules [76].In 2017, Konno and co-workers investigated the Pd-catalyzed Mizoroki-Heck reactions of aryldiazonium tetrafluoroborates with different types of CF2CF2-containing alkenes (Scheme 20) [76].A survey of the optimized reaction conditions revealed that the reactions of 4-bromo-3,3,4,4tetrafluoro-1-butene (98) with aryldiazonium salts (99) in the presence of 0.5 mol% Pd(OAc)2 in MeOH at 40 °C for 1 h gave the best yields of the products.The E-configured products (100) were exclusively obtained, and no Z-isomers were detected.In the cases of 4-bromo-3,3,4,4-tetrafluoro-1aryl-1-butenes (101), a bulky P(o-tolyl)3-coordinated palladium catalyst was found to be a good catalytic system, leading to an increased yield of the product (102).High stereoselectivity of the reaction was achieved if 102 containing an electron-deficient aromatic ring, whereas a slight decrease in the stereoselectivity was observed if 102 bearing an electron-donating substituent on the aromatic ring.In the reactions of 4-bromo-3,3,4,4-tetrafluoro-2-aryl-1-butenes (103) with 99, the geometry of the major isomers of 104 was determined as E-configuration on the basis of a proposed reaction mechanism [76].This protocol provided a convenient and highly stereoselective method for the preparation of multi-substituted alkenes (100, 102, and 104) bearing a tetrafluoroethylene fragment, which are promising building blocks for the synthesis of novel CF2CF2-containing organic molecules [76].
In a similar manner, Konno and co-workers examined the palladium-catalyzed Heck reactions of (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one (105a) with the readily available aryldiazonium salts (106) (Scheme 21) [77].The reactions allowed for easy and regio-and stereoselective access to a variety of 4,4,4-trifluoro-2-aryl-1-phenyl-2-buten-1-ones (107) in good yields.Aryldiazonium salts bearing electron-donating groups or halogens on the phenyl rings reacted nicely under the Heck-type cross-coupling conditions, preferentially forming the Z-isomers of the products (Z-107).However, substrates with electron-withdrawing groups or bulky groups on the aryldiazonium moieties didn't give the satisfactory results.The Michael addition adducts (108) were formed as byproducts in most cases [77].Later, the same research group extended the scope of the heck reaction to other types of fluorine-containing electron-deficient olefins (Scheme 21) [78].They found that the electron-withdrawing group (EWG) on alkenes had a big influence on the efficacy of the reaction.α,β-Unsaturated ester reacted with phenyldiazonium salt to provide the corresponding adduct in very low yield.Vinylphosphonate and vinylsulfone were found to be unreactive, with only the starting materials being recovered.In the case of nitroalkene, neither the starting material nor the desired Heck adduct was detected, and the reaction became very complicated.Additionally, changing the fluoroalkyl group from CF 3 to CF 2 H group caused a significant decrease in the chemical yield, although the relatively high regioselectivity was obtained.A plausible reaction mechanism was suggested in Scheme 21 [78].The reaction presumably proceeded via (1) oxidative addition of aryldiazonium salt (106) to Pd(0), leading to an arylpalladium complex (110), (2) coordination of the electron-deficient olefin (105) 107) in good yields.Aryldiazonium salts bearing electron-donating groups or halogens on the phenyl rings reacted nicely under the Heck-type crosscoupling conditions, preferentially forming the Z-isomers of the products (Z-107).However, substrates with electron-withdrawing groups or bulky groups on the aryldiazonium moieties didn't give the satisfactory results.The Michael addition adducts (108) were formed as byproducts in most cases [77].Later, the same research group extended the scope of the heck reaction to other types of fluorine-containing electron-deficient olefins (Scheme 21) [78].They found that the electronwithdrawing group (EWG) on alkenes had a big influence on the efficacy of the reaction.α,β-Unsaturated ester reacted with phenyldiazonium salt to provide the corresponding adduct in very low yield.Vinylphosphonate and vinylsulfone were found to be unreactive, with only the starting materials being recovered.In the case of nitroalkene, neither the starting material nor the desired Heck adduct was detected, and the reaction became very complicated.Additionally, changing the fluoroalkyl group from CF3 to CF2H group caused a significant decrease in the chemical yield, although the relatively high regioselectivity was obtained.A plausible reaction mechanism was suggested in Scheme 21 [78].The reaction presumably proceeded via (1) oxidative addition of aryldiazonium salt (106) to Pd(0), leading to an arylpalladium complex ( 110 Arylboronic acids are an important class of compounds for coupling reactions, which are stable in air and to moisture, and they are compatible with a broad range of common functional groups [62][63][64].In 2015, Lu and co-workers presented the first oxidative Heck-type reactions of arylboronic acids with fluoroalkylated olefin [79].The Pd-catalyzed cross-couplings of the commercially available 2,3,3,3-tetrafluoroprop-1-ene (116) with diverse arylboronic acids (115) provided a variety of (Z)-βfluoro-β-(trifluoromethyl)styrene derivatives (117) in good yields (Scheme 22) [79].The wide range Scheme 21.
The Heck-type reactions of fluorine-containing electron-deficient olefins with aryldiazonium salts.
Arylboronic acids are an important class of compounds for coupling reactions, which are stable in air and to moisture, and they are compatible with a broad range of common functional groups [62][63][64].In 2015, Lu and co-workers presented the first oxidative Heck-type reactions of arylboronic acids with fluoroalkylated olefin [79].The Pd-catalyzed cross-couplings of the commercially available 2,3,3,3-tetrafluoroprop-1-ene (116) with diverse arylboronic acids (115) provided a variety of (Z)-β-fluoro-β-(trifluoromethyl)styrene derivatives (117) in good yields (Scheme 22) [79].The wide range of substrates and the good functional group tolerance made this strategy facile and practical for the streamlined synthesis of functional styrenes.Furthermore, Pd-catalyzed Heck-type cyclization of 2-trifluoromethyl-1-alkenes (118) bearing an O-acyloxime moiety was accomplished (Scheme 23) [45,80].The reaction represented a rare example of 5-endo mode alkene insertion into transition-metal species via oxidative addition of the N-O bond (119).Although there were two possible pathways, namely β-fluorine elimination and βhydrogen elimination of 120 after ring formation, the former exclusively took place to form an exodifluoromethylene unit.This catalytic process provided facile access to 4-difluoromethylene-1pyrrolines (121).To elucidate the role of the CF3 group, the reaction of analogues (118′) bearing a hydrogen atom or a methyl group instead of the CF3 functionality on the alkene fragment was examined.When 118′ was subjected to the reaction conditions similar to those for 118, no cyclized product was obtained.The results indicated that the CF3 group played a crucial role in the 5-endo Heck-type cyclization, wherein the trifluoromethyl substituent seemed to activate the vinylic terminal carbon in 118 and stabilize the cyclized palladium intermediate 120.

Other Fluorine-Containing Alkenes as the Cross-Coupling Reagents
A series of fluorinated distyrylbenzene (DSB) derivatives (124 and 126) were synthesized by Pdcatalyzed Mizoroki-Heck cross-couplings (Scheme 24) [81].The reaction of 1,4-diiodobenzene (122a) with pentafluorostyrene (123) or 4-fluorostyrene (125b) in the presence of Pd(OAc)2 gave trans-trans-1,4-bis(pentafluorostyryl)benzene (124a) or trans-trans-bis(4-fluorostyryl)benzene (126a).The coupling of 1,4-dibromo-2,5-difluorobenzene (122b) with styrene (125a), 4-fluorostyrene (125b), or pentafluorostyrene (123) using Pd(OAc)2 provided 1,4-bis(styryl)-2,5-difluorobenzene (126b), 1,4bis(4-fluorostyryl)-2,5-difluorobenzene (126c), and 1,4-bis-(pentafluorostyryl)-2,5-difluorobenzene (124b), respectively.The products were employed to probe the effect of fluorine substitution on the molecular properties and on the arrangement of molecules in the solid state [81].The absorption spectroscopy showed that 124 and 126 had a λmax at approximately 350 nm, and addition of dimethylaniline to the hexane solutions led to exciplex emission with λmax ranging from 458 to 514 Furthermore, Pd-catalyzed Heck-type cyclization of 2-trifluoromethyl-1-alkenes (118) bearing an O-acyloxime moiety was accomplished (Scheme 23) [45,80].The reaction represented a rare example of 5-endo mode alkene insertion into transition-metal species via oxidative addition of the N-O bond (119).Although there were two possible pathways, namely β-fluorine elimination and β-hydrogen elimination of 120 after ring formation, the former exclusively took place to form an exo-difluoromethylene unit.This catalytic process provided facile access to 4-difluoromethylene-1-pyrrolines (121).To elucidate the role of the CF 3 group, the reaction of analogues (118 ) bearing a hydrogen atom or a methyl group instead of the CF 3 functionality on the alkene fragment was examined.When 118 was subjected to the reaction conditions similar to those for 118, no cyclized product was obtained.The results indicated that the CF 3 group played a crucial role in the 5-endo Heck-type cyclization, wherein the trifluoromethyl substituent seemed to activate the vinylic terminal carbon in 118 and stabilize the cyclized palladium intermediate 120.Furthermore, Pd-catalyzed Heck-type cyclization of 2-trifluoromethyl-1-alkenes (118) bearing an O-acyloxime moiety was accomplished (Scheme 23) [45,80].The reaction represented a rare example of 5-endo mode alkene insertion into transition-metal species via oxidative addition of the N-O bond (119).Although there were two possible pathways, namely β-fluorine elimination and βhydrogen elimination of 120 after ring formation, the former exclusively took place to form an exodifluoromethylene unit.This catalytic process provided facile access to 4-difluoromethylene-1pyrrolines (121).To elucidate the role of the CF3 group, the reaction of analogues (118′) bearing a hydrogen atom or a methyl group instead of the CF3 functionality on the alkene fragment was examined.When 118′ was subjected to the reaction conditions similar to those for 118, no cyclized product was obtained.The results indicated that the CF3 group played a crucial role in the 5-endo Heck-type cyclization, wherein the trifluoromethyl substituent seemed to activate the vinylic terminal carbon in 118 and stabilize the cyclized palladium intermediate 120.

Fluorinated Aryl Halides or Pseudo-Halides as the Coupling Agents
In 2011, Vallribera and co-workers reported the Pd-catalyzed arylation of both electron-rich and -poor olefins (134) with 4-(perfluorooctyl)benzenediazonium trifluoroacetate (133) (Scheme 27) [84].This Heck-type reaction supplied a variety of perfluoroalkylated aromatic compounds (135) by using Pd(OAc)2 or 4-hydroxyacetophenone oxime-derived palladacycle (136) as an efficient source of Pd nanoparticles.Ligand-free Pd(OAc)2 appeared to be a more general catalyst than palladacycle (136) for the reaction.The activity of 136 depended greatly on the nature of the alkene used.No external base was necessary for the conversion, and the reactions could be carried out at room temperature in the presence of 1 mol% of Pd(II) catalyst.Some intermediates derived from the oxidative addition of 133 to the catalyst were identified by ESI-MS experiments.The Pd(IV) species detected by this technique when 136 was used, did not seem to act as intermediates of the reaction.The TEM images of the reaction solutions showed, for the first time, the formation of nanoparticles with both catalysts under the Matsuda-Heck conditions.These Pd(0) nanoparticles might act as a reservoir of Pd(0) atoms involved in the reaction, which avoided the precipitation of black palladium and thus probably extended the lifetime of the catalyst.

Fluorinated Aryl Halides or Pseudo-Halides as the Coupling Agents
In 2011, Vallribera and co-workers reported the Pd-catalyzed arylation of both electron-rich and -poor olefins (134) with 4-(perfluorooctyl)benzenediazonium trifluoroacetate (133) (Scheme 27) [84].This Heck-type reaction supplied a variety of perfluoroalkylated aromatic compounds (135) by using Pd(OAc) 2 or 4-hydroxyacetophenone oxime-derived palladacycle (136) as an efficient source of Pd nanoparticles.Ligand-free Pd(OAc) 2 appeared to be a more general catalyst than palladacycle (136) for the reaction.The activity of 136 depended greatly on the nature of the alkene used.No external base was necessary for the conversion, and the reactions could be carried out at room temperature in the presence of 1 mol% of Pd(II) catalyst.Some intermediates derived from the oxidative addition of 133 to the catalyst were identified by ESI-MS experiments.The Pd(IV) species detected by this technique when 136 was used, did not seem to act as intermediates of the reaction.The TEM images of the reaction solutions showed, for the first time, the formation of nanoparticles with both catalysts under the Matsuda-Heck conditions.These Pd(0) nanoparticles might act as a reservoir of Pd(0) atoms involved in the reaction, which avoided the precipitation of black palladium and thus probably extended the lifetime of the catalyst.

Fluorinated Aryl Halides or Pseudo-Halides as the Coupling Agents
In 2011, Vallribera and co-workers reported the Pd-catalyzed arylation of both electron-rich and -poor olefins (134) with 4-(perfluorooctyl)benzenediazonium trifluoroacetate (133) (Scheme 27) [84].This Heck-type reaction supplied a variety of perfluoroalkylated aromatic compounds (135) by using Pd(OAc)2 or 4-hydroxyacetophenone oxime-derived palladacycle (136) as an efficient source of Pd nanoparticles.Ligand-free Pd(OAc)2 appeared to be a more general catalyst than palladacycle (136) for the reaction.The activity of 136 depended greatly on the nature of the alkene used.No external base was necessary for the conversion, and the reactions could be carried out at room temperature in the presence of 1 mol% of Pd(II) catalyst.Some intermediates derived from the oxidative addition of 133 to the catalyst were identified by ESI-MS experiments.The Pd(IV) species detected by this technique when 136 was used, did not seem to act as intermediates of the reaction.The TEM images of the reaction solutions showed, for the first time, the formation of nanoparticles with both catalysts under the Matsuda-Heck conditions.These Pd(0) nanoparticles might act as a reservoir of Pd(0) atoms involved in the reaction, which avoided the precipitation of black palladium and thus probably extended the lifetime of the catalyst.An efficient catalytic system for the Mizoroki-Heck reactions of fluoroaryl halides (143) with alkenes (144) was developed (Scheme 29) [86].Complex 145 (1 mol%) catalyzed the reaction of C6F5Br and styrene at 130 °C to give regioselectively trans-PhCH=CHArF (146a, ArF = C6F5) in almost quantitative yield.The studies indicated that CaCO3, KF, and Na2CO3 were the suitable bases, and that NMP was the best solvent for the reaction.[Pd(PPh3)4] failed to initiate the reaction of styrene with C6F5Br.If C6F5I was employed as a substrate under the optimized conditions, much lower yield of trans-PhCH=CHArF was obtained.C6F5Cl didn't react with styrene under the same conditions.The reaction was also efficient for other fluorinated aryl bromides such as p-XC6F4Br (X = CN, CF3, OMe) and p-FC6H4Br [86].For an activated alkene, such as methyl acrylate, the reaction proceeded fast even at 100 °C, and in this case, use of KF as a base led to higher conversion.1-Hexene and α-methylstyrene could also be functionalized.Electron-rich alkenes such as butylvinyl ether and 2,3-dihydrofuran gave very low yields of the desired products.The reaction with styrene was not affected by oxygen or galvinoxyl, which excluded a radical addition pathway [86].
Moreover, complex 145 in CDCl3 afforded immediately a 1:1.6 mixture of two isomers corresponding to the cis and trans arrangements of the two C6F5 groups in the dimer [86].If 145 was dissolved in NMP at room temperature and at low concentrations, 148 was observed as the main species, determined by 19 F NMR spectroscopy.Upon addition of Br − anion to 148, 149 was also detected.The equilibrium constants between 145, 148, and 149 in NMP at room temperature could be measured.At higher temperatures (e.g., 120 °C), the equilibria became fast, and the signals of these complexes collapsed.When the reaction of C6F5Br and styrene was monitored by 19 F NMR at 120 °C under catalytic conditions, only one set of ArF-Pd signals was observed.Based on these studies, a possible reaction mechanism was suggested in Scheme 29 [86].The first step of the catalytic cycle is the coordination and insertion of the alkene by 145, generating 151.This step is likely to be rate-Scheme 28.The Heck-type reactions of 4-(pentafluorosulfanyl)benzenediazonium tetrafluoroborate.An efficient catalytic system for the Mizoroki-Heck reactions of fluoroaryl halides (143) with alkenes (144) was developed (Scheme 29) [86].Complex 145 (1 mol%) catalyzed the reaction of C 6 F 5 Br and styrene at 130 • C to give regioselectively trans-PhCH=CHAr F (146a, Ar F = C 6 F 5 ) in almost quantitative yield.The studies indicated that CaCO 3 , KF, and Na 2 CO 3 were the suitable bases, and that NMP was the best solvent for the reaction.[Pd(PPh 3 ) 4 ] failed to initiate the reaction of styrene with C 6 F 5 Br.If C 6 F 5 I was employed as a substrate under the optimized conditions, much lower yield of trans-PhCH=CHAr F was obtained.C 6 F 5 Cl didn't react with styrene under the same conditions.The reaction was also efficient for other fluorinated aryl bromides such as p-XC 6 F 4 Br (X = CN, CF 3 , OMe) and p-FC 6 H 4 Br [86].For an activated alkene, such as methyl acrylate, the reaction proceeded fast even at 100 • C, and in this case, use of KF as a base led to higher conversion.1-Hexene and α-methylstyrene could also be functionalized.Electron-rich alkenes such as butylvinyl ether and 2,3-dihydrofuran gave very low yields of the desired products.The reaction with styrene was not affected by oxygen or galvinoxyl, which excluded a radical addition pathway [86].
Moreover, complex 145 in CDCl 3 afforded immediately a 1:1.6 mixture of two isomers corresponding to the cis and trans arrangements of the two C 6 F 5 groups in the dimer [86].If 145 was dissolved in NMP at room temperature and at low concentrations, 148 was observed as the main species, determined by 19 F NMR spectroscopy.Upon addition of Br − anion to 148, 149 was also detected.The equilibrium constants between 145, 148, and 149 in NMP at room temperature could be measured.At higher temperatures (e.g., 120 • C), the equilibria became fast, and the signals of these complexes collapsed.When the reaction of C 6 F 5 Br and styrene was monitored by 19 F NMR at 120 • C under catalytic conditions, only one set of Ar F -Pd signals was observed.Based on these studies, a possible reaction mechanism was suggested in Scheme 29 [86].The first step of the catalytic cycle is the coordination and insertion of the alkene by 145, generating 151.This step is likely to be rate-determining, which is supported by the observation of the signals of the complexes preceding this step and by the fact that the reaction rate of C 6 F 5 Br and styrene was simply dependent upon the concentration of styrene.Then, β-H elimination of 151 followed by reductive elimination of HX from 153 provides 146 and regenerates Pd(0) species (147), which is stabilized by bromide anions.The reaction outside the catalytic cycle showed that the insertion of styrene into the Pd-C 6 F 5 bond of 148 was retarded by addition of NBu 4 Br.If the catalytic reaction was carried out under bromide-free conditions, only 3% of 146a was obtained and the catalyst extensively decomposed.In addition to stabilizing the Pd(0) intermediate, the bromides might increase the rate of oxidative addition.Excess styrene increased the reaction rate by facilitating the coordination-insertion process, but a large excess of styrene stopped the reaction.Addition of NBu 4 Br to the latter reaction mixture could reactivate the process.It seemed that displacement of bromides on Pd(0) by alkene at high concentration severely slowed the oxidative addition, which became rate-determining instead of the coordination-insertion step [86,87].Thus, the success of this catalysis required a compromise between the optimal conditions for the oxidative addition and the coordination-insertion.determining, which is supported by the observation of the signals of the complexes preceding this step and by the fact that the reaction rate of C6F5Br and styrene was simply dependent upon the concentration of styrene.Then, β-H elimination of 151 followed by reductive elimination of HX from 153 provides 146 and regenerates Pd(0) species (147), which is stabilized by bromide anions.The reaction outside the catalytic cycle showed that the insertion of styrene into the Pd-C6F5 bond of 148 was retarded by addition of NBu4Br.If the catalytic reaction was carried out under bromide-free conditions, only 3% of 146a was obtained and the catalyst extensively decomposed.In addition to stabilizing the Pd(0) intermediate, the bromides might increase the rate of oxidative addition.Excess styrene increased the reaction rate by facilitating the coordination-insertion process, but a large excess of styrene stopped the reaction.Addition of NBu4Br to the latter reaction mixture could reactivate the process.It seemed that displacement of bromides on Pd(0) by alkene at high concentration severely slowed the oxidative addition, which became rate-determining instead of the coordination-insertion step [86,87].Thus, the success of this catalysis required a compromise between the optimal conditions for the oxidative addition and the coordination-insertion.In 2010, Zhang and co-workers reported the first Pd(OAc)2-catalyzed oxidative Heck-type reactions of the electron-deficient pentafluoroarene (154) with a broad range of alkenes (155) (Scheme 30) [88].The reactions provided a great variety of pentafluorophenyl substituted alkenes (156) in moderate to high yields and with moderate to high stereo-and regioselectivities.A survey of reaction conditions indicated that the solvent, oxidants, and Pd-catalysts were critical for the reaction efficiency.A mixed solvent system of 5% DMSO in DMF was found to be the optimum reaction medium.The reaction using Ag2CO3 as both the base and oxidant in the presence of Pd(OAc)2 (10 mol%) at 120 °C gave the best yield of the desired product.Electron-deficient olefins bearing ester, amide, phosphonate, or ketone groups worked well to give moderate to excellent yields and high stereoselectivities.Notably, nonactivated aliphatic olefins and electron-rich alkenes underwent smooth reactions in good yields, which were in sharp contrast to previous results [86,87].In the case of polyfluoroarenes (157), the reactions using PivOH (1.2 equiv) instead of DMSO (5%) afforded alkenylated products (159) in moderate yields with moderate to good regioselectivities.In general, In 2010, Zhang and co-workers reported the first Pd(OAc) 2 -catalyzed oxidative Heck-type reactions of the electron-deficient pentafluoroarene (154) with a broad range of alkenes (155) (Scheme 30) [88].The reactions provided a great variety of pentafluorophenyl substituted alkenes (156) in moderate to high yields and with moderate to high stereo-and regioselectivities.A survey of reaction conditions indicated that the solvent, oxidants, and Pd-catalysts were critical for the reaction efficiency.A mixed solvent system of 5% DMSO in DMF was found to be the optimum reaction medium.The reaction using Ag 2 CO 3 as both the base and oxidant in the presence of Pd(OAc) 2 (10 mol%) at 120 • C gave the best yield of the desired product.Electron-deficient olefins bearing ester, amide, phosphonate, or ketone groups worked well to give moderate to excellent yields and high stereoselectivities.Notably, nonactivated aliphatic olefins and electron-rich alkenes underwent smooth reactions in good yields, which were in sharp contrast to previous results [86,87].In the case of polyfluoroarenes (157), the reactions using PivOH (1.2 equiv) instead of DMSO (5%) afforded alkenylated products (159) in moderate yields with moderate to good regioselectivities.In general, the reactions with electron-rich alkenes afforded higher yields than those with electron-deficient ones.The most acidic C-H bonds located between two fluorine atoms were the primary reaction sites, which provided mostly the monoalkenylated products in higher yields.It was also possible to further derivatize the polyfluoroarylated alkenes through C-H functionalization.This strategy allowed the selective installation of substituents at different positions and provided a convenient access to highly functionalized fluoroarenes by catalytic methods.the reactions with electron-rich alkenes afforded higher yields than those with electron-deficient ones.The most acidic C-H bonds located between two fluorine atoms were the primary reaction sites, which provided mostly the monoalkenylated products in higher yields.It was also possible to further derivatize the polyfluoroarylated alkenes through C-H functionalization.This strategy allowed the selective installation of substituents at different positions and provided a convenient access to highly functionalized fluoroarenes by catalytic methods.Later, Zhang's research group again disclosed the thioether-promoted direct olefination of polyfluoroarenes (161) with alkenes (162) catalyzed by Pd(OAc)2 (Scheme 31) [89].Remarkably, the "inert" substrates, such as 3-substituted tetrafluorobenzenes, which previously furnished their corresponding products in low yields, afforded the alkenylated products (163) in high yields and with excellent stereoselectivities using only 1.0 equiv of alkene in this reaction.The results demonstrated the power of the thioether ligand PhSMe in the Pd-catalyzed reactions of polyfluoroarenes, offering a new choice to discover more efficient catalytic systems.Furthermore, a competitive reaction between electron-deficient and electron-rich alkenes with pentafluorobenzene was conducted, which provided their corresponding products in an almost 1:1 ratio, suggesting that the direct olefination of polyfluoroarenes has no bias on the nature of alkenes under these reaction conditions [89].By a similar strategy, a series of olefin-containing fluorinated benzothiadiazoles were synthesized from fluorinated benzothiadiazoles in the presence of 2.5 mol% Pd(TFA)2, 3.0 equiv AgOAc, 2.5 equiv PhCO2H, and 0.1 equiv benzoquinone [90].The reactions proceeded under mild conditions and showed good functional group compatibility.The products found important Later, Zhang's research group again disclosed the thioether-promoted direct olefination of polyfluoroarenes (161) with alkenes (162) catalyzed by Pd(OAc) 2 (Scheme 31) [89].Remarkably, the "inert" substrates, such as 3-substituted tetrafluorobenzenes, which previously furnished their corresponding products in low yields, afforded the alkenylated products (163) in high yields and with excellent stereoselectivities using only 1.0 equiv of alkene in this reaction.The results demonstrated the power of the thioether ligand PhSMe in the Pd-catalyzed reactions of polyfluoroarenes, offering a new choice to discover more efficient catalytic systems.Furthermore, a competitive reaction between electron-deficient and electron-rich alkenes with pentafluorobenzene was conducted, which provided their corresponding products in an almost 1:1 ratio, suggesting that the direct olefination of polyfluoroarenes has no bias on the nature of alkenes under these reaction conditions [89]. the reactions with electron-rich alkenes afforded higher yields than those with electron-deficient ones.The most acidic C-H bonds located between two fluorine atoms were the primary reaction sites, which provided mostly the monoalkenylated products in higher yields.It was also possible to further derivatize the polyfluoroarylated alkenes through C-H functionalization.This strategy allowed the selective installation of substituents at different positions and provided a convenient access to highly functionalized fluoroarenes by catalytic methods.Later, Zhang's research group again disclosed the thioether-promoted direct olefination of polyfluoroarenes (161) with alkenes (162) catalyzed by Pd(OAc)2 (Scheme 31) [89].Remarkably, the "inert" substrates, such as 3-substituted tetrafluorobenzenes, which previously furnished their corresponding products in low yields, afforded the alkenylated products (163) in high yields and with excellent stereoselectivities using only 1.0 equiv of alkene in this reaction.The results demonstrated the power of the thioether ligand PhSMe in the Pd-catalyzed reactions of polyfluoroarenes, offering a new choice to discover more efficient catalytic systems.Furthermore, a competitive reaction between electron-deficient and electron-rich alkenes with pentafluorobenzene was conducted, which provided their corresponding products in an almost 1:1 ratio, suggesting that the direct olefination of polyfluoroarenes has no bias on the nature of alkenes under these reaction conditions [89].By a similar strategy, a series of olefin-containing fluorinated benzothiadiazoles were synthesized from fluorinated benzothiadiazoles in the presence of 2.5 mol% Pd(TFA)2, 3.0 equiv AgOAc, 2.5 equiv PhCO2H, and 0.1 equiv benzoquinone [90].The reactions proceeded under mild conditions and showed good functional group compatibility.The products found important Scheme 31.Thioether-promoted direct olefination of polyfluoroarenes catalyzed by palladium.
By a similar strategy, a series of olefin-containing fluorinated benzothiadiazoles were synthesized from fluorinated benzothiadiazoles in the presence of 2.5 mol% Pd(TFA) 2 , 3.0 equiv AgOAc, 2.5 equiv PhCO 2 H, and 0.1 equiv benzoquinone [90].The reactions proceeded under mild conditions and showed good functional group compatibility.The products found important applications in optoelectronic materials.Significantly, the Pd-catalyzed aerobic direct olefination of polyfluoroarenes was also explored [91].The procedure made use of molecular O 2 as the terminal oxidant instead of silver(I) salt, providing a cost-efficient and environment-benign access to polyfluoroarene-alkenes.The silver species and the thioether ligand played important roles in the reactions, but the mechanisms remained unclear.
In addition, Liu and co-workers investigated the Pd(II)-catalyzed direct olefination of electron-deficient fluoroarenes (164) with allylic esters and ethers (165) (Scheme 32) [92].In this transformation, various γ-substituted allylic esters (mixtures of E/Zand B-isomers (166 and 166 )) were prepared in good to excellent yields by oxidative Heck reactions via β-H elimination, rather than β-OAc elimination.Typically, the desired products were obtained in good yields under conditions composed of Pd(OAc) 2 (5 mol%), AgOAc (2.0 equiv), DMSO (5%)/THF, 110 • C, and 12 h.A variety of fluorinated arenes proved to be very efficient substrates under the typical conditions, and the olefination generally took place at the more sterically accessible position.This selectivity might be attributed to the acidity of C-H bonds of the fluorinated arenes even though it was located at a more sterically hindered position.Tetrafluorobenzene and fluorinated arenes bearing an electron-donating methoxy group could also give the desired products.Yields of the products decreased with the decrease in the number of fluorine atoms substituted on the aromatic rings.Significantly, allyl acrylate and allyl methacrylate afforded the corresponding products in moderate to good yields.The oxidative olefination occurred at the allylic rather than the acrylic carbon-carbon double bond.This selectivity might be ascribed to the stability of the alkyl-Pd intermediate via chelation of Pd center by the carbonyl O-atom.This chelation effect could also result in the high regioselectivity as the (Pd)C-C(O) bond cannot rotate freely.applications in optoelectronic materials.Significantly, the Pd-catalyzed aerobic direct olefination of polyfluoroarenes was also explored [91].The procedure made use of molecular O2 as the terminal oxidant instead of silver(I) salt, providing a cost-efficient and environment-benign access to polyfluoroarene-alkenes.The silver species and the thioether ligand played important roles in the reactions, but the mechanisms remained unclear.
In addition, Liu and co-workers investigated the Pd(II)-catalyzed direct olefination of electrondeficient fluoroarenes (164) with allylic esters and ethers (165) (Scheme 32) [92].In this transformation, various γ-substituted allylic esters (mixtures of E/Z-and B-isomers (166 and 166′)) were prepared in good to excellent yields by oxidative Heck reactions via β-H elimination, rather than β-OAc elimination.Typically, the desired products were obtained in good yields under conditions composed of Pd(OAc)2 (5 mol%), AgOAc (2.0 equiv), DMSO (5%)/THF, 110 °C, and 12 h.A variety of fluorinated arenes proved to be very efficient substrates under the typical conditions, and the olefination generally took place at the more sterically accessible position.This selectivity might be attributed to the acidity of C-H bonds of the fluorinated arenes even though it was located at a more sterically hindered position.Tetrafluorobenzene and fluorinated arenes bearing an electron-donating methoxy group could also give the desired products.Yields of the products decreased with the decrease in the number of fluorine atoms substituted on the aromatic rings.Significantly, allyl acrylate and allyl methacrylate afforded the corresponding products in moderate to good yields.The oxidative olefination occurred at the allylic rather than the acrylic carbon-carbon double bond.This selectivity might be ascribed to the stability of the alkyl-Pd intermediate via chelation of Pd center by the carbonyl O-atom.This chelation effect could also result in the high regioselectivity as the (Pd)C-C(O) bond cannot rotate freely.

S-fluoroalkyl diphenylsulfonium triflates [Ph2SRfn]
[OTf] (168, Rfn = CF3, CH2CF3) were effective cross-coupling partners in the Pd-catalyzed Mizoroki-Heck-type reactions with alkenes (Scheme 33) [93].The functionalization of various conjugated and unconjugated alkenes (167) by 168 in the presence of 10 mol% Pd[P(t-Bu)3]2 and TsOH at room temperature provided the corresponding phenylation products (169) in good to high yields.The bases that benefited the traditional Mizoroki-Heck reactions severely inhibited this transformation, whereas the acids significantly improved the reaction.This protocol demonstrated a new class of cross-coupling participants for Heck-type reactions [93].

S-fluoroalkyl diphenylsulfonium triflates [Ph 2 SR fn ]
[OTf] (168, R fn = CF 3 , CH 2 CF 3 ) were effective cross-coupling partners in the Pd-catalyzed Mizoroki-Heck-type reactions with alkenes (Scheme 33) [93].The functionalization of various conjugated and unconjugated alkenes (167) by 168 in the presence of 10 mol% Pd[P(t-Bu) 3 ] 2 and TsOH at room temperature provided the corresponding phenylation products (169) in good to high yields.The bases that benefited the traditional Mizoroki-Heck reactions severely inhibited this transformation, whereas the acids significantly improved the reaction.This protocol demonstrated a new class of cross-coupling participants for Heck-type reactions [93].applications in optoelectronic materials.Significantly, the Pd-catalyzed aerobic direct olefination of polyfluoroarenes was also explored [91].The procedure made use of molecular O2 as the terminal oxidant instead of silver(I) salt, providing a cost-efficient and environment-benign access to polyfluoroarene-alkenes.The silver species and the thioether ligand played important roles in the reactions, but the mechanisms remained unclear.
Scheme 34.Synthesis of a fluorinated derivative of epibatidine via the Mizoroki-Heck reaction.
The β-selective, chelation-controlled Heck-type reaction was found to be a convenient and versatile method to synthesize a series of new lipophilic N-alkylated nipecotic acid derivatives (176) bearing a vinyl ether unit embedded in the spacer and an unsymmetrical bis-aromatic residue at the terminal position of the spacer (Scheme 35) [95].Most of the compounds displayed reasonable to good potencies and selectivities for mGAT1 (subtype of GABA transporter originating from murine cells).The influence of the presence and the position of fluorine substituents in the bis-aromatic residue concerning potency and selectivity of the compounds was defined.In general, all Z-isomers of the synthesized compounds were more potent than their corresponding E-isomers.The influence of fluorine substituents on the GAT1 uptake inhibition was generally more severe for the compounds with two aromatic rings being linked by a methanone bridge (Y = O).Substitution with fluorine in the 4-position of one aryl ring (R 4 = F) and an additional fluorine substituent at the para-position of the other aryl ring (R 3 = F) was the most beneficial combination, leading to one of the most potent compounds of the whole series.Additionally, four pyrimidine C-nucleosides (180) were built as mimics of 2′-deoxycytidine (dC) and 2′-deoxyuridine (dU).The key carbon-carbon bond formation between the readily available 2,6substituted pyridines (178) and the glycal (177) employed palladium-catalyzed Heck-type reactions (Scheme 36) [96].The minor groove functional group in each derivative was replaced by a fluorine or a methyl group.Each coupling reaction yielded only the β-anomer, in part because the bulky silyl protecting group at the 3′-hydroxyl moiety precluded addition of the heterocycle from the "lower" face of the sugar.Without separating the initial coupling products (179) from the starting glycal (177), the silyl group was removed from 179 and the corresponding ketones were easily purified.The β-selective, chelation-controlled Heck-type reaction was found to be a convenient and versatile method to synthesize a series of new lipophilic N-alkylated nipecotic acid derivatives (176) bearing a vinyl ether unit embedded in the spacer and an unsymmetrical bis-aromatic residue at the terminal position of the spacer (Scheme 35) [95].Most of the compounds displayed reasonable to good potencies and selectivities for mGAT1 (subtype of GABA transporter originating from murine cells).The influence of the presence and the position of fluorine substituents in the bis-aromatic residue concerning potency and selectivity of the compounds was defined.In general, all Z-isomers of the synthesized compounds were more potent than their corresponding E-isomers.The influence of fluorine substituents on the GAT1 uptake inhibition was generally more severe for the compounds with two aromatic rings being linked by a methanone bridge (Y = O).Substitution with fluorine in the 4-position of one aryl ring (R 4 = F) and an additional fluorine substituent at the para-position of the other aryl ring (R 3 = F) was the most beneficial combination, leading to one of the most potent compounds of the whole series.acetylcholine receptor (nAChR) agonist [94].In order to visualize and quantify these receptors in the human brain using positron emission tomography (PET) technique, exo-2-(2′-[ 18 F]fluoro-5′-pyridyl)-7-azabicyclo[2.2.1]heptane, a fluorine-18 (t1/2 = 110min) radiolabeled derivative of epibatidine, was synthesized from the nucleophilic aromatic substitution of the corresponding 2′-bromo-, 2′-iodo-or 2′-nitro exo-2-(5′-pyridyl)-7-azabicy-clo[2.2.1]heptane analogue with [ 18 F]FK-K222 [94].In this work, norchlorofluoroepibatidine (173) was employed as a reference compound, which was synthesized by reductive and stereoselective Pd-catalyzed Heck-type cross-coupling of 170 and 171 (Scheme 34) [94].
Scheme 34.Synthesis of a fluorinated derivative of epibatidine via the Mizoroki-Heck reaction.
The β-selective, chelation-controlled Heck-type reaction was found to be a convenient and versatile method to synthesize a series of new lipophilic N-alkylated nipecotic acid derivatives (176) bearing a vinyl ether unit embedded in the spacer and an unsymmetrical bis-aromatic residue at the terminal position of the spacer (Scheme 35) [95].Most of the compounds displayed reasonable to good potencies and selectivities for mGAT1 (subtype of GABA transporter originating from murine cells).The influence of the presence and the position of fluorine substituents in the bis-aromatic residue concerning potency and selectivity of the compounds was defined.In general, all Z-isomers of the synthesized compounds were more potent than their corresponding E-isomers.The influence of fluorine substituents on the GAT1 uptake inhibition was generally more severe for the compounds with two aromatic rings being linked by a methanone bridge (Y = O).Substitution with fluorine in the 4-position of one aryl ring (R 4 = F) and an additional fluorine substituent at the para-position of the other aryl ring (R 3 = F) was the most beneficial combination, leading to one of the most potent compounds of the whole series.Additionally, four pyrimidine C-nucleosides (180) were built as mimics of 2′-deoxycytidine (dC) and 2′-deoxyuridine (dU).The key carbon-carbon bond formation between the readily available 2,6substituted pyridines (178) and the glycal (177) employed palladium-catalyzed Heck-type reactions (Scheme 36) [96].The minor groove functional group in each derivative was replaced by a fluorine or a methyl group.Each coupling reaction yielded only the β-anomer, in part because the bulky silyl protecting group at the 3′-hydroxyl moiety precluded addition of the heterocycle from the "lower" face of the sugar.Without separating the initial coupling products (179) from the starting glycal (177), the silyl group was removed from 179 and the corresponding ketones were easily purified.Additionally, four pyrimidine C-nucleosides (180) were built as mimics of 2 -deoxycytidine (dC) and 2 -deoxyuridine (dU).The key carbon-carbon bond formation between the readily available 2,6-substituted pyridines (178) and the glycal (177) employed palladium-catalyzed Heck-type reactions (Scheme 36) [96].The minor groove functional group in each derivative was replaced by a fluorine or a methyl group.Each coupling reaction yielded only the β-anomer, in part because the bulky silyl protecting group at the 3 -hydroxyl moiety precluded addition of the heterocycle from the "lower" face of the sugar.Without separating the initial coupling products (179) from the starting glycal (177), the silyl group was removed from 179 and the corresponding ketones were easily purified.Stereospecific reduction of the ketones, followed by removal of the p-NPE protecting group if necessary, resulted in the target compounds (180) (Scheme 35).Two sets of organic dyes containing a stilbene backbone with fluorine substituents were constructed for a study on the quantum efficiency of dye-sensitized solar cells (DSSCs) (Scheme 37) [97].Compound 181 was coupled with the commercially available 4-bromobenzaldehyde (182a), 4bromo-2-fluorobenzaldehyde (182b), and 4-bromo-2,6-difluorobenzaldehyde (182c), respectively, by the Heck-type reactions to yield 183, which were condensed with cyanoacetic acid via Knöevenagel reactions to afford the final products (H-P, H-N, F-P, FF-P, F-N, and FF-N).The results revealed that a fluorine substituent on the phenyl group ortho to the cyanoacrylate could enhance the lightharvesting performance in comparison with the unsubstituted one.The monofluorinated dyes showed larger short-circuit photocurrent density (Jsc) values than the non-substituted ones, due to the extension of the conjugation.However, the difluorinated dyes exhibited a lower performance because of a twisted geometry between the difluorophenyl group and the cyanoacrylate moieties, which reduced the efficiency of π-conjugation and thus decreased the Jsc value.The well-defined polyimides bearing a charge transporting (CT) and nonlinear optical (NLO) functionality in each repeat unit were prepared via two methods [98,99].One of these methods was the Heck-type cross-coupling of a CF3-containing brominated polyimide derivative (184) with styrene phosphonate 185 (Scheme 38) [98,99].Polyimide 186 exhibited high thermal stabilities, and the electron-withdrawing phosphonate group was readily incorporated into the NLO moieties.Two sets of organic dyes containing a stilbene backbone with fluorine substituents were constructed for a study on the quantum efficiency of dye-sensitized solar cells (DSSCs) (Scheme 37) [97].Compound 181 was coupled with the commercially available 4-bromobenzaldehyde (182a), 4-bromo-2-fluorobenzaldehyde (182b), and 4-bromo-2,6-difluorobenzaldehyde (182c), respectively, by the Heck-type reactions to yield 183, which were condensed with cyanoacetic acid via Knöevenagel reactions to afford the final products (H-P, H-N, F-P, FF-P, F-N, and FF-N).The results revealed that a fluorine substituent on the phenyl group ortho to the cyanoacrylate could enhance the light-harvesting performance in comparison with the unsubstituted one.The monofluorinated dyes showed larger short-circuit photocurrent density (Jsc) values than the non-substituted ones, due to the extension of the conjugation.However, the difluorinated dyes exhibited a lower performance because of a twisted geometry between the difluorophenyl group and the cyanoacrylate moieties, which reduced the efficiency of π-conjugation and thus decreased the Jsc value.Two sets of organic dyes containing a stilbene backbone with fluorine substituents were constructed for a study on the quantum efficiency of dye-sensitized solar cells (DSSCs) (Scheme 37) [97].Compound 181 was coupled with the commercially available 4-bromobenzaldehyde (182a), 4bromo-2-fluorobenzaldehyde (182b), and 4-bromo-2,6-difluorobenzaldehyde (182c), respectively, by the Heck-type reactions to yield 183, which were condensed with cyanoacetic acid via Knöevenagel reactions to afford the final products (H-P, H-N, F-P, FF-P, F-N, and FF-N).The results revealed that a fluorine substituent on the phenyl group ortho to the cyanoacrylate could enhance the lightharvesting performance in comparison with the unsubstituted one.The monofluorinated dyes showed larger short-circuit photocurrent density (Jsc) values than the non-substituted ones, due to the extension of the conjugation.However, the difluorinated dyes exhibited a lower performance because of a twisted geometry between the difluorophenyl group and the cyanoacrylate moieties, which reduced the efficiency of π-conjugation and thus decreased the Jsc value.The well-defined polyimides bearing a charge transporting (CT) and nonlinear optical (NLO) functionality in each repeat unit were prepared via two methods [98,99].One of these methods was the Heck-type cross-coupling of a CF3-containing brominated polyimide derivative (184) with styrene phosphonate 185 (Scheme 38) [98,99].Polyimide 186 exhibited high thermal stabilities, and the electron-withdrawing phosphonate group was readily incorporated into the NLO moieties.The well-defined polyimides bearing a charge transporting (CT) and nonlinear optical (NLO) functionality in each repeat unit were prepared via two methods [98,99].One of these methods was the Heck-type cross-coupling of a CF 3 -containing brominated polyimide derivative (184) with styrene phosphonate 185 (Scheme 38) [98,99].Polyimide 186 exhibited high thermal stabilities, and the electron-withdrawing phosphonate group was readily incorporated into the NLO moieties.
The well-defined polyimides bearing a charge transporting (CT) and nonlinear optical (NLO) functionality in each repeat unit were prepared via two methods [98,99].One of these methods was the Heck-type cross-coupling of a CF3-containing brominated polyimide derivative (184) with styrene phosphonate 185 (Scheme 38) [98,99].Polyimide 186 exhibited high thermal stabilities, and the electron-withdrawing phosphonate group was readily incorporated into the NLO moieties.

RCF 2 X and R fn X as the Cross-Coupling Reagents
Since the fluoroalkyl groups (CF 2 R and R fn ) have found wide applications in the areas of medicinal chemistry and/or materials science, significant efforts have been devoted to the development of efficient catalytic systems and to the design of versatile reagents for mild, convenient, and direct fluoroalkylation [39][40][41][42][43][44][45].In 2012, Reutrakul and co-workers described the palladium-catalyzed Heck-type reactions of [(bromodifluoromethyl)sulfonyl]benzene (187) with styrenes and vinyl ethers (188), furnishing α-alkenyl-substituted α,α-difluoromethyl phenyl sulfones (189) in moderate yields (Scheme 39) [100].Although the efficiency of the reactions was ordinary, they provided an easy procedure for installation of (phenylsulfonyl)difluoromethylene group to olefins.The PhSO 2 CF 2 -containing compounds could be readily transformed.Reductive desulfonylation of the PhSO 2 CF 2 -bearing adduct (189) using Mg/HOAc/NaOAc afforded the corresponding CF 2 H-substituted product [100].Furthermore, addition of 3,5-di-tert-butyl-4-hydroxytoluene (BHT, 1.0 equiv) to a standard reaction mixture led to a slightly lower yield of the product, implying that the mechanistic pathway of the reaction might not proceed through a radical mechanism.This conversion represented the first report of Pd-catalyzed addition of a (phenylsulfonyl)difluoromethylene group to alkenes [100].

RCF2X and RfnX as the Cross-Coupling Reagents
Since the fluoroalkyl groups (CF2R and Rfn) have found wide applications in the areas of medicinal chemistry and/or materials science, significant efforts have been devoted to the development of efficient catalytic systems and to the design of versatile reagents for mild, convenient, and direct fluoroalkylation [39][40][41][42][43][44][45].In 2012, Reutrakul and co-workers described the palladiumcatalyzed Heck-type reactions of [(bromodifluoromethyl)sulfonyl]benzene (187) with styrenes and vinyl ethers (188), furnishing α-alkenyl-substituted α,α-difluoromethyl phenyl sulfones (189) in moderate yields (Scheme 39) [100].Although the efficiency of the reactions was ordinary, they provided an easy procedure for installation of (phenylsulfonyl)difluoromethylene group to olefins.The PhSO2CF2-containing compounds could be readily transformed.Reductive desulfonylation of the PhSO2CF2-bearing adduct (189) using Mg/HOAc/NaOAc afforded the corresponding CF2Hsubstituted product [100].Furthermore, addition of 3,5-di-tert-butyl-4-hydroxytoluene (BHT, 1.0 equiv) to a standard reaction mixture led to a slightly lower yield of the product, implying that the mechanistic pathway of the reaction might not proceed through a radical mechanism.This conversion represented the first report of Pd-catalyzed addition of a (phenylsulfonyl)difluoromethylene group to alkenes [100].Later, Zhang and co-workers reported a general method for palladium-catalyzed Mizoroki-Heck-type cross-couplings of alkenes (190) with perfluoroalkyl bromides (191) (Scheme 40) [101].The reactions proceeded under mild conditions with high efficiency and broad substrate scope, and provided a variety of fluoroalkylated alkenes (192) in good to high yields.The optimized reaction conditions included use of 1,2-dichloroethane (DCE) as a solvent, [PdCl2(PPh3)2] as a catalyst, and Cs2CO3 as a base.The bidentate ligand Xantphos was essential for the transformation as there was no reaction occurring when other phosphine ligands were used.The reaction could be extended to trifluoromethyl iodide, and other functional difluoromethyl bromides (193).The late-stage fluoroalkylation of bioactive compounds was also achieved in good yields, which supplied an efficient and straightforward route for application in drug discovery and development [101].Mechanistic studies including a radical-clock experiment suggested that the free fluoroalkyl radicals (Rfn•), initiated by Pd(0)/Xantphos complex through a single electron transfer (SET) process, might be involved in the Heck-type catalytic cycle (path A, Scheme 40).The formation of fluoroalkylated alkenes (192 and 194) by a bromine atom transfer from RfnBr or 196 to alkene (path B, Scheme 40), followed by base-assisted elimination of the resulting benzyl bromides (200), could be ruled out, as the reaction of styrene with C6F13Br in the presence of [Pd(PPh3)4] and Xantphos without base failed to form benzyl bromide (200).Nevertheless, Chen and co-workers had disclosed that fluoroalkyl iodides reacted with alkyl alkenes in the presence of catalytic amounts of Pd(PPh3)4 to give the Scheme 39.
Later, Zhang and co-workers reported a general method for palladium-catalyzed Mizoroki-Heck-type cross-couplings of alkenes (190) with perfluoroalkyl bromides (191) (Scheme 40) [101].The reactions proceeded under mild conditions with high efficiency and broad substrate scope, and provided a variety of fluoroalkylated alkenes (192) in good to high yields.The optimized reaction conditions included use of 1,2-dichloroethane (DCE) as a solvent, [PdCl 2 (PPh 3 ) 2 ] as a catalyst, and Cs 2 CO 3 as a base.The bidentate ligand Xantphos was essential for the transformation as there was no reaction occurring when other phosphine ligands were used.The reaction could be extended to trifluoromethyl iodide, and other functional difluoromethyl bromides (193).The late-stage fluoroalkylation of bioactive compounds was also achieved in good yields, which supplied an efficient and straightforward route for application in drug discovery and development [101].Mechanistic studies including a radical-clock experiment suggested that the free fluoroalkyl radicals (R fn •), initiated by Pd(0)/Xantphos complex through a single electron transfer (SET) process, might be involved in the Heck-type catalytic cycle (path A, Scheme 40).The formation of fluoroalkylated alkenes (192 and 194) by a bromine atom transfer from R fn Br or 196 to alkene (path B, Scheme 40), followed by base-assisted elimination of the resulting benzyl bromides (200), could be ruled out, as the reaction of styrene with C 6 F 13 Br in the presence of [Pd(PPh 3 ) 4 ] and Xantphos without base failed to form benzyl bromide (200).Nevertheless, Chen and co-workers had disclosed that fluoroalkyl iodides reacted with alkyl alkenes in the presence of catalytic amounts of Pd(PPh 3 ) 4 to give the corresponding adducts (200) in high yields [102].The reaction involved a radical-chain mechanism initiated by a single electron transfer (SET) from the Pd(0) species [102].Furthermore, other competitive side reactions, such as oligomerization of 197 with alkene (path C, Scheme 40) and dimerization of 197 (path D, Scheme 40), were also reasonable pathways, for which the corresponding byproducts (201 and 202) were observed in the conversions [101].Again, other functionalized difluoromethyl bromides (204 and 206) were employed as crosscoupling reagents in the Pd-catalyzed Mizoroki-Heck reactions by Zhang's research group (Scheme 41) [103,104].With an analogous catalytic system mentioned above, a variety of difluoroalkylated alkenes (205) were synthesized from 203 and 204 under mild reaction conditions, showing excellent functional group compatibility (Scheme 41a) [103].The mechanistic studies revealed again that free fluoroalkyl radicals initiated by [Pd(0)Ln] complexes via a SET pathway were involved in the catalytic cycle, and that the bidentate ligand Xantphos was essential for the transformation.This strategy was also successfully applied to the preparation of phosphonyldifluoromethylated alkenes (207) through Pd-catalyzed Heck-type reactions with bromodifluoromethylphosphonate (206) (Scheme 41b) [104].The steric effect of diisopropyl (bromodifluoromethyl)phosphonate was critical for the efficiency of the reaction.Advantage of the protocol was the synthetic simplicity, providing a facile access to biologically interesting molecules.
Pd(PPh3)4-catalyzed Mizoroki-Heck reactions of in situ-generated benzylic iodides with styrenes (208) were reported by Wu and co-workers (Scheme 42) [105].Under standard reaction conditions, a mass of perfluoroalkylated alkenes (210) were synthesized in moderate to excellent yields with good regio-and stereoselectivity.The transformation was totally inhibited when two equivalents of TEMPO were added, suggesting a radical mechanism (Scheme 42).Again, other functionalized difluoromethyl bromides (204 and 206) were employed as cross-coupling reagents in the Pd-catalyzed Mizoroki-Heck reactions by Zhang's research group (Scheme 41) [103,104].With an analogous catalytic system mentioned above, a variety of difluoroalkylated alkenes (205) were synthesized from 203 and 204 under mild reaction conditions, showing excellent functional group compatibility (Scheme 41a) [103].The mechanistic studies revealed again that free fluoroalkyl radicals initiated by [Pd(0)L n ] complexes via a SET pathway were involved in the catalytic cycle, and that the bidentate ligand Xantphos was essential for the transformation.This strategy was also successfully applied to the preparation of phosphonyldifluoromethylated alkenes (207) through Pd-catalyzed Heck-type reactions with bromodifluoromethylphosphonate (206) (Scheme 41b) [104].The steric effect of diisopropyl (bromodifluoromethyl)phosphonate was critical for the efficiency of the reaction.Advantage of the protocol was the synthetic simplicity, providing a facile access to biologically interesting molecules.Pd(PPh 3 ) 4 -catalyzed Mizoroki-Heck reactions of in situ-generated benzylic iodides with styrenes (208) were reported by Wu and co-workers (Scheme 42) [105].Under standard reaction conditions, a mass of perfluoroalkylated alkenes (210) were synthesized in moderate to excellent yields with good regio-and stereoselectivity.The transformation was totally inhibited when two equivalents of TEMPO were added, suggesting a radical mechanism (Scheme 42).Presumably, perfluoroalkyl radical (R fn •) and L n Pd(I)I species are first generated from R fn I and Pd(0)L n in the reaction.Then, the R fn • radical adds to alkene (208) to afford an alkyl radical (211), which reacts with L n Pd(I)I to give a benzylic iodide (212) (path A).Reaction of 212 with Pd(0)L n forms the key intermediate 213, which might also be obtained from the direct combination of 211 with L n Pd(I)I (path B).Subsequently, a Heck-type reaction of styrene with 213 generates a Pd(II) intermediate (214).Finally, reductive elimination of 214 produces 210 and regenerates the Pd(0)L n species under the assistant of DBU.Nonetheless, a pathway via radical addition of 211 to another molecule of styrene in which the resulting benzyl radical couples with L n Pd(I)I to form 214 cannot be excluded.The Pd-catalyzed Heck-type reaction of secondary fluoroalkylated alkyl halide with alkene remains a challenge due to the sluggish oxidative addition of alkyl halide to palladium and the facile β-hydride elimination of alkylpalladium species [106].Encouragingly, Zhang and co-workers described a convenient method for palladium-catalyzed Mizoroki-Heck-type couplings of secondary trifluoromethylated alkyl bromides (216) with alkenes (215), providing a variety of aliphatic alkenes bearing branched trifluoromethyl groups (217) (Scheme 43) [106].The reactions proceeded under mild conditions and showed good functional group tolerance and high efficiency, even towards substrates bearing the sensitive hydroxy, formyl, and phthalimide groups.The reaction could also be Scheme 41.
Pd-catalyzed Heck-type difluoroalkylation of alkenes with functionalized difluoromethyl bromides.The Pd-catalyzed Heck-type reaction of secondary fluoroalkylated alkyl halide with alkene remains a challenge due to the sluggish oxidative addition of alkyl halide to palladium and the facile β-hydride elimination of alkylpalladium species [106].Encouragingly, Zhang and co-workers described a convenient method for palladium-catalyzed Mizoroki-Heck-type couplings of secondary trifluoromethylated alkyl bromides (216) with alkenes (215), providing a variety of aliphatic alkenes bearing branched trifluoromethyl groups (217) (Scheme 43) [106].The reactions proceeded under mild conditions and showed good functional group tolerance and high efficiency, even towards substrates bearing the sensitive hydroxy, formyl, and phthalimide groups.The reaction could also be The Pd-catalyzed Heck-type reaction of secondary fluoroalkylated alkyl halide with alkene remains a challenge due to the sluggish oxidative addition of alkyl halide to palladium and the facile β-hydride elimination of alkylpalladium species [106].Encouragingly, Zhang and co-workers described a convenient method for palladium-catalyzed Mizoroki-Heck-type couplings of secondary trifluoromethylated alkyl bromides (216) with alkenes (215), providing a variety of aliphatic alkenes bearing branched trifluoromethyl groups (217) (Scheme 43) [106].The reactions proceeded under mild conditions and showed good functional group tolerance and high efficiency, even towards substrates bearing the sensitive hydroxy, formyl, and phthalimide groups.The reaction could also be extended to secondary difluoroalkylated alkyl iodide.The optimal reaction conditions were identified to use an assembly of PdCl 2 (PPh 3 ) 2 (5 mol%), Xantphos (7.5 mol%), and KOAc (2.0 equiv) in DCE at 80 • C for 16 h.The control experiments using 1,4-dinitrobenzene as an electron transfer scavenger and the catalytic hydroquinone as a radical inhibitor suggested that a secondary trifluoromethylated alkyl radical (218A) via a SET pathway was likely involved in the reaction.This hypothesis was also supported by the radical clock experiment.Based on these, a plausible reaction mechanism was proposed in Scheme 43 [106].Initially, reaction of [Pd(0)L n ] with 216 via a SET process generates an alkyl radical (218A), which adds to the carbon-carbon double bond of alkene to produce intermediate 218B.Then, 218B combines with [L n Pd(I)Br] to give an alkylpalladium(II) complex (219), which undergoes β-hydride elimination to form 217 and regenerate [Pd(0)L n ] in the presence of a base.extended to secondary difluoroalkylated alkyl iodide.The optimal reaction conditions were identified to use an assembly of PdCl2(PPh3)2 (5 mol%), Xantphos (7.5 mol %), and KOAc (2.0 equiv) in DCE at 80 °C for 16 h.The control experiments using 1,4-dinitrobenzene as an electron transfer scavenger and the catalytic hydroquinone as a radical inhibitor suggested that a secondary trifluoromethylated alkyl radical (218A) via a SET pathway was likely involved in the reaction.This hypothesis was also supported by the radical clock experiment.Based on these, a plausible reaction mechanism was proposed in Scheme 43 [106].Initially, reaction of [Pd(0)Ln] with 216 via a SET process generates an alkyl radical (218A), which adds to the carbon-carbon double bond of alkene to produce intermediate 218B.Then, 218B combines with [LnPd(I)Br] to give an alkylpalladium(II) complex (219), which undergoes β-hydride elimination to form 217 and regenerate [Pd(0)Ln] in the presence of a base.
The 3,3,3-trifluoropropenyl (CF 3 CH=CH-) group has found important implications in medicine and material fields [108].Conjugated aromatic systems with trifluoromethyl groups (e.g., β-trifluoromethylstyrenes) have been widely utilized in organic light emitting diodes (OLEDs) and other materials.In 2012, Prakash and co-workers described a simple and efficient elimination/Heck domino reaction sequence for the synthesis of β-trifluoromethylstyrene derivatives (226) (Scheme 45) [108].The procedure involved a ligand-free palladium-catalyzed Heck reaction between aryl halides (224) and 3,3,3-trifluoropropene, which was generated in situ from the commercially accessible 1-iodo-3,3,3-trifluoropropane (225) under basic conditions, providing interesting and previously unknown β-trifluoromethylstyrenes in moderate to good yields.The reactions avoided the use of a gaseous 1,1,1-trifluoropropene reagent as one of Palladium-catalyzed tandem C-C and C-F bond formation for bifunctionalization of allenes (247) was explored by Doyle and co-workers (Scheme 49) [113].The intramolecular Heck/fluorination cascade provided monofluoromethylated heteroarenes (248), while the intermolecular variant for the three-component couplings of allenes (249), aryl iodides (250), and AgF gave the corresponding linear or branched monofluoromethyl isomers (251 or 252).The regioselectivity of the latter case was dramatically dependent upon the structure of allene.The mechanistic studies indicated that a palladium fluoride, generated from the halide exchange with AgF, was the key intermediate in the reaction (Scheme 49).Nevertheless, the exact mechanism of the reaction remained unclear [113].to excellent enantioselectivies [112].These reactions promised powerful strategies for the difunctionalization of alkenes to chiral fluorinated molecules.Palladium-catalyzed tandem C-C and C-F bond formation for bifunctionalization of allenes (247) was explored by Doyle and co-workers (Scheme 49) [113].The intramolecular Heck/fluorination cascade provided monofluoromethylated heteroarenes (248), while the intermolecular variant for the three-component couplings of allenes (249), aryl iodides (250), and AgF gave the corresponding linear or branched monofluoromethyl isomers (251 or 252).The regioselectivity of the latter case was dramatically dependent upon the structure of allene.The mechanistic studies indicated that a palladium fluoride, generated from the halide exchange with AgF, was the key intermediate in the reaction (Scheme 49).Nevertheless, the exact mechanism of the reaction remained unclear [113].

Conclusions
In summary, the Mizoroki-Heck reaction has become a very powerful tool for building complex molecules [1][2][3][4][5][6].The straightforward incorporation of fluorine-containing moieties by Mizoroki-Heck reactions has proved to be attractive and advantageous, as these reactions efficiently construct the carbon-carbon double bonds bearing fluorinated functionalities by simple procedures.The key to the high efficiency of the reactions is the choice of suitable fluorine-containing reagents and catalytic systems.Furthermore, the fluorinated compounds have been extensively used in the areas of materials and life sciences due to the significant impacts of fluorine substitution on the physiochemical and biological properties of the molecules.Since most fluorinated organic compounds have to be manually synthesized, the development of general and selective fluorination/fluoroalkylation methods with broad functional group tolerance that enable mild and late-stage functionalization of complex molecules is a perpetual topic in the realm of synthetic organic chemistry.Mizoroki-Heck cross-coupling has been evidenced as one of the most convenient methods for the preparation of fluorine-substituted alkenes or variants under mild conditions, which are very useful building blocks in the synthesis of functional molecules.This review highlights the palladium-catalyzed Mizoroki-Heck reactions using fluorine-containing reagents as the coupling participants.The variants of the reactions with fluorine-containing reagents catalyzed by palladium catalysts are also briefly introduced.It is undoubted that new Mizoroki-Heck reactions using fluorine-containing coupling partners will be continuously and prosperously developed.Challenging unrealized programs, such as the incorporation of elusive fluorinated functionalities (e.g., SeR fn , SR fn , and OR fn groups) into the organic frameworks, the facile bifunctionalization of alkenes with rigid fluorine-containing reagents, and the asymmetric synthesis of complex fluorinated molecules via the Mizoroki-Heck cross-coupling reactions, will draw more attention in the future.

Scheme 1 .
Scheme 1.A possible mechanism for the Mizoroki-Heck reactions.

Scheme 22 .
Scheme 22.The oxidative Heck reactions of fluorinated olefins with arylboronic acids by palladium catalysis.

Scheme 32 .
Scheme 32.The Pd-catalyzed oxidative olefination of fluoroarenes with allyl esters.S-fluoroalkyl diphenylsulfonium triflates [Ph2SRfn][OTf] (168, Rfn = CF3, CH2CF3) were effective cross-coupling partners in the Pd-catalyzed Mizoroki-Heck-type reactions with alkenes (Scheme 33)[93].The functionalization of various conjugated and unconjugated alkenes (167) by 168 in the presence of 10 mol% Pd[P(t-Bu)3]2 and TsOH at room temperature provided the corresponding phenylation products (169) in good to high yields.The bases that benefited the traditional Mizoroki-Heck reactions severely inhibited this transformation, whereas the acids significantly improved the reaction.This protocol demonstrated a new class of cross-coupling participants for Heck-type reactions[93].

Scheme 34 .
Scheme 34.Synthesis of a fluorinated derivative of epibatidine via the Mizoroki-Heck reaction.

Scheme 38 .
Scheme 38.Synthesis of multifunctional polymers for photorefractive applications by the Mizoroki-Heck reactions.

Catalysts 2018, 8, 23 7 of 35 Catalysts 2018, 8
, 23; doi:10.3390/catal8010023www.mdpi.com/journal/catalysts • C).It was not necessary to exclude air or moisture, and the reactions could be conducted on >10 g scales.Only E-isomers of the products 82 were detected.Hydrogenation of thirteen representative products with Pd/C and balloon pressure H 2 gave Ar(CH 2 CH 2 R fn ) m in 92% average isolated yield.
Multi-gram scale and divergent preparation of fluorous-Fmoc reagents via the Mizoroki-Heck reactions.
to the metal center of 110 and subsequent insertion into the Ar-Pd bond to generate 112 other than 113, (3) carbon-carbon bond rotation of 112 to produce intermediate 114, and (4) reductive elimination of [HPd]BF 4 from 114 to finally afford tri-substituted alkene (107) and to regenerate the Pd(0) catalyst.
Catalysts 2018, 8, 23; doi:10.3390/catal8010023www.mdpi.com/journal/catalysts of substrates and the good functional group tolerance made this strategy facile and practical for the streamlined synthesis of functional styrenes.