catalysts

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

Jing Yang 1, Hua-Wen Zhao 1,*, Jian He 1 and Cheng-Pan Zhang 1,2,* ID

1 Department of Chemistry, College of Pharmacy, Army Medical University, Shapingba, Chongqing 400038, China; [email protected] (J.Y.); [email protected] (J.H.) 2 School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, China * Correspondence: [email protected] (H.-W.Z.); [email protected] (C.-P.Z.); Tel.: +86-023-6877-2357 (H.-W.Z. & C.-P.Z.)

Received: 27 December 2017; Accepted: 10 January 2018; Published: 14 January 2018

Abstract: 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.

Keywords: Mizoroki-Heck reaction; Pd-catalyzed; fluorine; cross-coupling; alkenes; halides

1. 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” [1–6]. The reaction was discovered independently by Heck and Mizoroki more than 45 years ago. Heck first reported the Li2PdCl4-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 PdCl2 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 (Scheme1)[ 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),

Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 2 of 35 whichCatalysts decomposes 2018, 8, 23 by elimination of a hydridopalladium halide ([H–Pd–X], 6) to form the substituted2 of 35 olefinic compound (5). Reductive elimination of HX from [H–Pd–X] in the presence of a certain base regenerates the Pd(0) species, maintaining the catalytic cycle. Formally speaking, the vinylic regenerates the Pd(0) species, maintaining the catalytic cycle. Formally speaking, the vinylic hydrogen hydrogen atom of alkene is substituted by the organic residue (R) of R–X in the reactions (Scheme 1). atom of alkene is substituted by the organic residue (R) of R–X in the reactions (Scheme1).

SchemeScheme 1. 1. AA possible possible mechanism mechanism for for the the Mizoroki-Heck Mizoroki-Heck reactions.reactions.

Due to to its itshigh high efficiency, efficiency, easy operation, easy operation, and good andchemo- good and chemo-stereoselectivity, and stereoselectivity, the Mizoroki- theHeck Mizoroki-Heck reaction has reactionbeen extensively has been extensivelyused for functi usedonalization for functionalization of various oforganic various scaffolds organic scaffoldssince its sincediscovery. its discovery. Currently, Currently, the Mizoroki-Heck the Mizoroki-Heck reaction ha reactions become has one become of the most one ofimportant the most tools important for the toolsformation for the of carbon-carbon formation of carbon-carbon double bonds double[1–6]. To bonds manifest [1–6 the]. To importance manifest theof the importance Mizoroki-Heck of the Mizoroki-Heckreaction, Richard reaction, F. Heck, Richard together F. Heck,with Ei-ichi together Negishi with Ei-ichi and Akira Negishi Suzuki, and Akirawas honored Suzuki, with was honoredthe 2010 withNobel the Prize 2010 in Nobel Chemistry Prize in for Chemistry their great for theircontribu greattion contribution in the development in the development of Pd-catalyzed of Pd-catalyzed cross- cross-couplingcoupling reactions reactions in organic in organic synthesis. synthesis. The Mizoro Theki-Heck Mizoroki-Heck reactions reactionshave exhibited have good exhibited functional good functionalgroup tolerance group with tolerance a wide with range a of wide substrates range ofunder substrates mild conditions. under mild At conditions.present, not At only present, aryl, notvinyl, only benzyl, aryl, and vinyl, alkyl benzyl, halides and [1–6], alkyl but halides also the [1 corresponding–6], but also the pseudo corresponding halides such pseudo as sulfonates halides such[10–12], as sulfonatessulfonyl chlorides [10–12], sulfonyl [13–15], chlorides carboxylic [13 –ac15id], carboxylicderivatives acid [16–18], derivatives diazonium [16–18 salts], diazonium [19–21], saltsiodonium [19–21 salts], iodonium [22,23], phosphonium salts [22,23], phosphonium salts [24], and salts sulfonium [24], and salts sulfonium [25], have salts been [25 ],successfully have been successfullyemployed as employedelectrophiles as electrophilesin Heck-type incross-coup Heck-typelings. cross-couplings. Both electron-poor Both electron-poorand -rich alkenes and (such -rich alkenesas acrylic (such esters, as enolethers, acrylic esters, and enolethers, ethylene) have and ethylene)proved to have be viable proved cross-coupling to be viable partners cross-coupling in the partnersreactions in [1–6]. the reactions The Mizoroki-Heck [1–6]. The Mizoroki-Heck reactions are reactions originally are originallycatalyzed catalyzedby palladium by palladium [1–6]. Other [1–6]. Othertransition transition metals,metals, such as suchnickel, as cobalt, nickel, copper, cobalt, go copper,ld, and gold, iron, andare also iron, active are also catalysts active for catalysts Heck-type for Heck-typereactions [26–33]. reactions The [26 visible–33]. Thelight-induced visible light-induced Pd-catalyzed Pd-catalyzed Mizoroki-Heck Mizoroki-Heck reactions between reactions sterically between stericallyhindered hinderedalkyl halides alkyl and halides vinyl andarenes vinyl ha arenesve been have accomplished, been accomplished, as well [34,35]. as well [34,35]. On the other hand, fluorinefluorine is a veryvery intriguingintriguing atom for itsits uniqueunique properties.properties. Introduction of fluorinefluorine atom(s)atom(s) into into organic organic molecules molecules usually usually brings aboutbrings a dramatic about impacta dramatic on the physicochemicalimpact on the andphysicochemical biological properties and biological of the moleculesproperties [of36 –the38]. molecules Fluorine-containing [36–38]. Fluorine-containing organic compounds organic have foundcompounds wide have application found wide in the application areas of chemistry,in the areas biology, of chemistry, and materials biology, scienceand materials over the science past severalover the decadespast several [39– decades45]. There [39–45]. have There been ashave many been asas 25%many of as pharmaceuticals 25% of pharmaceuticals and 30–40% and 30– of agrochemicals40% of agrochemicals on the on market the market containing containing at least at a least single a single fluorine fluorine atom atom [41]. [41]. Because Because only only a few a naturally-occurringfew naturally-occurring organofluorides organofluorides have been have discovered, been discovered, most ofthe most fluorinated of the fluorinated organic compounds organic havecompounds to be manually have to synthesizedbe manually [36 synthesized–51]. It is undoubted [36–51]. It that is theundo developmentubted that the of efficientdevelopment methods of toefficient construct methods fluorine-containing to construct moleculesfluorine-containin is of greatg molecules importance is [ 46of– 51great]. In general,importance the fluorinated[46–51]. In compoundsgeneral, the fluorinated can be synthesized compounds by can direct be synthesize fluorinationd by or direct fluoroalkylation, fluorination or or fluoroalkylation, through reactions or withthrough the reactions fluorine-containing with the fluorine-containing building blocks buildi [39–51ng]. blocks The [39–51]. incorporation The incorporation of fluorine-containing of fluorine- fragmentscontaining intofragments organic into frameworks organic frameworks by Pd-catalyzed by Pd-catalyzed Mizoroki-Heck Mizoroki-Heck reactions hasreactions proved has to proved be the simplestto be the and simplest most convenientand most pathwayconvenient to buildpathway diverse to build alkenes diverse bearing alkenes fluorinated bearing functionalities. fluorinated Thisfunctionalities. strategy includes This strategy the Pd-catalyzed includes the cross-couplings Pd-catalyzed cross-couplings of fluorinated alkenesof fluorinated with aryl alkenes halides with or pseudoaryl halides halides, or pseudo and Pd-catalyzed halides, and reactions Pd-catalyzed of alkenes reactions with of the alkenes fluorinated with arylthe fluorinated or alkyl halides aryl or pseudoalkyl halides halides. or Fluorine-containingpseudo halides. Fluorine-contain alkenes are versatileing alkenes building are blocks versatile in the building synthesis blocks of bioactive in the moleculessynthesis of for bioactive drug discovery molecules and for advanceddrug discovery materials and advanced for specific materials applications for specific (see Sections applications2–4). The(see concise,Sections straightforward, 2–4). The concise, selective, straightforward, and highly selective, efficient preparationand highly ofefficient the fluorinated preparation alkenes of the by thefluorinated Mizoroki-Heck alkenes reactionsby the Mizoroki-Heck has made these reaction compoundss has made easy to these access compounds and diversify. 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

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To our knowledge, there has been no review article systematically summarizing the Pd-catalyzed

Mizoroki-HeckCatalysts 2018, 8, 23 reactions using fluorine-containing agents as the cross-coupling partners. To3 of fill 35the gap in this area, we present an overview of the recent advances in the Pd-catalyzed Mizoroki-Heck reactionsMizoroki-Heck with the fluorinatedreactions with cross-coupling the fluorinated participants cross-coupling including participants the fluorinated including alkenes the fluorinated and/or the fluorinatedalkenes and/or aryl or the alkyl fluorinated halides. aryl This or reviewalkyl halides. offers This as a review guide tooffers both as younger a guide to and both more younger established and researchers,more established and is intendedresearchers, to attractand is moreintended attention to attract to andmore contributions attention to and in the contributions development in the of the Mizoroki-Heckdevelopment reactionsof the Mizoroki-Heck with fluorine-containing reactions with cross-couplingfluorine-containing reagents. cross-coupling reagents.

2. Mizoroki-Heck2. Mizoroki-Heck Reactions Reactions of of Aryl Aryl Halides Halides or or Pseudo-Halides Pseudo-Halides with Fluorine-Containing Alkenes Alkenes 2.1. Fluoroalkenes as Cross-Coupling Participants 2.1. Fluoroalkenes as Cross-Coupling Participants The Mizoroki-Heck reaction provides a convenient method for the arylation of olefins [1–6]. In mostThe cases, Mizoroki-Heck the vinylic hydrogen reaction provides atom is formallya convenient substituted method for by the arylation organic residue of olefins of [1–6]. an organic In halidemost under cases, thethe Heck-typevinylic hydrogen reaction atom conditions. is formally High substituted regioselectivities by the organi ofc theresidue arylation of an atorganic the less 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 substituted site of the carbon-carbon double bond of the unsymmetrically substituted olefins are usually observed, which may be attributed to the steric factors [1–6]. One of the key steps of the usually observed, which may be attributed to the steric factors [1–6]. One of the key steps of the reaction is β-hydride elimination. However, when aryl bromide or iodide (7) reacted with vinylidene reaction is β-hydride elimination. However, when aryl bromide or iodide (7) reacted with vinylidene difluoride (8) in the presence of Pd(OAc) , the expected β-H elimination product, β,β-difluorostyrene difluoride (8) in the presence of Pd(OAc)22, the expected β-H elimination product, β,β-difluorostyrene (9),(9 was), was formed formed only only in in a a very very small small amount amount (Scheme(Scheme 22))[ [45,52].45,52]. The The major major product product of ofthe the reaction reaction waswasα-fluorostyrene α-fluorostyrene (10 (10).). Moreover, Moreover, the the reaction reaction ofof vinyl fluoride fluoride (11 (11) )with with 7a7a gavegave styrene styrene (12 ()12 and) and stilbenestilbene (13 (),13 the), the ratio ratio of of which which strongly strongly dependeddepended on the the reaction reaction conditions. conditions. Treatment Treatment of of7a 7awithwith trifluoroethylenetrifluoroethylene (14 )(14 produced) produced an isomerican isomeric mixture mixture of 15 , of16 and15, 1617 (45%),and 17 with (45%),15 being with predominant15 being (86%predominant by GC). Unexpectedly, (86% by GC).15 Unexpectedly,again was the 15 product again was when the chlorotrifluoroethyleneproduct when chlorotrifluoroethylene (18) was treated with(187a) was. These treated results with suggested 7a. These theresults substitution suggested of the a vinylicsubstitution fluorine of a atomvinylic in fluorine all cases, atom which in all were distinctcases, from which the were known distinct Heck-type from the reactions known Heck-t with non-fluorinatedype reactions with olefins non-fluorinated [1–6]. The transformationsolefins [1–6]. representedThe transformations the first examples represented of charge-controlled the first examples Heck-type of charge-controlled reaction, which Heck-type was onlyreaction, significant which in thewas presence only significant of fluoroolefins in the presence [52]. of fluoroolefins [52].

SchemeScheme 2. 2.Pd-catalyzed Pd-catalyzed reactionsreactions of aromat aromaticic halides halides with with fluoroolefins. fluoroolefins.

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Mechanistically, thethe reaction reaction starts starts with with the formationthe formation of a palladium of a palladium adduct (adduct19) by the(19 oxidative) by the additionoxidative ofaddition the in of situ the generated in situ generated Pd(0) speciesPd(0) species with 7awith, which 7a, which undergoes undergoes olefin olefin coordination coordination to produceto produce complex complex20 20(Scheme (Scheme2)[ 2)52 [52].]. Then, Then, the the phenyl phenyl group group in in20 20transfers transfers fromfrom thethe PdPd centercenter to the CF2 sitesite of of 8,, affording affording 21..A A β-fluorine-fluorine elimination elimination of of 2121 yieldsyields αα-fluorostyrene-fluorostyrene ( 10a) as the final final product. CompoundCompound23 23would would be anbe intermediate,an intermediate, if the stericif the aspects steric wereaspects relevant, were andrelevant, a subsequent and a subsequentβ-hydride elimination β-hydride elimination of 23 could formof 23 9acould. However, form 9a the. However, formation the of formation23 must beof of23 lowmust probability, be of low asprobability, only trace as amounts only trace of 9a amountswere detected. of 9a were The detected. favorable The formation favorable of formation21 in the reaction of 21 in of the8 couldreaction be explainedof 8 could bybe theexplained charge-controlled by the charge-controlled mechanism, which mechanism, was verified which by was the MNDO-calculationsverified by the MNDO- [52]. Furthermore,calculations [52]. the Furthe reactionsrmore, of 7athewith reactions11 and of 147a withobeyed 11 and a mechanism 14 obeyed similara mechanis to thatm similar of 7a withto that8, andof 7a the with reaction 8, and ofthe7a reactionwith 18 ofunderwent 7a with 18 bothunderwent the olefinic both fluorinethe olefinic substitution fluorine substitution and the C–Cl and bond the reduction.C-Cl bond reduction. The β-fluorine The β elimination-fluorine elimination seemed to seemed be the to preferred be the preferred type of elimination, type of elimination, even though even thethough competitive the competitiveβ-hydride β-hydride elimination elimination was a possible was pathwaya possible [45 pathway,52]. This [45,52]. procedure This constituted procedure a convenientconstituted methoda convenient for the method preparation for the of preparationα-fluorostyrenes. of α-fluorostyrenes. More than fifteenfifteen years later, Patrick and co-workersco-workers found that 3-fluoro-3-buten-2-one 3-fluoro-3-buten-2-one ( 2626)) reacted smoothly smoothly with with aryl aryl iodides iodides (25 (25) )under under the the Heck-type Heck-type cross-coupling cross-coupling conditions conditions to togive give 3- 3-fluorobenzalacetonesfluorobenzalacetones (27 (27) in) in good good yields yields with with only only ZZ-stereoselectivity-stereoselectivity (Scheme (Scheme 33))[ [53].53]. The The reaction used Pd(OAc) Pd(OAc)2 2asas a catalyst, a catalyst, triphenylphosphine triphenylphosphine as a ligand, as a ligand, and triethylamine and triethylamine as a baseas in DMF. a base The in DMF.conjugate The addition conjugate products addition and products the fluoride and elimin the fluorideation products elimination were products not observed. were The not preferable observed. Thetrans preferable relationshiptrans betweenrelationship the betweenaryl and the acyl aryl groups and acyl during groups the during reaction the reactionwas maintained was maintained in the inconfiguration the configuration of the offinal the product final product (27). (The27). Therequired required syn-eliminationsyn-elimination of HPdL of HPdL2 in2 intermediatein intermediate 28 28sustainedsustained very very small small steric steric repulsion repulsion between between the the aryl aryl group group and and the the fluorine fluorine atom. atom.

Scheme 3. Pd-catalyzedPd-catalyzed Mizoroki-Heck reactions of aryl iodides with 3-fluoro-3-buten-2-one.3-fluoro-3-buten-2-one.

In 2016, Couve-Bonnaire and co-workers reported thethe ligand-freeligand-free palladium-catalyzedpalladium-catalyzed Mizoroki-Heck reactions of methyl α-fluoroacrylate (30) with aryl or heteroaryl iodides (29), leading Mizoroki-Heck reactions of methyl α-fluoroacrylate (30) with aryl or heteroaryl iodides (29), leading to to a cheap, efficient, and stereoselective synthesis of fluoroacrylate derivatives (31) in good to a cheap, efficient, and stereoselective synthesis of fluoroacrylate derivatives (31) in good to quantitative quantitative yields (Scheme 4) [54]. The transformation had good functional group tolerance and yields (Scheme4)[ 54]. The transformation had good functional group tolerance and could be extended could be extended to more steric hindered trisubstituted alkenes, which were previously the reluctant to more steric hindered trisubstituted alkenes, which were previously the reluctant substrates in the substrates in the Mizoroki-Heck reactions. The reactions of trisubstituted (E)-3-alkyl-2-fluoroacrylate Mizoroki-Heck reactions. The reactions of trisubstituted (E)-3-alkyl-2-fluoroacrylate (32) with 29 under (32) with 29 under the standard conditions gave the corresponding tetrasubstituted fluoroacrylates the standard conditions gave the corresponding tetrasubstituted fluoroacrylates (33) in fair to good (33) in fair to good yields [54]. These results constituted the first examples for the synthesis of yields [54]. These results constituted the first examples for the synthesis of tetrasubstituted alkenes tetrasubstituted alkenes by using the Mizoroki-Heck reaction. This methodology was also applicable by using the Mizoroki-Heck reaction. This methodology was also applicable to the preparation of a to the preparation of a fluorinated analogue of a therapeutic agent against inflammation and cancers. fluorinated analogue of a therapeutic agent against inflammation and cancers.

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Scheme 4. Pd-catalyzed Mizoroki-Heck reactions of methyl α-fluoroacrylates with aryl or heteroaryl Scheme 4. 4. Pd-catalyzedPd-catalyzed Mizoroki-Heck Mizoroki-Heck reactions reactions of methyl of methylα-fluoroacrylatesα-fluoroacrylates with aryl withor heteroaryl aryl or iodides. iodides.heteroaryl iodides.

Similarly, Hanamoto and co-worker disclosed the Mizoroki-Heck reactions of (1- Similarly, Hanamoto Hanamoto and and co-worker co-worker disclosed disclosed the the Mizoroki-Heck Mizoroki-Heck reactions reactions of (1- of fluorovinyl)methyldiphenylsilane (35) with aryl iodides (34) catalyzed by Pd(OAc)2 (5 mol%) in the (1-fluorovinyl)methyldiphenylsilanefluorovinyl)methyldiphenylsilane (35) ( 35with) with aryl aryliodides iodides (34) catalyzed (34) catalyzed by Pd(OAc) by Pd(OAc)2 (5 mol%)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 inpresence the presence of Ag2CO of3 Ag (3 equiv)CO (3 and equiv) 4 Å andMS in 4 1,4-dioxane Å MS in 1,4-dioxane (Scheme 5) (Scheme [55]. The5)[ reactions55]. The supplied reactions a series of (E)-β-aryl-(α2-fluorovinyl)methyldiphenylsilanes3 (36) in good yields with excellent seriessupplied of a series(E)-β-aryl-( of (E)-αβ-fluorovinyl)methyldiphenylsilanes-aryl-(α-fluorovinyl)methyldiphenylsilanes (36) in (36 good) in good yields yields with with excellent excellent stereoselectivity. Desilylation/protonation of the product gave the corresponding (E)-β-fluorostyrene stereoselectivity. Desilylation/protonationDesilylation/protonation of of the the product product gave gave the the corresponding corresponding ( E)-β-fluorostyrene-fluorostyrene derivative with complete retention of the configuration of the double bond, which illustrated the derivative with complete retention of the configurationconfiguration of the double bond, which illustrated the synthetic scope of this method. synthetic scope of this method.

Scheme 5. Pd-catalyzed Mizoroki-Heck reactions of (1-fluorovinyl)methyldiphenylsilane with aryl Scheme 5. 5. Pd-catalyzedPd-catalyzed Mizoroki-Heck Mizoroki-Heck reactions reactions of (1-fluorovinyl)methyldiphenylsilane of (1-fluorovinyl)methyldiphenylsilane with witharyl iodides. iodides.aryl iodides.

Moreover, the the Mizoroki-Heck Mizoroki-Heck reaction reaction of ethyl of ethyl (Z)-3-fluoropropenoate (Z)-3-fluoropropenoate (Z-37 ()Z or-37 ethyl) or ( ethylE)-3- fluoropropenoate (E-37) with iodobenzene in the presence of Pd(OAc)2 (5 mol%) produced ethyl 3- (fluoropropenoateE)-3-fluoropropenoate (E-37) (withE-37) iodobenzene with iodobenzene in the presence in the presence of Pd(OAc) of Pd(OAc)2 (5 mol%)2 (5 produced mol%) produced ethyl 3- fluoropropenoateethyl 3-fluoropropenoate (Z-39) as (Z a-39 sole) as product a sole product(Scheme (Scheme 6) [56]. The6)[ 56reaction]. The reactionproceeded proceeded smoothly smoothly at the β- positionat the β-position with specific with stereoselectivity. specific stereoselectivity. The stereochemistry The stereochemistry of E-37 was of Ecompletely-37 was completely inverted and inverted only Zand-39 onlywas Zproduced.-39 was produced. Meanwhile, Meanwhile, compound compound 40 was formed40 was as formed a side asproduct a side via product loss of via a lossfluorine of a atom.fluorine It atom.was possible It was possible that the that ca thetalyst catalyst system system caused caused the the isomerization. isomerization. However, However, the the exact mechanism for the high stereoselectivitystereoselectivity ofof thethe reactionreaction remainedremained unclear.unclear.

Scheme 6. 6. Pd-catalyzedPd-catalyzed Mizoroki-Heck Mizoroki-Heck reactions reactions of ethyl of ethyl (E)- (andE)- ( andZ)-3-fluoropropenoate (Z)-3-fluoropropenoate with Scheme 6. Pd-catalyzed Mizoroki-Heck reactions of ethyl (E)- and (Z)-3-fluoropropenoate with withiodobenzene. iodobenzene. iodobenzene.

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CatalystsPd-Catalyzed2018, 8, 23 intramolecular cyclization of O-(3,3-difluoroallyl)phenyl triflate (41) and6 of3,3- 35 difluoroallyl ketone oximes (46) by the Mizoroki-Heck reactions of the polarized carbon-carbon Catalysts 2018, 8, 23 6 of 35 double bonds of the 1,1-difluoro-1-alkene moieties was accomplished (Scheme 7) [45,57,58]. In the Pd-Catalyzed intramolecular cyclization of O-(3,3-difluoroallyl)phenyl triflate (41) and first step ofPd-Catalyzed the reactions, intramolecular an arylpalladium cyclization or aminopalladium of O-(3,3-difluoroallyl)phenyl intermediate triflate (42 or (4741)) bearingand 3,3- a 2,2- 3,3-difluoroallyl ketone oximes (46) by the Mizoroki-Heck reactions of the polarized carbon-carbon difluorovinyldifluoroallyl group ketone is formed oximes from (46) by41 orthe 46 Mizoroki-Heck, respectively. reactions Then, intermediate of the polarized 42 or carbon-carbon 47 undergoes a 5- double bonds of the 1,1-difluoro-1-alkene moieties was accomplished (Scheme7)[ 45,57,58]. In the endo-trigdouble alkene bonds insertion of the 1,1-difluoro-1-alkene and subsequent moietiesβ-fluorine was elimination accomplished to (Schemeafford ring-fluorinated 7) [45,57,58]. In the indene first stepfirst step of the of the reactions, reactions, an an arylpalladiumarylpalladium or or aminopalladium aminopalladium intermediate intermediate (42 or 47 (42) bearingor 47) a bearing 2,2- a (45) or 3H-pyrroles (49). In both cases, the CF2 unit was very essential for the cyclization as the 2,2-difluorovinyldifluorovinyl groupgroup is formed formed from from 4141 oror 46,46 respectively., respectively. Then, Then, intermediate intermediate 42 or 4742 undergoesor 47 undergoes a 5- a corresponding monofluoroalkene, fluorine-free alkene, dichloroalkene, and dibromoalkene didn’t 5-endo-trigendo-trig alkene alkene insertion insertion and and subsequentsubsequent ββ-fluorine-fluorine elimination elimination to toafford afford ring-fluorinated ring-fluorinated indene indene give the cyclized products under the same reaction conditions [57,58]. (45) or 3H-pyrroles (49). In both cases, the CF2 unit was very essential for the cyclization as the (45) or 3H-pyrroles (49). In both cases, the CF2 unit was very essential for the cyclization as the correspondingcorresponding monofluoroalkene, monofluoroalkene, fluorine-free fluorine-free alkene, alkene, dichloroalkene, dichloroalkene, and and dibromoalkene dibromoalkene didn’t give give the cyclized products under the same reaction conditions [57,58]. the cyclized products under the same reaction conditions [57,58].

Scheme 7. Heck-type 5-endo-trig cyclization promoted by vinylic fluorines. SchemeScheme 7. Heck-type7. Heck-type 5-endo-trig 5-endo-trig cyclizationcyclization promoted promoted by by vinylic vinylic fluorines. fluorines.

2.2. Fluorine-Containing 2.2. Fluorine-Containing Vinyl Vinyl Sulfur Sulfur CompoundsCompou Compoundsnds asas the Cross-Coupling Cross-Coupling Participants Participants EthenesulfonylEthenesulfonyl fluoride fluoride fluoride (ESF) (ESF) (ESF) is is isa ahighly ahighly highly reactive reactive reactive andand versatile andversatile versatile reagent reagent reagentin thein the synthesis insynthesis the of synthesis a wideof a wide of avariety widevariety of variety organosulfur of organosulfur of organosulfur compounds, compounds, compounds, which which behavesbehaves which asas behaves aa strong strong Michael as Michael a strong acceptor acceptor Michael or aor Diels-Alder acceptora Diels-Alder or a dienophiledienophile to conveniently to conveniently introduce introduce an an SO SO22FF groupgroup [59].[59]. In In 2016, 2016, Wu Wu and and Sharpless Sharpless described described a Pd- a Pd- Diels-Alder dienophile to conveniently introduce an SO2F group [59]. In 2016, Wu and Sharpless catalyzed Heck-Matsuda process for the synthesis of the otherwise difficult to access β- describedcatalyzed aHeck-Matsuda Pd-catalyzed Heck-Matsuda process for processthe synt forhesis the synthesisof the otherwise of the otherwise difficult difficult to access to access β- arylethenesulfonyl fluorides (Scheme 8) [60]. In this reaction, ethenesulfonyl fluoride (51) underwent arylethenesulfonylβ-arylethenesulfonyl fluorides fluorides (S (Schemecheme 8)8)[ [60].60]. In In this this reaction, reaction, ethenesulfonyl ethenesulfonyl fluoride fluoride ( (5151)) underwent underwent β-arylationβ-arylation with with the thestable stable and and readily readily preppreparedared arenediazoniumarenediazonium tetrafluoroborates tetrafluoroborates (50) (in50 )the in the β-arylationpresence with of catalytic the stable palladium(II) and readily acetate prepared to afford arenediazonium the E-isomer tetrafluoroborates sulfonyl analogues (50 of) cinnamoyl in the presence presence of catalytic palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl of catalyticfluoride palladium(II) (52) in 43–97% acetate yield. The toafford products the 52E -isomerproved to sulfonyl be selectively analogues addressable of cinnamoyl bis-electrophiles fluoride (52) fluoride (52) in 43–97% yield. The products 52 proved to be selectively addressable bis-electrophiles in 43–97%for sulfur(VI) yield. The fluoride products exchange52 proved (SuFEx) to click be selectivelychemistry, in addressable which either bis-electrophiles the alkenyl moiety for or sulfur(VI) the fluoridefor sulfur(VI)sulfonyl exchange fluoride fluoride (SuFEx) group exchange clickcould chemistry, (SuFEx)be exclusively click in which chemattacked eitheristry, by theinnucleophiles which alkenyl either moiety under the ordefined alkenyl the sulfonyl conditions, moiety fluoride or the groupsulfonylmaking could fluoride these be exclusively simplegroup cores could attacked attractive be exclusively by for nucleophiles covalent attacked drug under discovery by definednucleophiles [60]. conditions, under makingdefined these conditions, simple coresmaking attractive these simple for covalent cores attractive drug discovery for covalent [60]. drug discovery [60].

Scheme 8. Heck-Matsuda reactions of ethenesulfonyl fluoride (ESF) with aryldiazonium salts. Scheme 8. Heck-Matsuda reactions of ethenesulfonyl fluoride (ESF) with aryldiazonium salts. SchemeLater, 8.Qin Heck-Matsuda and Sharpless reactions employed of ethenesulfonyl a similar fluoride strategy (ESF) withfor aryldiazoniumthe synthesis salts.of 2- (hetero)arylethenesulfonylfluorides (54) and 1,3-dienylsulfonyl fluorides (56) (Scheme 9) [61]. They Later,found thatQin Qin a andcombination and Sharpless Sharpless of catalyticemployed employed Pd(OAc) a a2si milarwith similar a strategystoichiometric strategy for foramountthe thesynthesis of synthesis silver(I) of of2- 2-(hetero)arylethenesulfonylfluorides(hetero)arylethenesulfonylfluoridestrifluoroacetate enabled the coupling (54 process ()54 and) and 1,3-dienylsulfonyl between 1,3-dienylsulfonyl either an (hetero)aryl fluorides fluorides (or56 alkenyl) (Scheme (56) (Schemeiodide 9) ([61].539 or)[ They 61]. Theyfound55 found)that and ethenesulfonyl thata combination a combination fluoride of catalytic(ESF, of catalytic 51). ThePd(OAc) Pd(OAc)reaction2 waswith2 with demonstrated a astoichiometric stoichiometric in the successful amount amount synthesis of of silver(I) trifluoroacetatetrifluoroacetate enabled the coupling process between either an (hetero)aryl or alkenyl iodide ( 53 or Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts 55) and ethenesulfonylethenesulfonyl fluoridefluoride (ESF, (ESF,51 51).). The The reaction reaction was was demonstrated demonstrated in in the the successful successful synthesis synthesis of eighty-eight compounds in up to 99% yields, including the unprecedented 2-heteroarylethenesulfonyl Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts CatalystsCatalysts2018 2018, 8,, 8 23, 23 7 of7 35 of 35 Catalysts 2018, 8, 23 7 of 35 of eighty-eight compounds in up to 99% yields, including the unprecedented 2- fluoridesheteroarylethenesulfonylof eighty-eight and 1,3-dienylsulfonyl compounds fluorides fluoridesin upand [61to1,3-dienylsulfonyl]. These99% substitutedyields, includingfluorides ethenesulfonyl [61].the unprecedentedThese fluorides substituted are useful2- heteroarylethenesulfonyl fluorides and 1,3-dienylsulfonyl fluorides [61]. These substituted buildingethenesulfonylCatalysts blocks 2018, 8 for, 23fluorides consequent are useful synthetic building transformations blocks for consequent [61]. synthetic transformations7 [61]. of 35 ethenesulfonyl fluorides are useful building blocks for consequent synthetic transformations [61]. 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].

SchemeScheme 9. 9.Palladium-catalyzed Palladium-catalyzed fluorosulfonylvinylationfluorosulfonylvinylation of of organic organic iodides. iodides. Scheme 9. Palladium-catalyzed fluorosulfonylvinylation of organic iodides. Furthermore, the oxidative Heck cross-coupling reactions have become attractive for modern Furthermore, the oxidative Heck cross-coupling reactions have become attractive for modern organicFurthermore, synthesis duethe oxidativeto advantages Heck such cross-coupling as efficiency, reactions mild reaction have become conditions, attractive good for functional modern organic synthesis dueScheme to advantages9. Palladium-catalyzed such as fluorosulfonylvinylation efficiency, mild reaction of organic conditions, iodides. good functional grouporganic tolerance, synthesis and due widespread to advantages applications such as effici[62–64].ency, In mild2017, reaction Arvidsson conditions, and co-workers good functional reported group tolerance, and widespread applications [62–64]. In 2017, Arvidsson and co-workers reported an angroup operationally tolerance,Furthermore, andsimple the widespread oxidative method Heckapplicationsfor ligand- cross-coupling and[62–64]. additive-free reactions In 2017, haveArvidsson oxidative become and Heckattractive co-workers couplings for modern reported of aryl operationallyboronicanorganic operationally acids synthesis simple (57) simplewith methoddue ESF to method advantages (51 for) (Scheme ligand- for ligand-such and10) as [65]. additive-free efficiand The ency,additive-free reactions mild oxidative reaction proceeded oxidative Heckconditions, at Heck couplingsroom good couplingstemperature offunctional aryl of boronic witharyl acidsgoodboronicgroup (57 chemoselectivity) withacidstolerance, ESF(57) with (and51) andwidespread (SchemeESF E(51-selectivity) (Scheme 10 applications)[65 ].and 10) The [65].offered reactions[62–64]. The facile reactions In proceeded 2017,access Arvidssonproceeded to a atwide room and atrange room temperatureco-workers of temperature β-aryl/heteroaryl reported with with good chemoselectivityethenesulfonylgoodan chemoselectivityoperationally fluorides and simpleE -selectivityand ( 58 methodE)-selectivity from andforthe ligand-commercially offeredand offered and facile additive-free facile available access access toboronic oxidativeto a a wide wide acids rangeHeckrange (57 ).couplingsof The ββ-aryl/heteroaryl-aryl/heteroaryl products of aryl (58 ) ethenesulfonylhaveethenesulfonylboronic a “dual acids warhead” fluorides fluorides(57) with with (ESF 58(58) )two from( 51from) (Schemeelectrophilicthe the commerciallycommercially 10) [65]. sites The that reactionsavailable have been proceeded boronic boronic used as acids acidsatcovalent room (57 (57 ).temperature ).enzymeThe The products products inhibitors with (58 ()58 ) haveandhavegood a as “duala “dualsynthetic chemoselectivity warhead” warhead” reagents with with and [65]. two Etwo-selectivity The electrophilic electrophilic authors and also offered sitessites demonstrated that facile have have access been been that to used a used aryl-substitutedwide as as rangecovalent covalent of β enzyme-aryl/heteroaryl enzymeβ-sultams inhibitors inhibitors could andbeand as ethenesulfonylprepared as synthetic synthetic through reagents reagentsfluorides a [one-pot65 [65].(].58 The) fromThe procedure authors authorsthe commercially also inalso which demonstrated demonstrated availablean excess thatboronic thatof aryl-substitutedprimary aryl-substituted acids amine(57). The wasβ β-sultamsproducts-sultams added ( couldto58could )the be preparedreactionbe haveprepared througha mixture“dual through warhead” a before one-pot a one-potworkup with procedure two procedure[65]. electrophilic in which in siteswhich an that excess an have excess of been primary of used primary amineas covalent amine was enzyme added was added toinhibitors the to reaction the mixturereactionand beforeas mixture synthetic workup before reagents [65 workup]. [65]. The [65]. 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].

Scheme 10. The oxidative Heck couplings of boronic acids with ethenesulfonyl fluoride. SchemeScheme 10. 10.The The oxidative oxidative Heck Heck couplingscouplings of boronic acids acids with with ethenesulfonyl ethenesulfonyl fluoride. fluoride.

Likewise,Scheme Qin 10. Theand oxidative co-workers Heck couplings disclosed of boronic acidsthe with base-freeethenesulfonyl palladium-catalyzed fluoride. fluorosulfonylvinylationLikewise,Likewise, QinQin and andof (hetero)arylboronic co-workersco-workers discloseddisclosed acids (60 ) withthe the ESFbase-freebase-free (51) under palladium-catalyzedoxidative palladium-catalyzed conditions fluorosulfonylvinylation of (hetero)arylboronic acids (60) with ESF (51) under oxidative conditions fluorosulfonylvinylation(SchemeLikewise, 11) [66]. Aryl-Qin ofandand (hetero)arylboronic heteroaryl-boronic co-workers disclosed acids acids ( 60( 60)) with thereacted ESFbase-free with (51) underESF palladium-catalyzed in oxidative the presence conditions of a (Scheme 11) [66]. Aryl- and heteroaryl-boronic acids (60) reacted with ESF in the presence of a (Schemecatalyticfluorosulfonylvinylation 11 amount)[66]. of Aryl- Pd(OAc) and of2 (hetero)arylboronic heteroaryl-boronicand excess 2,3-dichloro-5,6-dicyano-p-benzoqui-none acids acids (60 () 60with) reacted ESF (51 with) under ESF oxidative in (DDQ) the conditions presence or AgNO of3 a incatalytic (SchemeAcOH amount to 11) stereoselectively [66]. of Pd(OAc)Aryl- and2 and affordheteroaryl-boronic excess the 2,3-dichloro-5,6-dicyano-p-benzoqui-none corresponding acids (60 E) -isomerreacted ofwith β-arylethenesulfonyl ESF in the (DDQ) presence or fluoride AgNOof a 3 catalytic amount of Pd(OAc)2 and excess 2,3-dichloro-5,6-dicyano-p-benzoqui-none (DDQ) or AgNO3 inproducts catalyticAcOH (61 toamount )stereoselectively in up of to Pd(OAc) 99% yield.2 andafford The excess theutility 2,3-dichloro-5,6-dicyano-p-benzoqui-none corresponding of the reactions E-isomer was exemplified of β-arylethenesulfonyl by an(DDQ) expanded or AgNO fluoride scope3 in AcOH to stereoselectively afford the corresponding E-isomer of β-arylethenesulfonyl fluoride ofproducts in47 AcOHexamples (61 to) in stereoselectivelyincluding up to 99% N yield.-, O -,afford andThe Sutilitythe-containing corresponding of the heteroaromatics,reactions E-isomer was exemplified of demonstrating β-arylethenesulfonyl by an chemoselectivity expanded fluoride scope products (61) in up to 99% yield. The utility of the reactions was exemplified by an expanded scope of overof products47 arylexamples iodides (61) includingin [66]. up to 99% N-, yield. O-, and The S utility-containing of the reactionsheteroaromatics, was exemplified demonstrating by an expanded chemoselectivity scope 47over examplesof 47aryl examples iodides including including[66].N -, O -,N-, and O-,S and-containing S-containing heteroaromatics, heteroaromatics, demonstrating demonstrating chemoselectivity chemoselectivity over aryl iodidesover aryl [ 66iodides]. [66].

Scheme 11. The oxidative Heck reactions of arylboronic acids with ethenesulfonyl fluoride. Scheme 11. The oxidative Heck reactions of arylboronic acids with ethenesulfonyl fluoride. Scheme 11. The oxidative Heck reactions of arylboronic acids with ethenesulfonyl fluoride. Catalysts Scheme2018, 8, 23; 11. doi:10.3390/catal8010023The oxidative Heck reactions of arylboronic acids with ethenesulfonylwww.mdpi.com/journ fluoride.al/catalysts Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 8 of 35

Catalysts 2018, 8, 23 8 of 35 It should be noted that the sulfur-containing olefins (e.g., vinyl sulfides, sulfoxides) are the It should be noted that the sulfur-containing olefins (e.g., vinyl sulfides, sulfoxides) are the least least investigated substrates in the Mizoroki-Heck reactions, as these substrates may poison the investigated substrates in the Mizoroki-Heck reactions, as these substrates may poison the Pd- Pd-catalysts to form stable metal-sulfur complexes [67]. To date, only a handful of successful Heck catalysts to form stable metal-sulfur complexes [67]. To date, only a handful of successful Heck cross- cross-couplingcoupling reactions reactions based based on sulfoxides on sulfoxides have have been been reported, reported, even even though though these these moieties moieties have have potentialpotential forfor manymany syntheticsynthetic applications.applications. Among Among this this type type of of molecule, molecule, perfluoroalkyl perfluoroalkyl vinyl vinyl sulfoxidessulfoxidespossess possess aa stronglystrongly polarizedpolarized doubledouble bond and is highly reactive, reactive, which which makes makes them them interestinginteresting for for investigation. investigation. In In 2015, 2015, Sokolenko Sokolenko an andd co-workers co-workers explored explored the the Heck-type Heck-type reactions reactions of oftrifluoromethyl trifluoromethyl or or tridecafluorohexyl tridecafluorohexyl vinyl vinyl sulfoxides sulfoxides (62 (62) with) with aryl aryl iodides iodides (63 (63) (Scheme) (Scheme 12) 12 [67].)[67 ]. Palladium(II)Palladium(II) acetate acetate waswas foundfound to be the the most most suitab suitablele catalyst catalyst for for the the reactions. reactions. By Bythis this method, method, a aseries series of of EE-1-aryl-2-perfluoroalkylsulfinylethylenes-1-aryl-2-perfluoroalkylsulfinylethylenes (64 (64) were) were synthesized. synthesized. Styrenes Styrenes (65) ( 65without) without a aperfluoroalkylsulfinyl perfluoroalkylsulfinyl group group were were also also formed formed (a (ass byproducts) byproducts) in in these these ca cases.ses. The The perfluoroalkyl perfluoroalkyl vinylvinyl sulfoxides sulfoxides (62 (62) may) may undergo undergo both both terminal terminal and and internal internal additions additions of of the the aryl aryl group group (Scheme (Scheme 12 ). In12). the In former the former case, βcase,-elimination β-elimination of the of palladium the palladium species species and hydrideand hydride from from67 yields 67 yields64. In 64 the. In latterthe case,latterβ -eliminationcase, β-elimination of the of palladium the palladium species species and and perfluoroalkylsulfinyl perfluoroalkylsulfinyl group group from from68 68leads leads to to65 . The65. formationThe formation of stable of stable Pd–S Pd–S bonds bonds might might facilitate facilitate the the latter latter process. process.

SchemeScheme 12. 12.The The Mizoroki-HeckMizoroki-Heck reactionsreactions of perfluoroalkylperfluoroalkyl vinyl vinyl sulfoxides sulfoxides with with aryl aryl iodides. iodides.

2.3.2.3. Fluoroalkylated Fluoroalkylated Alkenes Alkenes asas thethe Cross-CouplingCross-Coupling PartnersPartners PerfluoroalkylatedPerfluoroalkylated alkenes alkenes are are important important feedstocks feedstocks for the for synthesis the synthesis of useful of fluorine-containing useful fluorine- molecules.containing Inmolecules. 1981, Ojima In 1981, and Ojima co-workers and co-workers reported thereported Pd-catalyzed the Pd-catalyzed Mizoroki-Heck Mizoroki-Heck reactions ofreactions 3,3,3-trifluoropropene of 3,3,3-trifluoropro or pentafluorostyrenepene or pentafluorostyrene (70) with (70 aromatic) with aromatic halides halides (71) (Scheme(71) (Scheme 13)[ 13)68 ]. The[68]. cross-couplings The cross-couplings proceeded proceeded smoothly smoothly by simply by heatingsimply heating the mixtures the mixtures of aryliodides of aryl oriodides bromides, or bromides, trifluoropropene or pentafluorostyrene, a Pd-catalyst (1 mol%), and a base (such as Et3N trifluoropropene or pentafluorostyrene, a Pd-catalyst (1 mol%), and a base (such as Et3N or KOAc), or KOAc), which gave a variety of trans-β-trifluoromethylstyrenes or trans-β- which gave a variety of trans-β-trifluoromethylstyrenes or trans-β-pentafluorophenylstyrenes (72) in pentafluorophenylstyrenes (72) in good to high yields via a one-step procedure. The arylation was good to high yields via a one-step procedure. The arylation was not sensitive to the electronic not sensitive to the electronic nature of the substituents on the aryl halides but was rather sensitive nature of the substituents on the aryl halides but was rather sensitive to the steric hindrance. to the steric hindrance. However, aryl chlorides such as chlorobenzene and chlorotoluene were However, aryl chlorides such as chlorobenzene and chlorotoluene were unreactive under the same unreactive under the same reaction conditions. reaction conditions.

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Scheme 13. The Heck-type reactions of aryl halides with 3,3,3-trifluoropropene or pentafluorostyrene. Scheme 13. TheThe Heck-type Heck-type reactions reactions of of aryl aryl halides halides with with 3, 3,3,3-trifluoropropene3,3-trifluoropropene or or pentafluorostyrene. pentafluorostyrene. In 2001, Xiao and co-workers found that Pd-catalyzed olefination of aryl halides (73) with 1H,1InHIn,2 2001,2001,H-perfluoro-1-alkenes XiaoXiao andand co-workersco-workers (74) provided foundfound thatthat trans Pd-catalyzedPd-catalyzed-fluorous ponytail-substolefination olefinationolefination of ofituted aryl aryl halideshalidesaryl compounds ((73)) withwith 11(75HH,1,1,1) HinH,2,2 ,2goodHH-perfluoro-1-alkenes-perfluoro-1-alkenes-perfluoro-1-alkenes to excellent yields ((Scheme74((74))) provided providedprovided 14) [69].trans transtrans Typically,-fluorous-fluorous-fluorous the ponytail-substituted ponytail-substponytail-subst reactions of 73itutedituted with aryl 74arylaryl compounds in thecompoundscompounds presence (75) in((of75 goodNaOAc)) inin goodgood to excellentand toto excellentexcellent the Herrmann-Beller yields yieldsyields (Scheme (Scheme(Scheme 14 palladacycle)[ 14)69 ].[69]. Typically, Typically, catalyst the the reactions(0.5–1 reactions mol%) of 73 of in with73 DMF withwith74 suppliedin74 theinin thethe presence presencepresencethe trans of NaOAcofolefins NaOAc 75 and in and themore the Herrmann-Beller than Herrmann-Beller 90% isolated palladacycle yieldspalladacycle in catalystmost catalyst cases (0.5–1 without (0.5–1 mol%) mol%)optimization. in DMF in suppliedDMF Purification supplied the trans the ofolefins 75transtrans by 75olefinsflashin morechromatography 75 inin than moremore 90% thanthan isolated allowed90%90% isolatedisolated yields easy inyieldsyieldsre mostduction inin cases mostmost of withoutthe casescases C=C withoutwithout optimization.double optimization.optimization. bonds Purificationof 75 Purification Purificationunder ofthe75 standard byofof 75 flash byby chromatographyflashflashPd/C- chromatographychromatography or Rh/C-catalyzed allowed allowedallowed hydrogenation easy reduction easyeasy rereduction conditions of the C=C of the [69]. double C=C This bondsdouble method of bonds75 wasunder successfullyof 75 the underunder standard appliedthethe Pd/C-standardstandard to the or Rh/C-catalyzedPd/C-synthesis or Rh/C-catalyzed of binaphathols hydrogenation hydrogenation bearing conditions fluorinated conditions [69]. ponytails, This [69]. method This which was method are successfully potential was successfully appliedligands tofor applied the catalysis synthesis to the in synthesis of binaphathols bearing fluorinated ponytails, which are potential ligands for catalysis in ofsynthesisscCO binaphathols2 and of fluorous binaphathols bearing solvents fluorinated bearing [69,70]. fluorinated ponytails, The application whichponytails, are of potentialwhich these areligands ligands potential in forthe ligands catalysis ruthenium-catalyzed for in catalysis scCO2 and in fluorousscCOhydrogenation22 andand solvents fluorousfluorous of [ 69dimethyl ,solventssolvents70]. The itaconate application[69,70].[69,70]. TheTherevealed of applicationapplication these that ligands the ofof fluorous inthesethese the ruthenium-catalyzedligandsligands ponytails inin thethe on ruthenium-catalyzedruthenium-catalyzedthe ligands hydrogenation imposed ofhydrogenationsignificant dimethyl effects itaconate of ondimethyl the revealed hydrogenation itaconate that the fluorousrevealed activity, ponytailsthat but thenot fluorous on the ligandsenantioselectivity ponytails imposed on the significant [70]. ligands effectsimposed on thesignificant hydrogenation effects on activity, the hydrogenation but not on the activity, enantioselectivity but not on the [70 ].enantioselectivity [70].

Scheme 14. The Mizoroki-Heck reactions between perfluoroalkyl alkenes and aryl halides. Scheme 14. TheThe Mizoroki-HeckMizoroki-Heck reactions reactions between between perfluoroalkyl perfluoroalkylperfluoroalkyl alkenesalkenes andand arylaryl halides.halides. Later, Cai and co-worker developed a PCP Pincer-Pd catalyst (77), which was favorably used in Mizoroki-HeckLater, Cai and cross-couplings co-worker co-worker developed developed between a aperfluoroalkyl PCP PCP Pincer-Pd Pincer-Pd alkenes catalyst catalyst ((7477 (77)),), and ),whichwhich which aryl waswas washalides favorablyfavorably favorably (78) usedusedfor used the inin inMizoroki-Heckpreparation Mizoroki-Heck of cross-couplingsperfluoroalkenylated cross-couplings between between aryl perfluoroalkyl compounds perfluoroalkyl (79alkenes alkenes) (Scheme (74 (74)) and)and15) and [71].arylaryl aryl halideshalidesDue halides to (( (the7878))) foruniquefor thethe preparationpreparationtridentate coordination ofof perfluoroalkenylated perfluoroalkenylated architecture, aryl thearyl compounds Pincer compounds complex (79) (Scheme(79 was)) (Scheme(Scheme stable, 15)[71 selective,15)].15) Due [71].[71]. to theandDueDue unique highly toto thethe tridentate reactive, uniqueunique coordinationtridentatetridentateand it permitted coordinationcoordination architecture, low catalyst architecture,architecture, the Pincerloadings complex thethe and PincerPincer gave was thecomplex stable,complex possibility selective, waswas stable,stable,of and fine-tuning highly selective,selective, reactive, the andand catalytic andhighlyhighly it properties permitted reactive,reactive, lowandof the catalystit permittedmetal loadingscenter. low Catalyst andcatalyst gave 77 loadings the showed possibility and high gave ofcatalytic fine-tuning the possibility activity the in catalyticof this fine-tuning reaction properties theand catalytic ofthe the corresponding metal properties center. Catalystofarylated the metal 77productsshowed center. wereCatalyst high catalyticobtained 77 showedshowed activityin mo highhighderate in catalyticcatalytic this to reaction excellent activityactivity and inyields.in the thisthis corresponding reactionreactionMoreover, andand 77 thethe arylated could correspondingcorresponding productsbe easily werearylatedseparated obtained products by F-SPE in moderate were (Fluorous obtained to excellentsolid in phasemo yields.derate extrac to Moreover,tion) excellent technique77 yields.could and Moreover, be reused easily threeseparated77 couldcould times bybebe without F-SPEeasilyeasily (Fluorousseparatedsignificant solid byloss F-SPE phaseof activity. (Fluorous extraction) solid technique phase and extrac reusedtion)tion) three techniquetechnique times withoutandand reusedreused significant threethree times losstimes of withoutwithout activity. significant loss of activity.

Scheme 15.15.The The Mizoroki-Heck Mizoroki-Heck cross-couplings cross-couplings of aryl of halidesaryl halides with perfluoroalkyl-substituted with perfluoroalkyl-substituted alkenes. Schemealkenes. 15. TheThe Mizoroki-HeckMizoroki-Heck cross-couplingscross-couplings ofof arylaryl halideshalides withwith perfluoroalkyl-substitutedperfluoroalkyl-substituted alkenes.

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Gladysz andand co-workersco-workers reportedreported a a convenient convenient and and scalable scalable procedure procedure for for the the cross-couplings cross-couplings of fluorousof fluorous alkenes alkenes (80 )(80 with) with aryl aryl bromides bromides (81) ( using81) using a modified a modified Jeffery Jeffery version version of the of Mizoroki-Heck the Mizoroki- reactionHeck reaction (Scheme (Scheme 16)[72]. 16) Fluorous [72]. Fluorous alkenes (80 alkenes) reacted (80 with) reacted aryl monobromides with aryl monobromides and polybromides and (polybromides81), such as (81 1,3-), such and as 1,4-C 1,3- 6andH4Br 1,4-C2, 1,3,5-C6H4Br2,6 1,3,5-CH3Br3,6H 1,3,5-C3Br3, 1,3,5-C6H3Br62HCl,3Br2 1,4-XCCl, 1,4-XC6H46BrH4Br (X (X = = CF3,, C8FF1717, ,COCH COCH3,3 ,CN, CN, 1,4-OC 1,4-OC6H6H4Br),4Br), 1,2-O 1,2-O2NC2NC6H64HBr,4 Br,5-bromo-isoquinoline, 5-bromo-isoquinoline, 5-bromopyrimidine, 5-bromopyrimidine, 3- 3-bromo-5-methoxypyridine,bromo-5-methoxypyridine, and and 3,5-dibromopyridin 3,5-dibromopyridine,e, under under the the modified modified Mizoroki-Heck Mizoroki-Heck coupling conditions to afford the corresponding fluorophilic fluorophilic adducts ( 82)) in good to high yields. Typically, Typically, 1.2–2.4 equiv. ofof alkenealkene werewere employedemployed perper Ar-BrAr-Br bond,bond, togethertogetherwith withPd(OAc) Pd(OAc)22 (4–5(4–5 mol%/Ar-Brmol%/Ar-Br bond), n-Bu44NBrNBr (0.8–1.0 (0.8–1.0 equiv/Ar-Br equiv/Ar-Br bond), bond), NaOAc NaOAc (1.2–2.4 (1.2–2.4 equiv/Ar-Br equiv/Ar-Br bond), bond), and and DMF/THF DMF/THF (3:1 (3:1w/w)w as/w solvent) as solvent (120 (120°C). ◦ItC). was It wasnot necessary not necessary to exclude to exclude air or air moisture, or moisture, and and the thereactions reactions could could be beconducted conducted on on>10 >10 g scales. g scales. Only Only E-isomersE-isomers of of the the products products 8282 werewere detected. Hydrogenation of thirteen representativerepresentative productsproducts withwith Pd/CPd/C andand balloonballoon pressurepressure HH22gave gaveAr(CH Ar(CH22CHCH22RRfnfn)m inin 92% average isolated yield.

Scheme 16. 16. TheThe Mizoroki-Heck Mizoroki-Heck reactions reactions of aromatic of aromatic bromides bromides and polybromides and polybromides with fluorous with fluorousalkenes. alkenes.

In addition, a family of diazonium-functionalized oligo(phenylene vinylene)s (OPVs) tetramers 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- were synthesized by alternating the Mizoroki-Heck cross-coupling and the Horner-Wadswoth-Emmons Emmons (HWE) reaction using fluorous mixture synthesis (FMS) technology (Scheme 17) [73]. The (HWE) reaction using fluorous mixture synthesis (FMS) technology (Scheme 17)[73]. The FMS FMS technology was found to be superior to the solid-phase organic synthesis (SPOS) techniques. 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 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 palladacycle catalyst which proved to be a better catalyst than Pd(OAc) . Hydrogenation of the coupled alkenes (85) followed by removal of the Boc groups gave secondary2 amines as fluorous tags 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 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 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 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 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]. surface-grafting moieties in hybrid silicon/molecule assemblies [73]. Genêt and co-workers described the palladium-catalyzed Mizoroki-Heck reactions between 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 aryldiazonium salts (91) and perfluoroalkyl alkenes (92) (Scheme 18)[74]. The reactions carried in methanol at 40 °C in the presence of 0.5 mol% of Pd(OAc)2 afforded a series of long-chain out in methanol at 40 ◦C in the presence of 0.5 mol% of Pd(OAc) afforded a series of long-chain perfluoroalkyl-substituted aromatic compounds (93) in good to excellent2 yields. However, coupling perfluoroalkyl-substituted aromatic compounds (93) in good to excellent yields. However, coupling of of 4-iodotoluene (91f) under the same reaction conditions failed to give the desired product (93bb; R 4-iodotoluene (91f) under the same reaction conditions failed to give the desired product (93bb; = CH3, Rfn = C8F17). Coupling of aryl iodide in the presence of Pd(PPh3)4 and triethylamine in toluene R = CH3,Rfn = C8F17). Coupling of aryl iodide in the presence of Pd(PPh3)4 and triethylamine in didn’t form the expected product neither. Interestingly, under Jeffery’s conditions (Pd(OAc)2, DMF, toluene didn’t form the expected product neither. Interestingly, under Jeffery’s conditions (Pd(OAc)2, NaHCO3, n-Bu4NHSO4), the reaction of 4-iodotoluene (91f) with 92b (Rfn = C8F17) afforded 93bb in DMF, NaHCO , n-Bu NHSO ), the reaction of 4-iodotoluene (91f) with 92b (R = C F ) afforded 80% yield, but3 4-bromotoluene4 4 (91g) remained much less reactive. Thanks to thefn difference8 17 in the 93bb in 80% yield, but 4-bromotoluene (91g) remained much less reactive. Thanks to the difference in reactivity of these functionalities, the Heck-type reaction of 92b with 4-bromobenzenediazonium 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 tetrafluoroborate (91c) produced 93cb (R = Br, R = C F ) exclusively, showing good chemoselectivity. chemoselectivity. Hydrogenation of the carbon-carbonfn 8 17 double bond of 93 afforded the fluorous Hydrogenation of the carbon-carbon double bond of 93 afforded the fluorous aromatic compounds. aromatic compounds. Perfluoroalkyl-substituted aryl bromides and anilines were also accessed by Perfluoroalkyl-substituted aryl bromides and anilines were also accessed by this method. This protocol this method. This protocol represented one of the most efficient methods to install a perfluoroalkyl represented one of the most efficient methods to install a perfluoroalkyl chain onto an aromatic ring. chain onto an aromatic ring. The simple purification and the high purities of products allowed an The simple purification and the high purities of products allowed an easy scale up of this procedure. easy scale up of this procedure.

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Scheme 17. Preparation of diazonium-functionalized oligo(phenylenevinylene)s by FMS technology. Scheme 17. Preparation of diazonium-functionalized o oligo(phenylenevinylene)sligo(phenylenevinylene)s by FMS technology.

Scheme 18. Scheme 18. The Heck-type reactions between perfluoroalkylperfluoroalkyl alkenes and aryldiazonium salts.salts. Scheme 18. The Heck-type reactions between perfluoroalkyl alkenes and aryldiazonium salts.

In 2015,2015, MatsugiMatsugi andand co-workersco-workers synthesizedsynthesized f-Fmoc f-Fmoc reagents reagents ( 97(97)) bearing bearing C 3CF37F,C7, C4F4F99,, oror C C66FF1313 In 2015, Matsugi and co-workers synthesized f-Fmoc reagents (97) bearing C3F7, C4F9, or C6F13 chains by the the Pd(OAc) Pd(OAc)22-catalyzed-catalyzed Mizoroki-Heck Mizoroki-Heck reaction reaction of of 9494 withwith 95a95a, 95b, 95b, or, or95c95c, followed, followed by chains by the Pd(OAc)2-catalyzed Mizoroki-Heck reaction of 94 with 95a, 95b, or 95c, followed by byhydroxymethylation hydroxymethylation and andintroduction introduction of the of N the-hydroxysuccinimideN-hydroxysuccinimide grou groupp (Scheme (Scheme 19) [75].19)[ The75]. hydroxymethylation and introduction of the N-hydroxysuccinimide group (Scheme 19) [75]. The Themethod method applied applied on a multi-gram on a multi-gram scale after scale eight after steps eight gave steps the gave desired the desiredproducts products 97a, 97b,97a and, 97b 97c, method applied on a multi-gram scale after eight steps gave the desired products 97a, 97b, and 97c andwith97c overallwith overallyields yieldsof 73%, of 73%,60%, 60%,and and90%, 90%, respectively. respectively. The The Pd-catalyzed Pd-catalyzed doubly doubly tagging tagging Heck with overall yields of 73%, 60%, and 90%, respectively. The Pd-catalyzed doubly tagging Heck reaction of 94 withwith aa mixturemixture ofof thethe fluorousfluorous alkenesalkenes ((9595)) waswas alsoalso studied,studied, leadingleading toto anan encodedencoded reaction of 94 with a mixture of the fluorous alkenes (95) was also studied, leading to an encoded mixture synthesissynthesis of of f-Fmoc f-Fmoc reagents. reagents. Addition Addition of 95 ofin 95 an in order an order of 95c of, 95b 95c, 95a, 95bto, the95a reaction to the reaction mixture mixture synthesis of f-Fmoc reagents. Addition of 95 in an order of 95c, 95b, 95a to the reaction wasmixture found was to found be an effectiveto be an effective condition condition in the mixed in the tagging mixed Hecktagging reaction. Heck reaction. The target The f-Fmoc target reagents f-Fmoc mixture was found to be an effective condition in the mixed tagging Heck reaction. The target f-Fmoc withreagents C3F 7with,C4F C93,F and7, C4 CF69,F and13 groups C6F13 groups couldbe could separated be separated owing owing to the differentto the different fluorine fluorine content content of the reagents with C3F7, C4F9, and C6F13 groups could be separated owing to the different fluorine content molecules.of the molecules. This method This method provided provided a reasonable a reasonable solution solution to obtain tovarious obtain various f-Fmoc reagentsf-Fmoc reagents in a one-pot in a of the molecules. This method provided a reasonable solution to obtain various f-Fmoc reagents in a procedure.one-pot procedure. These f-Fmoc These reagents f-Fmoc wouldreagents be would useful protectingbe useful groupsprotecting for thegroups effective for the synthesis effective of one-pot procedure. These f-Fmoc reagents would be useful protecting groups for the effective peptidesynthesis isomer of peptide libraries. isomer libraries. synthesis of peptide isomer libraries.

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Scheme 19. 19. Multi-gramMulti-gram scale scale and divergent and divergent preparation preparation of fluorous-Fmoc of fluorous-Fmoc reagents reagentsvia the Mizoroki- via the HeckMizoroki-Heck reactions. reactions.

In 2017, Konno and co-workers investigated the Pd-catalyzed Mizoroki-Heck reactions of In 2017, Konno and co-workers investigated the Pd-catalyzed Mizoroki-Heck reactions aryldiazonium tetrafluoroborates with different types of CF2CF2-containing alkenes (Scheme 20) [76]. of aryldiazonium tetrafluoroborates with different types of CF2CF2-containing alkenes A survey of the optimized reaction conditions revealed that the reactions of 4-bromo-3,3,4,4- (Scheme 20)[76]. A survey of the optimized reaction conditions revealed that the reactions of tetrafluoro-1-butene (98) with aryldiazonium salts (99) in the presence of 0.5 mol% Pd(OAc)2 in 4-bromo-3,3,4,4-tetrafluoro-1-butene (98) with aryldiazonium salts (99) in the presence of 0.5 mol% MeOH at 40 °C for 1 h gave the best yields of the products. The E-configured products (100) were Pd(OAc) in MeOH at 40 ◦C for 1 h gave the best yields of the products. The E-configured exclusively2 obtained, and no Z-isomers were detected. In the cases of 4-bromo-3,3,4,4-tetrafluoro-1- products (100) were exclusively obtained, and no Z-isomers were detected. In the cases of aryl-1-butenes (101), a bulky P(o-tolyl)3-coordinated palladium catalyst was found to be a good 4-bromo-3,3,4,4-tetrafluoro-1-aryl-1-butenes (101), a bulky P(o-tolyl) -coordinated palladium catalyst catalytic system, leading to an increased yield of the product (1023 ). High stereoselectivity of the was found to be a good catalytic system, leading to an increased yield of the product (102). reaction was achieved if 102 containing an electron-deficient aromatic ring, whereas a slight decrease High stereoselectivity of the reaction was achieved if 102 containing an electron-deficient aromatic ring, in the stereoselectivity was observed if 102 bearing an electron-donating substituent on the aromatic whereas a slight decrease in the stereoselectivity was observed if 102 bearing an electron-donating ring. In the reactions of 4-bromo-3,3,4,4-tetrafluoro-2-aryl-1-butenes (103) with 99, the geometry of substituent on the aromatic ring. In the reactions of 4-bromo-3,3,4,4-tetrafluoro-2-aryl-1-butenes the major isomers of 104 was determined as E-configuration on the basis of a proposed reaction (103) with 99, the geometry of the major isomers of 104 was determined as E-configuration on mechanism [76]. This protocol provided a convenient and highly stereoselective method for the the basis of a proposed reaction mechanism [76]. This protocol provided a convenient and highly preparation of multi-substituted alkenes (100, 102, and 104) bearing a tetrafluoroethylene fragment, stereoselective method for the preparation of multi-substituted alkenes (100, 102, and 104) bearing which are promising building blocks for the synthesis of novel CF2CF2-containing organic molecules a tetrafluoroethylene fragment, which are promising building blocks for the synthesis of novel [76]. CF2CF2-containing organic molecules [76].

Scheme 20. The Mizoroki-Heck reactions of CF2CF2-containing alkenes with Scheme 20. The Mizoroki-Heck reactions of CF2CF2-containing alkenes with aryldiazonium aryldiazonium tetrafluoroborates. tetrafluoroborates.

In a similarsimilar manner,manner, KonnoKonno andand co-workersco-workers examinedexamined thethe palladium-catalyzedpalladium-catalyzed Heck reactions of (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one)-4,4,4-trifluoro-1-phenyl-2-buten-1-one ( (105a105a)) with with the readily availableavailable aryldiazoniumaryldiazonium salts (106) (Scheme 21) [77]. The reactions allowed for easy and regio- and stereoselective access to a variety

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Catalysts 2018, 8, 23 13 of 35 (106) (Scheme 21)[77]. The reactions allowed for easy and regio- and stereoselective access to a varietyof 4,4,4-trifluoro-2-aryl-1-phenyl-2-buten-1-ones of 4,4,4-trifluoro-2-aryl-1-phenyl-2-buten-1-ones (107) in (good107) inyields. good Aryldiazonium yields. Aryldiazonium salts bearing salts electron-donatingbearing electron-donating groups or groups halogens or halogens on the phen on theyl phenylrings reacted rings reacted nicely under nicely the under Heck-type the Heck-type cross- couplingcross-coupling conditions, conditions, preferentially preferentially forming forming the theZ-isomersZ-isomers of ofthe the products products ( (ZZ--107107).). However, However, substrates with electron-withdrawing groups or bu bulkylky groups on the aryldiazonium moieties didn’t give the the satisfactory satisfactory results. results. The The Michael Michael addition addition adducts adducts (108 ()108 were) were formed formed as byproducts as byproducts in most in casesmost [77]. cases Later, [77]. the Later, same theresearch same group research extended group the extended scope of the the scopeheck reaction of the heckto other reaction types of to fluorine-containingother types of fluorine-containing electron-deficient electron-deficient olefins (Scheme olefins 21) (Scheme[78]. They 21 )[found78]. They that foundthe electron- that the withdrawingelectron-withdrawing group (EWG) group on (EWG) alkenes on alkeneshad a big had influence a big influence on the onefficacy the efficacy of the of reaction. the reaction. α,β- Unsaturatedα,β-Unsaturated ester ester reacted reacted with with phenyldiazonium phenyldiazonium salt salt to toprovide provide the the corresponding corresponding adduct adduct in in very very low yield. Vinylphosphonate Vinylphosphonate and and vi vinylsulfonenylsulfone were were found to be unre unreactive,active, with only the starting materials beingbeing recovered.recovered. In In the the case case of of nitroalkene, nitroalkene, neither neither the the starting starting material material nor thenor desired the desired Heck Heckadduct adduct was detected, was detected, and the and reaction the reaction became verybecame complicated. very complicated. Additionally, Addi changingtionally, the changing fluoroalkyl the fluoroalkyl group from CF3 to CF2H group caused a significant decrease in the chemical yield, group from CF3 to CF2H group caused a significant decrease in the chemical yield, although the althoughrelatively the high relatively regioselectivity high regioselectivity was obtained. was A plausibleobtained. reactionA plausible mechanism reaction was mechanism suggested was in suggestedScheme 21 [in78 ].Scheme The reaction 21 [78]. presumably The reaction proceeded presumably via (1) proceeded oxidative additionvia (1) oxidative of aryldiazonium addition salt of (aryldiazonium106) to Pd(0), leadingsalt (106 to) to an Pd(0), arylpalladium leading to complex an arylpalladium (110), (2) coordinationcomplex (110), of (2) the coordination electron-deficient of the electron-deficientolefin (105) to the olefin metal ( center105) to of the110 metaland center subsequent of 110 insertionand subsequent into the insertion Ar-Pd bond into the to generate Ar-Pd bond112 toother generate than 113 112, (3)other carbon-carbon than 113, (3) bond carbon-carbon rotation of bond112 to rotation produce of intermediate 112 to produce114 ,intermediate and (4) reductive 114, and (4) reductive elimination of [HPd]BF4 from 114 to finally afford tri-substituted alkene (107) and elimination of [HPd]BF4 from 114 to finally afford tri-substituted alkene (107) and to regenerate the toPd(0) regenerate catalyst. the Pd(0) catalyst.

Scheme 21.21. TheThe Heck-type Heck-type reactions reactions of of fluorine-con fluorine-containingtaining electron-deficient electron-deficient olefins olefins with aryldiazonium salts.

Arylboronic acidsacids areare anan importantimportant class class of of compounds compounds for for coupling coupling reactions, reactions, which which are are stable stable in inair air and and to to moisture, moisture, and and they they are are compatible compatible with with a broad a broad range range of commonof common functional functional groups groups [62 –[62–64]. 64].In 2015, In 2015, Lu Lu and and co-workers co-workers presented presented the the first first oxidative oxidative Heck-type Heck-type reactions reactions ofof arylboronicarylboronic acids with fluoroalkylatedfluoroalkylated olefinolefin [[79].79]. The Pd-catalyzed cross-couplings of the commercially available 2,3,3,3-tetrafluoroprop-1-ene2,3,3,3-tetrafluoroprop-1-ene (116 (116) )with with diverse diverse arylboronic arylboronic acids acids (115 ()115 provided) provided a variety a variety of (Z)- ofβ- fluoro-β-(trifluoromethyl)styrene derivatives (117) in good yields (Scheme 22) [79]. The wide range

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Catalysts 2018, 8, 23 14 of 35 (Z)-β-fluoro-β-(trifluoromethyl)styrene derivatives (117) in good yields (Scheme 22)[79]. The wide rangeof substrates of substrates and the and good the goodfunctional functional group group toleranc tolerancee made made this strategy this strategy facile facile and andpractical practical for the for thestreamlined streamlined synthesis synthesis of functional of functional styrenes. styrenes.

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

Furthermore, Pd-catalyzed Heck-type cyclization of 2-trifluoromethyl-1-alkenes2-trifluoromethyl-1-alkenes (118) bearingbearing an O-acyloxime moiety was accomplished (Scheme 23))[ [45,80].45,80]. The reaction represented a rare example of of 5-endo 5-endo mode mode alkene alkene insertion insertion into into tran transition-metalsition-metal species species via ox viaidative oxidative addition addition of the ofN-O the bond N–O (119 bond). Although (119). there Although were two there possible were pathways, two possible namely pathways, β-fluorine namely eliminationβ-fluorine and β- eliminationhydrogen elimination and β-hydrogen of 120 after elimination ring formation, of 120 after the former ring formation, exclusively the took former place exclusively to form an tookexo- placedifluoromethylene to form an exo-difluoromethyleneunit. This catalytic process unit. pr Thisovided catalytic facile processaccess to provided 4-difluoromethylene-1- facile access to pyrrolines (121). To elucidate the role of the CF3 group, the reaction of analogues (118′) bearing a 4-difluoromethylene-1-pyrrolinespyrrolines (121). To elucidate the (121 role). Toof elucidatethe CF group, the role the of thereaction CF3 group, of analogues the reaction (118 of′) analoguesbearing a hydrogen0 atom or a methyl group instead of the CF3 functionality on the alkene fragment was (hydrogen118 ) bearing atom a hydrogenor a methyl atom group or ainstead methyl of group the CF instead functionality of the CF 3onfunctionality the alkene fragment on the alkene was fragmentexamined. was When examined. 118′ was When subjected1180 was to the subjected reaction to conditions the reaction similar conditions to those similar for 118 to those, no cyclized for 118, product was obtained. The results indicated that the CF3 group played a crucial role in the 5-endo noproduct cyclized was product obtained. was The obtained. results The indicated results that indicated the CF that group the CF played3 group a playedcrucial arole crucial in the role 5-endo in the 5-endoHeck-type Heck-type cyclization, cyclization, wherein wherein the trifluoromethy the trifluoromethyll substituent substituent seemed seemed to toactivate activate the the vinylic terminal carbon in 118 and stabilize the cyclized palladiumpalladium intermediateintermediate 120120..

Scheme 23. Pd-catalyzed Heck-type cyclization of 2-(trifluoromethyl)allyl 2-(trifluoromethyl)allyl ketone oximes.

2.4. Other Fluorine-Containing Alkenes as the Cross-Coupling Reagents A series of of fluorinated fluorinated distyrylbenzene distyrylbenzene (DSB) (DSB) derivatives derivatives (124 (124 andand 126126) were) were synthesized synthesized by Pd- by Pd-catalyzedcatalyzed Mizoroki-Heck Mizoroki-Heck cross-couplings cross-couplings (Scheme (Scheme 24) [81]. 24)[ The81]. reaction The reaction of 1,4-diiodobenzene of 1,4-diiodobenzene (122a) (with122a pentafluorostyrene) with pentafluorostyrene (123) or (4-fluorostyrene123) or 4-fluorostyrene (125b) in (the125b presence) in the of presence Pd(OAc) of2 gave Pd(OAc) trans2-trans-gave trans1,4-bis(pentafluorostyryl)benzene-trans-1,4-bis(pentafluorostyryl)benzene (124a) or (124atrans) or-transtrans-bis(4-fluorostyryl)benzene-trans-bis(4-fluorostyryl)benzene (126a). ( 126aThe). Thecoupling coupling of 1,4-dibromo-2,5-difluorobenzene of 1,4-dibromo-2,5-difluorobenzene (122b (122b) with) with styrene styrene (125a (125a), 4-fluorostyrene), 4-fluorostyrene (125b (125b), or), orpentafluorostyrene pentafluorostyrene (123 (123) using) using Pd(OAc) Pd(OAc)2 provided2 provided 1,4-bis(styryl)-2,5-difluorobenzene 1,4-bis(styryl)-2,5-difluorobenzene (126b (126b), 1,4-), 1,4-bis(4-fluorostyryl)-2,5-difluorobenzenebis(4-fluorostyryl)-2,5-difluorobenzene (126c (126c), ),and and 1,4-bis-(pentafluorostyryl)-2,5-difluorobenzene 1,4-bis-(pentafluorostyryl)-2,5-difluorobenzene (124b), respectively.respectively. TheThe productsproducts werewere employedemployed to probeprobe the effect of fluorinefluorine substitution on the molecular properties and on the arrangementarrangement of moleculesmolecules inin thethe solidsolid statestate [[81].81]. TheThe absorptionabsorption 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

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Catalysts 2018, 8, 23 15 of 35 Catalystsspectroscopy 2018, 8, 23 showed that 124 and 126 had a λmax at approximately 350 nm, and addition15 of of35 dimethylaniline to the hexane solutions led to exciplex emission with λmax ranging from 458 to 514 nm, nm, depending on the positions of fluorine substitution. Moreover, the X-ray diffraction experiments nm,depending depending on the on positionsthe positions of fluorine of fluorine substitution. substitution. Moreover, Moreover, the the X-ray X-ray diffraction diffraction experiments experiments for for the lattice properties of 124a, 124b, 126b, and 126c indicated two possible structural motifs. One forthe the lattice lattice properties properties of 124a of 124a, 124b, 124b, 126b, 126b, and, and126c 126cindicated indicated two two possible possible structural structural motifs. motifs. One One is to is to stack the DSB framework cofacially to form vertical “columns” within the crystal. The other is isstack to stack the DSB the DSB framework framework cofacially cofacially to form to form vertical vertical “columns” “columns” within within the crystal.the crystal. The The other other is the is the alignment of these “columns” to maximize C–H···F electrostatic registry. thealignment alignment of these of these “columns” “columns” to maximize to maximize C–H C–H···F··· electrostaticF electrostatic registry. registry.

SchemeScheme 24. 24. SynthesisSynthesis of of fluorinated fluorinated distyrylbenzene distyrylbenzene chromophores by Heck-type reactions.

In addition, ligand-free Pd-catalyzed Mizoroki-Heck alkenylation of iodoarenes (127) with In addition, addition, ligand-free ligand-free Pd-catalyzed Pd-catalyzed Mizoroki-Heck Mizoroki-Heck alkenylation alkenylation of iodoarenes of iodoarenes (127) with (127) trifluoroethyl 2-acetoxyacrylate (128) was explored, which stereoselectively produced trifluoroethyl trifluoroethylwith trifluoroethyl 2-acetoxyacrylate 2-acetoxyacrylate (128) was (128 explored,) was which explored, stereoselectively which stereoselectively produced trifluoroethyl produced (Z)-2-acetoxycinnamates (129) in good yields (Scheme 25) [82]. Compounds 129 underwent (trifluoroethylZ)-2-acetoxycinnamates (Z)-2-acetoxycinnamates (129) in good (129yields) in (Scheme good yields 25) (Scheme[82]. Compounds 25)[82]. Compounds129 underwent129 deacetylation followed by acylation to yield isomerically pure trifluoro-ethyl (Z)-2- deacetylationunderwent deacetylation followed by followed acylation by acylationto yield toisomerically yield isomerically pure trifluoro-ethyl pure trifluoro-ethyl (Z)-2- (arylacetoxy)cinnamates. t-BuOK-Mediated Dieckmann condensations of these products furnished a (arylacetoxy)cinnamates.(Z)-2-(arylacetoxy)cinnamates. t-BuOK-Mediatedt-BuOK-Mediated Dieckmann Dieckmann condensations condensations of these products of these furnished products a variety of pulvinone derivatives. varietyfurnished of pulvinone a variety of derivatives. pulvinone derivatives.

Scheme 25. Pd-catalyzed Mizoroki-Heck reactions of iodoarenes with trifluoroethyl 2-acetoxyacrylate. Scheme 25. Pd-catalyzed Mizoroki-Heck reactions of iodoarenes with trifluoroethyl 2- acetoxyacrylate. The D-A-D-type chromophores (132) with a hexafluorocyclopentene thiophene “core” flanked by triphenylamineThe D-A-D-type units chromophores were synthesized (132) with bya hexafluorocyclopentene facile procedures, including thiophene the “core” Pd-catalyzed flanked byMizoroki-Heck triphenylamine reactions units were (Scheme synt hesized26)[83]. by The facile triphenylamine procedures, groupincluding caused the Pd-catalyzed the open-ring Mizoroki- isomer of Heckhexafluorocylopentene reactions (Scheme thiophene 26) [83]. to The close, triphenyla which resultedmine ingroup intramolecular caused thep-conjugation open-ring isomer extension, of hexafluorocylopentenethus broadening the absorption thiophene spectra to clos ranginge, which from resulted 200 toin 850intramolecular nm with high p-conjugation optical densities. extension, thus broadening the absorption spectra ranging from 200 to 850 nm with high optical densities.

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Scheme 26. Synthesis of triphenylamine derivatives with a hexafluorocyclopentene unit via the Pd- Scheme 26. SynthesisSynthesis of of triphenylamine triphenylamine derivatives derivatives with with a hexafluorocy a hexafluorocyclopenteneclopentene unit unit via the via Pd- the catalyzed Mizoroki-Heck cross-couplings. catalyzedPd-catalyzed Mizoroki-Heck Mizoroki-Heck cross-couplings. cross-couplings.

3. Mizoroki-Heck Reactions of Fluorinated Halides or Pseudo-Halides with Alkenes

3.1. 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-poor olefinsolefins ((134)) withwith 4-(perfluorooctyl)benzenediazonium4-(perfluorooctyl)benzenediazonium trifluoroacetate trifluoroacetate ( (133133)) (Scheme (Scheme 27)27)[ [84].84]. This Heck-type reaction supplied a variety of perfluoroalkylated perfluoroalkylated aromatic compounds (135) by using Pd(OAc)2 oror 4-hydroxyacetophenone ox oxime-derivedime-derived palladacycle palladacycle ( (136136)) as as an an efficient efficient source source of Pd Pd(OAc)2 or 4-hydroxyacetophenone oxime-derived palladacycle (136) as an efficient source of Pd nanoparticles. Ligand-free Ligand-free Pd(OAc) 2 appearedappeared to to be be a a more more general catalyst than palladacycle ( 136136)) nanoparticles. Ligand-free Pd(OAc)22 appeared to be a more general catalyst than palladacycle (136) for the reaction. The activity of 136 depended greatly on the nature of the alkenealkene used.used. No external base was necessary necessary for for the the conversion, conversion, and and the the reacti reactionsons could could be be carried carried out out at atroom room temperature temperature in thein the presence presence of of1 mol% 1 mol% of ofPd(II) Pd(II) catalyst. catalyst. Some Some intermediates intermediates derived derived from from the the oxidative oxidative addition addition of 133of 133 to tothe the catalyst catalyst were were identified identified by by ESI-MS ESI-MS ex experiments.periments. The The Pd(IV) Pd(IV) species species detected detected by by this technique whenwhen 136136 waswas used,used,did did not not seem seem to to act act as as intermediates intermediates of of the the reaction. reaction. The The TEM TEM images images of ofthe the reaction reaction solutions solutions showed, showed, for for the the first first time, time, the the formation formation of of nanoparticlesnanoparticles withwith bothboth catalysts under the Matsuda-Heck conditions. These These Pd(0) Pd(0) na nanoparticlesnoparticles might might act act as as a a reservoir reservoir of of Pd(0) atoms involved in the reaction, which avoided the pr precipitationecipitation of black palladium and thus thus probably probably extended the lifetime of the catalyst.

Scheme 27. The Heck-type reactions of alkenes with arenediazonium trifluoroacetate. Scheme 27. TheThe Heck-type Heck-type reactions of alkenes wi withth arenediazonium trifluoroacetate.trifluoroacetate.

A series of SF5-bearing alkenes (139, 141, and 142) were synthesized by employing the Matsuda- A series of SF5-bearing alkenes (139, 141, and 142) were synthesized by employing the Matsuda- Heck reactions of 4-(pentafluorosulfanyl)benzenediazonium tetrafluoroborate (137) with alkenes Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 17 of 35

CatalystsA 2018 series, 8, 23 of SF5-bearing alkenes (139, 141, and 142) were synthesized by employing17 of the 35 Matsuda-Heck reactions of 4-(pentafluorosulfanyl)benzenediazonium tetrafluoroborate (137) with alkenes(138 and ( 138140)and (Scheme140) (Scheme28) [85]. Compound28)[85]. Compound 137 was readily137 was synthesized readily synthesized and isolated and as a isolated stable salt as afor stable a wide salt assortment for a wide of assortmenttransformations. of transformations. The cross-couplings The of cross-couplings 137 with styrene of and137 4-substitutedwith styrene andstyrenes 4-substituted in the presence styrenes of incatalytic the presence Pd(OAc) of catalytic2 in ethanol Pd(OAc) gave 2thein ethanolcorresponding gave the 4′ corresponding-substituted 4- 0 4(pentafluorosulfan-yl)stilbenes-substituted 4-(pentafluorosulfan-yl)stilbenes in good yields. The in reaction good yields. run in Theionic reaction liquid [BMIM][BF run in ionic4] instead liquid [BMIM][BFof EtOH resulted4] instead in lower of EtOH isolated resulted yield indue lower to the isolated increased yield formation due to theof homo-coupling increased formation product. of homo-couplingReaction of 137 with product. methyl Reaction acrylate of in137 thewith presence methyl of Pd(OAc) acrylate2 inin the95% presence EtOH afforded of Pd(OAc)2 methyl in trans 95%- EtOH3-[4-(pentafluorosulfanyl)phenyl]prop-2-enoate afforded methyl trans-3-[4-(pentafluorosulfanyl)phenyl]prop-2-enoate in 85% yield without cis-isomer. in However, 85% yield coupling without cisof -isomer.137 with However, methyl methacrylate coupling of 137(140 with) in 95% methyl EtOH methacrylate or [BMIM][BF (140)4] in gave 95% a EtOH mixture or [BMIM][BF4]of methyl 2- gavemethyl-3-[4-(pentafluorosulfanyl)phenyl]prop-2-enoate a mixture of methyl 2-methyl-3-[4-(pentafluorosulfanyl)phenyl]prop-2-enoate (141) and methyl (141) and methyl2-{[4- 2-{[4-(pentafluorosulfanyl)phenyl]methyl}prop-2-enoate(pentafluorosulfanyl)phenyl]methyl}prop-2-enoate (142) (142in )up in upto to99% 99% yield. yield. Furthermore, Furthermore, 137 enabled couplings couplings with with fluorous fluorous olefins olefins to form to form the thecorresponding corresponding fluorinated fluorinated adducts adducts in good in yields good yields[85]. Unfortunately, [85]. Unfortunately, the Matsuda-Heck the Matsuda-Heck reaction reaction of 137 with of 137 ethylwith cinnamate ethyl cinnamate or norbornene or norbornene in EtOH, in ◦ EtOH,MeOH, MeOH, or [BMIM][BF or [BMIM][BF4] at room4] at temperature room temperature or 70 °C or failed 70 C to failed give tothe give desired the desired product product [85]. [85].

Scheme 28. The Heck-type reactions of 4-(pentafluorosu 4-(pentafluorosulfanyl)benzenediazoniumlfanyl)benzenediazonium tetrafluoroborate.tetrafluoroborate.

An efficientefficient catalytic system for the Mizoroki-HeckMizoroki-Heck reactions of fluoroarylfluoroaryl halides (143) with alkenes ( (144144)) was was developed developed (Scheme (Scheme 29) 29 [86].)[86 Complex]. Complex 145 (1145 mol%)(1 mol%) catalyzed catalyzed the reaction the reaction of C6F5Br of ◦ F F 6 5 Cand6F5 Brstyrene and styrene at 130 at °C 130 to Cgive to give regioselectively regioselectively transtrans-PhCH=CHAr-PhCH=CHAr (F146a(146a, Ar, Ar F== C CF6F)5 )in in almost 3 2 3 quantitative yield.yield. TheThe studies studies indicated indicated that that CaCO CaCO3, KF,, KF, and and Na 2NaCOCO3 were were the the suitable suitable bases, bases, and thatand 3 4 NMPthat NMP was thewas best the solventbest solvent for the for reaction. the reaction. [Pd(PPh [Pd(PPh3)4] failed) ] failed to initiate to initiate the reaction the reaction of styrene of styrene with 6 5 6 5 Cwith6F5 Br.C F IfBr. C 6IfF 5CIF wasI was employed employed as as a substratea substrate under under the the optimized optimized conditions, conditions, muchmuch lowerlower yield F 6 5 of trans-PhCH=CHAr-PhCH=CHArF waswas obtained. obtained. C CF6ClF5 Cldidn’t didn’t react react with with styrene styrene under under the same the same conditions. conditions. The 6 4 3 Thereaction reaction was wasalso alsoefficient efficient for other for other fluorinated fluorinated aryl bromides aryl bromides such suchas p-XC as pF-XCBr 6(XF4 =Br CN, (X =CF CN,, OMe) CF3, 6 4 OMe)and p-FC andHp-FCBr [86].6H4 BrFor [86 an]. activated For an activated alkene, such alkene, as meth suchyl as acrylate, methyl acrylate,the reaction the proceeded reaction proceeded fast even fastat 100 even °C, and at 100 in this◦C, case, and inuse this of KF case, as a use base of led KF to as higher a base conversion. led to higher 1-Hexene conversion. and α-methylstyrene 1-Hexene and αcould-methylstyrene also be functionalized. could also be Electron-rich functionalized. alkene Electron-richs such as butylvinyl alkenes such ether as and butylvinyl 2,3-dihydrofuran ether and 2,3-dihydrofurangave very low yields gave of verythe desi lowred yields products. of the The desired reaction products. with styrene The reaction was not with affected styrene by wasoxygen not affectedor galvinoxyl, by oxygen which or excluded galvinoxyl, a radical which addition excluded pathway a radical [86]. addition pathway [86]. 3 Moreover, complex 145 in CDClCDCl3 afforded immediately a 1: 1:1.61.6 mixture of two isomers 6 5 corresponding to to the the ciscis andand transtrans arrangementsarrangements of of the the two two C CF 6 Fgroups5 groups in the in thedimer dimer [86]. [ 86If ].145 If was145 wasdissolved dissolved in NMP in NMP at room at room temperature temperature and and at atlow low concentrations, concentrations, 148148 waswas observed observed as as the the main species, determined by 1919F NMR spectroscopy. Upon addition of Br− anionanion to to 148148,, 149 was also detected. The equilibrium constants constants between between 145145,, 148148,, and and 149 in NMP at roomroom temperaturetemperature couldcould be measured. measured. At At higher higher temperatures temperatures (e.g., (e.g., 120 120 °C),◦C), the theequilibria equilibria became became fast, fast,and the and signals the signals of these of complexes collapsed. When the reaction of C6F5Br and styrene was monitored by 19F 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-

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19 these complexes collapsed. When the reaction of C6F5Br and styrene was monitored by 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 Catalysts 2018, 8, 23 18 of 35 cycle is the coordination and insertion of the alkene by 145, generating 151. This step is likely to be rate-determining,determining, which which is supported is supported by the by observatio the observationn of the of signals the signals of the of complexes the complexes preceding preceding this thisstep step and and by the by thefact fact that that the thereaction reaction rate rate of C of6F C5Br6F and5Br andstyrene styrene was wassimply simply dependent dependent upon upon the theconcentration concentration of styrene. of styrene. Then, Then, β-H βelimination-H elimination of 151 of followed151 followed by reductive by reductive elimination elimination of HX offrom HX from153 provides153 provides 146 and146 regeneratesand regenerates Pd(0) Pd(0) species species (147), ( 147which), which is stabilized is stabilized by bromide by bromide anions. anions. The Thereaction reaction outside outside the thecatalytic catalytic cycle cycle showed showed thatthat the insertion the insertion of styrene of styrene into intothe Pd-C the Pd-C6F5 bond6F5 bond of 148 of 148waswas retarded retarded by byaddition addition of ofNBu NBu4Br.4Br. If Ifthe the catalytic catalytic reaction reaction wa wass carried carried out out under under bromide-free bromide-free conditions,conditions, onlyonly 3%3% of 146a was obtained obtained and and the the catalyst catalyst extensively extensively decomposed. decomposed. In addition In addition to tostabilizing stabilizing the the Pd(0) Pd(0) intermediate, intermediate, the bromides the bromides migh mightt increase increase the rate the of rateoxidative of oxidative addition. addition. Excess Excessstyrene styrene increased increased the reaction the reactionrate by facilitating rate by facilitating the coordination-insertion the coordination-insertion process, but process,a large excess but a largeof styrene excess stopped of styrene the reaction. stopped Addition the reaction. of NBu Addition4Br to the latter of NBu reaction4Br to mi thexture latter could reaction reactivate mixture the couldprocess. reactivate It seemed the that process. displacement It seemed of bromides that displacement on Pd(0) by of alkene bromides at high on Pd(0) concentration by alkene severely at high concentrationslowed the oxidative severely addition, slowed thewhich oxidative became addition, rate-determining which became instead rate-determining of the coordination-insertion instead of the coordination-insertionstep [86,87]. Thus, the success step [86 of,87 this]. Thus, catalysis the successrequired of a this compromise catalysis requiredbetween the a compromise optimal conditions between thefor optimal the oxidative conditions addition for theand oxidative the coordination-insertion. addition and the coordination-insertion.

SchemeScheme 29.29. TheThe Mizoroki-HeckMizoroki-Heck reactions of fluoroaryl fluoroaryl halides with with alkenes. alkenes.

In 2010, Zhang and co-workers reported the first Pd(OAc)2-catalyzed oxidative Heck-type In 2010, Zhang and co-workers reported the first Pd(OAc)2-catalyzed oxidative Heck-type reactionsreactions of the the electron-deficient electron-deficient pentafluoroarene pentafluoroarene (154 ()154 with) witha broad a range broad of range alkenes of (155 alkenes) (Scheme (155 ) (Scheme30) [88]. 30The)[88 reactions]. The reactions provided provided a great variet a greaty of variety pentafluorophenyl of pentafluorophenyl substituted substituted alkenes (156 alkenes) in moderate to high yields and with moderate to high stereo- and regioselectivities. A survey of reaction (156) in moderate to high yields and with moderate to high stereo- and regioselectivities. A survey of conditions indicated that the solvent, oxidants, and Pd-catalysts were critical for the reaction 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 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 medium. The reaction using Ag CO as both the base and oxidant in the presence of Pd(OAc) mol%) at 120 °C gave the best yield2 of3 the desired product. Electron-deficient olefins bearing ester,2 (10 mol%) at 120 ◦C gave the best yield of the desired product. Electron-deficient olefins bearing 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,

Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 19 of 35 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 alkenylatedCatalysts 20182018 products,, 88,, 2323 (159) in moderate yields with moderate to good regioselectivities. In1919 general, ofof 3535 the reactions with electron-rich alkenes afforded higher yields than those with electron-deficient ones. thethe reactionsreactions withwith electron-richelectron-rich alkenesalkenes affordedafforded hihigher yields than those with electron-deficient The most acidic C–H bonds located between two fluorine atoms were the primary reaction sites, ones. The most acidic C-H bonds located between two fluorinefluorine atomsatoms werewere thethe primaryprimary reactionreaction sites,sites, whichwhich provided provided mostly mostly the the monoalkenylated monoalkenylated productsproducts in in higherhigher yields.yields. yields. ItItIt waswas was alsoalso also possiblepossible possible toto furtherfurther to further derivatizederivatize the the polyfluoroarylated polyfluoroarylated alkenes alkenes throughthrough C–H functionalization. functionalization. This This strategy strategy allowed allowed the the selectiveselectiveselective installation installationinstallation of ofof substituents substituentssubstituents at atat different differentdifferent positions and and provided provided a aconvenient convenient access access to highly to highly functionalizedfunctionalizedfunctionalized fluoroarenes fluoroarenesfluoroarenes by byby catalytic catalyticcatalytic methods. methods.methods.

Scheme 30. Pd(OAc)Pd(OAc)22-catalyzed-catalyzed oxidativeoxidative olefinationolefination ofof highlyhighly electron-deficientelectron-deficient fluoroarenesfluoroarenes withwith Scheme 30. Pd(OAc)2-catalyzed oxidative olefination of highly electron-deficient fluoroarenes withalkenes.alkenes. alkenes.

Later, Zhang’s research group again disclosed thethe thioether-promotedthioether-promoted directdirect olefinationolefination ofof Later, Zhang’s research group again disclosed the thioether-promoted direct olefination of polyfluoroarenes (161)) withwith alkenesalkenes ((162)) catalyzedcatalyzed byby Pd(OAc)Pd(OAc)22 (Scheme(Scheme 31)31) [89].[89]. Remarkably,Remarkably, thethe polyfluoroarenes“inert” substrates, (161 such) with as alkenes3-substituted (162) tetrafluorobenzenes, catalyzed by Pd(OAc) wh2ichich(Scheme previouslypreviously 31)[ furnishedfurnished89]. Remarkably, theirtheir thecorrespondingcorresponding “inert” substrates, productsproducts such inin as lowlow 3-substituted yields,yields, affordedafforded tetrafluorobenzenes, thethe alkenylatedalkenylated productsproducts which previously((163)) inin highhigh furnished yieldsyields andand their correspondingwith excellent products stereoselectivities in low yields, using afforded only the1.0 alkenylatedequiv of alkene products in this (163 )reaction. in high yieldsThe results and with excellentdemonstrated stereoselectivities the power using of the only thioether 1.0 equiv ligand of alkene PhSMe in this in reaction. the Pd-catalyzed The results reactions demonstrated of thepolyfluoroarenes, power of the thioether offering ligand a new PhSMe choice into discover the Pd-catalyzed moremore efficientefficient reactions catalyticcatalytic of polyfluoroarenes, systems.systems. Furthermore,Furthermore, offering aa a newcompetitivecompetitive choice to discoverreactionreaction betweenbetween more efficient electron-deficientelectron-deficient catalytic systems. anand electron-rich Furthermore, alkenes a competitive with pentafluorobenzene reaction between electron-deficientwas conducted, andwhich electron-rich provided their alkenes corresponding with pentafluorobenzene products in an almost was conducted, 1:1 ratio, suggesting which provided that theirthethe correspondingdirectdirect olefinationolefination products ofof polyfluoroarenespolyfluoroarenes in an almost hashas nono 1:1 bibi ratio,as on the suggesting nature of thatalkenes the under direct these olefination reaction of polyfluoroarenesconditionsconditions [89].[89]. has no bias on the nature of alkenes under these reaction conditions [89].

F F Pd(OAc) (10(10 mol%)mol%) R11 H 22 R11 R Ag22CO33 (2.0(2.0 equiv)equiv) + R 22 PhSCH (2.8(2.8 equiv)equiv) R F 33 R22 F 162 oo 33 DMF, 120 C, 9 h R R33 161 163 up to 94% yield R11 = R22 = R33 = F E/Z-isomers in most cases R11 = R33 = H; R22 = F 11 33 22 R = R = F; R = H, OMe, Me, Ar, CH22Ar

SchemeScheme 31. 31.Thioether-promoted Thioether-promoted directdirect olefinationolefination of of polyfluoroarenes polyfluoroarenes catalyzed catalyzed by by palladium. palladium.

By a similar strategy, a series of olefin-containing fluorinated benzothiadiazoles were synthesizedsynthesized fromfrom fluorinatedfluorinated benzothiadiazobenzothiadiazolesles inin thethe presencepresence ofof 2.52.5 mol%mol% Pd(TFA)Pd(TFA)22,, 3.03.0 equivequiv AgOAc, 2.5 equiv PhCO22H, and 0.1 equiv benzoquinone [90]. The reactions proceeded under mild conditionsconditions andand showedshowed goodgood functionalfunctional groupgroup compatibility.compatibility. TheThe productsproducts foundfound importantimportant

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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 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)Catalysts salt, providing 2018, 8, 23 a cost-efficient and environment-benign access to polyfluoroarene-alkenes.20 of 35 The silver species and the thioether ligand played important roles in the reactions, but the mechanisms Catalystsapplications 2018, 8 , in23 optoelectronic materials. Significantly, the Pd-catalyzed aerobic direct olefination20 of of 35 remained unclear. polyfluoroarenes was also explored [91]. The procedure made use of molecular O2 as the terminal Inapplications addition,oxidant instead in Liu optoelectronic of and silver(I) co-workers salt,materials. providing investigatedSignifican a cotly,st-efficient the the Pd-catalyzed Pd(II)-catalyzedand environment-benign aerobic direct direct olefination access olefination to of of electron-deficientpolyfluoroarenespolyfluoroarene-alkenes. fluoroarenes was also The explored (164 silver) with species[91]. allylicThe and procedure the esters thioether made and ligand ethersuse of played molecular (165 )important (Scheme O2 as theroles 32 terminal)[ in 92the]. In this transformation,oxidantreactions, instead variousbut the ofmechanisms γsilver(I)-substituted salt, remained providing allylic unclear. esters a cost-efficient (mixtures and of E/Zenvironment-benign- and B-isomers access (166 andto 1660)) were preparedpolyfluoroarene-alkenes.In addition, in good Liu to excellent and Theco-workers silver yields species investigated by oxidative and the the thioether Pd(II)-catalyzed Heck reactions ligand playeddirect via βolefination important-H elimination, ofroles electron- in ratherthe than reactions,deficient butfluoroarenes the mechanisms (164) remainedwith allylic unclear. esters and ethers (165) (Scheme 32) [92]. In this β-OAc elimination. Typically, the desired products were obtained in good yields under conditions transformation,In addition, various Liu and γ co-workers-substituted investigated allylic esters the (mixtures Pd(II)-catalyzed of E/Z- and direct B-isomers olefination (166 of and electron- 166′)) ◦ composeddeficientwere of prepared Pd(OAc) fluoroarenes in2 good(5 mol%), (to164 excellent) AgOAcwith yieldsallylic (2.0 byesters equiv),oxidative and DMSO Heckethers reactions(5%)/THF, (165) (Schemevia β-H 110 elimination,32)C, and[92]. 12 Inrather h.this A variety of fluorinatedtransformation,than β-OAc arenes elimination. various proved γ -substituted toTypically, be very the allylic efficient desired esters substratesproducts (mixtures were of under E/Z obtained- and the B -isomers typicalin good ( conditions,166yields and under 166′)) and the olefinationwereconditions generally prepared composed in took good of place toPd(OAc) excellent at the2 (5 yields moremol%), by sterically AgOAc oxidative (2.0 accessible Heckequiv), reactions DMSO position. (5%)/THF, via β-H This elimination, 110 selectivity °C, and rather 12 h. might be attributedthanA tovariety β the-OAc acidityof fluorinatedelimination. of C–H arenes Typically, bonds proved of the theto desiredbe fluorinated very productsefficient arenes substrates were evenobtained unde thoughr thein goodtypical it was yields conditions, located under at a more conditionsand the olefination composed generally of Pd(OAc) took2 (5 place mol%), at theAgOAc more (2.0 sterically equiv), accessibleDMSO (5%)/THF, position. 110 This °C, selectivity and 12 h. sterically hindered position. Tetrafluorobenzene and fluorinated arenes bearing an electron-donating Amight variety be attributedof fluorinated to the arenes acidity proved of C-H to bonds be very of the efficient fluorinated substrates arenes unde evenr thethough typical it was conditions, located methoxyandat group a themore olefination could sterically also generally hindered give thetook position. desiredplace atTetrafluorobenzene the products. more sterically Yields and accessible of fluorinated the productsposition. arenes This decreased bearing selectivity an with the decreasemightelectron-donating in the be number attributed ofmethoxy to fluorine the acidity group atoms of couldC-H substituted bonds also giveof the onthe fluorinated thedesired aromatic products.arenes rings. even Yields though Significantly, of itthe was products located allyl acrylate and allylatdecreased methacrylate a more withsterically the afforded decrease hindered the in correspondingposition.the number Tetrafluorobenzene of fl productsuorine atoms in and moderatesubstituted fluorinated toon good thearenes aromatic yields. bearing Therings. an oxidative olefinationelectron-donatingSignificantly, occurred allyl at the methoxyacrylate allylic and group rather allyl could methacrylate than also the give acrylic afforded the carbon–carbondesired the corresponding products.double Yields products of bond. thein moderate products This selectivity decreasedto good yields. with Thethe oxidativedecrease olefinationin the number occurred of fl atuorine the allylic atoms rather substituted than the on acrylic the aromaticcarbon–carbon rings. might be ascribed to the stability of the alkyl-Pd intermediate via chelation of Pd center by the carbonyl Significantly,double bond. allyl This acrylate selectivity and mightallyl methacrylate be ascribed affordedto the stability the corresponding of the alkyl-Pd products intermediate in moderate via O-atom.tochelation This good chelation yields. of Pd The center effectoxidative by couldthe olefination carbonyl also result Ooccurred-atom. in This at the the chelation high allylic regioselectivity rather effect than could the also acrylic as result the carbon–carbon (Pd)C–C(O)in the high bond cannot rotatedoubleregioselectivity freely. bond. This as the selectivity (Pd)C–C(O) might bond be cannotascribed rotate to thefreely 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.

SchemeScheme 32. The 32. Pd-catalyzedThe Pd-catalyzed oxidative oxidative olefinationolefination of offluoroarenes fluoroarenes with withallyl esters. allyl esters.

S-fluoroalkyl diphenylsulfonium triflates [Ph2SRfn][OTf] (168, Rfn = CF3, CH2CF3) were effective Scheme 32. The Pd-catalyzed oxidative olefination of fluoroarenes with allyl esters. S-fluoroalkylcross-coupling diphenylsulfonium partners in the Pd-catalyzed triflates Mizo [Phroki-Heck-type2SRfn][OTf] reactions (168,R withfn alkenes= CF (Scheme3, CH2 33)CF 3) were effective[93]. cross-coupling SThe-fluoroalkyl functionalization diphenylsulfonium partners of invarious the triflates Pd-catalyzedconjugated [Ph2 SRandfn][OTf] Mizoroki-Heck-typeunconjugated (168, Rfn =alkenes CF3, CH (1672CF reactions)3 ) bywere 168 effective in with the alkenes (Schemecross-couplingpresence 33)[93 of]. 10 The partners mol% functionalization Pd[P( in thet-Bu) Pd-catalyzed3]2 and ofTsOH Mizo various atroki-Heck-type room conjugated temperature reactions andprovided with unconjugated alkenesthe corresponding (Scheme alkenes 33) (167) phenylation products (169) in good to high yields. The bases that benefited the traditional Mizoroki- by 168 in[93]. the The presence functionalization of 10 mol%of various Pd[P( conjugatedt-Bu) ] andand unconjugated TsOH at room alkenes temperature (167) by 168 providedin the the Heck reactions severely inhibited this transformation,3 2 whereas the acids significantly improved the correspondingpresence phenylationof 10 mol% Pd[P( productst-Bu)3]2 and (169 TsOH) in goodat room to temperature high yields. provided The bases the corresponding that benefited the phenylationreaction. This products protocol (169 demonstrated) in good to high a new yields. clas Thes of bases cross-coupling that benefited participants the traditional for Heck-type Mizoroki- traditionalHeckreactions Mizoroki-Heck reactions [93]. severely reactionsinhibited this severely transformation, inhibited whereas this the transformation, acids significantly improved whereas the the acids significantlyreaction. improved This protocol the reaction.demonstrated This a new protocol class of demonstrated cross-coupling aparticipants new class for of Heck-type cross-coupling participantsreactions for Heck-type[93]. reactions [93].

Scheme 33. Pd-catalyzed Mizoroki-Heck reactions of [Ph2SRfn][OTf] with alkenes.

Epibatidine (exo-2-(2′-chloro-5′-pyridyl)-7-azabicyclo[2.2.1]heptane), a natural compound Scheme 33. Pd-catalyzed Mizoroki-Heck reactions of [Ph2SRfn][OTf] with alkenes. isolatedScheme from the 33. Pd-catalyzedskin of the Ecuadorian Mizoroki-Heck poison reactionsfrog Epipedobates of [Ph2SR tricolorfn][OTf], is with a potent alkenes. nicotinic Epibatidine (exo-2-(2′-chloro-5′-pyridyl)-7-azabicyclo[2.2.1]heptane), a natural compound isolatedCatalysts 2018 from, 8, 23;the doi:10.3390/catal8010023 skin of the Ecuadorian poison frog Epipedobates tricolorwww.mdpi.com/journ, is a potent al/catalystsnicotinic

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Epibatidine (exo-2-(20-chloro-50-pyridyl)-7-azabicyclo[2.2.1]heptane), a natural compound isolatedCatalysts 2018 from, 8, 23 the skin of the Ecuadorian poison frog Epipedobates tricolor, is a potent21 of 35 nicotinic acetylcholine receptor (nAChR) agonist [94]. In order to visualize and quantify theseacetylcholine receptors receptor in the (nAChR) human agonist brain [94]. using In orde positronr to visualize emission and tomography quantify these (PET) receptors technique, in the human brain0 18 using positron0 emission tomography (PET) technique, exo-2-(2′-[18F]fluoro-5′-pyridyl)- exo-2-(2human brain-[ F]fluoro-5 using positron-pyridyl)-7-azabicyclo[2.2.1]heptane, emission tomography (PET) technique, a fluorine-18 exo-2-(2 (t1/2 ′=-[ 110F]fluoro-5 min) radiolabeled′-pyridyl)- derivative7-azabicyclo[2.2.1]heptane, of epibatidine, a was fluorine-18 synthesized (t1/2 = from 110min) the radiolabeled nucleophilic deri aromaticvative substitutionof epibatidine, of was the correspondingsynthesized from 20-bromo-, the nucleophilic 20-iodo- oraromat 20-nitroic substitution exo-2-(50-pyridyl)-7-azabicy-clo[2.2.1]heptane of the corresponding 2′-bromo-, 2′ analogue-iodo- or 2′-nitro18 exo-2-(5′-pyridyl)-7-azabicy-clo[2.2.1]heptane analogue with [18F]FK-K222 [94]. In this work, with2′-nitro [ F]FK-Kexo-2-(5222′-pyridyl)-7-azabicy-clo[2.2.1]heptane[94]. In this work, norchlorofluoroepibatidine analogue with (173 )[ wasF]FK-K employed222 [94]. asIn athis reference work, compound,norchlorofluoroepibatidine which was synthesized (173) was employed by reductive as a reference and stereoselective compound, which Pd-catalyzed was synthesized Heck-type by cross-couplingreductive and stereoselective of 170 and 171 Pd-catal(Schemeyzed 34)[ Heck-type94]. cross-coupling of 170 and 171 (Scheme 34) [94].

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

The β-selective, chelation- chelation-controlledcontrolled Heck-type Heck-type reaction reaction was was found found to be a convenientconvenient andand 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 thethe spacerspacer (Scheme(Scheme 3535))[ [95]95].. Most of thethe compoundscompounds displayeddisplayed reasonable to good potencies and selectivities for mGAT1 (subtype(subtype of GABA transportertransporter originating from murine cells). The The influence influence of of the the presence and the positionposition of fluorinefluorine substituents in the bis-aromaticbis-aromatic residue concerningconcerning potencypotency and and selectivity selectivity of of the the compounds compounds was was defined. defined. In In general, general, all allZ-isomers Z-isomers of theof the synthesized synthesized compounds compounds were were more more potent potent than than their their corresponding correspondingE-isomers. E-isomers. The The influence influence of fluorineof fluorine substituents substituents on on the the GAT1 GAT1 uptake uptake inhibition inhibition was was generally generally more more severe severe forfor thethe compoundscompounds withwith twotwo aromaticaromatic ringsrings beingbeing linkedlinked byby aa methanonemethanone bridgebridge (Y(Y == O). SubstitutionSubstitution with fluorinefluorine in 4 the 4-position4-position ofof oneone arylaryl ringring (R(R44 = F) and an additional fluorinefluorine substituent at the parapara-position-position ofof 3 the otherother arylaryl ringring (R(R33 = F) was the most beneficialbeneficial combination, leading to one of the most potent compounds of the wholewhole series.series.

Scheme 35. 35. SynthesisSynthesis of fluorine-containing of fluorine-containing N-substitutedN-substituted nipecotic nipecotic acid derivatives acid derivatives by the Mizoroki- by the Mizoroki-HeckHeck reactions. reactions.

Additionally, four pyrimidine C-nucleosides (180) were built as mimics of 2′-deoxycytidine (dC) Additionally, four pyrimidine C-nucleosides (180) were built as mimics of 20-deoxycytidine (dC) and 2′-deoxyuridine (dU). The key carbon-carbon bond formation between the readily available 2,6- and 20-deoxyuridine (dU). The key carbon-carbon bond formation between the readily available substituted pyridines (178) and the glycal (177) employed palladium-catalyzed Heck-type reactions 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.

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(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 30-hydroxyl moiety precluded addition of the heterocycle from the “lower” Catalystsface of 2018 the, sugar.8, 23 Without separating the initial coupling products (179) from the starting22 glycal of 35 (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 StereospecificStereospecific reductionreduction of of the the ketones, ketones, followed followed by removal by removal of the p-ofNPE the protectingp-NPE protecting group if necessary,group if necessary, resulted in the target compounds (180) (Scheme 35). necessary,resulted in resulted the target in compoundsthe target compounds (180) (Scheme (180 35) (Scheme). 35).

Scheme 36. Synthesis of fluorine-containing pyridine C-nucleosides via the Mizoroki-Heck reactions. Scheme 36. Synthesis of fluorine-containing pyridine C-nucleosides via the Mizoroki-Heck reactions.

Two sets of organic dyes containingcontaining a stilbene backbone with fluorinefluorine substituents were constructed forfor aa studystudy on on the the quantum quantum efficiency efficiency of of dye-sensitized dye-sensitized solar solar cells cells (DSSCs) (DSSCs) (Scheme (Scheme 37)[ 9737)]. [97].Compound Compound181 181was was coupled coupled with withthe the commercially available available 4-bromobenzaldehyde 4-bromobenzaldehyde (182a (182a), 4-), bromo-2-fluorobenzaldehyde4-bromo-2-fluorobenzaldehyde (182b (182b), and), and 4-bromo-2,6-difluorobenzaldehyde 4-bromo-2,6-difluorobenzaldehyde (182c (182c), respectively,), respectively, by theby theHeck-type Heck-type reactions reactions to toyield yield 183183, which, which were were condensed condensed with with cyanoacetic cyanoacetic acid acid via via Knöevenagel Knöevenagel reactions to afford the finalfinal productsproducts (H-P,(H-P, H-N,H-N, F-P,F-P, FF-P, FF-P, F-N, F-N, and and FF-N). FF-N). The The results results revealed revealed that that a afluorine fluorine substituent substituent on theon phenylthe phenyl group grouportho toortho the cyanoacrylateto the cyanoacrylate could enhance could theenhance light-harvesting the light- harvestingperformance performance in comparison in comparison with the unsubstituted with the unsubstituted one. The monofluorinated one. The monofluorinated dyes showed largerdyes showedshort-circuit larger photocurrent short-circuit density photocurrent (Jsc) values density than (Jsc) the values non-substituted than the non-substituted ones, due to the ones, extension due to theof the extension conjugation. of the However,conjugation. the However, difluorinated the difluorinated dyes exhibited dyes a lower exhibited performance a lower performance because of a becausetwisted geometryof a twisted between geometry the difluorophenyl between the difluo grouprophenyl and the group cyanoacrylate and the moieties,cyanoacrylate which moieties, reduced whichthe efficiency reduced of theπ-conjugation efficiency of and π-conjugation thus decreased and thethus Jsc decreased value. the Jsc value.

SchemeScheme 37. 37. SynthesisSynthesis of of fluorine-containing fluorine-containing organic organic dyes by the Mizoroki-Heck cross-couplings.

The well-defined polyimides bearing a charge transporting (CT) and nonlinear optical (NLO) The well-defined 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 functionality in in each each repeat repeat unit unit were were prepared prepared via via two two methods methods [98,99]. [98,99 One]. One of these of these methods methods was the Heck-type cross-coupling of a CF3-containing brominated polyimide derivative (184) with styrene thewas Heck-type the Heck-type cross-coupling cross-coupling of a CF of3-containing a CF -containing brominated brominated polyimide polyimide derivative derivative (184) with (184 styrene) with phosphonate 185 (Scheme 38) [98,99]. Polyimide3 186 exhibited high thermal stabilities, and the phosphonatestyrene phosphonate 185 (Scheme185 (Scheme 38) [98,99]. 38)[98 ,Polyimide99]. Polyimide 186 186exhibitedexhibited high high thermal thermal stabilities, stabilities, and and the electron-withdrawing phosphonate group was readily incorporated into the NLO moieties. electron-withdrawing phosphonate group was readily incorporatedincorporated intointo thethe NLONLO moieties.moieties.

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Stereospecific reduction of the ketones, followed by removal of the p-NPE protecting group if necessary, resulted in the target compounds (180) (Scheme 35).

Scheme 36. Synthesis of fluorine-containing pyridine C-nucleosides via the Mizoroki-Heck reactions.

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.

Scheme 37. Synthesis of fluorine-containing organic dyes by the Mizoroki-Heck cross-couplings.

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 Catalysts 2018, 8, 23 23 of 35 electron-withdrawing phosphonate group was readily incorporated into the NLO moieties.

Catalysts 2018, 8, 23 23 of 35

Scheme 38. 38. SynthesisSynthesis of multifunctional of multifunctional polymers polymers for photorefractive for photorefractive applications applications by the Mizoroki- by the Mizoroki-HeckHeck reactions. reactions. Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts

3.2. RCF 2XX and and R RfnfnXX as as the the Cross-Coupling Cross-Coupling Reagents Reagents

Since the fluoroalkyl fluoroalkyl groups groups (CF (CF2R2R and and R Rfn)fn )have have found found wide wide applications applications in inthe the areas areas of ofmedicinal medicinal chemistry chemistry and/or and/or materials materials science, science, significant significant efforts efforts have have been been devoted devoted to to the development of of efficient efficient catalytic catalytic systems systems and to and the todesign the of design versatile of reagents versatile for reagents mild, convenient, for mild, convenient,and direct fluoroalkylation and direct fluoroalkylation [39–45]. In 2012, [39–45 Re].utrakul In 2012, and Reutrakul co-workers and co-workersdescribed the described palladium- the palladium-catalyzedcatalyzed Heck-type reactions Heck-type of reactions[(bromodifluoromethyl)sulfonyl]benzene of [(bromodifluoromethyl)sulfonyl]benzene (187) with styrenes (187) withand styrenesvinyl ethers and vinyl(188), ethersfurnishing (188), furnishingα-alkenyl-substitutedα-alkenyl-substituted α,α-difluoromethylα,α-difluoromethyl phenyl sulfones phenyl sulfones(189) in (moderate189) in moderate yields (Scheme yields (Scheme 39) [100]. 39 )[Although100]. Although the efficiency the efficiency of the ofreactions the reactions was ordinary, was ordinary, they theyprovided provided an easy an easy procedure procedure for forinstallation installation of of(phenylsulfonyl)difluoromethylene (phenylsulfonyl)difluoromethylene group group to to olefins. olefins. The PhSO2CFCF22-containing-containing compounds compounds could could be be readily readily tr transformed.ansformed. Reductive Reductive desulfonylation desulfonylation of ofthe thePhSO PhSO2CF2-bearingCF2-bearing adduct adduct (189) ( 189using) using Mg/HOAc/NaOAc Mg/HOAc/NaOAc afforded afforded the corresponding the corresponding CF2H- CFsubstituted2H-substituted product product [100]. [Furt100].hermore, Furthermore, addition addition of 3,5-di- of 3,5-di-tert-butyl-4-hydroxytoluenetert-butyl-4-hydroxytoluene (BHT, (BHT, 1.0 1.0equiv) equiv) to a to standard a standard reaction reaction mixture mixture led led to toa aslig slightlyhtly lower lower yield yield of of the the product, product, implying implying that the mechanistic pathwaypathway of of the the reaction reaction might might not proceed not proceed through through a radical a mechanism. radical mechanism. This conversion This representedconversion therepresented first report of Pd-catalyzedthe first additionreport of a (phenylsulfonyl)difluoromethyleneof Pd-catalyzed addition groupof toa alkenes(phenylsulfonyl)difluoromethyl [100]. ene group to alkenes [100].

Scheme 39. 39. Pd-catalyzedPd-catalyzed Heck-type Heck-type reactions reactions of [(b ofromodifluoromethyl)-sul [(bromodifluoromethyl)-sulfonyl]benzenefonyl]benzene with withalkenes. alkenes.

Later, Zhang and co-workers reported a general method for palladium-catalyzed Mizoroki- Later, Zhang and co-workers reported a general method for palladium-catalyzed Heck-type cross-couplings of alkenes (190) with perfluoroalkyl bromides (191) (Scheme 40) [101]. The Mizoroki-Heck-type cross-couplings of alkenes (190) with perfluoroalkyl bromides (191) reactions proceeded under mild conditions with high efficiency and broad substrate scope, and (Scheme 40)[101]. The reactions proceeded under mild conditions with high efficiency and provided a variety of fluoroalkylated alkenes (192) in good to high yields. The optimized reaction broad substrate scope, and provided a variety of fluoroalkylated alkenes (192) in good to high conditions included use of 1,2-dichloroethane (DCE) as a solvent, [PdCl2(PPh3)2] as a catalyst, and yields. The optimized reaction conditions included use of 1,2-dichloroethane (DCE) as a solvent, Cs2CO3 as a base. The bidentate ligand Xantphos was essential for the transformation as there was no [PdCl (PPh ) ] as a catalyst, and Cs CO as a base. The bidentate ligand Xantphos was essential for reaction2 occurring3 2 when other phosphine2 3 ligands were used. The reaction could be extended to the transformation as there was no reaction occurring when other phosphine ligands were used. trifluoromethyl iodide, and other functional difluoromethyl bromides (193). The late-stage The reaction could be extended to trifluoromethyl iodide, and other functional difluoromethyl fluoroalkylation of bioactive compounds was also achieved in good yields, which supplied an bromides (193). The late-stage fluoroalkylation of bioactive compounds was also achieved in good efficient and straightforward route for application in drug discovery and development [101]. yields, which supplied an efficient and straightforward route for application in drug discovery and Mechanistic studies including a radical-clock experiment suggested that the free fluoroalkyl radicals development [101]. Mechanistic studies including a radical-clock experiment suggested that the free (Rfn•), initiated by Pd(0)/Xantphos complex through a single electron transfer (SET) process, might fluoroalkyl radicals (R •), initiated by Pd(0)/Xantphos complex through a single electron transfer be involved in the Heck-typefn 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 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].

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(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 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 byproductsCatalysts (201 2018and, 8, 23 202 ) were observed in the conversions [101]. 24 of 35

SchemeScheme 40. Palladium-catalyzed 40. Palladium-catalyzed Heck-typeHeck-type fluoroalkylation fluoroalkylation of alkenes. of alkenes.

Again, other functionalized difluoromethyl bromides (204 and 206) were employed as cross- Again,coupling other reagents functionalized in the Pd-catalyzed difluoromethyl Mizoroki-Heck bromides reactions by ( 204Zhang’sand research206) group were (Scheme employed as cross-coupling41) [103,104]. reagents With an in analogous the Pd-catalyzed catalytic system Mizoroki-Heck mentioned above, reactions a variety by of Zhang’s difluoroalkylated research group (Schemealkenes 41)[ (205103), were104]. synthesized With an from analogous 203 and 204 catalytic under mild system reaction mentioned conditions, showing above, excellent a variety of difluoroalkylatedfunctional group alkenes compatibility (205) were (Scheme synthesized 41a) [103]. from The mechanistic203 and 204 studiesunder revealed mild again reaction that conditions,free fluoroalkyl radicals initiated by [Pd(0)Ln] complexes via a SET pathway were involved in the catalytic showing excellent functional group compatibility (Scheme 41a) [103]. The mechanistic studies revealed cycle, and that the bidentate ligand Xantphos was essential for the transformation. This strategy was again thatalso free successfully fluoroalkyl applied radicals to the preparation initiated by of [Pd(0)L phosphonyldifluoromethylatedn] complexes via a SET alkenes pathway (207) through were involved in the catalyticPd-catalyzed cycle, Heck-type and that reactions the bidentate with bromodifluoromethylphosphonate ligand Xantphos was essential (206) (Scheme for the 41b) transformation. [104]. This strategyThe steric was effect also of diisopropyl successfully (bromodifluoromethyl)phosphonate applied to the preparation ofwas phosphonyldifluoromethylated critical for the efficiency of alkenesthe (207 reaction.) through Advantage Pd-catalyzed of the protocol Heck-type was reactions the synthetic with simplicity, bromodifluoromethylphosphonate providing a facile access to (206) (Schemebiologically 41b) [104 ].interesting The steric molecules. effect of diisopropyl (bromodifluoromethyl)phosphonate was critical for Pd(PPh3)4-catalyzed Mizoroki-Heck reactions of in situ-generated benzylic iodides with styrenes the efficiency of the reaction. Advantage of the protocol was the synthetic simplicity, providing a facile (208) were reported by Wu and co-workers (Scheme 42) [105]. Under standard reaction conditions, a access tomass biologically of perfluoroa interestinglkylated alkenes molecules. (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 (Rfn•) and LnPd(I)I species are first generated from RfnI and Pd(0)Ln in the reaction. Then, the Rfn• radical adds to alkene (208) to afford an alkyl radical (211), which reacts with LnPd(I)I to give a benzylic iodide (212) (path A). Reaction of 212 with Pd(0)Ln forms the key intermediate 213, which might also be obtained from the direct combination of 211 with LnPd(I)I (path B). Subsequently, a

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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). Presumably, perfluoroalkyl radical (Rfn•) and LnPd(I)I species are first generated from RfnI and Pd(0)Ln in the reaction. Then, the Rfn• radical adds to alkene (208) to afford an alkyl radical (211), which reacts with LnPd(I)I to give a benzylic iodide (212) (path A). Reaction of 212 with Pd(0)Ln forms the key intermediate 213, which might also Catalysts 2018, 8, 23 25 of 35 be obtained from the direct combination of 211 with LnPd(I)I (path B). Subsequently, a Heck-type reactionHeck-type ofCatalysts styrene 2018 reaction with, 8, 23 213 of styrenegenerates with a Pd(II)213 generates intermediate a Pd(II) ( 214intermediate). Finally, (214 reductive). Finally, elimination reductive25 of 35 of 214 produces 210 and regenerates the Pd(0)Ln species under the assistantn of DBU. Nonetheless, a pathway eliminationHeck-type of reaction 214 produces of styrene 210 withand 213regenerates generates the a Pd(II)Pd(0)L intermediate species under (214 ).the Finally, assistant reductive of DBU. Nonetheless, a pathway211 via radical addition of 211 to another molecule of styrene in which the via radicalelimination addition ofof 214 producesto another 210 moleculeand regenerates of styrene the Pd(0)L in whichn species the under resulting the assistant benzyl of radicalDBU. couples with LnresultingPd(I)INonetheless, to benzyl form a radical214 pathwaycannot couples via beradical with excluded. LadditionnPd(I)I to of form 211 to214 another cannot moleculebe excluded. of styrene in which the resulting benzyl radical couples with LnPd(I)I to form 214 cannot be excluded.

Scheme 41. Pd-catalyzed Heck-type difluoroalkylation of alkenes with functionalized difluoromethyl Scheme 41.Scheme 41.Pd-catalyzed Pd-catalyzed Heck-type Heck-type difluoroalkylation difluoroalkylation of alkenes with of functionalized alkenes difluoromethyl with functionalized difluoromethylbromides.bromides. bromides.

Scheme 42.SchemePalladium-catalyzed 42. Palladium-catalyzed Mizoroki-Heck Mizoroki-Heck reaction reactionss of ofperfluoroalkyl perfluoroalkyl iodides iodides and styrenes. and styrenes. Scheme 42. Palladium-catalyzed Mizoroki-Heck reactions of perfluoroalkyl iodides and styrenes. The Pd-catalyzed Heck-type reaction of secondary fluoroalkylated alkyl halide with alkene The Pd-catalyzed Heck-type reaction of secondary fluoroalkylated alkyl halide with alkene remainsThe Pd-catalyzed a challenge due Heck-type to the sluggish reaction oxidative of secondary addition offluoroalkylated alkyl halide to palladiumalkyl halide and with the facile alkene remainsremains aβ challenge-hydride a challenge elimination due due to to theof the alkylpalladium sluggish sluggish oxidative oxidative specie additions [106]. addition ofEncouragingly, alkyl of halide alkyl toZhang halide palladium and to palladiumco-workersand the facile and the described a convenient method for palladium-catalyzed Mizoroki-Heck-type couplings of secondary facile β-hydrideβ-hydride eliminationelimination of of alkylpalladium alkylpalladium specie speciess [106]. [106 Encouragingly,]. Encouragingly, Zhang Zhang and co-workers and co-workers trifluoromethylated alkyl bromides (216) with alkenes (215), providing a variety of aliphatic alkenes described a convenient method for palladium-catalyzed Mizoroki-Heck-type couplings of secondary describedbearing a convenient branched method trifluoromethyl for palladium-catalyzed groups (217) (Scheme Mizoroki-Heck-type43) [106]. The reactions proceeded couplings under ofsecondary trifluoromethylated alkyl bromides (216) with alkenes (215), providing a variety of aliphatic alkenes mild conditions and showed good functional group tolerance and high efficiency, even towards bearingsubstrates branched bearing trif theluoromethyl sensitive hydroxy, groups formyl, (217) (Schemeand phthalimide 43) [106]. groups. The reactionsThe reaction proceeded could also under be mild conditions and showed good functional group tolerance and high efficiency, even towards substratesCatalysts 2018 bearing, 8, 23; doi:10.3390/catal8010023the sensitive hydroxy, formyl, and phthalimide groups.www.mdpi.com/journ The reaction couldal/catalysts also be

Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 26 of 35 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 beCatalysts extended 2018, 8,to 23 secondary difluoroalkylated alkyl iodide. The optimal reaction26 of conditions 35 were identified to use an assembly of PdCl2(PPh3)2 (5 mol%), Xantphos (7.5 mol%), and KOAc (2.0 equiv)extended in DCE to atsecondary 80 ◦C for difluoroalkylated 16 h. The control alkyl experiments iodide. Theusing optimal 1,4-dinitrobenzene reaction conditions as were an electron identified to use an assembly of PdCl2(PPh3)2 (5 mol%), Xantphos (7.5 mol %), and KOAc (2.0 equiv) transfer scavenger and the catalytic hydroquinone as a radical inhibitor suggested that a secondary in DCE at 80 °C for 16 h. The control experiments using 1,4-dinitrobenzene as an electron transfer trifluoromethylatedscavenger and alkylthe catalytic radical hydroquinone (218A) via aas SET a radical pathway inhibitor was suggested likely involved that a secondary in the reaction. This hypothesistrifluoromethylated was also alkyl supported radical (218A by) the via radicala SET pathway clock was experiment. likely involved Based in the on reaction. these, aThis plausible reactionhypothesis mechanism was wasalso supported proposed by in the Scheme radical 43clock[ 106 experiment.]. Initially, Based reaction on these, of [Pd(0)La plausiblen] reaction with 216 via a SET processmechanism generates was anproposed alkyl radicalin Scheme (218A 43 ),[106]. which Initially, adds reaction to the carbon-carbon of [Pd(0)Ln] with double 216 via bond a SET of alkene process generates an alkyl radical (218A), which adds to the carbon-carbon double bond of alkene to to produce intermediate 218B. Then, 218B combines with [LnPd(I)Br] to give an alkylpalladium(II) 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 complex (219), which undergoes β-hydride elimination to form 217 and regenerate [Pd(0)Ln] in the presencepresence of a base. of a base.

SchemeScheme 43. Pd-catalyzed 43. Pd-catalyzed Heck-type Heck-type reactions reactions of secondar of secondaryy trifluoromethylated trifluoromethylated alkyl bromides alkyl with bromides alkenes. with alkenes. 3.3. Fluoroalkylation Reagents as the Precursors of the Cross-Coupling Participants 3.3. Fluoroalkylation Reagents as the Precursors of the Cross-Coupling Participants In 2005, Vogel and co-worker reported the palladium-catalyzed Heck-type reactions between Interminal 2005, Vogel alkenes and and co-worker sulfonyl chlorides reported [107]. the Herrmann’s palladium-catalyzed palladacycle Heck-type(222) was found reactions to be an between terminalexcellent alkenes catalyst and sulfonylfor the Mizoroki-Heck-type chlorides [107]. reactions Herrmann’s of mono- palladacycle and disubustituted (222) olefins was found with to be arenesulfonyl chlorides. The reactions were not inhibited by radical scavenging agents. an excellentTrifluoromethanesulfonyl catalyst for the chloride Mizoroki-Heck-type (220) reacted with reactions an excess of styrene mono- (221a and) in disubustituted a sealed tube or olefins with arenesulfonylmicrowave oven chlorides. at 150 °C under The similar reactions conditio werens gave not the inhibited desired desu bylfitative radical Mizoroki-Heck scavenging agents. Trifluoromethanesulfonylcoupling product ((E)-3,3,3-trifluoro-1-phenylprop-1ene) chloride (220) reacted with an (223a excess) in 50% of yield styrene (Scheme (221a 44)) in[107]. a sealed The tube or microwavesame reaction oven with at 150 butyl◦C acrylate under ( similar221b) produced conditions butyl gave(E)-4,4,4-trifluorobut-2-enoate the desired desulfitative (223b Mizoroki-Heck) in 32% couplingyield. product ((E)-3,3,3-trifluoro-1-phenylprop-1ene) (223a) in 50% yield (Scheme 44)[107]. The same reaction with butyl acrylate (221b) produced butyl (E)-4,4,4-trifluorobut-2-enoate (223b) in 32% yield. The 3,3,3-trifluoropropenyl (CF3CH=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 inmoderate to good yields. The reactions avoided the use of a gaseous 1,1,1-trifluoropropene reagent as one of

Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 26 of 35

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.

Scheme 43. Pd-catalyzed Heck-type reactions of secondary trifluoromethylated alkyl bromides with alkenes.

3.3. Fluoroalkylation Reagents as the Precursors of the Cross-Coupling Participants In 2005, Vogel and co-worker reported the palladium-catalyzed Heck-type reactions between Catalysts 2018terminal, 8, 23 alkenes and sulfonyl chlorides [107]. Herrmann’s palladacycle (222) was found to be an 27 of 35 excellent catalyst for the Mizoroki-Heck-type reactions of mono- and disubustituted olefins with arenesulfonyl chlorides. The reactions were not inhibited by radical scavenging agents. the reactantsTrifluoromethanesulfonyl and showed a chloride broader (220 substrate) reacted with scope an excess than of styrene the previously (221a) in a sealed reported tube or methods. Mechanistically,microwave 1-iodo-3,3,3-trifluoropropane oven at 150 °C under similar conditio (225ns) gave may the first desired undergo desulfitative dehydrohalogenation Mizoroki-Heck to in coupling product ((E)-3,3,3-trifluoro-1-phenylprop-1ene) (223a) in 50% yield (Scheme 44) [107]. The situ formsame 3,3,3-trifluoropropene, reaction with butyl acrylate which (221b then) produced reacts butyl with (E224)-4,4,4-trifluorobut-2-enoatein the presence of a ( catalytic223b) in 32% amount of Pd(OAc)yield.2 Catalyststo yield 2018 the, 8, 23 final products (226). 27 of 35

Scheme 44. Pd-catalyzed desulfitative Mizoroki-Heck type reactions of trifluoromethanesulfonyl chlorides with terminal alkenes.

The 3,3,3-trifluoropropenyl (CF3CH=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 the reactants and showed a broader substrate scope Schemethan 44. thePd-catalyzed previously reported desulfitative methods. Mizoroki-HeckMechanistically, 1-iodo-3,3,3-trifluoropropane type reactions of trifluoromethanesulfonyl (225) may first undergo dehydrohalogenation to in situ form 3,3,3-trifluoropropene, which then reacts with 224 in chlorides with terminal alkenes. Catalyststhe presence 2018, 8, 23; of doi:10.3390/catal8010023 a catalytic amount of Pd(OAc)2 to yield the final products (www.mdpi.com/journ226). al/catalysts

Scheme 45. The Heck-type cross-couplings of iodoarenes with 1-iodo-3,3,3- trifluoropropane. Scheme 45. The Heck-type cross-couplings of iodoarenes with 1-iodo-3,3,3- trifluoropropane. 3. Variants of the Mizoroki-Heck Reactions with the Fluorine-Containing Reagents 4. Variants ofBifunctionalization the Mizoroki-Heck of alkenes Reactions triggered with by thethe Mizoroki-Heck Fluorine-Containing reactions has Reagents attracted great attention in organic synthesis. Jiang and co-workers reported the palladium-catalyzed Bifunctionalization of alkenes triggered by the Mizoroki-Heck reactions has attracted fluoroalkylative cyclization of olefins (227) with RfnI (228), which offered an efficient method for the great attentionconstruction in organic of Csp3-Rfnsynthesis. and C-O/N bonds Jiang in one and step, co-workers affording thereported corresponding the fluoroalkylated palladium-catalyzed fluoroalkylative2,3-dihydrobenzofuran cyclization ofand olefinsindolin derivatives (227) with (229 R) fninI( moderate228), which to excellent offered yields an (Scheme efficient 46) method [109]. When the reaction3 of 2-allylphenol (227aa) with ICF2CO2Et was performed in the presence of for the construction of Csp -Rfn and C–O/N bonds in one step, affording the corresponding 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO), the formation of 229aa (R1 = H, Rfn = CF2CO2Et) was fluoroalkylated 2,3-dihydrobenzofuran and indolin derivatives (229) in moderate to excellent yields totally inhibited and the adduct TEMPO-CF2CO2Et was produced in 30% yield. If 1,1- (Scheme 46diphenylethylene)[109]. When was the used reaction as a radical of scavenger 2-allylphenol in the same (227aa reaction,) with10% of ICF229aa2CO and2 51%Et wasof ethyl performed in the presence2,2-difluoro-4,4-diphenylbut-3-enoate of 2,2,6,6-tetramethyl-1-piperidinoxyl were obtained. These (TEMPO), preliminary the experiments formation indicated of 229aa that (R1 = H, a free •CF2CO2Et radical might be involved in the reaction. Thus, a plausible mechanism was Rfn = CF2CO2Et) was totally inhibited and the adduct TEMPO-CF2CO2Et was produced in 30% yield. suggested for the cyclization (Scheme 46) [109]. At the beginning, fluoroalkyl radical (Rfn•) and If 1,1-diphenylethylene was used as a radical scavenger in the same reaction, 10% of 229aa and 51% of Pd(I)LnI complex are formed from the interaction of Pd(0) and RfnI via a single electron transfer ethyl 2,2-difluoro-4,4-diphenylbut-3-enoateprocess. Subsequent electrophilic radical addition were obtained. of Rfn• to the These C=C preliminarybond of olefin ( experiments227a) provides indicated that a freean•CF alkyl2CO radical2Et radical(230). Reaction might of be 230 involved with Pd(I)L innI theyields reaction. an O-coordinated Thus, a Pd(II) plausible complex mechanism (231), was which undergoes reductive elimination to afford 229a (X = O) and regenerate the Pd(0) species. suggested for the cyclization (Scheme 46)[109]. At the beginning, fluoroalkyl radical (Rfn•) and However, an alternative pathway using Pd(0) as a radical initiator followed by an intramolecular SN2 Pd(I)LnI complexsubstitution are couldn’t formed be excluded from the [109]. interaction 2-Allylanilines of could Pd(0) also and undergo RfnI a via similar a single mechanism. electron transfer process. SubsequentLiang and electrophilic co-workers radicaldescribed addition an efficient of Rprocedurefn• to the for C=C Pd-catalyzed bond of olefindomino ( 227aHeck) provides an alkyl radicalreactions/alkylation (230). Reaction of electron of 230-deficientwith polyfluoroarenes Pd(I)LnI yields (232 an), Owhich-coordinated gave the corresponding Pd(II) complex (231), which undergoesalkylated polyfluoroarene reductive elimination products (234 to) affordin moderate229a to(X excellent = O) andyieldsregenerate under mild conditions the Pd(0) species. (Scheme 47) [110]. The method represented a convenient, operationally simple, and useful protocol However,for an the alternative preparation pathway of alkyl substituted using Pd(0) polyfluoroar as a radicalene derivatives. initiator It followed was also the by first an intramolecularexample of SN2 substitutioninstallation couldn’t of bea polyfluoroarene excluded [109 structure]. 2-Allylanilines involving an alkylpalladium(II) could also undergo intermediate. a similar A catalytic mechanism. Liangcycle and for co-workersthe conversion describedwas proposed an in Scheme efficient 47 [110]. procedure Initially, the for in Pd-catalyzed situ generated Pd(0)L dominon Heck reactions/alkylationspecies undergoes of electron-deficient oxidative addition of polyfluoroarenesthe C-I bond of 233 to (232 form), whichintermediate gave 235 the, which corresponding is converted through an intramolecular Heck-type reaction to yield alkylpalladium intermediate 236. alkylated polyfluoroarene products (234) in moderate to excellent yields under mild conditions (Scheme 47Catalysts)[110 2018]. The, 8, 23; doi:10.3390/catal8010023 method represented a convenient, operationallywww.mdpi.com/journ simple, andal/catalysts useful protocol for the preparation of alkyl substituted polyfluoroarene derivatives. It was also the first example of installation of a polyfluoroarene structure involving an alkylpalladium(II) intermediate. A catalytic Catalysts 2018, 8, 23 28 of 35

cycle for the conversion was proposed in Scheme 47[ 110]. Initially, the in situ generated Pd(0)Ln speciesCatalysts undergoes 2018,, 8,, 2323 oxidative addition of the C–I bond of 233 to form intermediate 23528 of, 35 which is converted through an intramolecular Heck-type reaction to yield alkylpalladium intermediate 236. Then, the silver salt abstracts iodide from 236, producing a palladium intermediate (237). Then, theThen, silver the salt silver abstracts salt abstracts iodide fromiodide236 from, producing 236, producing a palladium a palladium intermediate intermediate (237). Subsequently,(237). Subsequently, 237 goes through a concerted metalation/deprotonation/deprotonation processprocess toto provideprovide 238,, whichwhich 237 goes through a concerted metalation/deprotonation process to provide 238, which undergoes undergoes reductive elimination to produce 234 andand regenerateregenerate thethe Pd(0)LPd(0)Lnn speciesspecies forfor thethe nextnext reductivecatalytic elimination cycle. to produce 234 and regenerate the Pd(0)Ln species for the next catalytic cycle.

SchemeScheme 46. 46.Pd-catalyzed Pd-catalyzedPd-catalyzedfluoroalkylative fluoroalkylativefluoroalkylative cyclizationcyclization cyclization ofof oleole offins. olefins.

SchemeScheme 47. Pd-catalyzed 47. Pd-catalyzedPd-catalyzed Heck/intermolecular Heck/intermolecularHeck/intermolecular C–HC–H C–H bondbond bond functionalizationfunctionalization functionalization forfor thethe for synthesissynthesis the synthesis ofof of alkylatedalkylated polyfluoroarene polyfluoroarene derivatives. derivatives.

Toste and co-workers disclosed the Pd-catalyzed 1,2-fluoroarylation of styrenes (239)) withwith ® 239 Tostearylboronic and co-workers acids (240)) andand disclosed SelectfluorSelectfluor the® usingusing Pd-catalyzed amidesamides (e.g.,(e.g., 1,2-fluoroarylation 8-aminoquinoline8-aminoquinoline (AQ))(AQ)) of asas styrenes thethe directingdirecting ( ) with ® arylboronicgroups acids (Scheme (240 48)) and[111]. Selectfluor This strategy usingwas also amides successfully (e.g., used 8-aminoquinoline for the asymmetric (AQ)) 1,2- as the directingfluoroarylationfluoroarylation groups (Scheme ofof styrenes,styrenes, 48)[ furnishingfurnishing111]. This chiralchiral strategy monofluorinatedmonofluorinated was also compoundscompounds successfully ((242 used)) inin goodgood for yieldsyields the asymmetric andand 1,2-fluoroarylationwith high enantioselectivies. of styrenes, furnishing Later, palladium-catalyzed chiral monofluorinated 1,1-fluoroarylation compounds of amino-alkenes (242) in good (243 yields)) and using arylboronic acids (244) as an arene source and Selectfluor® as a fluorine source was developed with highusing enantioselectivies. arylboronic acids (244 Later,) as an palladium-catalyzed arene source and Selectfluor 1,1-fluoroarylation as a fluorine source of was amino-alkenes developed (243) by the same research group (Scheme 48) [112]. The transformation likely proceeded through an using arylboronic acids (244) as an arene source and Selectfluor® as a fluorine source was developed by oxidative Heck mechanism to afford 1,1-difunctionalized alkenes (245)) inin oneone potpot [112],[112], whichwhich waswas the samedifferent research from group the pathway (Scheme proposed 48)[112 for]. the The 1,2-fluoroarylation transformation [111]. likely The proceeded 1,1-fluoroarylation through could an oxidative Heck mechanismalso be extended to afford to an 1,1-difunctionalized asymmetric transforma alkenestion,tion, generatinggenerating (245) in chiralchiral one benzylicbenzylic pot [112 fluoridesfluorides], which ((246 was)) inin different goodgood from the pathway proposed for the 1,2-fluoroarylation [111]. The 1,1-fluoroarylation could also be extended to an asymmetricCatalysts 2018,, 8,, 23; transformation,23; doi:10.3390/catal8010023doi:10.3390/catal8010023 generating chiral benzylic fluorideswww.mdpi.com/journ (246) in goodal/catalysts to excellent enantioselectivies [112]. These reactions promised powerful strategies for the difunctionalization of alkenes to chiral fluorinated molecules. Catalysts 2018, 8, 23 29 of 35

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 linearCatalysts or 2018 branched, 8, 23 monofluoromethyl isomers (251 or 252). The regioselectivity of the latter29 of 35 case was dramatically dependent upon the structure of allene. The mechanistic studies indicated that a palladiumto excellent fluoride, enantioselectivies generated from [112]. the halideThese exchangereactions withpromised AgF, waspowerful the key strategies intermediate for inthe the reactiondifunctionalization (Scheme 49). of Nevertheless, alkenes to chiral the fluorinated exact mechanism molecules. of the reaction remained unclear [113].

Catalysts 2018, 8, 23 SchemeScheme 48. 48.Pd-catalyzed Pd-catalyzed enantioselective fluoroarylation fluoroarylation of of alkenes. alkenes. 30 of 35

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].

SchemeScheme 49. 49.Pd-catalyzed Pd-catalyzed cascade carb carbofluorinationofluorination of of allenes. allenes.

4. Conclusions In summary, the Mizoroki-Heck reaction has become a very powerful tool for building complex molecules [1–6]. 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 Catalyststo the high2018, 8,efficiency 23; doi:10.3390/catal8010023 of the reactions is the choice of suitable fluorine-containingwww.mdpi.com/journ reagentsal/catalysts 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., SeRfn, SRfn, and ORfn 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.

Acknowledgments: We thank the Army Medical University, the National Natural Science Foundation of China (21602165), the “Hundred Talent” Program of Hubei Province, and the Wuhan Youth Chen-Guang Project (2016070204010113) for financial support.

Catalysts 2018, 8, 23; doi:10.3390/catal8010023 www.mdpi.com/journal/catalysts Catalysts 2018, 8, 23 30 of 35

5. Conclusions In summary, the Mizoroki-Heck reaction has become a very powerful tool for building complex molecules [1–6]. 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., SeRfn, SRfn, and ORfn 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.

Acknowledgments: We thank the Army Medical University, the National Natural Science Foundation of China (21602165), the “Hundred Talent” Program of Hubei Province, and the Wuhan Youth Chen-Guang Project (2016070204010113) for financial support. Author Contributions: Jing Yang, Hua-Wen Zhao, Jian He and Cheng-Pan Zhang analyzed the data and wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

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