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-