Heck Reaction—State of the Art

Home , BINAP, Coupling reaction, Heck reaction, Stille reaction

catalysts

Review Heck Reaction—State of the Art

ID SangeetaReview Jagtap DepartmentHeck of Reaction—State Chemistry, Baburaoji Gholap College,of the Sangvi, Art Pune 411027, India; [email protected]; Tel.: +91-20-2728-0204 Sangeeta Jagtap Received: 20 August 2017; Accepted: 6 September 2017; Published: 11 September 2017 Department of Chemistry, Baburaoji Gholap College, Sangvi, Pune 411027, India; Abstract:[email protected];The Heck reaction is one Tel.: of+91 the‐20‐2728 most‐0204 studied coupling reactions and is recognized with the NobelReceived: Prize in 20 Chemistry.August 2017; Accepted: Thousands 6 September of articles, 2017; hundreds Published: 11 of September reviews and2017 a number of books have been published on this topic. All reviews are written exhaustively describing the various aspects of HeckAbstract: reaction The andHeck refer reaction to the is one work of donethe most hitherto. studied Looking coupling atreactions the quantum and is recognized of the monographs with published,the Nobel and Prize the in reviews Chemistry. based Thousands on them, of articles, we found hundreds a necessity of reviews to summarize and a number all of reviews books on have been published on this topic. All reviews are written exhaustively describing the various Heck reaction about catalysts, ligands, suggested mechanisms, conditions, methodologies and the aspects of Heck reaction and refer to the work done hitherto. Looking at the quantum of the compoundsmonographs formed published, via Heck and reaction the reviews in one based review on andthem, generate we found a resource a necessity of information.to summarize Oneall can ﬁnd almostreviews allon the Heck catalysts reaction used soabout far forcatalysts, Heck reaction ligands, in suggested this review. mechanisms, conditions, methodologies and the compounds formed via Heck reaction in one review and generate a resource Keywords:of information.Heck reaction; One can reviews;find almost C-C all coupling;the catalysts catalysis; used so far mechanism; for Heck reaction application in this review.

Keywords: Heck reaction; reviews; C‐C coupling; catalysis; mechanism; application

1. Introduction

The1. Introduction new era of research started after the introduction of coupling reactions, i.e., carbon–carbon bond forming reactions like Heck [1], Suzuki [2], Sonogoshira [3], Negishi [4], Kumada [5], Stille [6], The new era of research started after the introduction of coupling reactions, i.e., carbon–carbon Tsuji-Trostbond forming [7], etc. reactions These reactions like Heck have [1], Suzuki played [2], an Sonogoshira enormously [3], decisive Negishi and [4], importantKumada [5], role Stille in [6], shaping chemicalTsuji‐ synthesisTrost [7], etc. and These have reactions revolutionized have played the way an oneenormously thinks aboutdecisive synthetic and important organic role chemistry. in The Heckshaping reaction chemical (Equation synthesis (1))and ishave used revolutionized extensively the in manyway one syntheses, thinks about including synthetic agrochemical, organic fine chemicals,chemistry. The pharmaceutical, Heck reaction etc.(Equation The reaction(1)) is used was extensively introduced in bymany Mizoroki syntheses, [8] including and Heck [9] independentlyagrochemical, more fine thanchemicals, four pharmaceutical, decades ago. etc. It has The drawn reaction much was introduced attention by due Mizoroki to high [8] efficiency and and simplicity.Heck [9] independently Heck methodology more than is four attractive decades from ago. a It synthetic has drawn point much of attention view because due to of high its high chemoselectivityefficiency and andsimplicity. mild reactionHeck methodology conditions is attractive along with from low a synthetic toxicity point and of cost view of because the reagent of if, specifically,its high thechemoselectivity catalyst is recycled. and mild reaction conditions along with low toxicity and cost of the reagent if, specifically, the catalyst is recycled.

(1) (1)

The Heck reaction is described as a vinylation or arylation of olefins where a large variety of The Heck reaction is described as a vinylation or arylation of olefins where a large variety of olefins can be used, like derivatives of acrylates, styrenes or intramolecular double bonds. The aryl olefinshalide can variants be used, developed like derivatives in addition of to acrylates, typical aryl styrenes bromides or and intramolecular iodides are aromatic double triflates, bonds. aroyl The aryl halidechlorides, variants aryl developed sulfonyl in chlorides, addition aromatic to typical diazonium aryl bromides salts, aroyl and iodidesanhydrides, are aromatic aryl chlorides triflates, and aroyl chlorides,arylsilanols. aryl sulfonyl The catalyst chlorides, is the essential aromatic part of diazonium a reaction where salts, a aroyl variety anhydrides, of metals along aryl with chlorides a huge and arylsilanols.range of Theligands catalyst is studied. is the Significant essential progress part of a for reaction the preparation where a and variety characterization of metals along of variety with of a huge rangeligands of ligands and catalysts is studied. has Significantbeen made for progress avoiding for protection the preparation and deprotection and characterization procedures, therefore of variety of ligandsallowing and catalysts for syntheses has beento be carried made forout avoiding in fewer steps. protection Development, and deprotection novel catalytic procedures, properties thereforeand allowingextensive for syntheses mechanistic to studies be carried are summarized out in fewer in steps. several Development, reviews based novel on seminal catalytic work properties of many and researchers and reviewers as described in following sections. Palladium is usually the preferred metal extensive mechanistic studies are summarized in several reviews based on seminal work of many as it tolerates a wide variety of functional groups and it has a remarkable ability to assemble C‐C researchers and reviewers as described in following sections. Palladium is usually the preferred metal bonds between appropriately functionalized substrates. Most palladium based methodologies as it toleratesproceed with a wide stereo variety‐ and of regioselectivity functional groups and andwith it excellent has a remarkable yields. Generally, ability to the assemble less crowded C-C bonds between appropriately functionalized substrates. Most palladium based methodologies proceed with Catalysts 2017, 7, 267; doi:10.3390/catal7090267 www.mdpi.com/journal/catalysts

Catalysts 2017, 7, 267; doi:10.3390/catal7090267 www.mdpi.com/journal/catalysts Catalysts 2017, 7, 267 2 of 53 stereo- and regioselectivity and with excellent yields. Generally, the less crowded structure is preferred during Heck reaction, and often favours a trans product. Few mechanisms are also supported by the discussionCatalysts 2017 on, 7 the, 267 regioselectivity and stereoselectivity of Heck reaction. 2 of 53 Sometimes compounds such as TBAB (Tetra butyl ammonium bromide) are added in the reactionstructure mixture is preferred along with during organic Heck reaction, or inorganic and basesoften favours needed a for trans the product. sequestration Few mechanisms of acid generated. are Typicalalso supported solvents for by the discussion Heck reaction on the are regioselectivity dipolar aprotic and solvents stereoselectivity like DMF of Heck (dimethyl reaction. formamide) and NMPSometimes (N-methyl-2-pyrrolidone), compounds such as however, TBAB (Tetra the reaction butyl ammonium is also performed bromide) in manyare added other in different the reaction mixture along with organic or inorganic bases needed for the sequestration of acid solvents and in fact there are large numbers of reviews dedicated to the use of various solvents. generated. Typical solvents for the Heck reaction are dipolar aprotic solvents like DMF (dimethyl Besides these, many manuscripts describe the reaction in the absence of one of the component (other formamide) and NMP (N‐methyl‐2‐pyrrolidone), however, the reaction is also performed in many thanother substrates) different such solvents as ligand and in free,fact there organic are large solvent numbers free and of reviews so on. Recent dedicated publications to the use of also various describe howsolvents. to recover Besides used these, catalyst many specially manuscripts using aqueous describe medium the reaction which in implies the absence the potential of one forof greenerthe approachcomponent for organic (other than reactions. substrates) such as ligand free, organic solvent free and so on. Recent publicationsThere are aalso large describe number how of to excellent recover used reviews catalyst available specially on Heckusing reactionaqueous andmedium related which topics basedimplies on applications, the potential for mechanism, greener approach quest for for high organic turn reactions. over numbers (TONs), asymmetric synthesis, separationThere techniques, are a large etc. number In addition of excellent to this, reviews there are available a few manuscripts on Heck reaction that give and a generalrelated topics overview aboutbased Heck on reaction,applications, some mechanism, of them are quest detailed for high and turn some over are numbers not so descriptive. (TONs), asymmetric Many reviews synthesis, discuss variousseparation catalysis techniques, techniques etc. with In addition certain aspectsto this, wherethere are along a few with manuscripts the Heck reaction, that give other a general coupling reactionsoverview are about also Heck discussed, reaction, however some of for them the are present detailed review, and some only are the not Heck so descriptive. related chemistry Many is considered.reviews discuss It should various be noted catalysis that techniques for this review with certain only theaspects reviews where and along few with related the Heck articles reaction, covering Heckother chemistry coupling are reactions considered. are also Consideration discussed, however of book for articles, the present although review, informative, only the Heck is beyond related the chemistry is considered. It should be noted that for this review only the reviews and few related scope of this review. articles covering Heck chemistry are considered. Consideration of book articles, although 2. Reviewsinformative, on Catalystis beyond Development the scope of this review.

2. TheReviews majority on Catalyst of the work Development on Heck reaction has been focused on the catalyst development. There are numerous reviews based on this and hence are further categorized for better understanding. The majority of the work on Heck reaction has been focused on the catalyst development. There are numerous reviews based on this and hence are further categorized for better understanding. 2.1. Overviews 2.1.When Overviews the mechanism was not fully explored, the reaction and its possible mechanistic pathways are reviewedWhen bythe onemechanism of its pioneers, was not fully R.F. Heckexplored, [10– the12] reaction by focusing and its on possible possibilities mechanistic of the pathways intermediate formedare reviewed during Heck by one reaction of its pioneers, by considering R.F. Heck various [10–12] examples by focusing for on its possibilities support. These of the reviews intermediate mention theformed working during reaction Heck conditionsreaction by considering explored for various the reaction examples and for its focuses support. on These the requirements reviews mention of the substrates,the working bases, reaction solvents conditions and the explored conditions for to the be reaction used. It and was focuses observed on thatthe requirements the reaction isof usuallythe regioselectivesubstrates, bases, and stereospecific solvents and the and conditions is tolerant to ofbe almostused. It every was observed functional that group. the reaction Data is have usually proved thatregioselective the direction and of additionstereospecific of the and organopalladium is tolerant of almost complex every functional to the olefin group. depends Data have upon proved the steric andthat electronic the direction influence of addition of the substituentof the organopalladium present. The complex direction to the of addition olefin depends is most upon often the dominated steric byand steric electronic effects whereinfluence the of organic the substituent group present. is seen toThe be direction added toof theaddition least is substituted most often dominated carbon of the doubleby steric band. effects where the organic group is seen to be added to the least substituted carbon of the double band. Initially, the intermediate mono-organopalladium(II) species, RPdL2X, were prepared by exchange Initially, the intermediate mono‐organopalladium(II) species, RPdL2X, were prepared by reactions of mercurials in general, with palladium(II) salts (Scheme1a), however it suffered from the exchange reactions of mercurials in general, with palladium(II) salts (Scheme 1a), however it suffered disadvantage that, many such main group organometallics were not easily accessible and moreover from the disadvantage that, many such main group organometallics were not easily accessible and theymoreover were needed they were to be needed used into be stoichiometric used in stoichiometric amounts in amounts the synthesis in the synthesis of organic of compounds. organic Hence,compounds. the finely Hence,divided the palladiumfinely divided metal palladium or palladium(0) metal or palladium(0) phosphine complexes phosphine werecomplexes used were for such reactionsused for (Scheme such reactions1b). (Scheme 1b).

SchemeScheme 1. Initial1. Initial work work by by Heck Heck [ 10[10]] to to getget an active species species (a (a) )RPdL RPdL2X2 Xand and (b) ( bRPd(PR’) RPd(PR’3)2X.3 )2X.

Effects of different triaryl phosphines have also been studied. It is mentioned that, generally the reaction does not require anhydrous or anaerobic conditions although it is advisable to limit access

Catalysts 2017, 7, 267 3 of 53

Catalysts 2017, 7, 267 3 of 53 Effects of different triaryl phosphines have also been studied. It is mentioned that, generally the of oxygenreaction when does arylphosphines not require anhydrous are used as or a anaerobic component conditions of the catalyst. although Aryl, it isheterocyclic, advisable to benzyl, limit access or vinylof oxygenhalides whenare commonly arylphosphines employed are often used with as a component bromides and of theiodides catalyst. in comparison Aryl, heterocyclic, to halides benzyl, with anor easily vinyl halideseliminated are commonlybeta‐hydrogen employed atom (i.e., often alkyl with derivatives) bromides and since iodides they form in comparison only olefins to by halides elimination under the normal reaction conditions. Generally used bases are secondary or tertiary with an easily eliminated beta-hydrogen atom (i.e., alkyl derivatives) since they form only olefins amine, sodium or potassium acetate, carbonate, or bicarbonates. The catalyst is commonly palladium by elimination under the normal reaction conditions. Generally used bases are secondary or tertiary acetate, although palladium chloride or preformed triarylphosphine palladium complexes, as well as amine, sodium or potassium acetate, carbonate, or bicarbonates. The catalyst is commonly palladium palladium on charcoal, have been used. acetate, although palladium chloride or preformed triarylphosphine palladium complexes, as well as Triarylphosphine or a secondary amine is required when organic bromides are used although a palladium on charcoal, have been used. reactant, product, or solvent may serve as the ligand for reactions involving organic iodides. Solvents Triarylphosphine or a secondary amine is required when organic bromides are used although such as acetonitrile, dimethylformamide, hexamethylphosphoramide, N‐methylpyrrolidinone, and a reactant, product, or solvent may serve as the ligand for reactions involving organic iodides. methanol have been used, but are often not necessary. The procedure is applicable to a very wide Solvents such as acetonitrile, dimethylformamide, hexamethylphosphoramide, N-methylpyrrolidinone, range of reactants and yields are generally good to excellent. Temperature used is in the range of 50 and methanol have been used, but are often not necessary. The procedure is applicable to a very wide to 160 °C, where the reaction proceeds homogeneously. When nucleophilic secondary amines are range of reactants and yields are generally good to excellent. Temperature used is in the range of 50 to used as co‐reactants with most vinylic halides, a variation occurs that often produces tertiary allylic 160 ◦C, where the reaction proceeds homogeneously. When nucleophilic secondary amines are used as amines as major products. A comparison of Heck reaction with similar types of reaction where the co-reactants with most vinylic halides, a variation occurs that often produces tertiary allylic amines as organic halide is replaced by other reagents such as organometallics, diazonium salts, or aromatic major products. A comparison of Heck reaction with similar types of reaction where the organic halide hydrocarbons has also been discussed. is replaced by other reagents such as organometallics, diazonium salts, or aromatic hydrocarbons has De Meijere and Meyer [13] have reviewed mainly the Heck couplings with various also been discussed. oligohaloarenes along with an overall discussion on development in mechanism and catalysts until De Meijere and Meyer [13] have reviewed mainly the Heck couplings with various oligohaloarenes 1994. The review stresses upon the careful choice of substrates and skilful tailoring of reaction along with an overall discussion on development in mechanism and catalysts until 1994. The review conditions leading to impressive sequences. stresses upon the careful choice of substrates and skilful tailoring of reaction conditions leading to As exemplified in the review, the Heck reaction, together with other mechanistically related impressive sequences. palladium catalysed transformations with arene, alkene and alkyne derivatives, opens the door to a As exemplified in the review, the Heck reaction, together with other mechanistically related tremendous variety of elegant and highly convergent routes to structurally complex molecules. The palladium catalysed transformations with arene, alkene and alkyne derivatives, opens the door to reaction is not hindered by heteroatoms such as oxygen, nitrogen, sulphur and phosphorus in most a tremendous variety of elegant and highly convergent routes to structurally complex molecules. of the cases. With Heck reaction, a range of chemoselective and regioselective monocouplings of The reaction is not hindered by heteroatoms such as oxygen, nitrogen, sulphur and phosphorus in highly functionalized substrates with unsymmetrical and multisubstituted reaction partners could most of the cases. With Heck reaction, a range of chemoselective and regioselective monocouplings of be achieved. A number of examples are given that demonstrate the cascade reactions in which three, highly functionalized substrates with unsymmetrical and multisubstituted reaction partners could be four, five, and even eight new C‐C bonds are formed to yield oligofunctional and oligocyclic products achieved. A number of examples are given that demonstrate the cascade reactions in which three, four, like 1–6 (Figure 1) with impressive molecular complexity. Cases are presented to establish the five, and even eight new C-C bonds are formed to yield oligofunctional and oligocyclic products like reactivity for enantioselective construction of complex natural products with quaternary 1–6 (Figure1) with impressive molecular complexity. Cases are presented to establish the reactivity for stereocenters as exemplified by the synthesis of (R,R)‐crinan 7, picrotoxinin 8, and morphine 9 (Figure enantioselective construction of complex natural products with quaternary stereocenters as exemplified 2). by the synthesis of (R,R)-crinan 7, picrotoxinin 8, and morphine 9 (Figure2). R Ph Me R R Ph H Ph Ph Ph R R Ph COOOMe Ph R 1 3 4

Figure 1. Cont.

Catalysts 2017, 7, 267 4 of 53

R CatalystsCatalysts 20172017, 7, 267, 7, 267 4 of 534 of 53 R Catalysts 2017, 7, 267 R 4 of 53 R R R R R R R R R R R R R R R R R R R R R R R R R 5 R R R R R 6 5 R R 6 Figure 1. Oligofunctional5 and oligocyclic products Rformed via Heck reaction. 6 FigureFigure 1. Oligofunctional 1. Oligofunctional and andoligocyclic oligocyclicO products products formed formed via Heck via Heck reaction. reaction. O OH FigureO 1. Oligofunctional and oligocyclic products formed via Heck reaction. H O N O O O O O OH OH O O O O MeN OH H OHO O O 7 (R,R)-N Crinan O O O H O 8 Picrotoxinin 9 (-) - MorphineOH N O O O O OH MeN OH 7 (R,R)- CrinanO OHO MeN Figure 2. Enantioselective construction of complex8 Picrotoxinin natural products9 reviewed(-) - Morphine by de Meijere and 7 (R,R)- Crinan O 9 (-) - Morphine FigureMeyer 2. Enantioselective [13]. construction of complex natural8 Picrotoxinin products reviewed by de Meijere and Meyer [13]. Figure 2. Enantioselective construction of complex natural products reviewed by de Meijere and MeyerSeveralFigureSeveral [13]. 2. examplesexamples Enantioselective for syntheses construction of natural of complex products natural 10 products–27 (Figure reviewed3 3)) have have by been beende Meijere provided provided and that that involveMeyer different [13]. typestypes ofof HeckHeck transformationstransformations asas oneone ofof thethe importantimportant keykey stepssteps like,like, Several examples for syntheses of natural products 10–27 (Figure 3) have been provided that  Heck reactions with intermolecular asymmetric induction where compounds with ee involve• differentHeckSeveral reactions examples types withof Heck for intermolecular syntheses transformations of asymmetric natural as one products induction of the important10– where27 (Figure compounds key 3)steps have like, with been ee provided (enantiomeric that (enantiomeric excess) up to 99%. involveexcess) different up to types 99%. of Heck transformations as one of the important key steps like,   HeckMultiple reactions component with intermolecular reactions and dominoasymmetric coupling induction reactions where performed compounds with several with alkenes ee • Multiple component reactions and domino coupling reactions performed with several alkenes  (enantiomericHeckand various reactions excess) haloarenes. with up to intermolecular99%. asymmetric induction where compounds with ee and various haloarenes.   Multiple(enantiomericPd‐catalysed component heteroannelations. excess) reactions up to and99%. domino coupling reactions performed with several alkenes • Pd-catalysed heteroannelations.  andMultipleIntramolecular various haloarenes.component Heck reactions.reactions and domino coupling reactions performed with several alkenes • Intramolecular Heck reactions.   Pd‐andPalladiumcatalysed various heteroannelations. catalysed haloarenes. additions to triple bonds and the coupling products derived from  • IntramolecularPalladiumPdnorbornene‐catalysed catalysed Heckand heteroannelations. dicyclopentadienereactions. additions to triple that bonds serve and as the precursors coupling products for diverse derived polycyclic from norbornene aromatic   PalladiumandIntramolecularcompound. dicyclopentadiene catalysed Heck additions reactions. that serve to triple as precursors bonds forand diverse the coupling polycyclic products aromatic derived compound. from  norbornenePalladium and catalysed dicyclopentadiene additions tothat triple serve bonds as precursors and the forcoupling diverse productspolycyclic derived aromatic from Thus, the review gives the expanse of Heck reaction which is one of thethe importantimportant synthetic compound.norbornene and dicyclopentadiene that serve as precursors for diverse polycyclic aromatic methods available to organic chemists.chemists. compound. Thus, the review gives the expanse of Heck reaction which is one of the important synthetic methodsThus, available the reviewto organic gives chemists. the expanse ofO Heck reaction which is oneCH ofOCH the CHimportantSiMe synthetic O 2 2 2 3 methods available to organic chemists. N O CHO 2OCH2 CH2SiMe 3 O O O N OH N CH2OCH2 CH2SiMe 3 O O N N H O O N MeO OHN MeOOC N H Me HOMe Br N OH N 10 (±)-DehydrotubifolineH 11 (±)-Tazettine MeO N MeOOC 12N Gelsemine derivative N HH Me H Me MeOOCBr MeO FigureN 3. Cont. 10 (±)-DehydrotubifolineN H Me 11 (±)-TazettineH Me Br 12 Gelsemine derivative 10 (±)-Dehydrotubifoline 11 (±)-Tazettine 12 Gelsemine derivative

Catalysts 2017, 7, 267 5 of 53 Catalysts 2017, 7, 267 5 of 53

OH O OH OCONH2 N OMe N O OH O N HO O NH O MeOOC N O 13 Camphothecin O 14 FR 900482 analogue 15 Lycoricidine O OH H MeHNOCO O NMe CHO N O CHO Me 16 Sterepolide 17 Merulidial 18 Physostigmine

OH O E E O H O (±)- 9(12)-Capnellane 19 20 Venolepin O 21 OMe COOMe R R2 OMe 1 MeOOC R2 N N OMe HN H E O OMe E O O 22 23 24 (±)-Duocarmycin SA O O

O O OMe E E 25 26 MeO

PhO2 S SO2Ph n 27 FigureFigure 3.3. NaturalNatural productsproducts involvinginvolving synthesissynthesis viavia differentdifferent types types of of Heck Heck transformations. transformations.

Catalysts 2017, 7, 267 6 of 53

Catalysts 2017, 7, 267 6 of 53 Kobeti´cand Biliškov [14] have summarized the basics of Heck reaction mechanism, various compositionsKobetić and of applicable Biliškov [14] catalyst, have summarized their developments the basics and of applications Heck reaction of mechanism, Heck reaction various until then. Sequentialcompositions development of applicable of catalyst, both homogeneous their developments and heterogeneous and applications catalysis of Heck has reaction been discussed until then. giving examples.Sequential Usedevelopment of palladium of both with homogeneous carbon, metal and oxides heterogeneous and their salts, catalysis silica, has porous been glass discussed tube, glass beadsgiving and examples. guanidinium Use of palladium phosphane with clay, carbon, zeolites metal and oxides molecular and their sieves, salts, MCM silica, 41, porous polymer, glass dendrimer, tube, etc.,glass are beads elaborated and guanidinium with their phosphane reaction conditions clay, zeolites and and yield. molecular Many sieves, of these MCM catalysts 41, polymer, shows good activitydendrimer, and etc., few are of themelaborated have with proved their to reaction be good conditions in recycle and study yield. as well.Many Theof these review catalysts also takes anshows account good of activity substrates, and few solvents of them and have reaction proved conditions to be good used. in recycle There study are few as well. examples The review of cascade andalso multiple takes an account coupling, of substrates, synthesis ofsolvents natural and and reaction biologically conditions active used. compounds There are few and examples enantioselective of Heck-typecascade and reactions. multiple Catalysts coupling,28 –synthesis36 (Figure 4of) arenatural seen toand give biologically yields in the active range compounds of 48 to 93%. and Out of allenantioselective these palladacycles, Heck‐type36 isreactions. the most Catalysts studied 28 and–36 most (Figure reviewed 4) are seen catalyst. to give In yields the review, in the range the use of of 48 to 93%. Out of all these palladacycles, 36 is the most studied and most reviewed catalyst. In the a phase transition catalyst (quaternary ammonium salts), and the solid base that accelerates the Heck review, the use of a phase transition catalyst (quaternary ammonium salts), and the solid base that reaction are considered to be big breakthrough discoveries. accelerates the Heck reaction are considered to be big breakthrough discoveries. Cl N N Pd N N Si Si O O Cl Si Si O Cl O Si Si N Si N N Pd N N Pd N AcO Cl OAc 28 29

PPh2 O H O Pd(dba) N O Si N H PPh2 PPh2 O Pd O 31 TFA PPh 30 2

( ) n

S PEG350OMe O P Pd Cl PdCl2 PPh N 2 P Si NH2 M(OAc)2 S PEG350OMe 35 32 33 34

Tol Tol O O Pd Pd O O Tol Tol 36 Figure 4. Ligands and catalysts employed for Heck reaction reported in review by Kobeti´cand Biliškov [14].

Catalysts 2017, 7, 267 7 of 53

Catalysts 2017, 7, 267 7 of 53 Figure 4. Ligands and catalysts employed for Heck reaction reported in review by Kobetić and Biliškov [14]. A review by Sahu and Sapkale [15] discusses the mechanism of palladium catalysed coupling reactions,A review details by aboutSahu palladiumand Sapkale metal, [15] itsdiscusses reactivity the and mechanism use for reaction of palladium like Heck, catalysed Suzuki, coupling Negishi, reactions,Hiyama, Stille,details Fukuyama, about palladium Sonogoshira, metal, its Buchwald reactivity Hartwig and use and for reaction their variants. like Heck, Suzuki, Negishi, Hiyama,The Stille, reactivity Fukuyama, of palladium Sonogoshira, is explained Buchwald on the Hartwig basis of fewand pointstheir variants. such as The reactivity of palladium is explained on the basis of few points such as • Electronegativity of palladium develops a polarised Pd-X bond leading to relatively strong Pd-H  Electronegativity of palladium develops a polarised Pd‐X bond leading to relatively strong Pd‐ and Pd-C bonds. H and Pd‐C bonds. • Its variable oxidation states such as Pd(0), Pd(II) and sometimes Pd(IV) are essential for processes  Its variable oxidation states such as Pd(0), Pd(II) and sometimes Pd(IV) are essential for such as oxidative addition, transmetalation and reductive elimination. processes such as oxidative addition, transmetalation and reductive elimination. •  OxidationOxidation states states such such as as Pd(I), Pd(I), Pd(III) Pd(III) and and Pd(IV) Pd(IV) are are also also known, known, where where Pd(IV) Pd(IV) species species are are essentialessential in in C C-H‐H activation activation mechanisms. mechanisms. AlthoughAlthough not not in in detail, detail, references references for for Heck Heck reaction reaction in in ionic ionic liquid liquid and and for for Amino Amino-Heck‐Heck are are given given alongalong with with the the mention mention of of application application of of Heck Heck reaction reaction in in the the synthesis synthesis of of an an alkaloid alkaloid Rhazinal Rhazinal 3737 (Figure(Figure 55),), an antimitotic agent obtained fromfrom thethe stem extract of Kopsia teoi and a promising starting pointpoint for for anticancer anticancer agent. agent. MOM MOM-Rhazinal‐Rhazinal (MOM (MOM = = Methoxymethyl Methoxymethyl ether) ether) derivative derivative is is made made from from thethe derivative derivative of of pyrrol pyrrol where where intramolecular intramolecular Heck Heck reaction reaction takes place in presence on Pd(OAc)2..

CHO

N MOM O 37 Figure 5. MOM-Rhazinal (MOM: Methoxymethyl ether). Figure 5. MOM‐Rhazinal (MOM: Methoxymethyl ether). 2.2. Catalysts Variants 2.2. Catalysts Variants Every research in catalysis mostly proceeds with the aim of improving the overall catalytic activityEvery for research a particular in catalysis reaction. mostly A progressive proceeds development with the aim targeting of improving the increase the overall in activity catalytic has activitybeen discussed for a particular thoroughly reaction. for Heck A progressive reaction as well.development Researchers targeting work hardthe increase to ﬁnd cheaper in activity ligands, has beencatalyst discussed system thoroughly with higher for activity Heck reaction so as to as minimize well. Researchers the load of work palladium hard to and find ligand cheaper and ligands, to ﬁnd catalystsuitable system systems with for thehigher processing activity of so aryl as to chlorides minimize too. the load of palladium and ligand and to find suitable systems for the processing of aryl chlorides too. 2.2.1. Overall Progress 2.2.1. Overall Progress Beletskaya and Cheprakov [16] have published a critical and profound review on Heck reaction thatBeletskaya systematically and gives Cheprakov details [16] of the have work published done up a to critical 2000. and It is stillprofound one of review the most on comprehensive Heck reaction thatreviews systematically on Heck reactions. gives details of the work done up to 2000. It is still one of the most comprehensive reviewsA number on Heck of reactions. examples are presented to elaborate the use of various catalysts and ligands for Heck reactionsA number like palladacycles, of examples are pincers, presented carbene to elaborate complexes, the etc. use The of various review catalysts supports and the mechanismligands for Heckinvolving reactions Pd(0)/Pd(II) like palladacycles, cycle by giving pincers, many carbene examples, complexes, however etc. the possibilityThe review of supports a mechanism the mechanisminvolving Pd(IV)/Pd(II) involving Pd(0)/Pd(II) cycle for few cycle ligands by giving has also many been examples, considered. however For the the reaction possibility of styrene of a mechanismand aryl halide involving with a Pd(IV)/Pd(II) mechanism involving cycle for few a Pd(0)/Pd(II) ligands has cycle, also been regiochemistry considered. of For the the addition reaction to ofstyrene styrene depends and aryl on halide the solvent with anda mechanism the nature involving of the anionic a Pd(0)/Pd(II) ligand. At cycle, higher regiochemistry solvent polarity of andthe additionthe weaker to styrene coordination depends ability on the of ligandsolvent there and the is a nature greater of contribution the anionic ofligand. a truly At cationic higher solvent form of polaritypalladium and complex, the weaker and coordination the higher relative ability yieldof ligand of 1,1-diphenylethylene there is a greater contribution instead of of stilbene. a truly cationic form Theof palladium review elaborates complex, onand the the necessity higher relative of the yield stability of 1,1 of‐diphenylethylene a catalyst, particularly instead for of recyclable stilbene. catalytic systems. Use of bidentate phosphines ligands are the better option for this, where use of

Catalysts 2017, 7, 267 8 of 53 Catalysts 2017, 7, 267 8 of 53

The review elaborates on the necessity of the stability of a catalyst, particularly for recyclable catalyticexcess ligand systems. is not Use necessary of bidentate to make phosphines stable complexes, ligands andare the a ratio better of 1:1 option leading for tothis, (L-L)Pd where complex use of excessis effective ligand for is more not necessary stable catalyst to make and stable thus leadingcomplexes, to higher and a TONs.ratio of 1:1 leading to (L‐L)Pd complex is effectiveThe problem for more of stable catalyst catalyst deactivation, and thus variousleading to solvent higher systems TONs. such as aqueous, molten salts, fluorous,The problem supercritical, of catalyst subcritical deactivation, fluids, Heck various reaction solvent under systems pressure such and as microwave aqueous, conditions molten salts, are fluorous,also discussed. supercritical, It has been subcritical seen that fluids, high Heck pressure reaction has aunder beneficial pressure effect and on microwave Heck reactions conditions where areoxidative also discussed. addition andIt has migratory been seen insertions that high steps pressure of the has Heck a beneficial cycles have effect a negative on Heck activation reactions volume where oxidativeand thus areaddition likely and to be migratory accelerated insertions by pressure. steps However,of the Heck the cycles PdH eliminationhave a negative can be activation retarded volumeby high and pressure, thus are leading likely to to a changebe accelerated of the productby pressure. distribution However, while the potentially PdH elimination extending can thebe retardedlifetime of by palladium high pressure, catalyst. leading For to microwave a change of assisted the product Heck distribution reaction, very while fast potentially heating by extending means of themicrowaves lifetime of lead palladium to shortening catalyst. of For the microwave reaction time, assisted while Heck the yieldsreaction, and very selectivity fast heating do not by greatlymeans ofdiffer microwaves when compared lead to shortening with the same of the reactions reaction carried time, while out using the yields conventional and selectivity heating. do not greatly differMany when examples compared of with recyclable the same (phase-separation) reactions carried catalysis out using of liquid-liquid conventional and heating. solid-liquid systems are discussedMany examples in the review.of recyclable Heck chemistry(phase‐separation) with less catalysis usual leaving of liquid groups‐liquid like and diazonium solid‐liquid salts, systemsthallium(III) are discussed and lead(IV) in the derivatives review. Heck and chemistry acid chlorides with less and usual anhydrides leaving are groups given like that diazonium provides salts,an alternative thallium(III) leaving and groupslead(IV) so derivatives as to have and more acid reactive chlorides substrates and anhydrides and milder are procedures. given that Aprovides section anon alternative reactions using leaving metals groups other so as than to have palladium more reactive like Cu, substrates Ni, Co, Rh, and Ir ismilder present procedures. in review A that section says ‘thoughon reactions none using of them metals can other rival than palladium palladium in synthetic like Cu, versatility,Ni, Co, Rh, some Ir is present features in may review complement that says ‘thoughHeck chemistry none of to them provide can eitherrival palladium cheaper catalysts in synthetic or catalysts versatility, capable some of effective features processing may complement of some Heckspecific chemistry substrates’. to provide either cheaper catalysts or catalysts capable of effective processing of some specificA number substrates’. of simple N-heterocyclic carbene (NHC) palladium-based complexes have emerged as effectiveA number catalysts of simple for a N variety‐heterocyclic of cross-coupling carbene (NHC) reactions palladium and have‐based been complexes proved tohave be emerged excellent assubstitutes effective forcatalysts phosphines for a variety ligands of in cross homogeneous‐coupling reactions catalysis and in a have wide been range proved of catalytic to be processes. excellent substitutesTheir efficiency for phosphines is not limited ligands to their in bindinghomogeneous ability tocatalysis any transition in a wide metal range as theyof catalytic also bind processes. to main Theirgroup efficiency elements is such not limited as beryllium, to their sulphur, binding and ability iodine. to any Because transition of their metal such as they specific also coordinationbind to main groupchemistry, elements they such both as stabilize beryllium, and sulphur, activate and metal iodine. centres Because in quite of their different such key specific catalytic coordination steps of chemistry,organic syntheses. they both stabilize and activate metal centres in quite different key catalytic steps of organicHillier syntheses. et al. [ 17] have reviewed the catalytic cross-coupling reactions mediated by palladium withHillier nucleophilic et al. [17] NHC have as ancillary reviewed ligands the catalytic of diazabutadienes cross‐coupling38– 40reactions(Figure 6mediated) mostly basedby palladium on their withown nucleophilic work. NHC as ancillary ligands of diazabutadienes 38–40 (Figure 6) mostly based on their own work. R R R R R R N N N N N N

38 39 40

R = for 38, 39, 40 = 2,4,6‐trimethylphenyl, 2,6‐di‐iso‐propylphenyl, cyclohexyl R = for 38 = 4‐methylphenyl, adamantly,2,6‐dimethylphenyl

Figure 6. N-heterocyclic carbene (NHC) ligands of diazabutadienes reviewed by Hillier et al. [17]. Figure 6. N‐heterocyclic carbene (NHC) ligands of diazabutadienes reviewed by Hillier et al. [17].

OnOn application of of these catalysts to Heck reactions, excellent yields except few were seen. In all cases,cases, thethe transtransproducts products were were selectively selectively obtained. obtained. However, However, no activity no activity was observed was observed for aryl chloridefor aryl chloridesubstrates. substrates. It was also It observedwas also thatobserved the reactions that the involving reactions the involving less reactive the less aryl reactive halides require aryl halides bulky requireelectron-donating bulky electron phosphines.‐donating Even phosphines. excess phosphine Even excess and higher phosphine Pd loading and higher is required Pd asloading they are is requiredprone to decompositionas they are prone under to decomposition Heck conditions under increasing Heck conditions the cost of increasing large-scale the processes. cost of large‐scale processes.Herrmann [18] has reviewed N-heterocyclic carbenes as ligands where ligands and metal complexesHerrmann41–51 [18](Figure has 7reviewed) are found N‐heterocyclic to be active towardscarbenes Heckas ligands reaction where giving ligands TONs and up tometal 1.7 6 complexes× 10 . These 41– ligands51 (Figure are 7) preferred are found mainly to be active for the towards reason thatHeck they reaction not only giving bind TONs to transition up to 1.7 metal× 106. Thesebut also ligands to main are grouppreferred elements. mainly Theyfor the are reason robust that and they found not toonly have bind high to transition thermal and metal hydrolytic but also todurability, main group easy elements. accessibility They and are require robust lower and found amount to of have loading. high Theythermal could and be hydrolytic derivatized durability, in future easyto have accessibility water-soluble and require catalysts lower (two-phase amount catalysis),of loading. immobilization, They could be derivatized and in chiral in future modiﬁcations. to have water‐soluble catalysts (two‐phase catalysis), immobilization, and in chiral modifications. However,

Catalysts 2017, 7, 267 9 of 53 Catalysts 2017, 7, 267 9 of 53

However,it was observed it was that observed it is necessary that it is necessaryto have bulky to have NHC bulky ligands NHC for ligands successful for successful reactions reactionswith catalysts with catalystsmade of these made ligands. of these ligands.

CH3 CH3 N N N N C Pd C N C X N C X N N N N H3C Pd Pd H2C C Pd C H C N C X 3 N C X N Br N N N CH3 CH3 CH CH3 3 44 41 42 43

BrH N N CH3 CH3 N N C N H3 C N N C N Pd Br CH3 Cl Pd CH3 C Cl N CH3 N N N CH3 N N

45 46 47

Br CH3 Cl N N N N C PPh2 C H H H C CH 3 3 48 49

H C CH H3C CH3 3 Cl 3 BF4 N N CH3 H C N N CH3 H3C C 3 C H H H C CH H3C CH3 3 3 50 51

Figure 7. N-heterocyclic carbene ligands and metal complexes reviewed by Herrmann [18]. Figure 7. N‐heterocyclic carbene ligands and metal complexes reviewed by Herrmann [18]. Herrmann et al. [19] presents an eloquent summary about catalytic applications of palladium Herrmann et al. [19] presents an eloquent summary about catalytic applications of palladium complexes with phosphorus ligands containing a metallated sp3-carbon centre (palladacycles) 36, complexes with phosphorus ligands containing a metallated sp3‐carbon centre (palladacycles) 36, 52 52 and with N-heterocyclic carbene ligands 41–46 and 53–62 (Figure8) for C-C and C-N coupling and with N‐heterocyclic carbene ligands 41–46 and 53–62 (Figure 8) for C‐C and C‐N coupling reactions of aryl halides. The activity of 36 was found to get increased to TONs of up to 4 × 104 after reactions of aryl halides. The activity of 36 was found to get increased to TONs of up to 4 × 104 after addition of tetrabutyl ammonium bromide in the reaction of aryl chlorides like 4-chloroacetophenone addition of tetrabutyl ammonium bromide in the reaction of aryl chlorides like 4‐chloroacetophenone with n-butyl acrylate under standard conditions. Recycling of this catalyst could be achieved by using with n‐butyl acrylate under standard conditions. Recycling of this catalyst could be achieved by using non-aqueous ionic liquids (NAILs) as media. non‐aqueous ionic liquids (NAILs) as media. A number of evidences are given for mechanistic discussions and about their role in the catalytic cycle. The catalytic activity of these complexes strongly depends on the steric bulk of the NHC ligand. Structural versatility is a great advantage of N‐heterocyclic carbenes where chirality,

Catalysts 2017, 7, 267 10 of 53

functionalization, immobilisation and chelate effects can be achieved by easy means. Few complexes Catalystscontain2017 both, 7, 267 NHC and phosphine ligands leading to combine the advantages of stability10 of of 53 bis(carbene) complexes with the good activity of phosphine complexes in C‐C coupling reactions.

R N N R Ar Me Me Ar PR Ar Me Me Ar 2 N I N Pd Cl N I N Pd Pd X N N Pd N I N N N N N I N PR2 Ar Me Ph Ph Me Ar 52 53 54 55

N N NC CN N N PR2 Pd O(CH2)n O N Pd N NC CN X Pd O N 58 X N 57 HO(H C) 56 2 n

N N N Pd O Pd O O N N N Pd O

N O O N

59 60

N N N N Pd C N N Pd P(oTol) 61 3 62

Figure 8. Palladium complexes with phosphorus and N-heterocyclic carbene ligands reviewed by Herrmann et al. [19]. Catalysts 2017, 7, 267 11 of 53

A number of evidences are given for mechanistic discussions and about their role in the catalytic cycle. The catalytic activity of these complexes strongly depends on the steric bulk of the NHC ligand. Structural versatility is a great advantage of N-heterocyclic carbenes where chirality, functionalization, immobilisationCatalysts 2017, 7, 267 and chelate effects can be achieved by easy means. Few complexes contain both11 of 53 NHC and phosphine ligands leading to combine the advantages of stability of bis(carbene) complexes with the goodFigure activity 8. Palladium of phosphine complexes complexes with phosphorus in C-C coupling and N‐heterocyclic reactions. carbene ligands reviewed by BeletskayaHerrmann andet al. Cheprakov [19]. [20] have given a critical survey on the application of palladacycles as catalysts for cross-coupling and similar reactions where the advantages and limitations of palladacycle catalystsBeletskaya are discussed. and Cheprakov The advantages [20] have given being a critical the slow survey release on the of application Pd(0) that of helps palladacycles to suppress as catalysts for cross‐coupling and similar reactions where the advantages and limitations of unwanted processes of nucleation and growth of large inactive Pd metal particles. Bulky ligands palladacycle catalysts are discussed. The advantages being the slow release of Pd(0) that helps to with electron-rich phosphines or heterocyclic carbenes are essential and should be used for desired suppress unwanted processes of nucleation and growth of large inactive Pd metal particles. Bulky selectivity. However, the phosphine-free chemistry has limited scope. These ligands can be combined ligands with electron‐rich phosphines or heterocyclic carbenes are essential and should be used for withdesired palladacycles selectivity. into However, hybrid the catalysts, phosphine which‐free retainchemistry the advantageshas limited scope. of both. These Such ligands complexes can be are usuallycombined not more with activepalladacycles than non-palladacyclic into hybrid catalysts, complexes which with retain the samethe advantages ligands. A reviewof both. of Such various palladacyclescomplexes are with usually subclass not of more phosphine-free active than non catalysts‐palladacyclic such as phosphine-derivedcomplexes with the palladacyclessame ligands. 36A , 56, 63–review68, phosphite of various palladacycles palladacycles69 with–71 ,subclass CN-palladacycles of phosphine including‐free catalysts imine such palladacycles as phosphine72‐derived–78, oxime palladacyclespalladacycles79 36–82, 56and, 63 some–68, phosphite miscellaneous palladacycles CN- 83– 9169,– CS-71, CN and‐palladacycles CO-palladacycles including92– 94imine, pincer palladacyclespalladacycles95 72–97–78, hybrid, oxime palladacyclic palladacycles catalysts 79–82 and98 –some102 andmiscellaneous couple of palladacyclesCN‐ 83–91, CS as‐ and structurally CO‐ definedpalladacycles catalysts 92103–94,, 104pincer(Figure palladacycles9) is taken. 95– It97 was, hybrid seen palladacyclic that in most catalysts of the cases 98–102 palladacycles and couple serveof aspalladacycles a source of highly as structurally active zero-valent defined catalysts palladium 103, species.104 (Figure 9) is taken. It was seen that in most of thePincer cases palladacycles catalysts are bis-chelatedserve as a source palladacycles of highly active of XCX zero (X‐ =valent P, N, palladium S) type. They species. are extremely stable. It was observedPincer catalysts that using are bis pincer‐chelated catalysts, palladacycles electron richof XCX phosphine (X = P, orN, NHC S) type. ligands, They theare Heckextremely reaction canstable. be carried It was outobserved with althoughthat using cheappincer butcatalysts, otherwise electron unreactive, rich phosphine chloroarenes. or NHC ligands, However, the basedHeck on a surveyreaction over can thebe carried application out with of palladacycles although cheap in catalysis,but otherwise it was unreactive, stated the chloroarenes. initial promises However, have not based on a survey over the application of palladacycles in catalysis, it was stated the initial promises been fulfilled. The catalysts, often announced as outstanding because of very high catalytic activity in have not been fulfilled. The catalysts, often announced as outstanding because of very high catalytic several test reactions, very rarely find applications in preparative chemistry. Neither enantioselectivity activity in several test reactions, very rarely find applications in preparative chemistry. Neither nor recyclability has been realized. Dozens of palladacycles of all imaginable classes have been enantioselectivity nor recyclability has been realized. Dozens of palladacycles of all imaginable studied in various cross-coupling reactions, but none appeared to be the well-defined catalyst, as was classes have been studied in various cross‐coupling reactions, but none appeared to be the well‐ thoughtdefined earlier. catalyst, as was thought earlier.

R2N NR2 Ph P O O NR2 N Pd Pd P P O O P NR N PPh 2 NR2 2 R2N Pd 66 Br 2 NR = NMe , N(CH ) , N(CH ) 63 64 65 2 2 2 4 2 5

Figure 9. Cont.

Catalysts 2017, 7, 267 12 of 53 Catalysts 2017, 7, 267 12 of 53

But

O R Ph R N O PR2 P P N P(i-Pr)2 But Pd Pd Pd Cl Cl 2 Pd Ph 2 OAc NMe2 OAc Cl R = Ph, iPr 67 68 69 70 t Bu O O Ph P(OAr) 2 N Ph Br N t Pd Bu Pd N Pd N Pd Cl 2 AcO Br Ph F3COCO 2 2 Ar = 2,4-(t-Bu)2C6H3 Ph 74 71 72 73

Ar R1 R1 N Pd N Ph NR SR1 Fe 1 X 2 Pd R Pd Pd R1 1 AcO AcO AcO 2 2 2 X = Cl, I 76 R = (CH ) C F 77 75 1 2 3 6 17 78

R N OH N-OH N OH Pd N-OH R Pd Fe Pd Pd Cl 2 Cl Cl 2 Cl 2 79 2 82 80 81 X

N Pd N Pd OAc N NMe OAc 2 2 Pd 2 PdCl X = CH2, O Cl 83 2 2 84 85 86 F R1

Br PPh2 N Pd Cl N N Ph R R Pd Cl Pd N 2 OAc Pd PdCl N N N N 90 2 Ph2P Br N 2 R, R1 = Me, CF3 Me 87 2 88 89 R2 = H, F Figure 9. Cont. Catalysts 2017, 7, 267 13 of 53 Catalysts 2017, 7, 267 13 of 53

R S R1 N SR Pd R Pd H O 2 OAc O N N Cl 2 S 2 2 O Pd Ph R, R = H, Me, OMe, CF 1 3 R = Me, t-Bu PdCl Cl R = H, F 2 2 2 91 92 93 94 N N

PR2 N N N H P PdI Pd PdR N N 1 N X PR N 2 N 95 96 97 98

L R

Me2 N PdOAc L N OH N HN Pd OAc Cl NPh O Pd N PhN L COOAr L = P(t-Bu)3 , PH(t-Bu)2, PHPAc2 , PHCy2, PCy3 etc. R = Me, Ph 99 100 101 102

N F3COCO 2 Pd Pd O R X Fe X N R O O Pd Fe N 104 103 O Figure 9. Ligands and palladacycles reviewed by Beletskaya and Cheprakov [20 ]. Figure 9. Ligands and palladacycles reviewed by Beletskaya and Cheprakov [20]. A review by Zafar et al. [21] is about the progress of palladium compounds as a catalyst for A review by Zafar et al. [21] is about the progress of palladium compounds as a catalyst for Heck-Mizoroki and Suzuki-Miyaura coupling reactions. Some synthesized palladium compounds and Heck‐Mizoroki and Suzuki‐Miyaura coupling reactions. Some synthesized palladium compounds their progress in terms of ligand modiﬁcation and other associated parameters up to early 2014 for and their progress in terms of ligand modification and other associated parameters up to early 2014 Heck-Mizorokifor Heck‐Mizoroki and Suzuki-Miyauraand Suzuki‐Miyaura coupling coupling reactions reactions are are summarized summarized in in it. it. It It was was observed observed that thethat electron the electron donating donating ligands ligands such as such carbenes, as carbenes, phosphines phosphines and nitrogen and nitrogen donor donor ligands ligands can increase can theincrease activity, the selectivity activity, selectivity and stability and stability of its catalysts. of its catalysts. Palladium Palladium nanoparticles nanoparticles and and palladacycle palladacycle can alsocan act also as act precatalysts as precatalysts for Heck for Heck and Suzukiand Suzuki coupling coupling reactions. reactions. The The technological technological hurdles hurdles in in using homogeneoususing homogeneous catalysts catalysts are minimized are minimized by putting by putting the catalyst the catalyst on a on polymer a polymer support. support.

2.2.2.2.2.2. Homogeneous Homogeneous Catalysis Catalysis

QuestQuest for for High High TON TON Herrmann et al. [22] have reviewed applications of metal complexes 36, 45, 52, 56, 105 and 106 (Figure 10) in Heck type reactions where detailed information about developments in palladium catalytic Catalysts 2017, 7, 267 14 of 53 Catalysts 2017, 7, 267 14 of 53 Herrmann et al. [22] have reviewed applications of metal complexes 36, 45, 52, 56, 105 and 106 (Figure 10) in Heck type reactions where detailed information about developments in palladium systemscatalytic and systems their and successful their successful approach approach towards activation towards activation of less reactive of less substrates reactive substrates like aryl chlorides like aryl ischlorides mentioned. is mentioned. Palladacycles Palladacycles are found are to befound active to againstbe active a broadagainst spectrum a broad ofspectrum reactions of andreactions have advantagesand have likeadvantages active towards like active more economictowards arylmore halides, economic high activityaryl halides, at low palladium:ligandhigh activity at ratiolow (1:1)palladium:ligand and improved ratio thermal (1:1) stabilityand improved and life-time thermal in stability solution. andThe life possible‐time in mechanisms solution. The involving possible Pd(0)/Pd(II)mechanisms involving or Pd(II)/Pd(IV) Pd(0)/Pd(II) catalytic or Pd(II)/Pd(IV) cycles has catalytic also been cycles reviewed has also for been this reviewed class of catalyst. for this Theclass mechanism of catalyst. of The Heck mechanism type reactions of Heck catalysed type reactions by palladacycles catalysed is thoughtby palladacycles to involve is active thought Pd(0) to speciesinvolve howeveractive Pd(0) the possibilityspecies however of a Pd(II)/Pd(IV) the possibility mechanism, of a Pd(II)/Pd(IV) working in mechanism, competition working is also not in ruledcompetition out. In is fact, also it not is stated ruled that, out. Pd(II):Pd(IV)In fact, it is stated could that, only Pd(II):Pd(IV) be a side mechanism could only which be a side cannot mechanism solely be responsiblewhich cannot for solely the high be responsible turnovers. for the high turnovers.

2 Ph Ph CH Ph Ph 2ClO4 CH3 4 N N N Hg Cr(CO)5 5 N N N Ph Ph CH Ph Ph CH3 105 106

Figure 10. Metal complexes reviewed by Herrmann et al. [22]. Figure 10. Metal complexes reviewed by Herrmann et al. [22].

FarinaFarina [23[23]] has has discussed discussed the problemsthe problems associated associated like scope, like purity, scope, impurity purity, profile, impurity throughput profile, andthroughput time for and developing time for developing high-turnover high catalysts‐turnover for catalysts the cross-coupling for the cross and‐coupling Heck and reactions. Heck Numerousreactions. Numerous examples examples are given are to given illustrate to illustrate the developments the developments in the in area the of area palladacycles of palladacycles and 107 109 coordinativelyand coordinatively unsaturated unsaturated Pd catalysts Pd catalysts featuring featuring bulky bulky phosphanes phosphanes of high of high denticity denticity like like –107– (Figure109 (Figure 11) including 11) including36, 52 36, 70, 52, 71, 70, 76, 71, 78, 76, 79, 78, 90, 79, 91, 90, 95, 91and, 95 few and more few similarmore similar compounds. compounds. TheseThese palladacyclespalladacycles areare reviewedreviewed fromfrom aa mechanisticmechanistic andand syntheticsynthetic standpoint,standpoint, andand comparedcompared withwith moremore traditionaltraditional catalystscatalysts obtainedobtained fromfrom conventionalconventional mono-mono‐ andand polydentatepolydentate NN andand P-basedP‐based ligands,ligands, asas wellwell asas PdPd catalystscatalysts withoutwithout strongstrong ligands,ligands, suchsuch asas Pd colloids or heterogeneous catalystscatalysts andand polymerpolymer supportedsupported catalysts.catalysts. CarbeneCarbene ligands,ligands, thoughthough lessless documenteddocumented untiluntil thenthen werewere believedbelieved toto havehave potentialpotential forfor high-TONhigh‐TON research because theythey are more robust than most phosphines ligands.

PR PR2 R Pd OCOCF R Pd OCOCF3 S

PR2 2 N Pd R = i-Pr, t-Bu Pd R OAc 108 109 2 108 109 Figure 11. Palladacycles and coordinatively unsaturated Pd catalysts featuring bulky phosphanes of highFigure denticity 11. Palladacycles in review by and Farina coordinatively [23]. unsaturated Pd catalysts featuring bulky phosphanes of high denticity in review by Farina [23]. Reactions Involving Aryl Chlorides and Bromides Reactions Involving Aryl Chlorides and Bromides For Heck reactions, aryl bromides and chlorides are the most desirable substrates being cheaper and moreFor Heck readily reactions, available; aryl however, bromides not and many chlorides are used are as the substrates most desirable as they are substrates lower in being reactivity cheaper due toand their more stronger readily C-X available; bonds and however, by far having not many lower are TONs used byas severalsubstrates orders as they of magnitude. are lower in This reactivity section describesdue to their few stronger reviews C that‐X bonds draw and attention by far to having future lower challenges TONs in by this several area orders by highlighting of magnitude. advances This concerningsection describes Heck reactions few reviews using that aryl draw bromides attention and chlorides. to future A challenges review by in Whitecombe this area by and highlighting others [24] discussadvances the concerning development Heck of reactions catalytic systemsusing aryl that bromides can activate and unreactivechlorides. A aryl review halide by towards Whitecombe Heck catalysis.and others The [24] lesser discuss yields the are development attributed toof thecatalytic poor reactivitysystems that of aryl can halidesactivate due unreactive to their C-Xaryl bondshalide

Catalysts 2017, 7, 267 15 of 53 Catalysts 2017, 7, 267 15 of 53 towards Heck catalysis. The lesser yields are attributed to the poor reactivity of aryl halides due to their C‐X bonds strength as well as the higher temperature used to activate aryl bromides and strengthchlorides as resulting well as the in the higher catalyst temperature decomposition used to where activate P‐C aryl bond bromides cleavage and takes chlorides place eventually resulting inleading the catalyst to metal decomposition precipitation. where This P-C is bonddemonstrated cleavage by takes giving place a eventuallynumber of leading examples to metal using precipitation.monodentate This phosphine is demonstrated ligands, or by chelating giving a diphosphine, number of examples phosphite, using phosphonium monodentate salt. phosphine However, ligands,there are or examples chelating of diphosphine, successful reactions phosphite, taking phosphonium place under salt. similar However, conditions there with are palladacycles, examples of successfulN‐heterocyclic reactions carbene taking complexes place under and similar pincers conditions (all previously with discussed palladacycles, structures) N-heterocyclic as they are carbene stable complexesat higher temperature. and pincers (all previously discussed structures) as they are stable at higher temperature. TheThe reactivity reactivity of of ArX ArX is is found found to to be be somewhat somewhat better better if if electron electron withdrawing withdrawing groups groups are are present present inin arylhalides; arylhalides; however, however, reactivity reactivity decreases decreases if if an an electron electron rich rich substituent substituent is is present present typically typically on on aryl aryl halide.halide. The The mechanistic mechanistic study study discussed discussed indicates indicates that, that, the prediction the prediction of single of mechanismsingle mechanism is no longer is no adequatelonger adequate and there and are stillthere unknown are still factorsunknown at play factors in Heck at play mechanism. in Heck Themechanism. review exhaustively The review elaboratesexhaustively the mechanismelaborates the involving mechanism classical involving Pd(0)/Pd(II) classical cycles Pd(0)/Pd(II) and also cycles Pd(II)/Pd(IV) and also cyclePd(II)/Pd(IV) (this is discussedcycle (this in is detail discussed in present in detail review in under present mechanism review under section). mechanism In addition section). to these In catalytic addition systems, to these heterogeneouscatalytic systems, catalyst heterogeneous and the catalysts catalyst using and metalsthe catalysts other thanusing palladium, metals other like than Ni, Cr,palladium, Fe and Co, like areNi, described Cr, Fe and where Co, are the described yield obtained where using the yield these obtained metals areusing reasonable; these metals however, are reasonable; they are used however, less thanthey Pd. are Use used of conditionsless than Pd. such Use as of molten conditions salts or such phosphine as molten free salts conditions or phosphine facilitates free the conditions product formationfacilitates at the a higherproduct rate. formation at a higher rate. AA review review by by Littke Littke and and Fu Fu[25] [ describes25] describes the progressive the progressive developments developments in the area in of the palladium area of ‐ palladium-catalysedcatalysed couplings couplings of aryl chlorides. of aryl chlorides. It was always It was observed always observed that the palladium that the palladium-catalysed‐catalysed coupling couplingprocesses processes show poor show reactivity poor reactivity towards towardsaryl chlorides, aryl chlorides, although althoughthey are more they areattractive more attractive substrates substratesthan the corresponding than the corresponding bromides, bromides, iodides, and iodides, triflates and in triflatesterms of in cost terms and of availability. cost and availability. Traditional Traditionalpalladium palladium triarylphosphane triarylphosphane catalysts catalysts are effective are effective only for only the for coupling the coupling of certain of certain activated activated aryl arylchlorides chlorides (for (for example, example, heteroaryl heteroaryl chlorides chlorides and and substrates substrates bearing bearing electron-withdrawingelectron‐withdrawing groups),groups), butbut not not for for aryl aryl chlorides chlorides in in general. general. However, However, catalysts catalysts using using bulky, bulky, electron-rich electron‐rich phosphine phosphine and and carbenecarbene ligands ligands have have proved proved to to be be mild mild and and versatile versatile for for aryl aryl chloride chloride coupling. coupling. InIn a a similar similar review review by by Zapf Zapf and and Beller Beller [ 26[26],], ligands ligands and and palladacycles palladacycles51 51, ,99 99and and110 110to to115 115 (Figure(Figure 12 12)) areare reviewed reviewed for for their their activity activity towards towards the the C‐C C-C and andC‐N C-Ncoupling coupling reactions reactions of aryl of halides, aryl halides,especially especially aryl chlorides. aryl chlorides. An important An important advantage advantage of this of this class class of of ligands ligands is theirtheir significantlysignificantly increasedincreased stability stability towards towards air air and and moisture. moisture. Due Due to to their their basicity basicity and and steric steric bulkiness, bulkiness, they they constitute constitute excellentexcellent ligands ligands for for palladium-catalysed palladium‐catalysed coupling coupling reactions. reactions. It It was was found found that that the the palladacycles palladacycles with with highhigh ligand–palladium ligand–palladium ratios ratios are are suitable suitable for for aryl-X aryl‐X activation activation reactions reactions at at elevated elevated temperatures. temperatures. However,However, specially specially designed designed basic basic and and sterically sterically demanding demanding phosphines phosphines show show superior superior performance performance underunder milder milder reaction reaction conditions. conditions. In In addition, addition, when when monocarbene monocarbene palladium(0) palladium(0) quinone quinone complexes complexes werewere tested tested for for the Heckthe Heck reaction reaction using tetra-n-butylammoniumusing tetra‐n‐butylammonium bromide bromide as an ionic as liquid, an ionic a reasonable liquid, a toreasonable good activity to good for both activity electron for both deficient electron and deficient electron and rich electron aryl chlorides rich aryl was chlorides obtained. was obtained.

P PR PR PR2 N 2 N 2 N

110 111 112 113

Figure 12. Cont.

Catalysts 2017, 7, 267 16 of 53 CatalystsCatalysts 2017, 7 2017, 267, 7, 267 16 of 5316 of 53

SO Na SO3N a 3

HO HO OH OH P P HO O PPhNaO SNaO3S HO O PPh2 2 3 OH OH

114 115 115SO NaSO3N a 114 3

Figure 12. Ligands reviewed by Zapf and Beller [26]. FigureFigure 12. Ligands 12. Ligands reviewed reviewed by Zapf by and Zapf Beller and [26].Beller [26]. 2.2.3. Heterogeneous Catalysis 2.2.3.2.2.3. Heterogeneous Heterogeneous Catalysis Catalysis Carbon—carbon bond coupling reactions—Suzuki, Heck and Stille—using catalyst on solid Carbon—carbon bond coupling reactions—Suzuki, Heck and Stille—using catalyst on solid supportCarbon—carbon has been bond reviewed coupling by Franzreactions—Suzuki,én [27]. Metal-catalysed Heck and Stille—using coupling reactions catalyst areon reportedlysolid support has been reviewed by Franzén [27]. Metal‐catalysed coupling reactions are reportedly supportefficient has been and reliablereviewed methods by Franzén for the [27]. introduction Metal‐catalysed of new coupling carbon-carbon reactions bonds are reportedly onto molecules efficient and reliable methods for the introduction of new carbon‐carbon bonds onto molecules efficientattached and reliable to a solid methods support. for A the concise introduction summary of of new the carbon use of‐ thesecarbon reactions, bonds onto in the molecules field of solid attached to a solid support. A concise summary of the use of these reactions, in the field of solid phase attachedphase to organica solid support. synthesis A resultingconcise summary in small of organic the use molecule of these reactions, libraries is in presented. the field of This solid involves phase the organic synthesis resulting in small organic molecule libraries is presented. This involves the organicpalladium-catalysed synthesis resulting intramolecular in small organic Heck reactionmolecule for libraries the solid-phase is presented. synthesis This of involves indole analogues the palladium‐catalysed intramolecular Heck reaction for the solid‐phase synthesis of indole analogues palladium116, cyclic‐catalysed tetrapeptide intramolecular derivative Heck via macrocyclizationreaction for the solid117,‐phase 2-substituted synthesis benzofuran of indole carboxylicanalogues acids 116, cyclic tetrapeptide derivative via macrocyclization 117, 2‐substituted benzofuran carboxylic 116, 118cyclic, phenyl tetrapeptide acetylene derivative oligomers via119 ,macrocyclizationα,β-unsaturated methyl117, 2‐substituted ester phenyl benzofuran Sulfonide 120 carboxylic, fused bicyclic acids 118, phenyl acetylene oligomers 119, α,β‐unsaturated methyl ester phenyl Sulfonide 120, fused acidsamino 118, phenyl acid derivatives acetylene oligomers121, β-keto 119 esters, α,β‐122unsaturatedand in the methyl generation ester of phenyl 1,2-disubstituted Sulfonide 120 olefin, fused libraries bicyclicbicyclic amino amino acid derivativesacid derivatives 121, β‐ 121keto, β‐ estersketo esters 122 and 122 in and the ingeneration the generation of 1,2 ‐ofdisubstituted 1,2‐disubstituted olefin olefin 123 (Figure 13). librarieslibraries 123 (Figure 123 (Figure 13). 13).

R2 R2 O O Me Me N N P PO O N N HOOCHOOC COOMeCOOMe R R O OR 1 R1 O O 116 116 117 117 118 118

COOMeCOOMe H H MeOOCMeOOC N N O O P P S S N N P Ts P SiMe3SiMe 3 O O Ts O O Ph 119 119 120 120 121 121 Ph O OO O R R P PCH2O CH2O CH2 OCH2 O P PO O 122 122 O 123O 123

Figure 13. Molecule made via solid-phase synthesis using Heck reaction reviewed by Franzén [27]. FigureFigure 13. Molecule 13. Molecule made madevia solid via‐ phasesolid‐ phasesynthesis synthesis using Heckusing reactionHeck reaction reviewed reviewed by Franzén by Franzén [27]. [27].

A reviewAA reviewreview by Biffis byby Bifﬁs Biffiset al. et et[28] al. al. articulately [ [28]28] articulately articulately describes describes describes the application thethe application application of palladium ofof palladiumpalladium metal metal metalcatalysts catalystscatalysts to Hecktoto HeckHeck reaction. reaction.reaction. The major TheThe majormajor advantages advantagesadvantages of supported ofof supportedsupported palladium palladiumpalladium metal metal metalare the areare simplification thethe simpliﬁcationsimplification of the of of thethe workwork-upwork‐up procedure‐up procedure procedure and and the and thepossibility the possibility possibility of facile of facileof facilerecovery recovery recovery of of the the of precious preciousthe precious metal. metal. metal. Initially, Initially, Initially, the the review the review gives givesgives a brief a briefoutline outline of the of historical the historical development development of heterogeneous of heterogeneous catalysis catalysis as applied as applied to the toHeck the Heck reactionreaction followed followed by the by discussionthe discussion on both on bothsupported supported metal metalcatalysts catalysts and stabilizedand stabilized colloidal colloidal

Catalysts 2017, 7, 267 17 of 53 a brief outline of the historical development of heterogeneous catalysis as applied to the Heck reaction followed by the discussion on both supported metal catalysts and stabilized colloidal palladium catalysts. Heterogeneous catalysts supported over different kinds of supports (carbon, inorganic oxides, molecular sieves, polymeric materials, etc.) are reviewed with particular attention to the metal leaching and the nature of catalysis. Ample of examples are given to suggest the presence of leaching, precautions to be taken to prevent leaching or use of methods like re-capture of the leached palladium species with some support. The data provide convincing evidences suggesting the catalytic cycle is sustained mainly by soluble species leached out from the starting solid material after using palladium metal catalysts, either supported or colloidal. The advantage of using heterogeneous catalysis is that it does not necessarily require ligand; the reaction temperature can be high enough for speeding up of the reaction and more of all, the recycling of catalyst is possible although not to a large extent due to extensive metal leaching, metal phase restructuring, structural damage of the support, fouling by carbonaceous deposits, etc., nevertheless systematic tailoring of support can overcome these problems. Recently, the state of the art, beneﬁts, and challenges of coupling microwave heating with heterogeneous Pd/C catalysis are discussed in the review by Cini et al. [29]. Microwave dielectric heating allowed a signiﬁcant acceleration of the C-C coupling reaction rate, shortening the reaction time from hours to minutes. The deactivation of catalyst was not observed when Pd/C-catalysed Mizoroki-Heck reaction was carried out under microwave heating and the recycling of catalyst was also possible. Palladium supported on macroscopic pattern-vertically-aligned carbon nanotubes (Pd/VA-CNTs (carbon nanotubes)) catalyst exhibits higher activity in comparison to Pd supported on simple activated charcoal under the same reaction conditions.

2.2.4. Industrial Catalysis A review on ‘Palladium-Catalysed C-C Coupling: Then and Now’ by Barnard [30] focuses on some of the early work in palladium-catalysed C-C bond formation and change in the methodologies during its developments. It talks about how catalyst has been developed from simple Pd compounds (chloride, acetate) with ligands like triphenylphosphine for variety of aryl halides with even sterically restricted partners, up to the development and applicability of stable, bulky and efﬁcient ligands like PCy3, P(tBu)3, biphenyldialkylphosphine, palladacycle, pincer and carbene complexes that can generate highly active species. The efforts made to develop supported Pd catalysts suitable for recycle, involving both ligandless and anchored ligand systems, the quest for achieving improved conditions allowing high turnover numbers for aryl bromides and reaction of less reactive aryl chlorides are also discussed. It also mentions about two important reviews, i.e., by Corbet and Mignani [31] on the range of patented cross-coupling technologies and by Yin and Liebscher [32] on C-C coupling by heterogeneous Pd catalysts.

2.2.5. Nano Catalysis Narayanan [33] has highlighted some of the advances in the application of noble metal nanoparticles as catalysts for Suzuki and Heck reactions. Metal nanoparticles suspended in colloidal solutions and those adsorbed onto bulk supports are attractive catalysts for a wide variety of organic and inorganic reactions, compared to bulk catalysts as they have a high surface-to-volume ratio and very active surface atoms. Important aspects such as shape dependence on the catalytic activity, novel types of supported metal nanoparticles as nanocatalysts and the use of bi-metallic, tri-metallic and multi-metallic nanoparticles as catalysts for the Suzuki and Heck cross-coupling reactions are considered. A review by Cai et al. [34] provides a summary of bimetallic nanomaterial-catalysed organic transformations and expresses the potential for such bimetallic nanoparticle catalysis to have signiﬁcant reaction scope, especially with palladium such as magnetically separable “quasi-homogeneous” Pd-Ni nanoalloys, Au-Pd particles conﬁned in silica nanorattles, carbon-supported bimetallic Pd-M (M = Ag, Catalysts 2017, 7, 267 18 of 53

Ni, and Cu) nanoparticles, etc. It was observed that the carbon-supported bimetallic nanoparticles Pd-Cu/CCatalysts 2017 prepared, 7, 267 by γ-irradiation at room temperature exhibits high catalytic efﬁciency in the Suzuki-18 of 53 and Heck-type coupling reactions. Baboo [[35]35] has reviewed the multimetallic nanomaterial based catalysis forfor the reactions like oxidation, hydrogenation, hydrogenation, coupling coupling reactions, reactions,viz. Heck, Suzukiviz. andHeck, Sonogoshira, Suzuki Hydrodechlorinationand Sonogoshira,, amidation,Hydrodechlorination, reductive amination amidation, and reductive hydrogenolysis. amination Although and hydrogenolysis. it is known Although that nanomaterial it is known based that catalystsnanomaterial can easilybased becatalysts separated can and easily reused be separated with same and catalytic reused activities, with same researchers catalytic haveactivities, paid moreresearchers attention have to paid the use more of multimetallicattention to the nano use catalysts of multimetallic that show nano excellent catalysts performance that show than excellent their monometallicperformance than nano their catalysts. monometallic It is mentioned nano that,catalysts. despite It is the mentioned great success that, of despite bimetallic the nanomaterials great success inof termsbimetallic of their nanomaterials application in to terms oxidation, of their hydrogenation, application to and oxidation, coupling hydrogenation, reactions, they and have coupling not yet foundreactions, a wider they applicationhave not yet in found the reactions a wider forapplication the synthesis in the of reactions complex for molecule. the synthesis The review of complex talks aboutmolecule. the use The of review Pd-based talks bimetallic about the nanomaterials use of Pd‐based and magnetically bimetallic nanomaterials separable “quasi-homogeneous” and magnetically Pd-Niseparable nanoalloys “quasi‐homogeneous” for coupling reactions. Pd‐Ni nanoalloys for coupling reactions. Recently, Labulo Labulo et et al. al. [36 [36]] have have reviewed reviewed the CNTs the CNTs as efﬁcacious as efficacious supports supports for palladium-catalysed for palladium‐ carbon–carboncatalysed carbon–carbon cross-coupling cross reactions.‐coupling Suchreactions. catalysts Such have catalysts shown have superior shown catalytic superior performance catalytic andperformance better recyclability and better for recyclability these reactions for asthese they reactions impart stability as they to impart the palladium stability catalyst. to the palladium The wide varietycatalyst. of The surface wide functionalization variety of surface techniques functionalization for CNTs techniques that improve for their CNTs properties that improve as catalyst their supports,properties as as well catalyst as the supports, methods as available well as the for methods loading available the catalyst for nanoparticles loading the catalyst onto the nanoparticles CNTs with aonto particular the CNTs focus with on a the particular effect of focus the solvent, on the baseeffect and of the catalyst solvent, loading base has and been catalyst discussed loading in has detail been in thisdiscussed review. in It detail was observed in this review. that the It yield was is observed largely affected that the by yield the choice is largely of solvent affected and by base the employed choice of forsolvent the catalytic and base reaction. employed An for improved the catalytic yield reaction. could be An achieved improved with yield para- could and be meta-substituted achieved with para aryl‐ halidesand meta and‐substituted not much improvementaryl halides and is seen not withmuch those improvement substituted is at seen the ortho-position.with those substituted Although at thisthe catalystortho‐position. possesses Although excellent this catalytic catalyst activities possesses compared excellent with commercialcatalytic activities Pd/C catalysts, compared it suffers with fromcommercial the problem Pd/C ofcatalysts, leaching. it suffers from the problem of leaching.

2.3. Array of Heck Type ReactionsReactions This sectionsection dealsdeals withwith thethe HeckHeck reactionreaction performedperformed withwith somesome modiﬁcations.modifications. Reviews are arranged inin thethe wayway theythey ﬁtfit bestbest intointo oneone ofof thethe categorycategory howeverhowever therethere areare few few with with interlinks. interlinks.

2.3.1. Dehydrogenative/Oxidative Heck Heck Reaction Reaction When Ar Ar-H‐H is is used used at at the the place place of ofAr‐ Ar-XX in Heck in Heck reaction reaction it is itcalled is called as dehydrogenative as dehydrogenative Heck Heckreaction reaction also known also known as Oxidative as Oxidative Heck reaction Heck reaction or Fujiwara or Fujiwara-Moritani‐Moritani [37] reaction [37] or reaction simply or Fujiwara simply Fujiwarareaction sometimes. reaction sometimes. The fact is this The version fact is thisof the version Mizoroki–Heck of the Mizoroki–Heck reaction was the reaction first catalytic was the Heck ﬁrst catalyticreaction Heckto be reactiondiscovered to bein discovered1968, where in the 1968, palladium(II) where the‐ palladium(II)-catalysedcatalysed arylation of olefins arylation from of oleﬁnsphenylmercuric from phenylmercuric chloride, using chloride, catalytic using amounts catalytic of copper(II) amounts chloride of copper(II) assisted chloride by oxygen assisted for the by oxygenregeneration for the of regeneration palladium(II) of palladium(II)was carried out. was carriedThis reaction out. This is reactionclosely related is closely to relatedthe classical to the classicalMizoroki–Heck Mizoroki–Heck reaction, reaction, where whereinstead instead of initiation of initiation by byoxidative oxidative addition addition process, process, it it follows transmetallationtransmetallation stepstep oror aa C-HC‐H activationactivation stepstep (Scheme(Scheme2 2).).

Scheme 2. Reaction scheme for C-H activation and transmetallation. Scheme 2. Reaction scheme for C‐H activation and transmetallation.

This is one of the important reactions with respect to atom economy principle since it directly uses the Ar‐H compounds thus eliminating additional synthetic step in many total syntheses for halogenations, i.e., in other words, C‐H activation of arenes eliminates the need for halogen. The best example of this reaction is the synthesis of benzofuran and dihydrobenzofuran. These structures are important components of numerous biologically active compounds and are preferred to be prepared by dehydrogenative Heck reaction.

Catalysts 2017, 7, 267 19 of 53

This is one of the important reactions with respect to atom economy principle since it directly uses the Ar-H compounds thus eliminating additional synthetic step in many total syntheses for halogenations, i.e., in other words, C-H activation of arenes eliminates the need for halogen. The best example of this reaction is the synthesis of benzofuran and dihydrobenzofuran. These structures are important components of numerous biologically active compounds and are preferred to be prepared by dehydrogenative Heck reaction. Gligorich and Sigman [38] presented a review on advancements and challenges of palladium(II) catalysed oxidation reactions with molecular oxygen as the sole oxidant, where reviewers have discussed some oxidative Heck reactions. The review paper highlights some of the developments until then in direct molecular oxygen-coupled Pd(II)-catalysed oxidation reactions. Although there are reports with positive results for the development of more efﬁcient ligand-modulated oxidative Heck reactions that can be performed under an air atmosphere at room temperature, the asymmetric oxidative Heck reaction still suffers from many limitations and requires further studies. Karimi et al. [39] have reviewed similar types of reactions describing the oxidative Heck reactions of organometallic compounds such as organomercuric acetates, organoboronic acids, organofluorosilicates and arylstannanes. A number of successful examples are given for the intermolecular, intramolecular, nonsymmetrical, asymmetrical oxidative Heck reaction in presence or in absence of air, with ligand-free or ligand based catalysts formed from palladium, polymer supported palladium(II), transition metal and organometallic catalysts other than palladium along with the examples of asymmetric reactions, intermolecular and intramolecular oxidative Heck reactions via C-H activation. However, the substrate scope of these transformations is still extremely limited and there is much room for the development of newer methods that working well under more convenient reaction conditions. A review by Su and Jiao [40] reveals the development in the area of palladium catalysed oxidative Heck reactions of alkenes with organometallic compounds, which are effective arylating or akenylating agents. It was observed that the organometallic compounds specially derived from Group III to Group VII like organoboronic. organothallium, organosilicon, organotin, organotin, organophosphorus, organoantimony, organobismuth, organotellurium, hypervalent iodonium salts or simply arenes are efﬁcient substrates for the oxidative Heck reaction. They are found to be remarkably stable and easy to prepare. In addition, various metals other than Pd, including Ru, Rh, Ir and Ni, though less explored for oxidative Heck reaction, are also discussed. The yields of product obtained using them are reasonable up to 72%. The mechanism based on many experimental studies has been reported where the evidence of detection of single charged cationic palladium (II) complexes are given. A review by Le Bras and Muzart [41] highlights the same subject particularly with respect to its progress of procedures. Numerous results of stoichiometric as well as catalytic palladium mediated arylations of various arenes and heteroarenes are presented. Most of these reactions use an excess of either the arene or the alkene, often with a relatively high Pd catalyst loading and require a terminal oxidant other than molecular oxygen. This becomes an expensive issue and can be a challenge for applications on large scales and even their compatibility with the atom economy principle. Thus, there is wide scope for researchers to work in this area. Yet another review by Le Bras and Muzart [42] covers the palladium-catalysed annelations of internal alkynes through reactions leading to the loss of only two hydrogens from the substrates. This process is explained with the mechanism that involves (i) dual C-H bond activation; (ii) both C-H and N-H bond activation; (iii) successive amino (or oxy) palladation and C-H bond activation; or (iv) C-H bond activation followed by a Heck-type process. Though not much work has been done in this area, such sustainable processes will become valuable tools for the synthesis of diverse carbocycles and heterocycles. A review by Lee [43] highlights the use of the oxidative Heck reaction (also referred to as oxidative boron Heck when boron is used in transmetallation reaction (Scheme2)) in enantioselective Heck-type couplings. This technique overcomes several limitations of the traditional Pd(0)-catalysed Heck coupling and has subsequently allowed for intermolecular couplings of challenging systems such as cyclic enones, Catalysts 2017, 7, 267 20 of 53 acyclic alkenes, and even site selectively on remote alkenes. This has also enabled enantioselective intermolecular couplings of more challenging systems such as desymmetrisation of quaternary centres, cyclic enones, acyclic alkenes and even site selectively on remote alkenes via a redox–relay coupling. CatalystsA number 2017 of, 7, examples267 have been cited along with probable mechanisms for its justification. 20 of 53

2.3.2. Reductive Reductive Heck Heck Reaction The termterm reductive reductive Heck Heck or reductiveor reductive arylation arylation is used is whenused thewhen intermediate the intermediate forms the forms conjugate the conjugateaddition productaddition in product palladium-catalysed in palladium Mizoroki-Heck‐catalysed Mizoroki reactions‐Heck instead reactions of givinginstead substitution of giving substitutionproduct via βproduct-hydride via elimination β‐hydride (Scheme elimination3). Reductive (Scheme 3). Heck Reductive product Heck is a regularly product observed is a regularly side observedproduct and side the product extent of and its formationthe extent in of the its reaction formation varies in greatly the reaction with base, varies temperature, greatly with substrate base, temperature,and solvent. substrate and solvent.

Scheme 3. CollapsingCollapsing of of intermediate intermediate to to form form conjugate conjugate addition addition product product or substitution substitution product via β‐β-hydridehydride elimination. elimination.

Xiaomei et al. [44] have reviewed the progress in reductive Heck reaction, where unsaturated Xiaomei et al. [44] have reviewed the progress in reductive Heck reaction, where unsaturated halides react with olefinic compounds at the similar Heck conditions to form the addition products. halides react with olefinic compounds at the similar Heck conditions to form the addition products. Discussion on catalytic systems, mechanism, applications and limitation in organic chemistry is Discussion on catalytic systems, mechanism, applications and limitation in organic chemistry is given. given. 2.3.3. Intramolecular Heck Reaction 2.3.3. Intramolecular Heck Reaction Intramolecular Heck reaction is generally more efficient than the intermolecular Heck reactions Intramolecular Heck reaction is generally more efficient than the intermolecular Heck reactions for many reasons like, in the intermolecular Heck reactions, only mono- and disubstituted olefins can for many reasons like, in the intermolecular Heck reactions, only mono‐ and disubstituted olefins can participate, while in the intramolecular case tri- and tetrasubstiuted olefins can readily get inserted; participate, while in the intramolecular case tri‐ and tetrasubstiuted olefins can readily get inserted; regiocontrol of olefin addition is difficult in the intermolecular for electronically neutral olefins whereas regiocontrol of olefin addition is difficult in the intermolecular for electronically neutral olefins the regioselectivity in intramolecular process is governed by ring-size of the newly formed cycle and whereas the regioselectivity in intramolecular process is governed by ring‐size of the newly formed is generally directed by steric considerations giving highly regioselective couplings. In addition, cycle and is generally directed by steric considerations giving highly regioselective couplings. In construction of cyclic compounds containing an endo- or exo-cyclic double bond can efficiently be addition, construction of cyclic compounds containing an endo‐ or exo‐cyclic double bond can brought about by using the intramolecular Heck reaction. efficiently be brought about by using the intramolecular Heck reaction. A review by Guiry and Kiely [45] summarizes the development of the intramolecular Heck A review by Guiry and Kiely [45] summarizes the development of the intramolecular Heck chemistry and the methodology used for the construction of carbocycles and heterocycles along with chemistry and the methodology used for the construction of carbocycles and heterocycles along with the mechanism. The review is mainly focused on the optimization of palladium catalysts derived from the mechanism. The review is mainly focused on the optimization of palladium catalysts derived various diphosphine and phoshinamine ligands for the preparation of a variety of cyclic products like from various diphosphine and phoshinamine ligands for the preparation of a variety of cyclic cis-decalins, hydrindans, indolizidines, diquinanes and the synthesis of quaternary carbon centres. products like cis‐decalins, hydrindans, indolizidines, diquinanes and the synthesis of quaternary A number of examples of the application of intramolecular Heck cyclization as the key step in the carbon centres. A number of examples of the application of intramolecular Heck cyclization as the preparation of many complex natural product syntheses are given. Some of their own work on ligand key step in the preparation of many complex natural product syntheses are given. Some of their own synthesis used for such reactions is also discussed. work on ligand synthesis used for such reactions is also discussed. A review by Oestreich [46] summarizes the exciting development of the enantioselective A review by Oestreich [46] summarizes the exciting development of the enantioselective intermolecular Heck reaction (particularly the Heck-Matsuda [47] reaction that uses arene diazonium intermolecular Heck reaction (particularly the Heck‐Matsuda [47] reaction that uses arene diazonium salts as an alternative to aryl halides and triflates) of acyclic alkenes and the synthetic utility of salts as an alternative to aryl halides and triflates) of acyclic alkenes and the synthetic utility of enantioselective intermolecular couplings of cyclic alkenes. Many such examples that give very high enantioselectivity for intermolecular Heck reactions are cited.

2.3.4. Asymmetric Heck Reaction A breakthrough in Heck reaction took place when in 1989 Shibasaki [48] and Overman [49] independently reported the first examples of asymmetric Heck reactions. They used chiral ligands

Catalysts 2017, 7, 267 21 of 53 enantioselective intermolecular couplings of cyclic alkenes. Many such examples that give very high enantioselectivity for intermolecular Heck reactions are cited.

2.3.4. Asymmetric Heck Reaction

CatalystsA breakthrough 2017, 7, 267 in Heck reaction took place when in 1989 Shibasaki [48] and Overman21 [49 of] 53 independently reported the ﬁrst examples of asymmetric Heck reactions. They used chiral ligands BINAPBINAP and and (R (R,R,R)-DIOP)‐DIOP for for such such reactions, reactions, respectively. respectively. A A classic classic example example of of the the intramolecular intramolecular Heck Heck reactionreaction in in action action is is Overman’s Overman’s synthesis synthesis of of (− (−)-scopadulcic)‐scopadulcic acid acid A A124 124(Figure (Figure 14 14),), where where a a tandem tandem doubledouble Heck Heck cyclisation cyclisation (6-exo-trig (6‐exo‐trig followed followed by by a a 5-exo-trig) 5‐exo‐trig) rapidly rapidly accesses accesses the the carbon carbon skeleton skeleton foundfound in in the the natural natural product. product.

H R 1 R2 OCOPh 124

Scopadulcic acid A : R 1 = COOH, R 2 = CH 2OH Scopadulcic acid B : R1 = Me, R2 = COOH

FigureFigure 14. 14.Scopadulcic Scopadulcic acid. acid.

From 2003, the catalytic asymmetric variant of Heck reaction emerged as a reliable method for From 2003, the catalytic asymmetric variant of Heck reaction emerged as a reliable method for enantioselective carbon‐carbon bond formation. Dounay and Overman [50] reviewed the application enantioselective carbon-carbon bond formation. Dounay and Overman [50] reviewed the application of of catalytic asymmetric Heck cyclization in natural product total synthesis for the formation of catalytic asymmetric Heck cyclization in natural product total synthesis for the formation of tertiary and tertiary and quaternary stereocenters by considering synthesis of some terpenoids (like ernolepin, quaternary stereocenters by considering synthesis of some terpenoids (like ernolepin, Oppositol and Oppositol and Prepinnaterpene, Desmethyl‐2‐methoxycalamenene, Capnellenols, Δ9(12)‐Capnellene, Prepinnaterpene, Desmethyl-2-methoxycalamenene, Capnellenols, ∆9(12)-Capnellene, Kaurene and Kaurene and Abietic Acid, Retinoids); Alkaloids (like Lentiginosine and Gephyrotoxin 209D, Abietic Acid, Retinoids); Alkaloids (like Lentiginosine and Gephyrotoxin 209D, 5-Epiindolizidine 167B 5‐Epiindolizidine 167B and 5E,9Z‐indolizidine, 223AB. Physostigmine and Physovenine, and 5E,9Z-indolizidine, 223AB. Physostigmine and Physovenine, Quadrigemine C and Psycholeine, Quadrigemine C and Psycholeine, Idiospermuline, Spirotryprostatin, Eptazocine); Polyketides (like Idiospermuline, Spirotryprostatin, Eptazocine); Polyketides (like Halenaquinone and Halenaquinol, Halenaquinone and Halenaquinol, Xestoquinone, Wortmannin). A brief discussion on Xestoquinone, Wortmannin). A brief discussion on understanding of the mechanisms of catalytic understanding of the mechanisms of catalytic reactions is provided necessary for the rational reactions is provided necessary for the rational development of efﬁcient asymmetric processes. development of efficient asymmetric processes. A review by Diéguez [51] covers reports on the ligands derived from carbohydrates for asymmetric A review by Diéguez [51] covers reports on the ligands derived from carbohydrates for catalysis until 2003. High enantioselectivities have been observed by using bidentate ligands, usually asymmetric catalysis until 2003. High enantioselectivities have been observed by using bidentate diphosphines and phosphine-oxazoline ligands. They also have excellent control on selectivity, based ligands, usually diphosphines and phosphine‐oxazoline ligands. They also have excellent control on on the properties of the ligand. Carbohydrate ligands have proved to be some of the most versatile selectivity, based on the properties of the ligand. Carbohydrate ligands have proved to be some of ligands for enantioselective catalysis. Examples of numerous carbohydrate based ligands are discussed the most versatile ligands for enantioselective catalysis. Examples of numerous carbohydrate based in the review, however, for Pd-catalysed Heck reaction, only the following kinds of carbohydrate ligands are discussed in the review, however, for Pd‐catalysed Heck reaction, only the following derivative ligands 125–127 (Figure 15) have been seen to be efﬁciently applied. kinds of carbohydrate derivative ligands 125–127 (Figure 15) have been seen to be efficiently applied.

Ph Ph Ph O O O O O O Me Ph2P P N O N O O Me

125 R Ph Ph R = Me, i-Pr, i-Bu, t-Bu, Ph, Bn 126 Ph Ph Ph Ph

O O O O P N N P O O Me Me O O Ph Ph Ph Ph 127

Catalysts 2017, 7, 267 21 of 53

BINAP and (R,R)‐DIOP for such reactions, respectively. A classic example of the intramolecular Heck reaction in action is Overman’s synthesis of (−)‐scopadulcic acid A 124 (Figure 14), where a tandem double Heck cyclisation (6‐exo‐trig followed by a 5‐exo‐trig) rapidly accesses the carbon skeleton found in the natural product.

H R 1 R2 OCOPh 124

Scopadulcic acid A : R 1 = COOH, R 2 = CH 2OH Scopadulcic acid B : R1 = Me, R2 = COOH Figure 14. Scopadulcic acid.

From 2003, the catalytic asymmetric variant of Heck reaction emerged as a reliable method for enantioselective carbon‐carbon bond formation. Dounay and Overman [50] reviewed the application of catalytic asymmetric Heck cyclization in natural product total synthesis for the formation of tertiary and quaternary stereocenters by considering synthesis of some terpenoids (like ernolepin, Oppositol and Prepinnaterpene, Desmethyl‐2‐methoxycalamenene, Capnellenols, Δ9(12)‐Capnellene, Kaurene and Abietic Acid, Retinoids); Alkaloids (like Lentiginosine and Gephyrotoxin 209D, 5‐Epiindolizidine 167B and 5E,9Z‐indolizidine, 223AB. Physostigmine and Physovenine, Quadrigemine C and Psycholeine, Idiospermuline, Spirotryprostatin, Eptazocine); Polyketides (like Halenaquinone and Halenaquinol, Xestoquinone, Wortmannin). A brief discussion on understanding of the mechanisms of catalytic reactions is provided necessary for the rational development of efficient asymmetric processes. A review by Diéguez [51] covers reports on the ligands derived from carbohydrates for asymmetric catalysis until 2003. High enantioselectivities have been observed by using bidentate ligands, usually diphosphines and phosphine‐oxazoline ligands. They also have excellent control on selectivity, based on the properties of the ligand. Carbohydrate ligands have proved to be some of the most versatile ligands for enantioselective catalysis. Examples of numerous carbohydrate based Catalystsligands2017 are, 7, 267 discussed in the review, however, for Pd‐catalysed Heck reaction, only the following22 of 53 kinds of carbohydrate derivative ligands 125–127 (Figure 15) have been seen to be efficiently applied.

Ph Ph Ph O O O O O O Me Ph2P P N O N O O Me

125 R Ph Ph R = Me, i-Pr, i-Bu, t-Bu, Ph, Bn 126 Ph Ph Ph Ph

O O O O P N N P O O Me Me O O Ph Ph Ph Ph Catalysts 2017, 7, 267 127 22 of 53

Figure 15. Carbohydrate based ligands reviewed by DiDiéguezéguez [[51].51].

McCartney and Guiry [[52]52] comprehensively reviewed the asymmetric inter-inter‐ and intramolecular Heck (Scheme4 4)) and and related related reactions reactions since since their their original original development development untiluntil 2011 2011 with with respect respect to to substrate scope, reactivity, regio-regio‐ andand enantioselectivity.enantioselectivity. The formationformation of products is supported by predicting mechanism. The classification classiﬁcation is based on the nature of ligands in in terms terms of of their their denticity, denticity, chirality andand nature nature of of donor donor atoms atoms involved involved so asso to as understand to understand the continued the continued development development of ligand of architecturalligand architectural design design and their and application.their application. The reviewThe review addresses addresses the the signiﬁcant significant improvements improvements in reactionin reaction times, times, a disadvantage a disadvantage of Heck of Heck reactions reactions performed performed in classical in classical way, use way, of microwave-assisteduse of microwave‐ protocolsassisted protocols and ligand and design. ligand design. The asymmetric The asymmetric Fujiwara-Moritani Fujiwara‐Moritani and oxidative and oxidative boron boron Heck-type Heck‐ reactionstype reactions and the and recent the recent additions additions to Heck to Heck type processes,type processes, are also are discussed. also discussed.

Scheme 4. Asymmetric inter-inter‐ and intramolecular Heck reaction.

2.3.5. Heck Reactions Involving Heteroatom A review by Daves and Hallberg Hallberg [53] [53] highlights typical typical heteroatom heteroatom-substituted‐substituted olefins to organopalladium reagents, where where a a new new carbon carbon-carbon‐carbon bond bond is isformed formed via via 1,2‐ 1,2-additionaddition of an of anorganopalladium organopalladium species species to tothe the often often strongly strongly polarized polarized carbon carbon-carbon‐carbon double double bond bond of of a a heteroatom heteroatom substituted olefinolefin.. TheseThese typestypes of reactionsreactions afford versatileversatile and efﬁcientefficient syntheticsynthetic routes to a wide variety ofof compounds.compounds. Heck and other similarsimilar typestypes ofof reactionsreactions involvinginvolving intermediateintermediate palladiumpalladium complex undergoing 1,2-additions1,2‐additions havehave beenbeen discussed.discussed. Compounds with heteroatoms O,O, N, S, P are considered to explore their reactivity towards such addition reaction. A number of examples with cyclic enol ethers, glycals, and cyclic enol ethers derived from carbohydrates, acyclic enol ethers like thioenol ethers, enol carboxylates, enamides and enamines, vinylsilanes and vinylphosphonates are given. Product formation is explained based on well accepted mechanism for Heck reaction involving Pd(0) complex. Increased understanding of the pathways by which these reactions occur, that include delineation of the factors determining reaction regio‐ and stereochemistry, and control of competing modes of σ‐organopalladium adduct decomposition to products, make possible the utilization of these reactions in the synthesis of complex structures. Bedford [54] has reviewed the use of palladacyclic catalysts in C‐C and C‐heteroatom bond‐ forming reactions. Palladacycles are air and moisture stable inexpensive catalysts, can easily be handled and stored, and act as clean sources of low‐coordinate palladium(0). They as pre‐catalysts play a significant role in a range of C‐C and C‐heteroatom bond forming reactions. Activity of the catalysts comprised of P‐C palladacyclic, Palladium P,C,P‐pincer complexes, L‐C palladacyclic, L,L,C‐ and L,C,L‐pincer based (where L = N, S) have been compared for the C‐C and C‐heteroatom bond‐forming reactions including discussion on the likely nature of the true active catalysts produced in situ. These catalysts show the TON ranging from a few thousand up to a few million. Consideration to the Aryl chlorides as substrates and the mechanism involving palladacycle for such reaction is

Catalysts 2017, 7, 267 23 of 53 considered to explore their reactivity towards such addition reaction. A number of examples with cyclic enol ethers, glycals, and cyclic enol ethers derived from carbohydrates, acyclic enol ethers like thioenol ethers, enol carboxylates, enamides and enamines, vinylsilanes and vinylphosphonates are given. Product formation is explained based on well accepted mechanism for Heck reaction involving Pd(0) complex. Increased understanding of the pathways by which these reactions occur, that include delineation of the factors determining reaction regio- and stereochemistry, and control of competing modes of σ-organopalladium adduct decomposition to products, make possible the utilization of these reactions in the synthesis of complex structures. Bedford [54] has reviewed the use of palladacyclic catalysts in C-C and C-heteroatom bond-forming reactions. Palladacycles are air and moisture stable inexpensive catalysts, can easily be handled and stored, and act as clean sources of low-coordinate palladium(0). They as pre-catalysts play a significant role in a range of C-C and C-heteroatom bond forming reactions. Activity of the catalysts comprised of P-C palladacyclic, Palladium P,C,P-pincer complexes, L-C palladacyclic, L,L,C- and L,C,L-pincer based (where L = N, S) have been compared for the C-C and C-heteroatom bond-forming reactions including discussion on the likely nature of the true active catalysts produced in situ. These catalysts show the TON ranging from a few thousand up to a few million. Consideration to the Aryl chlorides as substrates and the mechanism involving palladacycle for such reaction is thoroughly discussed. It was found that the complexes 36, 63 and 70 show reasonable activity with some, usually less electronically challenging substrates. The possibility of recyclability of a few catalysts for Heck and other reactions has been discussed. It was predicted previously that when the catalysts are immobilized on solid supports they could work as recyclable catalyst. Polystyrene-immobilized catalyst 74 shows comparable activity to homogeneous analogues in the Heck coupling of iodobenzene with styrene. However, in recycle study the filtrate after reaction and not the recovered catalyst that showed the activity comparable to that obtained in the first run. This activity was concluded to be due to formation of nanoparticulate palladium which is stabilized by an ammonium salt.

2.4. Methodology Various attempts have been made by researchers to improve the catalyst activity, lowering the cost of catalyst; hence different methodologies are adopted using non-conventional techniques for Heck reactions. Reviews based on these methodologies are described here.

2.4.1. For Improvement in Activity Use of tetraalkylammonium salts to improve the yields in Heck reactions particularly is considered to be a remarkable contribution in catalysis. The combination of such salts (phase-transfer catalysts) and insoluble bases accelerates the rate of reaction to great extent even at lower reaction temperatures and is commonly known as Jeffery conditions. A review of these salts in Heck type reactions is taken by Jeffery [55]. It was seen that, under appropriate conditions, tetraalkylammonium hydrogensulfate can just be as efﬁcient as tetraalkylammonium chloride or bromide for facilitating Heck-type reactions. Thus, an appropriate selection of the catalyst system (Pd/Base/QX) can allow this type of reactions to be efﬁciently realized at will, in a strictly anhydrous medium or in a water-organic solvent mixture or in water alone.

2.4.2. For Lowering the Cost Tucker and de Vries [56] describe their own efforts in the area of palladium- and nickel-catalysed aromatic substitution carbon-carbon bond formation reactions in the review titled ‘homogeneous catalysis for the production of ﬁne chemicals’. The main focus of this review is on low cost and low waste production methods. A number of examples are discussed to prove methodology for lowering production cost such as reducing the amount of catalyst, eliminating use of ligands or use of cheaper phosphite or phosphoramidite ligands, carrying out reactions at lower temperatures, replacing palladium by nickel, replacing aryl bromides or iodides with the cheaper chlorides and simpliﬁed Catalysts 2017, 7, 267 24 of 53 work-up. For waste free production methods, use of aromatic anhydrides as aryl donor is suggested. Methods for recycling of palladium in ligand-free Heck and Suzuki reactions is described that involves treatment of palladium black, precipitating at the end of the reaction, with a small excess of I2 prior to its re-use in the next run. Typically, the Heck reactions are catalysed by palladium, a precious metal. However, in many cases low cost transition metals are found to play a similar role which is reviewed by Wang and Yang [57]. This review focuses on low-cost transition metal catalysed Heck-type reactions. The cited examples indicate that some low-cost transition metals like Ni, Co, Cu, Fe are active for Heck-type reactions. Ni is found to give best performance among them; in fact, sometimes the results with Ni are comparable to that with Pd. Co and Cu exhibit outstanding activity to alkyl electrophile involved Heck- type reactions. This is attributed to their abilities to generate alkyl radical. It was also observed in a few cases that under certain conditions these low-cost transition metals may show unique catalytic properties, which are absent in Pd-mediated systems. Two mechanisms have been predicted for Heck-type reactions using these transition metals, cationic mechanism and radical mechanism based on the reacting species. Phenyl or benzyl halides predominantly take the cationic mechanism, whereas alkyl halides usually follow the radical mechanism, especially in Co- and Cu- catalysed systems because Co and Cu have good capacity of producing radical from alkyl halides. However, the investigations on low-cost transition metals catalysed Heck-type reactions highlight the extension of the substrate scope and draw a little attention to the development of catalysts, ligands and solvents. Hence, more study is needed in this area.

2.4.3. Non-Conventional Methodologies Beletskaya et al. [58] have published a critical overview on unconventional methodologies for transition-metal catalysed Heck reaction highlighting the efforts and interest in developing more efﬁcient processes according to the new requirements of chemistry. A vast array of non-conventional methodologies is described considering different parameters involved in the reaction like substrates, catalytic system, solvent, reaction conditions, or work-up. However, it is also stated that, although large numbers of interesting methodologies are available from an academic point of view, they are useless from a practical point of view. Hence, there is a need for reconsideration of a few points while performing Heck reactions at the industrial level such as:

• Most of the methodologies deal with the simpler reactions between the reactive substrates like aryl iodides or activated aryl bromides and acrylates in contrast to the more desirable, but less reactive aryl chlorides or other olefinic substrates such as electron-rich olefins. • More attention should be paid at the workup and separation of by-products formed during achieving a high regio- and stereoselective products. • Whenever possible, commercially available starting materials, reagents, ligands, catalysts, or solvents must be used and proper time should be given to experimental work needed to prepare the different reaction components. • The catalyst must be recyclable and/or display high TONs. • Heterogeneous catalysis or a use of ligandless catalysts, recoverable ligands or stabilized nanoparticles are preferred for better recovery and lower cost provided metal leaching is prevented. • An ideal recyclable catalyst is the one in which filtration of the reaction mixture produces a catalytically active solid and an inactive filtrate. • Use of high temperature with some stable catalysts may prove to be unfavourable for the selectivity of the product. • The expensive equipment or reaction medium utilized in some methodologies cannot compensate for the little or no improvement observed in many cases with respect to the conventional methodologies; in addition, the application of these methodologies is normally restricted to a small scale. Catalysts 2017, 7, 267 25 of 53

• Reproducibility, atom-economy, low-cost, scalable and practical procedures, are needed to extend the methodologies from the academic laboratory to the industrial plant.

Further research must be undertaken in order to clarify the reaction mechanisms involved in the different processes, which remain unclear in most cases; it is crucial to have a better knowledge of the nature and properties of the real catalytic species in order to improve any given reaction.

2.5. Selectivity Under the section Asymmetric Heck reaction (Sections2–4) reviews dealing with the generation of asymmetric centre by means of Heck reactions were summarized whereas under this section the progress of ligands and catalysts for the development of various regioselective and enantioselective transformations via Heck reactions are discussed. A review by Tietze et al. [59] on ‘enantioselective palladium catalysed transformation’ discusses many other important organic reactions including Heck reaction where enantioselectivity in intramolecular and intermolecular Heck reaction is discussed with lot of examples collected right from its ﬁrst example of such kind by Shibasaki [48] and Overman [49]. A number of examples with new improved ligands for development of various enantioselective transformations has been discussed Catalystsaiming 2017 at higher, 7, 267 (preferably over 95%) ee values. The review asserts that there is no ﬁeld25 where of 53 enantioselective Pd catalysis cannot be employed. However, the disadvantage of such catalysis is isthe the high high price price of of Pd Pd and and the the usually usually small small turnover turnover numbers, numbers, makingmaking thethe processes too expensive forfor industrial industrial use. Nevertheless, Nevertheless, novel novel chiral chiral Pd Pd catalysts catalysts resulting resulting in in high high turnover turnover number number can can be synthesizedsynthesized to to overcome overcome this this issue issue in addition to a broad range of enantioselective transformations suitablesuitable for the chemical industry. AlmostAlmost at at the the same same time, time, Shibasaki Shibasaki et et al. al. [60] [60 reviewed] reviewed a similar a similar topic topic particularly particularly aiming aiming at the at asymmetricthe asymmetric Heck Heck reaction. reaction. Since Since a variety a variety of carbocyclic, of carbocyclic, heterocyclic heterocyclic and spirocyclic and spirocyclic systems systems can be constructed,can be constructed, the asymmetric the asymmetric Heck reaction Heck reaction becomes becomes a powerful a powerful method method for the for synthesis the synthesis of both of tertiaryboth tertiary and quaternary and quaternary chiral chiral carbon carbon centres, centres, with withan enantiomeric an enantiomeric excess excess often often in the in range the range of 80% of to80% 99%. to 99%.The scope The scope of the of reaction the reaction with withrespect respect to the to product the product alkene alkene isomerization isomerization was limited was limited due todue regioselectivity, to regioselectivity, and and was was predicted predicted to be to besolved solved by by development development of of new new generation generation of of ligands ligands dissociatingdissociating more rapidly from the products, thus improving both enantio-enantio‐ and regiocontrol.regiocontrol. Oestreich [[61]61] describes describes the the evolution evolution of inter-of inter as well‐ as aswell intramolecular as intramolecular Heck reactions Heck reactions from regio- from to regiodiastereo-‐ to anddiastereo finally‐ toand enantioselective finally to enantioselective transformations transformations with a special reference with a to special heteroatom-directed reference to heteroatomHeck reactions‐directed in his Heck review. reactions The concept in his of review. “Chelation The Control” concept 128of ,“Chelation129 (Figure Control” 16) controls 128 regio-, 129 (Figureand stereoselectivity 16) controls withregio‐ theand aid stereoselectivity of attractive interactions with the betweenaid of attractive substrate interactions and reagent/catalyst between substrateis discussed. and reagent/catalyst is discussed.

FigureFigure 16. 16. ChelationChelation controlled controlled inter inter-‐ and and intramolecular intramolecular Heck reaction.

Several examplesexamples of removableof removable catalyst-directing catalyst‐directing groups developedgroups developed for the preferential for the regioselectivepreferential regioselectiveintermolecular intermolecular arylation of alkenes arylation are given of alkenes such as amino-directedare given such intermolecular as amino‐directed Heck reactionintermolecular of vinyl Heckethers. reaction Mono- versusof vinyl bidentate ethers. Mono phosphines‐ versus influence bidentate a regiochemical phosphines switchinfluence based a regiochemical on the bite angle switch and based on the bite angle and the mechanistic rationale for inverted regioselectivity is also discussed. Review covers the syntheses of stereodefined, multi‐arylated alkenes, the diastereoselective construction of tertiary and quaternary carbon centres, and also the combination of substrate with catalyst‐control in an enantioselective transformation. Many examples have been discussed to show the neighbouring‐group effects playing important role in Heck chemistry and expect few more discoveries in this field. The example of a substrate‐controlled enantioselective reaction illustrates that the enantioselection is sometimes discriminated not only by the chiral reagent but also by a suitably located donor.

2.6. Aqueous Media Nowadays, use of water has become increasingly popular for fine synthetic chemistry in industry for the reasons: water is non‐toxic, nonflammable, inexpensive, and environmentally friendly solvent and there by use of organic solvent can be avoided. In addition, one of the major drawbacks of homogeneous metal catalysis lies in the separation of the reaction product from the catalyst and requires costly procedures. The concept of transition metal catalysis in water is used where the catalyst is easily recovered by separation of the aqueous and organic phase if a biphasic system is used. Its popularity has been increased since the development of the Ruhrchemie–Rhone Poulenc process using a modified water‐soluble rhodium complex in the hydroformylation methodology. However, the limitations of aqueous phase catalysis are:

Catalysts 2017, 7, 267 26 of 53 the mechanistic rationale for inverted regioselectivity is also discussed. Review covers the syntheses of stereodefined, multi-arylated alkenes, the diastereoselective construction of tertiary and quaternary carbon centres, and also the combination of substrate with catalyst-control in an enantioselective transformation. Many examples have been discussed to show the neighbouring-group effects playing important role in Heck chemistry and expect few more discoveries in this field. The example of a substrate-controlled enantioselective reaction illustrates that the enantioselection is sometimes discriminated not only by the chiral reagent but also by a suitably located donor.

2.6. Aqueous Media Nowadays, use of water has become increasingly popular for fine synthetic chemistry in industry for the reasons: water is non-toxic, nonflammable, inexpensive, and environmentally friendly solvent and there by use of organic solvent can be avoided. In addition, one of the major drawbacks of homogeneous metal catalysis lies in the separation of the reaction product from the catalyst and requires costly procedures. The concept of transition metal catalysis in water is used where the catalyst is easily recovered by separation of the aqueous and organic phase if a biphasic system is used. Its popularity has been increased since the development of the Ruhrchemie–Rhone Poulenc process using a modified water-soluble rhodium complex in the hydroformylation methodology. Catalysts 2017, 7, 267 26 of 53 However, the limitations of aqueous phase catalysis are:  Stability of substrate or product in water. • Stability of substrate or product in water.  Partial solubility of substrate in the aqueous phase to avoid mass transfer limitation. • Partial solubility of substrate in the aqueous phase to avoid mass transfer limitation.  Necessity of preparation of water soluble ligands or dispersing agents to maintain catalyst in • Necessity of preparation of water soluble ligands or dispersing agents to maintain catalyst in aqueous phase. aqueous phase.  Challenges for future developments in this area to develop catalysts with scope and activity • Challenges for future developments in this area to develop catalysts with scope and activity comparable to the best organic‐phase catalyst systems. comparable to the best organic-phase catalyst systems. Nevertheless, there is still strong interest in developing efficient and recoverable catalysts for use inNevertheless, pharmaceutical there and is still other strong fine interest chemical in developingsynthetic processes, efficient and as can recoverable be seen catalystsfrom following for use inreviews. pharmaceutical and other fine chemical synthetic processes, as can be seen from following reviews. Genet and Savignac [[62]62] have reviewedreviewed thethe palladiumpalladium cross-couplingcross‐coupling reactions carried out in aqueous medium. Reactions like Heck, Sonogashira, Tsuji Tsuji-Trost,‐Trost, Suzuki, Stille as well as protectingprotecting group chemistry in aqueous media are discussed in the review. Although palladium is known to be unstable inin aqueous aqueous medium, medium, there there are reportsare reports of the excellentof the excellent compatibility compatibility of water-soluble of water palladium‐soluble catalystspalladium with catalysts water- soluble with phosphines water‐ suchsoluble as TPPTS phosphines (3,30,300-Phosphanetriyltris(benzenesulfonic such as TPPTS (3,3′,3′′‐ acid)Phosphanetriyltris(benzenesulfonic trisodium salt) 115, TPPMS (Sodium acid) Diphenylphosphinobenzene-3-sulfonate) trisodium salt) 115, TPPMS130 and(Sodium salts of acidDiphenylphosphinobenzene or amines 131, 132 (Figure‐3‐ sulfonate)17), offering 130 new and opportunities salts of acid or for amines such 131 reactions, 132 (Figure at mild 17), conditions offering andnew with opportunities new selectivity. for such reactions at mild conditions and with new selectivity.

- + SO3 Na

+ - Ph P PPh3 X 2 - + Me3N [Ph2P-CH2-COO ]Na 130 131 132

Figure 17. WaterWater-soluble‐soluble phosphines reviewed by Genet andand SavignacSavignac [[62].62].

It was seen that the careful selection of reaction conditions, co‐solvents and catalysts, is very It was seen that the careful selection of reaction conditions, co-solvents and catalysts, is very important for long life catalyst and new selectivities. The advantages of the two‐phase aqueous important for long life catalyst and new selectivities. The advantages of the two-phase aqueous system, i.e., easy separation of the products and recycling the expensive palladium can be obtained system, i.e., easy separation of the products and recycling the expensive palladium can be obtained by by using palladium catalysed reactions with water‐soluble phosphines that has increased the using palladium catalysed reactions with water-soluble phosphines that has increased the potential of potential of modern palladium catalysis. modern palladium catalysis. Li [63] has reviewed many organic reactions in aqueous media where water serves as a medium for various palladium‐catalysed reactions of aryl halides with acrylic acid or acrylonitrile to give the corresponding coupling products in high yields. In addition, reactions at superheated and microwave heating conditions with bulky phosphine ligands along with arenediazonium salts instead of aryl halides in the Heck‐type reaction are mentioned. The reason for a high yield of coupling product for reaction involving the use of Pd(OAc)2 with water‐soluble ligand, TPPTS, and formation of complex mixture was attributed to high dielectric constant of water. Examples of many transition metals other than palladium in water have been cited. Velazquez and Verpoort [64] have reviewed the reports on the use of N‐heterocyclic carbene transition metal complexes for catalysis in water. The typical phosphine and amine‐type ligands can thus be displaced by this type of catalysis because of their higher stability and reactivity. Palladium complex 133 and a complex of ligand 134 (Figure 18) are used for catalysing the Heck reaction successfully in water.

Catalysts 2017, 7, 267 27 of 53

Li [63] has reviewed many organic reactions in aqueous media where water serves as a medium for various palladium-catalysed reactions of aryl halides with acrylic acid or acrylonitrile to give the corresponding coupling products in high yields. In addition, reactions at superheated and microwave heating conditions with bulky phosphine ligands along with arenediazonium salts instead of aryl halides in the Heck-type reaction are mentioned. The reason for a high yield of coupling product for reaction involving the use of Pd(OAc)2 with water-soluble ligand, TPPTS, and formation of complex mixture was attributed to high dielectric constant of water. Examples of many transition metals other than palladium in water have been cited. Velazquez and Verpoort [64] have reviewed the reports on the use of N-heterocyclic carbene transition metal complexes for catalysis in water. The typical phosphine and amine-type ligands can thus be displaced by this type of catalysis because of their higher stability and reactivity. Palladium complex 133 and a complex of ligand 134 (Figure 18) are used for catalysing the Heck Catalystsreaction 2017 successfully, 7, 267 in water. 27 of 53

COOH R R R R

n = 1-3 N N N Ar N N ( ) N N Ar Pd O n N N Br Br Bu Br Bu Br 133 134

Figure 18. N-heterocyclic carbene ligand and transition metal complex for catalysis in water reviewed by Velazquez and Verpoort [64]. Figure 18. N‐heterocyclic carbene ligand and transition metal complex for catalysis in water reviewed byA Velazquez review by and Herv Verpoorté and [64]. Len [65] is based on both Heck and Sonogashira cross-coupling of nucleosides following two important aspects of the green chemistry, i.e., use of aqueous medium A review by Hervé and Len [65] is based on both Heck and Sonogashira cross‐coupling of and no protection/deprotection steps. It focuses on the study of C5-modified pyrimidines and nucleosides following two important aspects of the green chemistry, i.e., use of aqueous medium and C7-deaza or C8-modified purines where these chemical modifications have been developed using no protection/deprotection steps. It focuses on the study of C5‐modified pyrimidines and C7‐deaza palladium cross-coupling reactions. The review encompasses variations of the starting materials, or C8‐modified purines where these chemical modifications have been developed using palladium alkene and alkyne, nature of the solvent, palladium source and ligand at either room temperature or cross‐coupling reactions. The review encompasses variations of the starting materials, alkene and higher temperature. Heck cross-couplings were performed using Na2PdCl4 (80 mol %) and Pd(OAc)2 alkyne, nature of the solvent, palladium source and ligand at either room temperature or higher (5–10 mol %) in the presence of TPPTS as ligand in a mixture of CH3CN/H2O and in sole water. temperature. Heck cross‐couplings were performed using Na2PdCl4 (80 mol %) and Pd(OAc)2 (5–10 Using these procedures, yields up to 98% have been reported. mol %) in the presence of TPPTS as ligand in a mixture of CH3CN/H2O and in sole water. Using these procedures,3. Reviews onyields Mechanism up to 98% have been reported.

3. ReviewsThe mechanism on Mechanism of Heck reaction is discussed and reviewed by many researchers since 1972 when for the ﬁrst time it was given in complete detail by Heck and Nolley [9]. There are articles that argue the caseThe formechanism having a Pd(0)/Pd(II)of Heck reaction mechanism is discussed while others and reviewed favour the by Pd(II)/Pd(IV) many researchers mechanism since based1972 whenon evidential for the first data. time Few it discuss was given the speciﬁcin complete intermediate detail by formed Heck and during Nolley a particular [9]. There mechanism are articles while that argueothers the demonstrate case for having the presence a Pd(0)/Pd(II) of different mechanism intermediate. while others This favour section the deals Pd(II)/Pd(IV) with reviews mechanism on such basedreviews on on evidential mechanism data. of Heck Few reaction. discuss the specific intermediate formed during a particular mechanismA review while by Cabriothers and demonstrate Candiani [the66] presence explains theof different basis of aintermediate. common mechanistic This section hypothesis deals with for reviewsthe coordination-insertion on such reviews on process mechanism of unsaturated of Heck reaction. systems on palladium(I1) complexes based on the resultsA review obtained by untilCabri then and byCandiani several [66] research explains groups the basis on the of a Heck common reaction. mechanistic All of these hypothesis results for are theexplained coordination by the‐insertion commonly process accepted of unsaturated mechanism basedsystems on on Pd(0)/Pd(II) palladium(I1) cycle complexes (Scheme5 based). on the results obtained until then by several research groups on the Heck reaction. All of these results are explained by the commonly accepted mechanism based on Pd(0)/Pd(II) cycle (Scheme 5).

Catalysts 2017, 7, 267 28 of 53 Catalysts 2017, 7, 267 28 of 53

Catalysts 2017, 7, 267 28 of 53

Scheme 5. Mechanism based on Pd(0)/Pd(II) cycle by Cabri and Candiani [66]. Scheme 5. Mechanism based on Pd(0)/Pd(II) cycle by Cabri and Candiani [66]. This mechanisticScheme 5.model Mechanism gives baseda better on understandingPd(0)/Pd(II) cycle of by the Cabri scope and andCandiani limitations [66]. of the Heck This mechanistic model gives a better understanding of the scope and limitations of the Heck reaction. The steps involved in the mechanism of Heck reaction are: reaction.This Themechanistic steps involved model ingives the mechanisma better understanding of Heck reaction of the are: scope and limitations of the Heck step (a) Oxidative addition reaction. The steps involved in the mechanism of Heck reaction are: stepstep (b) (a) CoordinationOxidative addition‐insertion stepstepstep (a)(c) (b) β‐ OxidativeCoordination-insertionHydride addition elimination ‐dissociation stepstepstep (b)(d) (c) CoordinationRecyclingβ-Hydride of elimination-dissociationthe‐insertion L2Pd(0) step (c) β‐Hydride elimination‐dissociation stepSeveral (d) Recycling factors like of the leaving L2Pd(0) groups, neutral ligands, additives (like bases, salts, etc.), and olefin step (d) Recycling of the L2Pd(0) substituents play important roles in overall reaction course via coordination‐insertion process as Several factors like leaving groups, neutral ligands, additives (like bases, salts, etc.), and oleﬁn shownSeveral in Scheme factors 6. like leaving groups, neutral ligands, additives (like bases, salts, etc.), and olefin substituents play important roles in overall reaction course via coordination-insertion process as shown substituents play important roles in overall reaction course via coordination‐insertion process as in Scheme6. shown in Scheme 6. L L L L L L Pd R Pd L Path A R X X L Pd L L L R X Pd R Pd Path A L R X Pd X L L R X Pd - R X -X L L - Pd +X - R X -X L L L L Path B L L - Pd Pd R Pd +X R L L R L L Path B L L Pd Pd R Pd Scheme 6. OlefinR substituents via coordinationR ‐insertion process.

It is essential thatSchemeScheme the insertion 6. 6. OlefinOleﬁn process substituents substituents requires via via coordination coordination-insertion a coplanar‐ insertionassembly process. process. of the metal, ethylene, and the hydride and hence the insertion process is stereoselective and occurs in a syn manner. In addition, the energyItIt is is essential barrier thatthat for thethethe insertion insertiongeneration process process of the requires requires reactive a coplanaraconfiguration coplanar assembly assembly in a of tetracoordinated of the the metal, metal, ethylene, ethylene, complex and and the is thelowhydride hydride with and respect and hence hence to the a thepentacoordinated insertion insertion process process one. is is stereoselective stereoselective Therefore, pentacoordinated and and occurs occurs in in a a synsynspecies manner. are possibly In In addition, addition, not theinvolvedthe energy energy in barrier barrier the coordination for for the the generation process. ofThe of the the β‐ hydride reactive eliminationconfiguration conﬁguration is alsoin in a stereoselectivetetracoordinated and complex complex occurs inis is lowa syn with manner. respect Its efficiencyto a pentacoordinated is related to the one. dissociation Therefore, of pentacoordinated the olefin from the species palladium(I1) are possibly‐hydride not involved in the coordination process. The β‐hydride elimination is also stereoselective and occurs in a syn manner. Its efficiency is related to the dissociation of the olefin from the palladium(I1)‐hydride

Catalysts 2017, 7, 267 29 of 53

Catalystslow with 2017 respect, 7, 267 to a pentacoordinated one. Therefore, pentacoordinated species are possibly29 of not 53 involved in the coordination process. The β-hydride elimination is also stereoselective and occurs in complex.a syn manner. It was Its also efficiency observed is related that, tothe the presence dissociation of a base of the is olefin necessary from thein order palladium(I1)-hydride to transform the Lcomplex.2Pd(H)X into It was the also starting observed L2Pd(0) that, complex the presence and complete of a base the iscatalytic necessary cycle. in order to transform the L2Pd(H)XThe mechanism into the starting is also L supported2Pd(0) complex by the and discussion complete on the the catalytic regioselectivity cycle. and stereoselectivity of HeckThe reaction. mechanism It was is also observed supported that by the the preferential discussion on formation the regioselectivity of the branched and stereoselectivity products in the of arylationHeck reaction. of heterosubstituted It was observed olefins that the like preferential enol ethers, formation enol amides, of the branched vinyl acetate, products allyl in alcohols, the arylation and homoallylof heterosubstituted alcohols olefinswas independent like enol ethers, of the enol substituents amides, vinyl on acetate, the aromatic allyl alcohols, ring, and the homoallyl reaction temperature,alcohols was independentand the solvent of theand substituents is related only on the to the aromatic coordination ring, the‐insertion reaction pathway, temperature, though and the stereoselectivitysolvent and is related was dependent only to the on coordination-insertion the added base. In the pathway, intramolecular though asymmetric the stereoselectivity Heck reaction, was sometimesdependent the on enantioselectivity the added base. was In the related intramolecular to the geometry asymmetric of the substrate Heck reaction, olefin. sometimes the enantioselectivityA review by wasCrisp related [67] examines to the geometry the implications of the substrate of details olefin. on the mechanism of the Heck reactionA review using by both Crisp traditional [67] examines and thenon implications‐traditional ofcatalytic details onsystems. the mechanism It is mentioned of the Heck that, reaction while studyingusing both the traditional intermediate and non-traditionalformed during catalyticoxidative systems. addition It of is aryl mentioned halide that,to Pd while complex, studying the conventionallythe intermediate thought formed duringintermediate oxidative ArPdL addition2X ofis aryl not halide produced to Pd complex, rather thean conventionallyintermediate ArPd(PPhthought intermediate3)2(OAc) is formed. ArPdL2 XThe is not formation produced of rather this species an intermediate is also supported ArPd(PPh by3) 2Amator(OAc) is and formed. co‐ workersThe formation [68]. It of was this observed species isthat also the supported styrene on by reaction Amator with and preformed co-workers PhPd(PPh [68]. It was3)2 observed(OAc) during that the styrenecarbon–carbon on reaction bond with forming preformed step PhPd(PPhof the Heck3)2 (OAc)reaction during in DMF the carbon–carbonat room temperature bond forming forms stilbenestep of thewhereas Heck on reaction reaction in with DMF PhPdI(PPh at room temperature3)2 under similar forms conditions, stilbene whereas stilbene onwas reaction not formed. with Further,PhPdI(PPh when3)2 under acetate similar anion conditions, was added stilbene to a mixture was not of formed. PhPdI(PPh Further,3)2 and when styrene, acetate the anion formation was added of stilbeneto a mixture was ofobserved PhPdI(PPh at room3)2 and temperature. styrene, the These formation observations of stilbene are was consistent observed with at room the temperature.dissociation ofThese acetate observations ion from PhPd(PPh are consistent3)2(OAc) with to the form dissociation an equilibrium of acetate mixture ion from containing PhPd(PPh the cationic3)2(OAc) complex to form + [PhPd(PPhan equilibrium3)2]+ (Scheme mixture containing7). the cationic complex [PhPd(PPh3)2] (Scheme7).

Scheme 7. IntermediatesIntermediates generated in in Heck reaction mechanism.

The observations using various reaction conditions for inter and intramolecular Heck couplings, The observations using various reaction conditions for inter and intramolecular Heck in presence of different ligands (PPh3/P(o‐tolyl)3/Chelating phosphine ligands), bases couplings, in presence of different ligands (PPh /P(o-tolyl) /Chelating phosphine ligands), bases (organic/inorganic), solvent (polar/nonpolar) and/3 or TBAB are3 cited. In addition to this, the recent (organic/inorganic), solvent (polar/nonpolar) and/ or TBAB are cited. In addition to this, the recent modifications to traditional reaction conditions are also reviewed and interpreted that, for modifications to traditional reaction conditions are also reviewed and interpreted that, for intermolecular intermolecular couplings involving reactive electrophiles (aryl or vinyl iodides) and alkenes couplings involving reactive electrophiles (aryl or vinyl iodides) and alkenes containing an electron containing an electron withdrawing group, a traditional catalyst system such as Pd(OAc)2 with 2–4 withdrawing group, a traditional catalyst system such as Pd(OAc)2 with 2–4 equivalents of L [L = PPh3 equivalents of L [L = PPh3 or P(o‐tolyl)3] or PdL2Cl2 or PdL4 along with organic or inorganic base or P(o-tolyl) ] or PdL Cl or PdL along with organic or inorganic base should suffice. Such systems should suffice.3 Such 2systems2 require4 temperatures in the range 50–100 °C. In order to lower the require temperatures in the range 50–100 ◦C. In order to lower the temperature, the most effective temperature, the most effective protocol is to add R4NX (X = Cl, Br) and use an aqueous solvent with protocol is to add R4NX (X = Cl, Br) and use an aqueous solvent with K2CO3 as the base. For aryl or K2CO3 as the base. For aryl or vinyl triflates with alkenes containing an electron withdrawing group, vinyl triﬂates with alkenes containing an electron withdrawing group, a traditional catalyst system a traditional catalyst system can also be used. For alkenes not containing an electron withdrawing can also be used. For alkenes not containing an electron withdrawing group, a halide free condition, group, a halide free condition, achieved by either using aryl or vinyl triflates as the electrophile or adding a halide sequestering agent (Ag+) for aryl or vinyl halides, will be advantageous. However, for electrophiles (like aryl bromides with electron donating groups or aryl chlorides) undergoing oxidative addition more slowly, high temperatures (above 120 °C) are usually required and a stable metal‐ligand system that does not decompose at higher temperature is essential for prolonged life of

Catalysts 2017, 7, 267 30 of 53 achieved by either using aryl or vinyl triflates as the electrophile or adding a halide sequestering agent (Ag+) for aryl or vinyl halides, will be advantageous. However, for electrophiles (like aryl bromides with electron donating groups or aryl chlorides) undergoing oxidative addition more slowly, high Catalysts 2017, 7, 267 30 of 53 temperatures (above 120 ◦C) are usually required and a stable metal-ligand system that does not thedecompose catalyst atand higher hence temperature PPh3 will is not essential be suitable for prolonged ligand lifein such of the cases. catalyst For and intramolecular hence PPh3 will Heck not cyclizations,be suitable ligand the reaction in such conditions cases. For intramolecularappear to vary Heck depending cyclizations, on the the ring reaction size, stereochemistry conditions appear of theto vary alkene depending and whether on the a ringtertiary size, or stereochemistry quaternary centre of the is being alkene formed. and whether The presence a tertiary of or halides quaternary does notcentre appear is being to impede formed. the The cyclization presence ofat halideselevated does temperatures not appear and to impede can be thebeneficial cyclization for high at elevated ee’s in asymmetrictemperatures Heck and couplings. can be beneficial The use for of high halide ee’s free in asymmetricconditions can Heck produce couplings. rapid The Heck use couplings of halide freebut variableconditions ee’s can are produce seen for rapid asymmetric Heck couplings cyclization. but variable ee’s are seen for asymmetric cyclization. TheThe AmatoreAmatore group group of researchersof researchers have have invested invested much effortmuch into effort investigations into investigations of the mechanism of the mechanismof Heck reaction. of Heck Kinetic reaction. evidences Kinetic and electrochemicalevidences and techniqueselectrochemical like steady techniques state voltammetry like steady alongstate voltammetrywith spectroscopic along techniques with spectroscopic like UV (Ultra techniques violet like spectroscopy), UV (Ultra violet NMR spectroscopy), (Nuclear Magnetic NMR Resonance (Nuclear MagneticSpectroscopy) Resonance was used Spectroscopy) for the elucidation was used of for mechanisms the elucidation of palladium-catalysed of mechanisms of reactions palladium [69‐]. catalysedTheir work reactions emphasizes [69]. theTheir crucial work role emphasizes played by the the crucial anions role born played by the by precursors the anions of palladium(0)born by the precursorscomplexes of and palladium(0) rationalize empiricalcomplexes findings and rationalize dispersed empirical in literature findings concerning dispersed the specificityin literature of concerningpalladium catalyticthe specificity systems. of palladium A new adequate catalytic catalytic systems. cycle A new has beenadequate proposed catalytic for Heckcycle has reactions been proposedwhere the fundamentalfor Heck reactions role of chloridewhere the or acetatefundamental ions brought role of by chloride palladium(II) or acetate complexes, ions brought precursors by palladium(II)of palladium(0) complexes, complexes, precursors is established of palladium(0) (Scheme8). complexes, is established (Scheme 8).

SchemeScheme 8. 8. AA new new catalytic catalytic cycle cycle reviewed reviewed by by Amatore Amatore et al. [69]. [69].

ItIt is is proposed that the new reactive anionic palladium(0) complexes species species are are formed formed where palladium(0) is ligated by either chloride ions Pd(0)(PPh3)2Cl−− or by acetate ions Pd(0)(PPh3)2(OAc)−. palladium(0) is ligated by either chloride ions Pd(0)(PPh3)2Cl or by acetate ions Pd(0)(PPh3)2(OAc) . The reactivity of such anionic palladium(0) complexes complexes in in oxidative oxidative addition addition to to aryl aryl iodides iodides strongly strongly dependsdepends on on the anion ligated to the palladium(0). The structure of the arylpalladium(II) complexes formedformed in in the the oxidative addition also depends on the anion. The existence of intermediate anionic pentacoordinated arylpalladium(II) complexes ArPdI(Cl)(PPh3)2− 135 and ArPdI(OAc)(PPh3)2− 136 (Figure 19) are also predicted based on evidences. Their stability and reactivity is discussed depending on the presence of chloride or acetate anion. ArPdI(Cl)(PPh3)2− is found to be more stable and it affords trans ArPdI(PPh3)2, whereas, ArPdI(OAc)(PPh3)2− is quite unstable and rapidly affords the stable trans ArPd(OAc)(PPh3)2 complex.

Catalysts 2017, 7, 267 31 of 53

The existence of intermediate anionic pentacoordinated arylpalladium(II) complexes − − ArPdI(Cl)(PPh3)2 135 and ArPdI(OAc)(PPh3)2 136 (Figure 19) are also predicted based on evidences. Their stability and reactivity is discussed depending on the presence of chloride or acetate − anion. ArPdI(Cl)(PPh3)2 is found to be more stable and it affords trans ArPdI(PPh3)2, whereas, − CatalystsArPdI(OAc)(PPh 2017, 7, 267 3)2 is quite unstable and rapidly affords the stable trans ArPd(OAc)(PPh3)2 complex.31 of 53

PPh 3 PPh 3 X X Ar Pd Ar Pd Cl OAc PPh 3 PPh3 135 136

FigureFigure 19. 19. IntermediateIntermediate anionicanionic pentacoordinated pentacoordinated arylpalladium(II) arylpalladium(II) complexes complexes formed in formed Heck reaction. in Heck reaction. Another review by Amator and Jutand [70] is the resurgence on the mechanism of Heck reaction. ItAnother aims at givingreview the by evidences Amator and of anionic Jutand Pd(0) [70] and is the Pd(II) resurgence intermediates on the in mechanism palladium-catalysed of Heck Heck reaction. It aimsand at cross-coupling giving the evidences reactions. of It anionic was proved Pd(0) that and the Pd(II) anions intermediates of PdCl2L2 and in Pd(OAc) palladium2, precursors‐catalysed of Heck and palladium(0)cross‐coupling play reactions. a crucial role It was during proved the reaction. that the Thus, anions Pd(0)L of 2PdCl, postulated2L2 and as Pd(OAc) the common2, precursors catalyst of palladium(0)in catalytic play systems, a crucial is not role formed during as athe main reaction. intermediate, Thus, Pd(0)L instead,2, previouslypostulated unsuspected as the common reactive catalyst 0 − 0 − in catalytictricoordinated systems, anionic is not complex formed speciesas a main Pd intermediate,L2Cl and Pd Linstead,2(OAc) previouslyare found tounsuspected be the effective reactive tricoordinatedcatalysts. These anionic anions complex also affect species the kinetics Pd0L of2Cl the−and oxidative Pd0L2 addition(OAc)− toare ArI found as well to as be the the structure effective catalysts.and reactivity These anions of the also arylpalladium(II) affect the kinetics complexes of the produced oxidative in addition this reaction. to ArI The as pentacoordinated well as the structure anionic complexes ArPdI(Cl)L − or ArPdI(OAc)L − are formed in the reaction. and reactivity of the arylpalladium(II)2 complexes2 produced in this reaction. The pentacoordinated An alternative mechanism via Pd(II)/Pd(IV) cycle (Scheme9) specially proposed for PCP anionic complexes ArPdI(Cl)L2− or ArPdI(OAc)L2− are formed in the reaction. complexes (pincer palladacycle with Phosphorous as donor ligands) is described in the review by WhitecombAn alternative [24]. Themechanism initiation ofvia the Pd(II)/Pd(IV) catalytic cycle takescycle place(Scheme via the 9) oxidative specially addition proposed of a vinylfor PCP complexes (pincer palladacycle with Phosphorous as donor ligands) is described in the review by C-H of CH2 = CHR to the palladium (II) complex (step a). This is followed by the reductive elimination Whitecombof HCl from [24]. theThe Pd(IV) initiation species of the (step catalytic b) and iscycle a rate takes determining place via step the oxidative to generate addition Pd(II) species. of a vinyl C‐H Oneof CH more2 = CHR oxidative to the addition palladium of ArCl (II) complex (step c) generates(step a). This another is followed Pd(IV) species by the reductive collapsing elimination further of HClgiving from out the coupled Pd(IV) product species via (step reductive b) and elimination is a rate determining to restore the step catalyst to generate (step d). ThePd(II) mechanism species. One moreis oxidative different than addition a classical of ArCl Pd(0)/Pd(II) (step c) asgenerates it involves another the successive Pd(IV) species oxidative collapsing addition of further both aryl giving out coupledhalide and product alkene substratesvia reductive and eliminates elimination the needto restore for the the migratory catalyst insertion (step d). step. The Formation mechanism of is differentintermediate than a afterclassical a reversible Pd(0)/Pd(II) step a, hasas it been involves supported the bysuccessive NMR studies oxidative using deuterium. addition of both aryl Cavell and McGuinness [71] have reviewed the redox process involving N-heterocyclic carbene halide and alkene substrates and eliminates the need for the migratory insertion step. Formation of complexes and associated imidazolium salts in conjunction with Group 10 metals. The mechanistic intermediate after a reversible step a, has been supported by+ NMR studies using deuterium. studies with stoichiometric reaction of the [(tmiy)2Pd(Ar)] cation (where Ar = p-nitrophenyl) with butylacrylateCavell and McGuinness was seen to give[71] have a complex reviewed mixture the of redox products. process It wasinvolving observed N‐heterocyclic that the product carbene complexesdistribution and associated was dependent imidazolium on temperature salts in and conjunction other reaction with conditions. Group 10 For metals. example, The at mechanistic−30 ◦C studiesonly with the reductivestoichiometric elimination reaction products of the 2-(4-nitrophenyl)-1,3,4,5-tetramethylimidazolium [(tmiy)2Pd(Ar)]+ cation (where Ar = p‐nitrophenyl) ion, and with butylacrylatetraces of thewas 2-substituted-imidazolium seen to give a complex ion mixture were observed.of products. On It warming was observed to −20 ◦thatC, the the Heck product distributioncoupling was product, dependentn-butyl ( Eon)-4-nitrocinnamate, temperature and and other a further reaction product, conditions. 1,3,4,5-tetramethyl For example, imidazolium at −30 °C onlysalt, the werereductive observed. elimination At room products temperature, 2‐(4‐nitrophenyl) the main products‐1,3,4,5 were‐tetramethylimidazolium the Heck product and ion, the and traces1,3,4,5-tetramethylimidazolium of the 2‐substituted‐imidazolium salt. This ion were indicates observed. that the On raise warming in temperature to −20 °C, leads the to Heck the Heck coupling product,coupling n‐butyl product (E)‐ more4‐nitrocinnamate, rapidly, i.e., the and rates a of further migratory product, insertion 1,3,4,5 plus β‐tetramethyl-elimination, asimidazolium required for salt, Heck catalysis, become more competitive with reductive elimination. When the process is run under were observed. At room temperature, the main products were the Heck product and the 1,3,4,5‐ catalytic conditions, i.e., base with an excess of p-nitrophenyliodide and butylacrylate at around 120 ◦C, tetramethylimidazolium salt. This indicates that the raise in temperature leads to the Heck coupling only the Heck product is observed with high turnover frequencies (TOF) and TON and no products product more rapidly, i.e., the rates of migratory insertion plus β‐elimination, as required for Heck catalysis, become more competitive with reductive elimination. When the process is run under catalytic conditions, i.e., base with an excess of p‐nitrophenyliodide and butylacrylate at around 120 °C, only the Heck product is observed with high turnover frequencies (TOF) and TON and no products generated from the reductive elimination reaction were observed. This indicates the thermodynamic parameters such as activation barriers and relative exothermicities play a crucial role.

Catalysts 2017, 7, 267 32 of 53 generated from the reductive elimination reaction were observed. This indicates the thermodynamic Catalystsparameters 2017, 7 such, 267 as activation barriers and relative exothermicities play a crucial role. 32 of 53

PR2 Oxidative Ar Pd Cl Addition R R PR2 Reductive Elemination step d step a

PR2 R PR2 R Pd H Pd Ar Cl Cl PR2 PR 2 step b step c

PR2 R HCl Oxidative Ar-Cl Addition Pd Reductive Elemination PR2 Scheme 9. An alternative mechanism for Heck reaction via Pd(II)/Pd(IV) cycle. Scheme 9. An alternative mechanism for Heck reaction via Pd(II)/Pd(IV) cycle.

Trzeciak and Ziolkowski [72] have reviewed the catalytic activity of palladium in C‐C bond Trzeciak and Ziolkowski [72] have reviewed the catalytic activity of palladium in C-C bond forming processes in respect to Heck and carbonylation reactions. Catalytic systems based on forming processes in respect to Heck and carbonylation reactions. Catalytic systems based on palladium complexes with phosphorus ligands and phosphine‐free systems and based on the Pd(0) palladium complexes with phosphorus ligands and phosphine-free systems and based on the Pd(0) colloid are discussed by giving a number of examples. These examples reveal that, both colloid are discussed by giving a number of examples. These examples reveal that, both monomolecular monomolecular Pd(0) phosphine complexes and nanosized Pd(0) colloids can act as active catalysts. Pd(0) phosphine complexes and nanosized Pd(0) colloids can act as active catalysts. This review This review supports the formation of conventional oxidative addition complex PhPdL2X on the basis supports the formation of conventional oxidative addition complex PhPdL X on the basis of evidences. of evidences. The possibility of typical monomolecular Pd(0) complexes2 (e.g., [Pd(0)P4], P = The possibility of typical monomolecular Pd(0) complexes (e.g., [Pd(0)P4], P = phosphorus ligand) phosphorus ligand) undergoing partial decomposition during the catalytic process to form nanosized undergoing partial decomposition during the catalytic process to form nanosized phosphine-free Pd(0) phosphine‐free Pd(0) particles is predicted. Palladium in the form of a colloid was observed to be a particles is predicted. Palladium in the form of a colloid was observed to be a good catalyst for Heck good catalyst for Heck and carbonylation reactions, especially when applied in an ammonium salt and carbonylation reactions, especially when applied in an ammonium salt ([R4N]X) or an ionic liquid ([R4N]X) or an ionic liquid (IL) medium. Ammonium salts efficiently contribute to the formation of (IL) medium. Ammonium salts efﬁciently contribute to the formation of soluble, monomolecular soluble, monomolecular Pd(0) compounds of probably higher catalytic activity than bigger‐sized Pd(0) compounds of probably higher catalytic activity than bigger-sized clusters. The study reveals clusters. The study reveals that carboxylate salts used as bases in the Heck reactions, can act as that carboxylate salts used as bases in the Heck reactions, can act as effective Pd(II) to Pd(0) reducing effective Pd(II) to Pd(0) reducing agents, and therefore they also may initiate the formation of agents, and therefore they also may initiate the formation of colloidal nanoparticles. colloidal nanoparticles. Phan et al. [73] have a critical review on the nature of the active species in palladium catalysed Phan et al. [73] have a critical review on the nature of the active species in palladium catalysed Mizoroki–Heck and Suzuki–Miyaura couplings using homogeneous or heterogeneous catalysis. Mizoroki–Heck and Suzuki–Miyaura couplings using homogeneous or heterogeneous catalysis. Regardless of what palladium precatalyst is used, it is critical for researchers to understand the Regardless of what palladium precatalyst is used, it is critical for researchers to understand the nature nature of the true catalytic species generally used in their studies because of palladium deactivation of the true catalytic species generally used in their studies because of palladium deactivation via via clustering, leaching and redeposition processes. The review summarizes each type of precatalyst of clustering, leaching and redeposition processes. The review summarizes each type of precatalyst of palladium, proposed to be truly active in the various form of catalysts like discrete soluble palladium palladium, proposed to be truly active in the various form of catalysts like discrete soluble palladium complexes, solid-supported metal ligand complexes, supported palladium nano- and macroparticles, complexes, solid‐supported metal ligand complexes, supported palladium nano‐ and macroparticles, soluble palladium nanoparticles, soluble ligandfree palladium and palladium-exchanged oxides. soluble palladium nanoparticles, soluble ligandfree palladium and palladium‐exchanged oxides. A A considerable focus is placed on solid precatalysts and on evidence for and against catalysis by solid considerable focus is placed on solid precatalysts and on evidence for and against catalysis by solid surfaces vs. soluble species when starting with a range of precatalysts. surfaces vs. soluble species when starting with a range of precatalysts. Based on various control experiments and tests to assess the homogeneity or heterogeneity Based on various control experiments and tests to assess the homogeneity or heterogeneity of of catalyst systems, it was concluded that, the Heck reactions using NC, SC, PC, SCS and PCP catalyst systems, it was concluded that, the Heck reactions using NC, SC, PC, SCS and PCP palladacycles (catalysts with N, O, P or S donor ligands) operates by Pd(0)/Pd(II) mechanism only palladacycles (catalysts with N, O, P or S donor ligands) operates by Pd(0)/Pd(II) mechanism only and there is no proven example of catalysts operating by a Pd(II)/Pd(IV) catalytic cycle in Heck or Suzuki coupling reactions. Knowles and Whiting [74] have reviewed advances in the mechanistic perspective of the Heck reaction aiming to review and compare work undertaken on the mechanism until 2007. The data

Catalysts 2017, 7, 267 33 of 53 and there is no proven example of catalysts operating by a Pd(II)/Pd(IV) catalytic cycle in Heck or Suzuki coupling reactions. Knowles and Whiting [74] have reviewed advances in the mechanistic perspective of the Heck reaction aiming to review and compare work undertaken on the mechanism until 2007. The data provided give the evidence for a mechanism where the oxidative addition strongly depends on the conditions, particularly whether the reaction is saturated with halide. Eventually, the authors concluded that it is not possible to explain all the phenomena observed for the oxidative addition on the basis of single mechanism only and there may be several mechanisms in operation, either independently, depending on the reaction conditions, or in parallel. Although the electron rich and chelating nature of the phosphines is required to activate aryl chlorides, it disfavors carbometallation or dissociation. It is also assumed that the rate determining step comes after initial oxidative addition; however, the nature of this step is yet unclear and has a strong dependence on the nature of the species produced in the oxidative addition step. Kumar and co-workers [75] have reviewed the status regarding in situ generation of palladium chalcogenides phases or Pd(0) protected with organochalcogen fragments when Palladium(II) complexes of organochalcogen ligands (e.g., Pd(II) complex of an (S,C,S) pincer ligand) are used as viable alternatives to complexes of phosphine/carbene ligands for Suzuki−Miyaura and Heck C-C cross coupling reactions. These ligands are thermally stable, easy to handle and air and moisture sensitivity are not impediments with many of them. Recently, Eremin and Ananikov [76] summarized the studies mentioning the behaviour of a “Cocktail” of catalysts and mechanistic investigations regarding the evolution of transition metal species during catalytic cycles. They have considered the transformations of molecular catalysts, leaching, aggregation and various interconversions of metal complexes, clusters and nanoparticles that occur during catalytic processes termed as “Cocktail”-type systems. These systems are considered from the perspective of the development of a new generation of efﬁcient, selective and re-usable catalysts for synthetic applications. It also attempts to determine “What are the true active species?” in mechanism specially in coupling reactions like Heck. It has been concluded that there is nothing static in catalysis and catalytic system is always dynamic where “Cocktail”-type catalytic systems are formed when the transformation of a metal species occurs during the overall catalytic process. It was observed that the “Cocktail” picture can exist not only in homogeneous catalysis in solution but also in a heterogeneous catalytic system.

4. Reviews on Applications The palladium-catalysed cross-coupling reactions particularly Heck reaction have great signiﬁcance for both academic and industrial research and in the production of number of compounds on a large industrial scale. Fine chemicals—including pharmaceuticals, agricultural chemicals, and high-tech materials—that beneﬁt society when designed properly in addition to the new reactivities, increased product selectivity and reduced volatile organic consumption, can lead to a great breakthrough in industrial research. Reviews targeting such chemicals are given below.

4.1. Fine Chemical Production An overview by Blaser et al. [77] describes the industrial application of homogeneous catalysts for the chemical industry. Along with theoretical background of organometallic complexes and homogeneous catalysis, a description of the prerequisites and current problems for their industrial application mainly for manufacture of intermediates for pharmaceuticals and agrochemicals are discussed. Production processes for octyl-4-methoxycinnamate, the most common UVB sunscreen (UVB—Ultra Violet B: These rays penetrate the upper layers of the skin) developed by Dead Sea Company (Scheme 10); Naproxen, a generic analgesic, developed by Albemarle (Scheme 11) and sodium 2-(3,3,3,-triﬂuoropropyl)- benzenesulfonate, a key intermediate for Novartis’ sulfonylurea Catalysts 2017, 7, 267 34 of 53

herbicideCatalysts 2017 Prosulfuron, 7, 267 (Scheme 12) are mentioned, where, Heck reaction is one of the key34 stepof 53 in its Catalysts 2017, 7, 267 34 of 53 process,Catalysts 2017 along, 7, 267 with their yield and selectivity. 34 of 53 O O O O Br O Pd on Carbon OC8H17 Br2 Br O Pd on Carbon OC8H17 Br2 NaBr Br OC8H17 Pd on Carbon OC8H17 CHBrCOOH2 NaBr 3 OC8H17 Na2CO3 / NMP MeO MeO CH3COOH MeO Na CO / NMP NaBr OC8H17 2 3 MeO Octyl-4-methoxycinnamate MeO CH3COOH MeO Na2CO3 / NMP MeO 137 MeO MeO 137 Octyl-4-methoxycinnamate 137 Octyl-4-methoxycinnamate

SchemeScheme 10. SyntheticSynthetic route route for for Octyl Octyl-4-methoxy‐4‐methoxy cinnamate cinnamate by Dead by Dead Sea Company. Sea Company. Scheme 10. Synthetic route for Octyl‐4‐methoxy cinnamate by Dead Sea Company. Scheme 10. Synthetic route for Octyl‐4‐methoxy cinnamate by Dead Sea Company.

CO / H2O Br2 Br COOH CO / H2O COOH Br2 Br CO / H O CHBr3COOH 2 COOH MeO 2 Br Pd/Phosphine MeO MeO CH3COOH Pd/Phosphine MeO MeO MeO Na2CO3/ NMP MeO Naproxen MeO CH3COOH Pd/Phosphine MeO 138 MeO Na2CO3/ NMP MeO 138 Naproxen MeO Na2CO3/ NMP 138 Naproxen

Scheme 11. Synthetic route for Naproxen by Albemarle. Scheme 11. Synthetic route for Naproxen by Albemarle. Scheme 11. Synthetic route for Naproxen by Albemarle. Scheme 11. Synthetic route for Naproxen by Albemarle. - + - + SO3 - SO3Na SO3 Na - SO3 Pd(dba)2 + 1. charcoal - + SO3 diazotization - SO3Na SO3 Na - SO3 Pd(dba)2 + 1. charcoal - + Prosulfuron SO diazotization - SO Na 2. H2 SO3 Na 3 SO3 Pd(dba)2 3 1. charcoal Prosulfuron + diazotization CH2=CH-CF 3 2. H 139 NH3 + CF3 2 CF3 Prosulfuron + N2 CH2=CH-CF 3 139 NH + CF 2. H2 CF3 3 N2 CH2=CH-CF3 3 139 + + CF3 NH3 N2 CF3 Scheme 12. Synthetic route for Prosulfuron intermediate by Ciba-Geigy/Novartis.

Scheme 12. Synthetic route for Prosulfuron intermediate by Ciba‐Geigy/Novartis. Scheme 12. Synthetic route for Prosulfuron intermediate by Ciba‐Geigy/Novartis. ‘The HeckScheme reaction 12. Synthetic in the production route for Prosulfuron of fine intermediate chemicals’ by by Ciba deVries‐Geigy/Novartis. [78], is an overview mainly focusing‘The the Heck commercial reaction in products the production produced of fine on chemicals’ a scale in by excess deVries of [78], 1 ton/year is an overview and using mainly Heck or ‘The Heck reaction in the production of fine chemicals’ by deVries [78], is an overview mainly Heckfocusing‘The type theHeck reaction commercial reaction as one in products the of production the produced steps during of onfine a scalechemicals’ synthesis. in excess by The ofdeVries 1 synthetic ton/year [78], andis methods an using overview Heck for production ormainly Heck of focusing the commercial products produced on a scale in excess of 1 ton/year and using Heck or Heck afocusing sunscreentype reaction the agent,commercial as one 2-ethylhexyl of products the steps producedp-methoxy-cinnamate during onsynthesis. a scale in The excess137 synthetic; of a 1 nonsteroidal ton/year methods and forusing anti-inflammatory production Heck or Heck of a drug, type reaction as one of the steps during synthesis. The synthetic methods for production of a typesunscreen reaction agent, as one2‐ethylhexyl of the steps p‐methoxy during ‐cinnamatesynthesis. The137 ; synthetica nonsteroidal methods anti for‐inflammatory production drug,of a Naproxensunscreen 138agent,; an 2 herbicide,‐ethylhexyl Prosulfuron p‐methoxy‐cinnamate139; an antiasthma 137; a nonsteroidal agent, Singulair anti‐inflammatory140 and monomers drug, for sunscreenNaproxen agent,138; an 2 herbicide,‐ethylhexyl Prosulfuron p‐methoxy 139‐cinnamate; an antiasthma 137; a agent,nonsteroidal Singulair anti 140‐inflammatory and monomers drug, for coatings,Naproxen divinyltetramethyldisiloxanebisbenzocyclobutene 138; an herbicide, Prosulfuron 139; an antiasthma agent,141 (Figure Singulair 20 140) have and been monomers discussed for along Naproxencoatings, 138divinyltetramethyldisiloxanebisbenzocyclobutene; an herbicide, Prosulfuron 139; an antiasthma agent,141 (Figure Singulair 20) 140 have and been monomers discussed for withcoatings, the conditions divinyltetramethyldisiloxanebisbenzocyclobutene used for their synthesis. Herbicide prosulfuron 141 (Figure is synthesized 20) have been via Matsuda discussed reaction coatings,along with divinyltetramethyldisiloxanebisbenzocyclobutene the conditions used for their synthesis. Herbicide 141prosulfuron (Figure is20) synthesized have been via discussed Matsuda usingalong arenediazonium with the conditions salts used as for an their alternative synthesis. to Herbicide aryl halides prosulfuron and triflates, is synthesized whereas via theMatsuda production alongreaction with using the conditions arenediazonium used for salts their assynthesis. an alternative Herbicide to prosulfuronaryl halides isand synthesized triflates, viawhereas Matsuda the ofreaction sunscreen using agent arenediazonium 2-ethylhexyl saltsp-methoxy-cinnamate as an alternative to aryl uses halides Pd/C asand catalyst. triflates, Naproxenwhereas the and the reactionproduction using of sunscreenarenediazonium agent 2salts‐ethylhexyl as an alternativep‐methoxy ‐cinnamateto aryl halides uses Pd/Cand triflates,as catalyst. whereas Naproxen the production of sunscreen agent 2‐ethylhexyl p‐methoxy‐cinnamate uses Pd/C as catalyst. Naproxen monomersproductionand the monomers are of sunscreen synthesized are synthesized agent via 2 bromo‐ethylhexyl via derivatives,bromo p‐methoxy derivatives, whereas‐cinnamate whereas Heck uses Heck reaction Pd/C reaction as on catalyst. allylic on allylic alcohol Naproxen alcohol is carried and the monomers are synthesized via bromo derivatives, whereas Heck reaction on allylic alcohol outandis forcarried the the monomers productionout for the are production ofsynthesized antiasthma of antiasthmavia agent bromo Singulair. derivatives,agent Singulair. The whereas review The alsoreviewHeck talks reaction also about talks on theabout allylic use the alcohol of use metals of and is carried out for the production of antiasthma agent Singulair. The review also talks about the use of ligandsismetals carried as and out a partligands for the of catalyst asproduction a part forof catalyst of industrial antiasthma for industrial production. agent Singulair. production. Although The Although review palladium also palladium talks has about proved has theproved to use be of to the best metals and ligands as a part of catalyst for industrial production. Although palladium has proved to metalmetalsbe the to andbest be usedligands metal for to as Heck be a part used reaction, of for catalyst Heck from forreaction, industrial the economic from production. the standpoint economic Although standpoint its cost palladium becomes its cost has thebecomes proved biggest theto hurdle be the best metal to be used for Heck reaction, from the economic standpoint its cost becomes the atbebiggest industrial the best hurdle metal level. at toindustrial be used level. for Heck reaction, from the economic standpoint its cost becomes the biggest hurdle at industrial level. biggestSimilarly, hurdle despite at industrial the fact level. that palladacycles, pincers and bulky ligands are robust, they work only on few reactive substrates. Hence ligandless catalysis seems to be attractive for production. In addition, various techniques of recycling of catalyst has been discussed like immobilization of catalysts by attaching ligands to solid support, etc., however, was not found to be useful, because of leaching and reduced activity issues.

Catalysts 2017, 7, 267 35 of 53 Catalysts 2017, 7, 267 35 of 53

O COOH

MeO MeO 138 Naproxen 137 Octylmethoxy cinnamate

COOH

O N N O O S OH N N N OMe H H Cl N S

CF3 140 139 Prosulfuron Singular

O Si Si

141 Figure 20. Fine chemical products produced on a scale in excess of 1 ton/year using Heck or Heck type Figurereaction 20. reviewed Fine chemical by deVries products [78]. produced on a scale in excess of 1 ton/year using Heck or Heck type reaction reviewed by deVries [78]. A review by Zapf and Beller [79] published in succeeding year gives the importance of Similarly, despite the fact that palladacycles, pincers and bulky ligands are robust, they work several palladium-catalysed reactions like Heck, Suzuki, Sonogashira, telomerization [80] and only on few reactive substrates. Hence ligandless catalysis seems to be attractive for production. In carbonylation [81], developed and optimized to a stage that enables application on an industrial scale. addition, various techniques of recycling of catalyst has been discussed like immobilization of In addition to Naproxen 138, Prosulfuron 139 and divinyltetramethyldisiloxane-bisbenzocyclobutene catalysts by attaching ligands to solid support, etc., however, was not found to be useful, because of 141, use of Heck reaction in the synthesis of L-699,392 142, resveratrol 143, eletriptan 144, cincalcet 145 leaching and reduced activity issues. and montelukast sodium (Salt of Singulair) 146 (Figure 21) by different industries are discussed. A review by Zapf and Beller [79] published in succeeding year gives the importance of several Much later, a review published by Picquet [82] edited by Beller and Blaser presents the palladium‐catalysed reactions like Heck, Suzuki, Sonogashira, telomerization [80] and carbonylation state-of-the-art in the industrial use of organometallic or coordination complexes as catalysts for [81], developed and optimized to a stage that enables application on an industrial scale. In addition the production of ﬁne chemicals. The review illustrates the great potential of platinum group to Naproxen 138, Prosulfuron 139 and divinyltetramethyldisiloxane‐bisbenzocyclobutene 141, use of metal (pgm) complexes as valuable tools in this ﬁeld for many organic transformations, where these Heck reaction in the synthesis of L‐699,392 142, resveratrol 143, eletriptan 144, cincalcet 145 and reactions involve platinum group metal complexes as catalysts. Heck reaction for the production montelukast sodium (Salt of Singulair) 146 (Figure 21) by different industries are discussed. of compounds Naproxen 138, Prosulfuron 139, Resveratrol 143, Cinacalcet 145 and Montelukast 146 is discussed. The authors are from the industrial world so were also able to describe the technical challenges encountered in scaling up the reactions from small quantities to production amounts and also tackle issues related to it by taking numerous examples of production processes, pilot plant or bench-scale reactions.

Catalysts 2017, 7, 267 36 of 53 Catalysts 2017, 7, 267 36 of 53

COOH OH

O HO Cl N S

142 OH 143 L-699,392 Resveratrol

Me O O N S N H N 144 H 145 Cinacalcet Eletriptan CF3

COONa

OH Cl N S

146 Montelukast Sodium

FigureFigure 21.21. Additional ﬁnefine chemical products producedproduced onon industrialindustrial scalescale usingusing HeckHeck reactionreaction reviewedreviewed by by Zapf Zapf and and Beller Beller [ [79].79].

Much later, a review published by Picquet [82] edited by Beller and Blaser presents the state‐of‐ 4.2. Pharmaceuticals the‐art in the industrial use of organometallic or coordination complexes as catalysts for the productionA review of fine by Sharma chemicals. [83 ]The shows review the illustrates importance the of great cinnamic potential acid of derivatives platinum group (CADs) metal147 (pgm), 148 (Figurecomplexes 22) foras valuable its various tools biological in this field activities for many like antioxidant, organic transformations, hepatoprotective, where anxiolytic, these reactions insect repellent,involve platinum antidiabetic group and anticholesterolemic,metal complexes as etc. catalysts. Heck reaction for the production of compoundsIt is mentioned Naproxen that 138 the, Prosulfuron various methods 139, forResveratrol the preparation 143, Cinacalcet of cinnamic 145 acidand derivativesMontelukast such 146 as is Perkindiscussed. reaction The [ 84authors], enzymatic are from method, the industrial Knoevenagel world condensation, so were also phosphorous able to describe oxychloride the technical method andchallenges Claisen–Schmidt encountered condensations in scaling up hasthe reactions some or the from other small drawbacks quantities or to loopholesproduction like amounts low yield, and lossalso of tackle catalytic issues activity related of to enzyme, it by taking long numerous duration of examples reaction time,of production ozone layer processes, depletion pilot caused plant by or CClbench4 and‐scale tedious reactions. synthetic procedure, etc. Hence, the Heck reaction using various novel supported catalystsCatalysts 2017 is, by 7, 267 far the best for the synthesis of cinnamic acid derivatives. 37 of 53 4.2. Pharmaceuticals O A review by Sharma [83] shows the importance of cinnamic acid derivatives (CADs) 147, 148 MeO (Figure 22) for its various biological activities like antioxidant, hepatoprotective, anxiolytic, insect O OCH2CH3 repellent, antidiabetic and anticholesterolemic, etc. HO It is mentioned that the various methods for the preparation of cinnamic acid derivatives such OCH3 MeO as Perkin reaction [84], enzymatic method, Knoevenagel condensation,OMe phosphorous oxychloride method and Claisen–SchmidtHO condensations147 has some or the other drawbacks148 or loopholes like low yield, loss of catalytic activityMethyl of enzyme, caffeate long duration Ethyl-3,4,5-trimethoxycinnamate of reaction time, ozone layer depletion caused by CCl4 and tedious synthetic procedure, etc. Hence, the Heck reaction using various novel supported Figure 22. Cinnamic acid derivatives (CADs) reviewed by Sharma [83]. catalysts is by far the best for the synthesis of cinnamic acid derivatives. Figure 22. Cinnamic acid derivatives (CADs) reviewed by Sharma [83].

Biajoli et al. [85] have reported the applications of Pd‐catalysed C‐C cross‐coupling reactions for the synthesis of drug components or drug candidates. The review is written in context with two

earlier independent reviews by Pfizer researchers Magano and Dunetz on the large‐scale applications of transition metal‐catalysed coupling reactions for the manufacture of drug components in the pharmaceutical industry [86] and by Torborg and Beller [87] on the applications of Pd‐catalysed coupling reactions, both covering the material till 2010. Hence, the period after that until July 2014 is covered in their review. Cross coupling reactions like Heck, Suzuki, Negishi, Sonogashira, Stille and Kumada are discussed with number of examples. Heck reactions are intensely exploited for inter and intramolecular coupling involving double bonds for the synthesis of a idebenone 149 used for the treatment of Alzheimer’s, Parkinson’s diseases, free radical scavenging and action against some muscular illnesses; ginkgolic acid (13:0) 150, a tyrosinase inhibitor; olopatadine 151 an antihistaminic drug; the vascular endothelial growth factor (VEGF) inhibitor axitinib 152; caffeine‐styryl compounds 153 possessing a dual A2A antagonist/MAO‐B inhibition properties and with potential application in Parkinson’s disease; styryl analogues of piperidine alkaloids (+)‐caulophyllumine B 154 displaying a high anti‐cancer activity in vitro; (R)‐tolterodine 155, a drug employed in urinary incontinence treatment; ectenascidin 743, the anti‐cancer tetrahydroisoquinoline alkaloid 156; bioactive compounds the abamines 157, 158 and naftifine 159 (Figure 23).

Me O OH

MeO O OMe 149 Idebenone O

COOH

O N Me 150 Ginkgolic acid 151 OH OH Me Olopatadine

Catalysts 2017, 7, 267 37 of 53

O Catalysts 2017, 7, 267 MeO 37 of 53 O OCH2CH3 HO Biajoli et al. [85] have reported theOCH applications3 MeO of Pd-catalysed C-C cross-coupling reactions for the synthesis of drug components or drug candidates. TheOMe review is written in context with two earlier independentHO reviews by Pﬁzer147 researchers Magano and Dunetz148 on the large-scale applications of transition metal-catalysedMethyl coupling caffeate reactions forEthyl-3,4,5-trimethoxycinnamate the manufacture of drug components in the pharmaceutical industry [86] and by Torborg and Beller [87] on the applications of Pd-catalysed coupling reactions,Figure both covering22. Cinnamic the acid material derivatives till 2010. (CADs) Hence, reviewed the period by Sharma after [83]. that until July 2014 is covered in their review. CrossBiajoli coupling et al. [85] reactions have reported like Heck, the Suzuki, applications Negishi, of Pd Sonogashira,‐catalysed C Stille‐C cross and‐ Kumadacoupling are reactions discussed for withthe synthesis number of of examples. drug components Heck reactions or drug are intenselycandidates. exploited The review for inter is written and intramolecular in context with coupling two involvingearlier independent double bonds reviews for theby Pfizer synthesis researchers of a idebenone Magano149 andused Dunetz for theon the treatment large‐scale of Alzheimer’s, applications Parkinson’sof transition diseases, metal‐catalysed free radical coupling scavenging reactions and actionfor the against manufacture some muscular of drug illnesses;components ginkgolic in the acidpharmaceutical (13:0) 150, a tyrosinaseindustry [86] inhibitor; and by olopatadine Torborg and151 Belleran antihistaminic [87] on the drug; applications the vascular of Pd endothelial‐catalysed growthcoupling factor reactions, (VEGF) both inhibitor covering axitinib the material152; caffeine-styryl till 2010. Hence, compounds the period153 afterpossessing that until aJuly dual 2014 A2A is antagonist/MAO-Bcovered in their review. inhibition properties and with potential application in Parkinson’s disease; styryl analoguesCross ofcoupling piperidine reactions alkaloids like (+)-caulophyllumine Heck, Suzuki, Negishi, B 154 displayingSonogashira, a highStille anti-cancer and Kumada activity are indiscussed vitro; (R)-tolterodine with number155 of, a drugexamples. employed Heck in reactions urinary incontinenceare intensely treatment; exploited ectenascidin for inter 743,and theintramolecular anti-cancer tetrahydroisoquinolinecoupling involving double alkaloid bonds156 for; bioactive the synthesis compounds of a idebenone the abamines 149 157used, 158 forand the naftiﬁnetreatment159 of(Figure Alzheimer’s, 23). Parkinson’s diseases, free radical scavenging and action against some muscularLab scaleillnesses; preparation ginkgolic ofacid three (13:0) other 150, a drugs:tyrosinase cinacalcet inhibitor; hydrochloride olopatadine 151160 an, antihistaminic alverine 161 anddrug; tolpropamine the vascular endothelial162 are also growth discussed factor (VEGF) using inhibitor typically axitinib Heck-Matsuda 152; caffeine reaction‐styryl (Figurecompounds 24). Cinacalcet153 possessing hydrochloride a dual A2A isantagonist/MAO a calcimimetic‐B drug inhibition commercialized properties underand with the potential trade names application Sensipar in andParkinson’s Mimpara, disease; and is styryl therapeutically analogues useful of piperidine for the treatment alkaloids of(+) secondary‐caulophyllumine hyperthyroidism B 154 displaying and also a indicatedhigh anti against‐cancer hypercalcemiaactivity in vitro; in patients (R)‐tolterodine with parathyroid 155, a drug carcinoma. employed Alverine in urinary is a smooth incontinence muscle relaxanttreatment; used ectenascidin for the treatment 743, ofthe gastrointestinal anti‐cancer disorderstetrahydroisoquinoline such as diverticulitis alkaloid and irritable156; bioactive bowel syndromecompounds and the tolpropamine abamines 157 is, 158 an antihistaminic and naftifine 159 drug (Figure used for23). the treatment of allergies.

Me O OH

MeO O OMe 149 Idebenone O

COOH

O N Me 150 Ginkgolic acid 151 OH OH Me Olopatadine

Figure 23. Cont.

Catalysts 2017, 7, 267 38 of 53 Catalysts 2017, 7, 267 38 of 53

O NHMe

H S N O Me N Me N R1 R2 N X O N Y R3 Me 152 Axitinib N 153 caffeine-styryl derivative

N Me Me N(i-Pr)2 154 OH OH (+)-caulophyllumine B 155 (R)-Tolterodine OMe OAc HO Me H Me H H COOMe OMe O S N OMe N Me O H MeO N O HO H HO O NH

157 Abamine- SG 156 Ectenascidin 743 F

OMe COOMe OMe Me N Ph N

158 Abamine 159 Naftifine F

Figure 23. Drug components or drug candidates exploited for inter and intramolecular Heck coupling byFigure Biajoli 23. et Drug al. [85 components]. or drug candidates exploited for inter and intramolecular Heck coupling by Biajoli et al. [85].

Lab scale preparation of three other drugs: cinacalcet hydrochloride 160, alverine 161 and tolpropamine 162 are also discussed using typically Heck‐Matsuda reaction (Figure 24). Cinacalcet hydrochloride is a calcimimetic drug commercialized under the trade names Sensipar and Mimpara, and is therapeutically useful for the treatment of secondary hyperthyroidism and also indicated against hypercalcemia in patients with parathyroid carcinoma. Alverine is a smooth muscle relaxant

Catalysts 2017, 7, 267 39 of 53

Catalysts 2017, 7, 267 39 of 53 used for the treatment of gastrointestinal disorders such as diverticulitis and irritable bowel Catalysts 2017, 7, 267 39 of 53 syndromeused for andthe tolpropaminetreatment of isgastrointestinal an antihistaminic disorders drug used such for as the diverticulitis treatment of and allergies. irritable bowel syndrome and tolpropamine is an antihistaminic drug used for the treatment of allergies. Et NEt N Me Me N Me H .HCl N N Me H .HCl NMe Me CF Me 160 Cinacalcet hydrochloride 3 161 Alverine Me 162 Tolpropamine CF 160 Cinacalcet hydrochloride 3 161 Alverine 162 Tolpropamine Figure 24. Lab scale preparation drugs reviewed by Biajoli et al. [85].

4.3. Total Synthesis Figure 24. Lab scale preparation drugs reviewed by Biajoli et al. [85]. The Heck reactionFigure has 24. been Lab scale used preparation in synthesis drugs of morereviewed than by 100Biajoli different et al. [85]. natural products and biologically active compounds. Taxol is the first example where Heck reaction was employed for 4.3. Total Synthesis creating4.3. Total the Synthesis eight-membered ring during its synthesis. Reviews in this section give glimpses of all suchThe compounds. Heck reaction has been used in synthesis of more than 100 different natural products and The Heck reaction has been used in synthesis of more than 100 different natural products and biologicallyNicolaou active et al. compounds. have corroborated Taxol theis the role first of palladium example catalyzedwhere Heck cross-coupling reaction was reactions employed in total for biologically active compounds. Taxol is the first example where Heck reaction was employed for creatingsynthesis the [88 eight]. The‐membered review highlights ring during number its ofsynthesis. selected Reviews examples in of this synthesis section using give most glimpses commonly of all creating the eight‐membered ring during its synthesis. Reviews in this section give glimpses of all suchapplied compounds. palladium-catalyzed carbon–carbon bond forming reactions including Heck reactions. such compounds. Nicolaou et al. have corroborated the role of palladium catalyzed cross‐±coupling reactions in The involvementNicolaou et ofal. intramolecularhave corroborated Heck the reaction role of palladium in the total catalyzed synthesis cross of‐ (coupling)-dehydrotubifoline reactions in total synthesis [88]. The review highlights number of selected examples of synthesis using most 163totalwith synthesis justification [88]. based The review on Jeffery highlights modification number [89 ]of for selected the previously examples formed of synthesis unwanted using derivative most commonly applied palladium‐catalyzed carbon–carbon bond forming9(12) reactions including Heck hascommonly been discussed. applied Syntheticpalladium routes‐catalyzed for ( −carbon–carbon)-quadrigemine bond C 164 forming, ∆ -capnellene-3reactions includingβ,8β,10 Heckα-triol reactions. The involvement 9(12)of intramolecular Heck reaction in the total synthesis of ()‐ 165reactions., estrone The166, taxolinvolvement167, ∆ of-capnellene-3 intramolecularβ,8 βHeck,10α,14-tetraol reaction 168in ,the (+)-calcidiol total synthesis169, Okaramine of ()‐ dehydrotubifoline 163 with justification based on Jeffery modification [89] for the previously formed Ndehydrotubifoline170, α-tocopherol 163171 with(Figure justification 25), scopadulcic based on acid-B Jeffery124 modificationand singulair [89]140 forare the given. previously Few examples formed unwanted derivative has been discussed. Synthetic routes for (−)‐quadrigemine C 164, 9(12)‐ ofunwanted zipper polycyclization derivative has172 beendeveloped discussed. by Trost Synthetic group [routes90,91] arefor also(−)‐quadrigemine mentioned. C 164, 9(12)‐ capnellene‐3β,8β,10α‐triol 165, estrone 166, taxol 167, 9(12)‐capnellene‐3β,8β,10α,14‐tetraol 168, (+)‐ capnelleneAll these‐3β,8 processesβ,10α‐triol are 165 impressive, estrone 166 since, taxol they 167,  do9(12) not‐capnellene require‐3 theβ,8β preparation,10α,14‐tetraol of 168 reactive, (+)‐ calcidiolintermediatescalcidiol 169 169, Okaramine, prior Okaramine to the carbon–carbonN N 170 170, α‐, α‐tocopheroltocopherol bond forming 171171 (Figure(Figure event 25), since scopadulcicscopadulcic they proceed acidacid‐ by‐BB 124 activation124 and and singulair singulair of stable 140and140 are readily are given. given. available Few Few examples examples starting of materialsof zipper zipper polycyclizationpolycyclization in situ and, therefore, 172 developed are both byby more TrostTrost practical group group [90,91] and[90,91] often are are also more also mentioned.efficientmentioned. in terms of overall yield.

Me Me H NN H H Me H HH NNHH N NN

NN NNMeMe HH N H HH NN 164164 HH MeMe (-)-(-)- Quadrigemine Quadrigemine C C N NMe 163(dl)-Dehyotubifoline(dl)-Dehyotubifoline H 163 H H

Figure 25. Cont.

Catalysts 2017, 7, 267 40 of 53 Catalysts 2017, 7, 267 40 of 53

HO OH Me H Me Me O

H H Me HO H H

 Capnellene- 3,8, 10-triol HO Estrone 165 166

HO AcO O OH OH Me H Me HO Me Me Ph O Me H O Me H HO BzHN O OH OAc OBz  Capnellene- 3,8, 10 14- tetraol OH 167 Taxol 168

Me Me

Me N Me H Me OH O N Me H H H N O

N H Me Me 169 HO OH (+)-Calcidiol 170 Okaramine N

Me HO Me Me Me

Me O Me Me Me 171 Tocopherol

MeO

PhO 2S

PhO 2S 172 Figure 25. Heck reaction in Total synthesis reviewed by Nicolaou et al. [88 ].

Catalysts 2017, 7, 267 41 of 53

Figure 25. Heck reaction in Total synthesis reviewed by Nicolaou et al. [88].

All these processes are impressive since they do not require the preparation of reactive intermediates prior to the carbon–carbon bond forming event since they proceed by activation of stableCatalysts and2017 readily, 7, 267 available starting materials in situ and, therefore, are both more practical and 41often of 53 more efficient in terms of overall yield.

4.4.4.4. Targeted Targeted Compounds Compounds InIn addition addition to to all all above above distinctive distinctive natural natural products, products, Heck Heck reaction reaction is is also also used used in in the the production production ofof some some particular particular compounds compounds such such as asaryl aryl glycosides glycosides or heterocycles. or heterocycles. A review A review by Wellington by Wellington and Bennerand Benner [92] is [92 about] is about using using Heck Heck reaction reaction for the for synthesis the synthesis of aryl of arylglycosides glycosides (also (also termed termed as C as‐ glycosidesC-glycosides or C or‐nucleosides) C-nucleosides) though though there thereare many are manyreports reports of synthesis of synthesis of such compounds of such compounds via non‐ Heckvia non-Heck methods. methods.Synthesis of Synthesis glycosides of pyrimidine glycosides pyrimidinec‐nucleosides, c-nucleosides, purine c‐nucleosides, purine c-nucleosides, monocyclic, bicyclic,monocyclic, and bicyclic,tetracyclic and C‐ tetracyclicnucleosides C-nucleosides 173–185 (Figure173– 26)185 via(Figure Heck 26 reaction) via Heck are reaction discussed. are discussed.

OMe OMe

Beta-D N N N N TrO 85% O OMe Alpha - L OMe OMe 7% Alpha-D TrO N O O 94% TrO N 175 173 174 OMe

HN Ph O O

N NH HN NH HN NH O OMe HO HO TrO O HO O O H O N O Beta- L N 87% N OH 65% OH 99% OH 63% OMe 176 177 178 179

O NH2 NH2 H3C NH N N N HO HO HO O O O 74% 66% 60% OH Catalysts 2017, 7, 267 OH OH 42 of 53 180 181 182 NH2 NH NH2 2 Cl O2N N NH N HO HO N HO O NH2 O O O

86% 55% OH OH 183 184 185 Figure 26. Glycosides synthesized via Heck reaction reviewed by Wellington and Benner [92]. Figure 26. Glycosides synthesized via Heck reaction reviewed by Wellington and Benner [92].

The review describes the subsequent conversion with respective reagents and conditions of the Heck products corresponding to target molecules and their application. Pd(OAc)2‐AsPh3 was observed to be serving well for most of the synthesis although few other palladium‐ligand combinations have to be used in some cases. Iodides were found to be more reactive than other halides. Bidentate ligand accelerates the Heck coupling reaction and results in a higher yield of the product. A review by Zeni and Larock [93] covers a wide range of palladium catalyzed processes involving oxidative addition‐ reductive elimination chemistry developed to prepare heterocycles, with the emphasis on fundamental processes used to generate the ring systems themselves. A number of examples are given for preparation of heterocycles via intramolecular Heck cyclization of aryl halides, vinylic halides, vinylic and aryl triflates. intermolecular annulation, and via asymmetric Heck cyclization.

5. Reviews on Reuse of Catalyst Homogeneous catalysts are of great interest for synthesizing fine‐chemical, specialty chemical, pharmaceutical products for their advantages of high activity and selectivity. However, the main disadvantages of traditional organic phase reactions employing homogeneous transition metal catalysts are the difficulties associated with separating the catalyst from the product and solvent albeit having less aggressive reaction conditions and increased selectivity. Hence, it is important to discuss the catalyst product separation techniques for heck reactions. This section aims to provide an overview of the current reviews on the separation/recycling methods of homogeneous transition metal catalysts.

5.1. Recapitulation of All Methods A succinct review by Bhanage and Arai [94] describes all the various catalyst‐product separation methodologies developed for Heck reactions until 2001. The review gives information about the various catalyst‐product separation methodologies developed for Heck reactions until then and is illustrated with number of examples. The separation techniques are classified into two major categories: heterogeneous catalysts and heterogenized homogeneous catalysts. Heterogeneous catalysts can easily be removed by physical separation methods. In addition, they are stable at higher temperatures and hence become interesting for the activation of less reactive but less expensive chloroaryls substrates. However, the heterogeneous catalysts have a major drawback of poor selectivity toward Heck coupling products. Heterogeneous catalysts include

 Conventional supported metal catalysts such as Pd/C, Pd/SiO2, Pd/Al2O3 and Pd/BaSO4 and also nonpalladium based catalysts like Ni/HY zeolite, Ni/Al2O3, Cu/Al2O3 and Co/Al2O3. However most of them end up in leaching of metal and hence making it difficult to do effective recovery and recycling of the active metal.

Catalysts 2017, 7, 267 42 of 53

The review describes the subsequent conversion with respective reagents and conditions of the Heck products corresponding to target molecules and their application. Pd(OAc)2-AsPh3 was observed to be serving well for most of the synthesis although few other palladium-ligand combinations have to be used in some cases. Iodides were found to be more reactive than other halides. Bidentate ligand accelerates the Heck coupling reaction and results in a higher yield of the product. A review by Zeni and Larock [93] covers a wide range of palladium catalyzed processes involving oxidative addition- reductive elimination chemistry developed to prepare heterocycles, with the emphasis on fundamental processes used to generate the ring systems themselves. A number of examples are given for preparation of heterocycles via intramolecular Heck cyclization of aryl halides, vinylic halides, vinylic and aryl triﬂates. intermolecular annulation, and via asymmetric Heck cyclization.

5. Reviews on Reuse of Catalyst Homogeneous catalysts are of great interest for synthesizing ﬁne-chemical, specialty chemical, pharmaceutical products for their advantages of high activity and selectivity. However, the main disadvantages of traditional organic phase reactions employing homogeneous transition metal catalysts are the difﬁculties associated with separating the catalyst from the product and solvent albeit having less aggressive reaction conditions and increased selectivity. Hence, it is important to discuss the catalyst product separation techniques for heck reactions. This section aims to provide an overview of the current reviews on the separation/recycling methods of homogeneous transition metal catalysts.

5.1. Recapitulation of All Methods A succinct review by Bhanage and Arai [94] describes all the various catalyst-product separation methodologies developed for Heck reactions until 2001. The review gives information about the various catalyst-product separation methodologies developed for Heck reactions until then and is illustrated with number of examples. The separation techniques are classiﬁed into two major categories: heterogeneous catalysts and heterogenized homogeneous catalysts. Heterogeneous catalysts can easily be removed by physical separation methods. In addition, they are stable at higher temperatures and hence become interesting for the activation of less reactive but less expensive chloroaryls substrates. However, the heterogeneous catalysts have a major drawback of poor selectivity toward Heck coupling products. Heterogeneous catalysts include

• Conventional supported metal catalysts such as Pd/C, Pd/SiO2, Pd/Al2O3 and Pd/BaSO4 and also nonpalladium based catalysts like Ni/HY zeolite, Ni/Al2O3, Cu/Al2O3 and Co/Al2O3. However most of them end up in leaching of metal and hence making it difﬁcult to do effective recovery and recycling of the active metal. • Zeolite-encapsulated catalysts include palladium-grafted mesoporous MCM-41, Pd-TMS11, etc. However, depending on zeolite structure the leaching of active Pd species was observed with this type of catalyst as well. • Colloids–nanoparticles primarily palladium based are reported showing high activity. • Intercalated metal compound,s e.g., palladium-graphite type catalyst, Pd-chloride- and Cu-nitrate-intercalated montmorillonite K10 clays, etc., are reported to be active for Heck reaction.

The heterogenized metal complex catalysts operate under relatively mild conditions as compared with heterogeneous catalysts, and hence can be applied to the production of pharmaceuticals and ﬁne chemicals. The homogeneous metal complexes are heterogenized using following strategies:

• Modiﬁed silica catalysts where metal is adsorbed onto a silica support. • Polymer-supported catalysts, where Pd anchored to phosphinated polystyrene. Catalysts 2017, 7, 267 43 of 53

 Zeolite‐encapsulated catalysts include palladium‐grafted mesoporous MCM‐41, Pd–TMS11, etc. However, depending on zeolite structure the leaching of active Pd species was observed with this type of catalyst as well.  Colloids–nanoparticles primarily palladium based are reported showing high activity.  Intercalated metal compound,s e.g., palladium‐graphite type catalyst, Pd‐chloride‐ and Cu‐ nitrate‐intercalated montmorillonite K10 clays, etc., are reported to be active for Heck reaction. The heterogenized metal complex catalysts operate under relatively mild conditions as compared with heterogeneous catalysts, and hence can be applied to the production of pharmaceuticals and fine chemicals. The homogeneous metal complexes are heterogenized using following strategies: Catalysts 2017, 7, 267 43 of 53  Modified silica catalysts where metal is adsorbed onto a silica support.  Polymer‐supported catalysts, where Pd anchored to phosphinated polystyrene. • Biphasic catalysis, another exciting area of environmentally responsible catalysis. This system  Biphasic catalysis, another exciting area of environmentally responsible catalysis. This system uses two liquid phases such that the catalyst exists in one phase while reactants and products uses two liquid phases such that the catalyst exists in one phase while reactants and products are present in the other phase. The maximum studied catalyst of this category is sulphonated are present in the other phase. The maximum studied catalyst of this category is sulphonated triphenylphosphine like 115, 130 complexed mainly with palladium although few other metals triphenylphosphine like 115, 130 complexed mainly with palladium although few other metals are also known to react. This catalyst has proven its efficiency for many other reactions too. are also known to react. This catalyst has proven its efficiency for many other reactions too. • Supported liquid-phase catalysts, where the catalyst-containing phase is dispersed as a thin film  Supported liquid‐phase catalysts, where the catalyst‐containing phase is dispersed as a thin film on a hydrophilic support like silica and is used in another immiscible solvent leading to the on a hydrophilic support like silica and is used in another immiscible solvent leading to the enhancement in reaction rate. enhancement in reaction rate. •  NAILSNAILS alsoalso knownknown asas moltenmolten saltssalts provideprovide aa mediummedium inin which the catalyst is generally dissolved allowingallowing thethe productproduct toto bebe easilyeasily separated.separated. TheThe catalystcatalyst andand ionicionic liquidliquid cancan then then be be recycled. recycled. • PerfluorinatedPerfluorinated solventssolvents usesuses fluorousfluorous phasephase andand perfluorinatedperfluorinated ligandligand basedbased organometallicorganometallic catalystcatalyst and is segregated segregated from from reagents reagents and and products, products, either either during during the the process process or during or during the theworkup. workup. InIn additionaddition to to all all above, above, recyclable recyclable homogeneous homogeneous complexes complexes (where (where they are they recovered are recovered by solvent by precipitation),solvent precipitation), catalysts catalysts giving High giving TON High (as TON even (as after even non-recovery after non‐recovery of the catalyst of the it catalyst becomes it affordable)becomes affordable) and supercritical and supercritical solvents are solvents discussed. are discussed.

5.2.5.2. Heterogeneous CatalystsCatalysts AA reviewreview byby WallWall etet al.al. [[95]95] mainlymainly focusesfocuses discussiondiscussion onon thethe HeckHeck reactionreaction followedfollowed byby reviewreview onon cinnamiccinnamic acidacid synthesissynthesis usingusing heterogeneousheterogeneous catalyst,catalyst, Pd/CPd/C in particular.particular. Progress mademade untiluntil then,then, mechanismmechanism andand thethe conditionsconditions requiredrequired forfor successfulsuccessful HeckHeck reactionreaction areare discusseddiscussed includingincluding thethe factorsfactors contributingcontributing toto electronicelectronic controlcontrol forfor α‐ α- ororβ β‐-arylation.arylation. LimitationsLimitations toto thethe homogeneoushomogeneous reactionreaction alongalong withwith possiblepossible reasonsreasons andand needneed forfor proceeding withwith heterogeneous catalysts,catalysts, althoughalthough thethe mechanismmechanism forfor whichwhich isis notnot knownknown areare mentionedmentioned byby givinggiving aa numbernumber ofof examples.examples. TheirTheir effortsefforts inin thethe ﬁeldfield of of development development of of methods methods for for the the production production of cinnamicof cinnamic acids, acids, used used as substrates as substrates for thefor synthesisthe synthesis of unnatural of unnatural amino amino acids acids by employing by employing phenylalanine phenylalanine ammonialyase ammonialyase are given. are given. HeerbeekHeerbeek etet al. al. [ 96[96]] have have reviewed reviewed the the use use of dendrimersof dendrimers as supportas support for recoverablefor recoverable catalysts catalysts and reagents.and reagents. Phosphonated Phosphonated DAB-dendr-[N(CH DAB‐dendr‐[N(CH2PPh22PPh)2]162)dendrimer2]16 dendrimer dimethylpalladium dimethylpalladium complex complex186 (Figure186 (Figure 27) is 27) the is ﬁrst the such first successful such successful dendritic dendritic catalyst tocatalyst recover to through recover a through precipitation a precipitation procedure whereprocedure no metallic where no palladium metallic palladium was observed was unlike observed monomeric unlike monomeric catalysts and catalysts was recycled and was however recycled withhowever lesser with yields lesser in successive yields in successive runs. runs.

Ph Ph P Cl N Pd P Cl Ph Ph 16 186 FigureFigure 27.27. DendrimerDendrimer supportedsupported catalysts.catalysts.

Solid supports have become valuable tools for catalysts immobilization nowadays for simplified product isolation and catalyst recycling. Horn et al. [97] reviewed such non-covalently solid-phase bound catalysts for organic synthesis. Immobilization of catalysts by non-covalent bonding like hydrogen bridges, or ionic, hydrophobic or fluorous interactions on solid support is found to be an alternative to covalent attachment. Such non-covalent approaches increase the flexibility in the choice of the support material, reaction conditions and work-up strategies compared to covalent attachment. Numerous catalytic reactions employing one of these non-covalent bonding strategies are given along with the examples of Heck reaction with catalyst immobilization by ionic interactions. Catalysts 2017, 7, 267 44 of 53

The problems, potential and recent advances with general approach in heterogeneously catalyzed Heck reactions especially with supported palladium catalyst such as Pd on activated carbon, oxides, polymers and in zeolites has been reviewed by Kohler et al. [98]. The advantages and limitations for practical applications are considered. A thorough literature for less activated or deactivated compounds is discussed along with the new approaches and strategies for the activation of such compounds by heterogeneous catalysts. Particular attention is given to the relation between homogeneous and heterogeneous catalysis from the mechanistic point of view. It is concluded that palladium species dissolved from the support are proven to be responsible for high activity and selectivity in Heck reactions in supported catalysis. The careful choice of optimum catalyst and reaction conditions can activate even deactivated aryl chlorides with high yields within few hours of reaction time. Polshettiwar and Molnar [99] have reviewed the Heck coupling with silica supported catalyst and palladium redeposition. Mechanisms for these catalysts considering both less common Pd(II)/Pd(IV) catalytic cycle and the most accepted Pd(0)/Pd(II) cycle are given. A number of examples are cited for the Heck reaction in presence of silica-supported Pd complexes and the structural investigations of functionalized mesoporous silica-supported Pd catalysts. New emerging fields like sol–gel entrapped silica–Pd catalysts, nanosized Pd particles embedded in silica catalysts, colloid palladium layer–silica catalysts, silica/ionic liquid Pd catalysts and silica-supported Pd–TPPTS liquid-phase catalysts are also discussed along with testing of palladium leaching by poisoning test using pyridine and mercury. Another review on this topic by Molnar [100] gives an account of efficient, selective, and recyclable palladium catalysts in carbon-carbon coupling reactions. The review gives a comprehensive survey, thorough analysis of the available data and discusses critically the questions related to recyclability in general. Publications reporting a stable and well characterized catalyst with high yield and minimum five recycles are cited. It is reported that, both amorphous and ordered silica materials are useful supports for palladium nanoparticles. The combined use of varied ionic liquids and related homogeneous complexes has shown interesting results. The best performance with respect to cumulative TON numbers are reported for catalyst Pd-SBA, 3.9% Pd-HS-Si(HIPE), and 4.1% Pd-grHSSi(HIPE) (HIPE = high internal phase emulsion). Thus, the catalytically active species, Pd particles and immobilized species, or the support material employed may play the decisive role in efficient catalysis.

5.3. Heterogenization of Homogeneous Catalysts The development of new, highly efficient heterogenized catalysts is an active and important area in fine chemicals production research as it gives the maximum advantages of both homogeneous and heterogeneous catalysis. It offers several significant practical advantages for synthetic chemistry and industrial research. Reviews about various techniques used for heterogenization are given in following subsections.

5.3.1. Ionic Liquid These days, ionic liquids are proposed as greener alternative to the classical cross-coupling procedure. They have replaced organic solvents in many metal catalyzed reactions and have gained much attention in recent times mainly because they lack the vapour pressure. However, several factors like toxicity, stability, cost, ease of processing, etc., still need to be addressed before this new technology is to be accepted by industry. A review by Sheldon [101] is one of the ﬁnest written reviews on ionic liquids. Discovery of ionic liquids, historical development and progression for various types of reactions in them until 2001 are summarized eloquently. Scientists and industrial researchers are seriously considering ionic liquids as better replacement for toxic and/or hazardous volatile organic compounds and consider that, the use of ionic liquids as novel reaction media may offer a convenient solution to both the solvent emission and the catalyst recycling problem. Ionic liquids also provide a medium for performing clean reactions with minimum waste generation. It was observed that use of ionic liquids (Figure 28) as reaction Catalysts 2017, 7, 267 45 of 53 factors like toxicity, stability, cost, ease of processing, etc., still need to be addressed before this new technology is to be accepted by industry. A review by Sheldon [101] is one of the finest written reviews on ionic liquids. Discovery of ionic liquids, historical development and progression for various types of reactions in them until 2001 are summarized eloquently. Scientists and industrial researchers are seriously considering ionic liquids as better replacement for toxic and/or hazardous volatile organic compounds and consider that, the use of ionic liquids as novel reaction media may offer a convenient solution to both the solvent Catalysts 2017, 7, 267 45 of 53 emission and the catalyst recycling problem. Ionic liquids also provide a medium for performing clean reactions with minimum waste generation. It was observed that use of ionic liquids (Figure 28) mediaas reaction for catalytic media for transformations catalytic transformations or, in some cases, or, in as some the catalyst cases, as itself the can catalyst have aitself profound can have effect a onprofound activities effect and on selectivities. activities and selectivities.

Figure 28. StructureStructure of ionic liquids used for Heck reaction reviewed by Sheldon [[101].101].

The first example of a Heck coupling in an ionic liquid was reportedly carried out in 1996, where The first example of a Heck coupling in an ionic liquid was reportedly carried out in 1996, in ionic liquids tetraalkylammonium and tetraalkylphosphonium bromide salts, high yields for Heck where in ionic liquids tetraalkylammonium and tetraalkylphosphonium bromide salts, high yields for reaction were obtained. No leaching of palladium was observed, the product was isolated by Heck reaction were obtained. No leaching of palladium was observed, the product was isolated by distillation from the ionic liquid and the ionic liquid was recycled for two more times. Similarly, ionic distillation from the ionic liquid and the ionic liquid was recycled for two more times. Similarly, ionic liquids like Bu4NBr, bmimPF6 and n‐hexylpyridinium PF6 are also reported to give improved activity liquids like Bu NBr, bmimPF and n-hexylpyridinium PF are also reported to give improved activity for Heck reaction.4 In comparison6 to pyridinium analogues,6 the imidazolium ionic liquids were found for Heck reaction. In comparison to pyridinium analogues, the imidazolium ionic liquids were found to to have greater catalytic activity when the reactions performed in it. The selectivity of α over β— have greater catalytic activity when the reactions performed in it. The selectivity of α over β—product product for the Heck arylation of electron‐rich enol ethers in ionic liquids was found to be >99% in for the Heck arylation of electron-rich enol ethers in ionic liquids was found to be >99% in comparison comparison with other solvents generally leading to a mixture of regio isomers owing to competition with other solvents generally leading to a mixture of regio isomers owing to competition between between cationic and neutral pathways. cationic and neutral pathways. Singh et al. [102] reviewed the use of ionic liquids medium for many palladium catalyzed Singh et al. [102] reviewed the use of ionic liquids medium for many palladium catalyzed reactions like Heck, Suzuki, Stille, Negishi, Trost–Tsuji and Sonogoshira coupling. A comprehensive reactions like Heck, Suzuki, Stille, Negishi, Trost–Tsuji and Sonogoshira coupling. A comprehensive literature about the versatility of ionic liquid in conjunction with palladium for these reactions is literature about the versatility of ionic liquid in conjunction with palladium for these reactions cited. The studies have shown that the classical transition‐metal catalyzed reactions can be performed is cited. The studies have shown that the classical transition-metal catalyzed reactions can be in ionic liquids. They are supposed to be a medium for clean reactions with minimal waste and performed in ionic liquids. They are supposed to be a medium for clean reactions with minimal efficient product extraction. In addition to the basic ionic liquids discussed by Sheldon [101] ionic waste and efficient product extraction. In addition to the basic ionic liquids discussed by Sheldon [101] liquids specially introduced after 2001 are discussed in detail. Apart from regularly studied ionic ionic liquids specially introduced after 2001 are discussed in detail. Apart from regularly studied liquids, results of few specially studied ionic liquids using palladium catalyst such as functionalized ionic liquids, results of few specially studied ionic liquids using palladium catalyst such as ionic liquids like [bmim][TPPMS] and [bmim][OAc]; N‐butyronitrile pyridinium functionalized ionic liquids like [bmim][TPPMS] and [bmim][OAc]; N-butyronitrile pyridinium bis(trifluoromethylsulphonyl) imide with PdCl2; palladium acetate immobilized on amorphous silica bis(trifluoromethylsulphonyl) imide with PdCl2; palladium acetate immobilized on amorphous silica with the aid of an ionic liquid [Bmim][PF6]; palladium(II) complex from pyrazolylfunctionalized with the aid of an ionic liquid [Bmim][PF6]; palladium(II) complex from pyrazolylfunctionalized hemilabile NHC; Pd(OAc)2/[PEG‐mim][Cl], Pd/C‐catalyzed Heck reaction in ionic liquid and Pd(0) hemilabile NHC; Pd(OAc)2/[PEG-mim][Cl], Pd/C-catalyzed Heck reaction in ionic liquid and Pd(0) nanoparticles (~2 nm diameter), immobilized in [bmim][PF6] are also discussed. Most of them showed nanoparticles (~2 nm diameter), immobilized in [bmim][PF ] are also discussed. Most of them showed reasonable efficiency in recycle studies. Pd‐nanoparticles 6were found to be much more efficient in reasonable efficiency in recycle studies. Pd-nanoparticles were found to be much more efficient TBAB than in pyridinium, phosphonium and imidazolium ionic liquids in catalyzing the Heck in TBAB than in pyridinium, phosphonium and imidazolium ionic liquids in catalyzing the Heck reactions. Few reports of reactions in ionic liquids using ultrasonic irradiation and microwaves are reactions. Few reports of reactions in ionic liquids using ultrasonic irradiation and microwaves are also mentioned to show better activity. also mentioned to show better activity. Bellina and Chiappe [103] have reviewed the progress and challenges for the Heck reaction in Bellina and Chiappe [103] have reviewed the progress and challenges for the Heck reaction in ionic liquids. Developments in the application of ionic liquids and related systems like supported ionic liquids. Developments in the application of ionic liquids and related systems like supported ionic ionic liquids; ionic polymers, etc., in the Heck reaction have been reviewed. Merits and achievements liquids; ionic polymers, etc., in the Heck reaction have been reviewed. Merits and achievements of ionic liquids were analysed and discussed considering the possibility of increasing the effectiveness of industrial processes. Numerous examples for homogeneous and heterogeneous conditions used for Heck reactions in ionic liquids are discussed to prove that, the ionic liquids are not only suitable solvents for Heck reaction, but their unique physico-chemical properties have ability to change the course of the reaction, activate and/or stabilize the intermediates or transition states in the reaction mechanisms. It is observed that Heck reactions performed in ionic liquids have higher reaction rates, and may be characterized by a higher control on the regio- and stereoselectivity of the coupling Catalysts 2017, 7, 267 46 of 53 products. Examples with involvement of carbene complex, palladium nanoparticles and palladium anionic complexes have been discussed for the evidence. However, the study of Heck reactions in ionic liquid is still limited to the development of the ionic liquids where only simple reactions such as the coupling of aryl halides with cinnamates or styrene have been investigated. Thus, the use of ionic liquids in Heck reactions involving more complicated substrates that could give important indications about possibility of application of these alternative media on large scale need to be explored further. Mastrorilli et al. [104] have surveyed the significant developments and the beneficial effect of the ionic liquids in terms of activity, selectivity and recyclability for palladium-catalyzed cross-coupling reactions performed in them. Insights into the reaction mechanisms reveal that, the effect of the ionic liquid on C-C bond forming reactions manifests itself not only in the energy lowering of polar transition states (or intermediates), involved in the catalytic cycles but also, depending on the cases, in the stabilization of palladium nanoparticles, in the synthesis of molecular Pd complexes with the ionic liquid anions or in the enhancement of the chemical reactivity of reactants, etc. The synergistic effect found by using appropriate mixtures of ionic liquids is also discussed. Santos et al. [105] have reviewed Heck-Mizoroki reactions in ionic liquids, reported to be a possible green alternative to the classical cross-coupling procedure. In this review, the different approaches and achievements on the use of ionic liquids as solvents in Heck-Mizoroki coupling reactions is revisited along with a brief reference to supported ionic liquids. The results show that ionic liquids are able to modify the reaction course and activate and stabilize intermediates or transitions states. However, the examples show that, though there are large numbers of studies in this topic, most of the works involve the coupling of simple aryl halides and olefins and hence we expect more research on the use of ionic liquids in Heck reactions that include more complicated substrates affording environmentally benign chemical processes in the future. Recently, Limberger et al. [106] have published a review on charge-tagged ligands, where there is an insertion of an ionic side chain into the molecular skeleton of a known ligand. This technique has become a useful protocol for anchoring ligands, and consequently catalysts, in polar and ionic liquid phases. The ionic modification confers a particular solubility profile making catalyst/product recovery possible, and often improving the activity of the catalytic species compared to the parent tag-free analogue. Usability of charge-tagged ligands is increasing and it has become a valuable tool in organometallic catalysis because in this, water can be used as an anchoring medium, thereby combining sustainability and efficiency. It is predicted that this technique can also be used to detect reaction intermediates in organometallic catalysis where the insertion of an ionic tag ensures the charge on the intermediates. Hence, these ligands have been used as ionic probes in mechanistic studies for several catalytic reactions. This review summarizes the selected examples on the use of charge-tagged ligands (CTLs) 187–190 (Figure 29) as immobilising agents in organometallic catalysis and as probes for studying mechanisms through ESI-MS (electrospray ionisation mass spectrometry). In these CTLs, a coordinating imidazole, pyrazole or pyridine group was attached to either C2 or C1 of the imidazolium moiety. These CTLs with palladium salts were found to be active for Heck reaction with the yields ranging from 70 to 99%. Moreover, it could be recycled several times and they can also be used as the solvent and ligand to stabilize the palladium species in Heck reaction. Catalysts 2017, 7, 267 47 of 53 Catalysts 2017, 7, 267 47 of 53 Catalysts 2017, 7, 267 Bu 47 of 53 N N N Bu NN NN N Bu Bu - N N PF6 Bu NTf - 187 188 2 N N N N Bu Bu PF - Bu - 6 NTf2 187 188 Bu Bu N N Bu Bu N N NN Me N N N N N N - - Me N NTf2 N NTf2 N N Me - 189 - 190 NTf2 NTf2 Me 189 190 Figure 29. Charge‐tagged ligands (CTLs) reviewed by Limberger et al. [106]. Figure 29. Charge-tagged ligands (CTLs) reviewed by Limberger et al. [106 ]. 5.3.2. Catalysis inFigure Multiphase 29. Charge Systems‐tagged and ligands Supercritical (CTLs) reviewed Carbon by Dioxide Limberger et al. [106]. 5.3.2. Catalysis in Multiphase Systems and Supercritical Carbon Dioxide 5.3.2.Bhanage Catalysis et in al. Multiphase [107] have Systems reviewed and Supercriticalthe multiphase Carbon Heck Dioxide reactions using various types of catalysts.Bhanage The etmultiphase al. [107] have Heck reviewed systems the are multiphase prepared Heck by using reactions different using types various of types catalyst of catalysts. phases, Theincluding multiphaseBhanage biphasic et Heckal. catalysis, [107] systems have supported are reviewed prepared liquid the by multiphasephase using catalysts different Heck and types reactions solvent of catalyst usingof supercritical phases, various including types carbon of dioxidebiphasiccatalysts. which catalysis, The multiphasereplaces supported the Heck conventional liquid systems phase organicare catalysts prepared solvents. and solventby usingThese of supercriticaldifferentsolvent systems types carbon of were catalyst dioxide found phases, which to be beneficialreplacesincluding the towardsbiphasic conventional catalysis,easy organiccatalyst supported solvents.‐product liquid Theseseparation phase solvent andcatalysts systems catalyst and were recycling.solvent found toof beSupercriticalsupercritical beneficial towards carboncarbon dioxideeasydioxide catalyst-product canwhich serve replaces as a separationbetter the conventional solvent and system catalyst organic for recycling. Heck solvents. reaction Supercritical These under solvent homogeneous, carbon systems dioxide were heterogeneous can found serve to asbe andabeneficial better multiphase solvent towards system systems easy for provided catalyst Heck reaction‐ productthe problem under separation homogeneous,of leaching and is catalyst solved. heterogeneous recycling. and Supercritical multiphase systemscarbon provideddioxideA review can the serve problem by asSkouta a of better leaching [108] solvent presents is solved. system an foroverview Heck reaction of some under selected homogeneous, metal‐catalysed heterogeneous chemical reactionsand multiphaseA review developed by systems Skouta in supercritical provided [108] presents the carbon problem an overviewdioxide, of leaching water, of someis solved.and selected ionic liquids. metal-catalysed Heck reaction chemical was foundreactionsA to review give developed 55% by yieldSkouta in supercritical of [108]the coupling presents carbon products an dioxide,overview in average water, of some andwhen selected ionic was liquids. performed metal‐ Heckcatalysed in super reaction chemical critical was reactions developed in supercritical carbon dioxide, water, and ionic liquids. Heck reaction was COfound2. The to give water 55%‐soluble yield of phosphine the coupling compounds products in m average‐TPPTC when [tris(m was‐carboxyphenyl) performed in super phosphine critical found to give 55% yield of the coupling products in average when was performed in super critical trilithiumCO2. The water-solublesalt], and p‐TPPTC phosphine 191 (Figure compounds 30) in m-TPPTC addition [tris(m-carboxyphenyl)to sulphonated phosphines phosphine like TPPTS trilithium 115, etc.,salt],CO2 .were andThe p-TPPTCefficient water‐ solublein191 organo(Figure phosphine‐aqueous 30) in addition palladiumcompounds to‐ sulphonatedcatalysed m‐TPPTC Heck phosphines [tris(mreactions,‐carboxyphenyl) like and TPPTS the excellent115 ,phosphine etc., results were obtainedefficienttrilithium in are salt], organo-aqueous presumably and p‐TPPTC because palladium-catalysed 191 (Figureof the steric 30) in and addition Heck electronic reactions, to sulphonated effects and of the the excellent phosphines carboxylic results likegroup obtained TPPTS in meta 115, are‐ presumablyposition.etc., were efficient because in of organo the steric‐aqueous and electronic palladium effects‐catalysed of the Heck carboxylic reactions, group and in the meta-position. excellent results obtained are presumably because of the steric and electronic effects of the carboxylic group in meta‐ position.

Figure 30. (tris(m‐carboxyphenyl) phosphine trilithium salt (m‐TPPTC)) and (p‐TPPTC) (TPPTC: Figure 30. (tris(m-carboxyphenyl) phosphine trilithium salt (m-TPPTC)) and (p-TPPTC) (TPPTC: tris(mtris(m-carboxyphenyl)‐carboxyphenyl) phosphine trilithium salt). Figure 30. (tris(m‐carboxyphenyl) phosphine trilithium salt (m‐TPPTC)) and (p‐TPPTC) (TPPTC: 5.3.3.tris(m Catalysis ‐carboxyphenyl) in Continuous phosphine Flow trilithium salt).

5.3.3.Gürsel Catalysis et al. in [Continuous[109]109] givesgives an anFlow overviewoverview onon thethe separation/recyclingseparation/recycling methods for homogeneous transition metal catalysts in continuous flow flow on the lab lab-‐ and industrial scale by methods like Gürsel et al. [109] gives an overview on the separation/recycling methods for homogeneous heterogenization, scavenging, using biphasic systems and organic solvent nanofiltration.nanofiltration. There are transition metal catalysts in continuous flow on the lab‐ and industrial scale by methods like numerous successful demonstrations on the laboratory scale and industrial scale. Examples of Heck heterogenization, scavenging, using biphasic systems and organic solvent nanofiltration. There are reaction using supported ionic liquid phase (SILP) with compressed CO2 as the flowing medium in reaction using supported ionic liquid phase (SILP) with compressed CO2 as the flowing medium in continuousnumerous successful flow; use ofdemonstrations ionic liquid as on the the recycling laboratory reaction scale mediumand industrial in an automatedscale. Examples microreactor of Heck reaction using supported ionic liquid phase (SILP) with compressed CO2 as the flowing medium in continuous flow; use of ionic liquid as the recycling reaction medium in an automated microreactor

Catalysts 2017, 7, 267 48 of 53 continuous ﬂow; use of ionic liquid as the recycling reaction medium in an automated microreactor system catalysed by Pd catalyst immobilized in ionic liquid phase; in situ separation of the catalyst with the membrane within the reactor/separator unit, etc., are mentioned. All these methods have the advantage of ease of separation and low energy requirement compared to classical separation methods like distillation.

6. Summary The Heck reaction has proved to be a remarkably robust and efficient method for carbon–carbon bond formation and remains a flourishing area of research. The enthusiasm and rational optimism of researchers promotes new discoveries resulting in better and efficient catalysts production and providing solutions for old problems. With the use of such reactions, many protection-deprotection procedures during organic synthesis may be reduced so as to reduce the number of steps when designed systematically in addition to the new reactivities, increasing product selectivity and reducing volatile organic consumption. The great functional group tolerance of palladium makes Heck reactions possible on even the most sensitive substrates. In addition, the intramolecular Heck reaction is an incredibly powerful method for the construction of many compounds with quaternary and/or asymmetric carbon centers. The well accepted mechanism for Heck reaction is based on intermediate species involving Pd(0)/Pd(II), however the feasibility of the Pd(II)/Pd(IV) mechanism is not ruled out by many. The Pd(II)/Pd(IV) mechanism is believed to take place when a Pd(0) to Pd(II) conversion is not available clearly or when the Pd(II) species cannot readily undergo β-hydride or reductive elimination. The prospects for application of Heck reaction for many transformations look very good via homogeneous, heterogeneous and even with heterogenized catalysis using organometallic complexes. Some of them are already scaled at an industrial level. Ironically, although a large number of metal-based catalysts are described in the literature promoting Heck reaction for the manufacture of bulk chemicals, when these reactions need to be applied for the synthesis of complex molecules like pharmaceuticals, agrochemicals or fragrances production, Pd(OAc)2, Pd2(dba)3, Pd/C, PdCl2L2, Pd(PPh3)4 and PdCl2(dppf)2 still happen to be catalysts of choice. Ample study has been made and yet a lot remains to be done. There are several challenges and expectations from the research community that need to be overcome in order to have an economic, robust and reliable industrial process, such as:

• A chase for catalyst precursor and ligands allowing high turnover numbers (TON) and turnover frequencies (TOF), making the process economically attractive, is still a challenge. • Scaling from laboratory to production level needs a better and a cheaper catalyst precursor and ligands. • Preparation of air and moisture stable catalyst, since the reactions easily get poisoned by molecular oxygen. In fact, preparation of such a catalyst that works better in aqueous media too. • Standardizing the reaction conditions that are mild and also allowing lower catalyst loadings. • Development of new generation of palladacycles promising to be excellent in future applications in industrial processes. • Understanding of mechanism of heterogeneous catalysis is still rhetoric. • Increased use of cheaper and easily available starting materials, especially chloroarenes and chloroalkenes, is a niche and much is needed to be done as far as ﬁnding newer protocols, along with catalyst and ligand design is concerned. • Understanding the reasons and thereby successfully prohibiting the precipitation of metal. • Development of the catalyst where cheaper ﬁrst-row transition elements are used would truly add to the applicable research. • Improvements in catalyst efficiency along with catalyst recycling, especially for use in pharmaceutical and other fine chemical synthetic processes. Catalysts 2017, 7, 267 49 of 53

• Solving the issue of contamination of the product at the end with palladium that needs further puriﬁcation steps.

Thus, the ever-growing expansion of this coupling reaction is in the phase of new outlook that surely will enable more impressive accomplishments in the future. The useful and practical catalytic systems allowing the Heck reactions involving cheaper transition metals or the easy recovery of metal especially palladium will emerge by further research. This review aims at the stimulation of advance work in these directions.

Conﬂicts of Interest: The author declares no conﬂict of interest.

References

1. Heck, R.F. Acylation, methylation, and carboxyalkylation of olefins by group VIII metal derivatives. J. Am. Chem. Soc. 1968, 90, 5518–5526. [CrossRef] 2. Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Lett. 1979, 20, 3437–3440. [CrossRef] 3. Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and brompyridines. Tetrahedron Lett. 1975, 16, 4467–4470. [CrossRef] 4. King, A.O.; Okukado, N.; Negishi, E. Highly general stereo-, regio-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalyzed reaction of alkynylzinc reagents with alkenyl halides. J. Chem. Soc. Chem. Commun. 1977, 683–684. [CrossRef] 5. Tamao, K.; Sumitani, K.; Kumada, M. Selective carbon-carbon bond formation by cross-coupling of Grignard reagents with organic halides. Catalysis by nickel-phosphine complexes. J. Am. Chem. Soc. 1972, 94, 4374–4376. [CrossRef] 6. Milstein, D.; Stille, J.K. A general, selective, and facile method for ketone synthesis from acid chlorides and organotin compounds catalyzed by palladium. J. Am. Chem. Soc. 1978, 100, 3636–3638. [CrossRef] 7. Trost, B.M.; Fullerton, T.J. New synthetic reactions. Allylic alkylation. J. Am. Chem. Soc. 1973, 95, 292–294. [CrossRef] 8. Mizoroki, T.; Mori, K.; Ozaki, A. Arylation of olefin with aryl iodide catalyzed by palladium. Bull. Chem. Soc. Jpn. 1971, 44, 581. [CrossRef] 9. Heck, R.F.; Nolley, J.P. Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides. J. Org. Chem. 1972, 37, 2320–2322. [CrossRef] 10. Heck, R.F. New applications of palladium in organic syntheses. Pure Appl. Chem. 1978, 50, 691–701. [CrossRef] 11. Heck, R.F. Palladium-catalyzed reactions with olefins. Acc. Chem. Res. 1979, 12, 146–151. [CrossRef] 12. Heck, R.F. Palladium catalysed vinylation of organic halides. Org. React. 1982, 27, 345–390. [CrossRef] 13. De Meijere, I.A.; Meyer, F.E. Fine feathers make fine birds: The Heck reaction in modern garb. Angew. Chem. Int. Ed. Engl. 1994, 33, 2379–2411. [CrossRef] 14. Kobetić,R.; Biliškov, N. The Heck reaction—A powerful tool in contemporary organic synthesis. Chem. Ind. 2007, 56, 391–402. 15. Sahu, M.; Sapkale, P. A review on palladium catalyzed coupling reactions. Int. J. Pharm. Chem. Sci. 2013, 2, 1159–1170. 16. Beletskaya, I.P.; Cheprakov, A.V. The Heck reaction as a sharpening stone of palladium catalysis. Chem. Rev. 2000, 100, 3009–3066. [CrossRef][PubMed] 17. Hillier, A.C.; Grasa, G.A.; Viciu, M.S.; Lee, H.M.; Yang, C.; Nolan, S.P. Catalytic cross-coupling reactions mediated by palladium/nucleophilic carbene systems. J. Organomet. Chem. 2002, 653, 69–82. [CrossRef] 18. Herrmann, W.A. N-heterocyclic carbenes: A newconcept in organometallic catalysis. Angew. Chem. Int. Ed. 2002, 41, 1290–1309. [CrossRef] 19. Herrmann, W.A.; Öfele, K.; Preysing, D.V.; Schneider, S.K. Phospha-palladacycles and N-heterocyclic carbene palladium complexes: Efficient catalysts for C-C-coupling reactions. J. Organomet. Chem. 2003, 687, 229–248. [CrossRef] Catalysts 2017, 7, 267 50 of 53

20. Beletskaya, I.P.; Cheprakov, A.V. Palladacycles in catalysis—A critical survey. J. Organomet. Chem. 2004, 689, 4055–4088. [CrossRef] 21. Zafar, M.N.; Mohsin, M.A.; Danish, M.; Nazar, M.F.; Murtaza, S. Palladium catalyzed Heck-Mizoroki and Suzuki–Miyaura coupling reactions. Russ. J. Coord. Chem. 2014, 40, 781–800. [CrossRef] 22. Herrmann, W.A.; Böhm, V.P.; Reisinger, C.P. Application of palladacycles in Heck type reactions. J. Organomet. Chem. 1999, 576, 23–41. [CrossRef] 23. Farina, V. High-turnover palladium catalysts in cross-coupling and Heck chemistry: A critical overview. Adv. Synth. Catal. 2004, 346, 1553–1582. [CrossRef] 24. Whitecombe, N.I.; Hii, K.K.M.; Gibson, S.E. Advances in the Heck chemistry of aryl bromide and chlorides. Tetrahedron 2001, 57, 7449–7476. [CrossRef] 25. Littke, A.; Fu, G. Palladium-Catalyzed Coupling Reactions of Aryl Chlorides. Angew. Chem. Int. Ed. 2002, 41, 4176–4211. [CrossRef] 26. Zapf, A.; Beller, M. The development of efficient catalysts for palladium-catalyzed coupling reactions of aryl halides. Chem. Commun. 2005, 28, 431–440. [CrossRef][PubMed] 27. Franzén, R. The Suzuki, the Heck, and the Stille reaction—Three versatile methods for the introduction of new C-C bonds on solid support. Can. J. Chem. 2000, 78, 957–962. [CrossRef] 28. Biffis, A.; Zecca, M.; Basato, M. Palladium metal catalysts in Heck C-C coupling reactions. J. Mol. Catal. A Chem. 2001, 173, 249–274. [CrossRef] 29. Cini, E.; Petricci, E.; Taddei, M. Pd/C Catalysis under Microwave Dielectric Heating. Catalysts 2017, 7, 89. [CrossRef] 30. Barnard, C. Palladium-catalysed C-C Coupling: Then and now. Platinum Met. Rev. 2008, 52, 38–45. [CrossRef] 31. Corbet, J.-P.; Mignani, G. Selected patented cross-coupling reaction technologies. Chem. Rev. 2006, 106, 2651–2710. [CrossRef][PubMed] 32. Yin, L.; Liebscher, J. Carbon-carbon coupling reactions catalyzed by heterogeneous palladium catalysts. Chem. Rev. 2007, 107, 133–173. [CrossRef][PubMed] 33. Narayanan, R. Recent advances in noble metal nanocatalysts for Suzuki and Heck cross-coupling reactions. Molecules 2010, 15, 2124–2138. [CrossRef][PubMed] 34. Cai, S.; Wang, D.; Niu, Z.; Li, Y. Progress in organic reactions catalyzed by bimetallic nanomaterials. Chin. J. Catal. 2013, 34, 1964–1974. [CrossRef] 35. Baboo, R. Multimetallic nanomaterial based catalysis. Int. J. Curr. Res. Acad. Rev. 2015, 3, 153–157. 36. Labulo, A.H.; Martincigh, B.S.; Omondi, B.; Nyamori, V.O. Advances in carbon nanotubes as efficacious supports for palladium-catalysed carbon-carbon cross-coupling reactions. J. Mater. Sci. 2017, 52, 9225–9248. [CrossRef] 37. Moritanl, I.; Fujiwara, Y. Aromatic substitution of styrene-palladium chloride complex. Tetrahedron Lett. 1967, 8, 1119–1122. [CrossRef] 38. Gligorich, K.M.; Sigman, M.S. Recent advancements and challenges of palladiumII-catalyzed oxidation reactions with molecular oxygen as the sole oxidant. Chem. Commun. (Camb.) 2009, 26, 3854–3867. [CrossRef] [PubMed] 39. Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan, P.F.; Esfahani, F.K.; Zamani, A. Transition-metal-catalyzed oxidative Heck reactions. Synthesis 2010, 1399–1427. [CrossRef] 40. Su, Y.; Jiao, N. Palladium-catalyzed oxidative Heck reaction. Curr. Org. Chem. 2011, 15, 3362–3388. [CrossRef] 41. Le Bras, J.; Muzart, J. Intermolecular dehydrogenative Heck reactions. Chem. Rev. 2011, 111, 1170–1214. [CrossRef][PubMed] 42. Le Bras, J.; Muzart, J. Dehydrogenative Heck Annelations of Internal Alkynes. Synthesis 2014, 46, 1555–1572. [CrossRef] 43. Lee, A.L. Enantioselective oxidative boron Heck reactions. Org. Biomol. Chem. 2016, 14, 5357–5366. [CrossRef] [PubMed] 44. Xiaomei, Y.; Sha, M.; Yanni, D.; Yunhai, T. Progress in reductive Heck reaction. Chin. J. Org. Chem. 2013, 33, 2325–2333. [CrossRef] 45. Guiry, P.J.; Kiely, D. The Development of the intramolecular asymmetric Heck Reaction. Curr. Org. Chem. 2004, 8, 781–794. [CrossRef] 46. Oestreich, M. Breaking News on the Enantioselective Intermolecular Heck Reaction. Angew. Chem. Int. Ed. 2014, 53, 2282–2285. [CrossRef][PubMed] Catalysts 2017, 7, 267 51 of 53

47. Kikukawa, K.; Matsuda, T. Reaction of Diazonium Salts with Transition Metals. I. Arylation of Olefins with Arenediazonium Salts Catalyzed by Zero Valent Palladium. Chem. Lett. 1977, 2, 159–162. [CrossRef] 48. Sato, Y.; Sodeoka, M.; Shibasaki, M. Catalytic asymmetric carbon-carbon bond formation: Asymmetric synthesis of cis-decalin derivatives by palladium-catalyzed cyclization of prochiral alkenyl iodides. J. Org. Chem. 1989, 54, 4738–4739. [CrossRef] 49. Carpenter, N.E.; Kucera, D.J.; Overman, L.E. Palladium-catalyzed polyene cyclizations of trienyl triflates. J. Org. Chem. 1989, 54, 5846–5848. [CrossRef] 50. Dounay, A.B.; Overman, L.E. The asymmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev. 2003, 103, 2945–2963. [CrossRef][PubMed] 51. Diéguez, M.; Pàmies, O.; Claver, C. Ligands derived from carbohydrates for asymmetric catalysis. Chem. Rev. 2004, 104, 3189–3216. [CrossRef][PubMed] 52. McCartney, D.; Guiry, P.J. The asymmetric Heck and related reactions. Chem. Soc. Rev. 2011, 40, 5122–5150. [CrossRef][PubMed] 53. Daves, G.D.; Hallberg, A. 1,2-Additions to heteroatom-substituted olefins by organopalladium reagents. Chem. Rev. 1989, 89, 1433–1445. [CrossRef] 54. Bedford, R.B. Palladacyclic catalysts in C-C and C-heteroatom bond-forming reactions. Chem. Commun. 2003, 1787–1796. [CrossRef] 55. Jeffery, T. On the efficiency of tetraalkylammonium salts in Heck type reactions. Tetrahedron 1996, 52, 10113–10130. [CrossRef] 56. Tucker, C.E.; de Vries, J.G. Homogeneous catalysis for the production of fine chemicals. Palladium- and nickel-catalysed aromatic carbon-carbon bond formation. Top. Catal. 2002, 19, 111–118. [CrossRef] 57. Wang, S.S.; Yang, G.Y. Recent developments in low-cost TM-catalyzed Heck-type reactions (TM = transition metal, Ni, Co, Cu, and Fe). Catal. Sci. Technol. 2016, 6, 2862–2876. [CrossRef] 58. Alonso, F.; Beletskaya, I.P.; Yus, M. Non-conventional methodologies for transition-metal catalysed carbon-carbon coupling: A critical overview. Part 1: The Heck reaction. Tetrahedron 2005, 61, 11771–11835. [CrossRef] 59. Tietze, L.F.; Ila, H.; Bell, H.P. Enantioselective palladium-catalyzed transformations. Chem. Rev. 2004, 104, 3453–3516. [CrossRef][PubMed] 60. Shibasaki, M.; Vogl, E.M.; Ohshima, T. Asymmetric Heck reaction. Adv. Synth. Catal. 2004, 346, 1533–1552. [CrossRef] 61. Oestreich, M. Neighbouring-group effects in Heck reactions. Eur. J. Org. Chem. 2005, 783–792. [CrossRef] 62. Genet, J.P.; Savignac, M. Recent developments of palladium(0) catalyzed reactions in aqueous medium. J. Organomet. Chem. 1999, 576, 305–317. [CrossRef] 63. Li, C. Organic reactions in aqueous media with a focus on carbon-carbon bond formations: A decade update. Chem. Rev. 2005, 105, 3095–3165. [CrossRef][PubMed] 64. Velazquez, H.D.; Verpoort, F. N-heterocyclic carbene transition metal complexes for catalysis in aqueous media. Chem. Soc. Rev. 2012, 41, 7032–7060. [CrossRef][PubMed] 65. Hervé, G.; Len, C. Heck and Sonogashira couplings in aqueous media—Application to unprotected nucleosides and nucleotides. Sustain. Chem. Process. 2015, 3, 3. [CrossRef] 66. Cabri, W.; Candiani, I. Recent developments and new perspectives in the Heck reaction. Acc. Chem. Res. 1995, 28, 2–7. [CrossRef] 67. Crisp, G.T. Variations on a theme—Recent developments on the mechanism of the Heck reaction and their implications for synthesis. Chem. Soc. Rev. 1998, 27, 427–436. [CrossRef] 68. Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M.A.; Meyer, G. Evidence for the Ligation of Palladium(0) Complexes by Acetate Ions: Consequences on the Mechanism of Their Oxidative Addition with Phenyl

Iodide and PhPd(OAc)(PPh3)2 as Intermediate in the Heck Reaction. Organometallics 1995, 14, 5605–5614. [CrossRef] 69. Amatore, C.; Jutand, A. Mechanistic and kinetic studies of palladium catalytic systems. J. Organomet. Chem. 1999, 576, 254–278. [CrossRef] 70. Amatore, C.; Jutand, A. Anionic Pd(0) and Pd(II) intermediates in palladium-catalyzed Heck and cross-coupling reactions. Acc. Chem. Res. 2000, 33, 314–321. [CrossRef][PubMed] Catalysts 2017, 7, 267 52 of 53

71. Cavell, K.J.; McGuinness, D.S. Redox processes involving hydrocarbylmetal (N-heterocyclic carbene) complexes and associated imidazolium salts: Ramifications for catalysis. Coord. Chem. Rev. 2004, 248, 671–681. [CrossRef] 72. Trzeciak, A.M.; Ziółkowski, J.J. Structural and mechanistic studies of Pd-catalyzed C-C bond formation: The case of carbonylation and Heck reaction. Coord. Chem. Rev. 2005, 249, 2308–2322. [CrossRef] 73. Phan, N.T.S.; DerSluys, M.V.; Jones, C.W. On the Nature of the Active Species in Palladium Catalyzed Mizoroki–Heck and Suzuki–Miyaura Couplings—Homogeneous or Heterogeneous Catalysis, A Critical Review. Adv. Synth. Catal. 2006, 348, 609–679. [CrossRef] 74. Knowles, J.P.; Whiting, A. The Heck–Mizoroki cross-coupling reaction: A mechanistic perspective. Org. Biomol. Chem. 2007, 5, 31–44. [CrossRef][PubMed] 75. Kumar, A.; Rao, G.K.; Kumar, S.; Singh, A.K. Formation and Role of Palladium Chalcogenide and Other Species in Suzuki−Miyaura and Heck C-C Coupling Reactions Catalyzed with Palladium(II) Complexes of Organochalcogen Ligands: Realities and Speculations. Organometallics 2014, 33, 2921–2943. [CrossRef] 76. Eremin, D.B.; Ananikov, V.P. Understanding active species in catalytic transformations: From molecular catalysis to nanoparticles, leaching, “Cocktails” of catalysts and dynamic systems. Coord. Chem. Rev. 2017, 346, 2–19. [CrossRef] 77. Blaser, H.U.; Indolese, A.; Schnyder, A. Applied homogeneous catalysis by organometallic complexes. Curr. Sci. 2000, 78, 1336–1344. 78. De Vries, J.G. The Heck reaction in the production of fine chemicals. Can. J. Chem. 2001, 79, 1086–1092. [CrossRef] 79. Zapf, A.; Beller, M. Fine chemical synthesis with homogeneous palladium catalysts: Examples, status and trends. Top. Catal. 2002, 19, 101–109. [CrossRef] 80. Olovnikov, A.M. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 1973, 41, 181–190. [CrossRef] 81. Zoeller, J.R.; Agreda, V.H.; Cook, S.L.; Lafferty, N.L.; Polichnowski, S.W.; Pond, D.M. Eastman Chemical Company Acetic Anhydride Process. Catal. Today 1992, 13, 73–91. [CrossRef] 82. Picquet, M. Organometallics as catalysts in the fine chemical industry. Platinum Metals Rev. 2013, 57, 272–280. [CrossRef] 83. Sharma, P.Cinnamic acid derivatives: A new chapter of various pharmacological activities. J. Chem. Pharm. Res. 2011, 3, 403–423. 84. Perkin, W.H. On the artificial production of coumarin and formation of its homologues. J. Chem. Soc. 1868, 21, 53–61. [CrossRef] 85. Biajoli, A.F.P.; Schwalm, C.; Limberger, J.; Claudino, T.S.; Monteiro, A.L. Recent progress in the use of Pd-catalyzed C-C cross-coupling reactions in the synthesis of pharmaceutical compounds. J. Braz. Chem. Soc. 2014, 25, 2186–2214. [CrossRef] 86. Magano, J.; Dunetz, J.R. Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem. Rev. 2011, 111, 2177–2250. [CrossRef][PubMed] 87. Torborg, C.; Beller, M. Recent applications of palladium-catalyzed coupling reactions in the pharmaceutical, agrochemical, and fine chemical industries. Adv. Synth. Catal. 2009, 351, 3027–3043. [CrossRef] 88. Nicolaou, K.C.; Bulger, P.G.; Sarlah, D. Palladium-catalyzed cross-coupling reactions in total synthesis. Angew. Chem. Int. Ed. 2005, 44, 4442–4489. [CrossRef][PubMed] 89. Jeffery, T. Heck-type reactions in water. Tetrahedron Lett. 1994, 35, 3051–3054. [CrossRef] 90. Trost, B.M.; Shi, Y. A palladium-catalyzed zipper reaction. J. Am. Chem. Soc. 1991, 113, 701–703. [CrossRef] 91. Trost, B.M. Atom economy—A challenge for organic synthesis: Homogeneous catalysis leads the way. Angew. Chem. Int. Ed. Engl. 1995, 34, 259–281. [CrossRef] 92. Wellington, K.W.; Benner, S.A. A review: Synthesis of aryl C-glycosides via the Heck coupling reaction. Nucleotides Nucleic Acids 2006, 25, 1309–1333. [CrossRef][PubMed] 93. Zeni, G.; Larock, R.C. Synthesis of heterocycles via palladium-catalyzed oxidative addition. Chem. Rev. 2006, 106, 4644–4680. [CrossRef][PubMed] 94. Bhanage, B.M.; Arai, M. Catalyst product separation techniques in Heck reaction. Catal. Rev. 2001, 43, 315–344. [CrossRef] 95. Wall, V.M.; Eisenstadt, A.; Ager, D.J.; Laneman, S.A. The Heck reaction and cinnamic acid synthesis by heterogeneous catalysis. Platinum Met. Rev. 1999, 43, 138–145. Catalysts 2017, 7, 267 53 of 53

96. Van Heerbeek, R.; Kamer, P.C.; van Leeuwen, P.W.; Reek, J.N. Dendrimers as support for recoverable catalysts and reagents. Chem. Rev. 2002, 102, 3717–3756. [CrossRef][PubMed] 97. Horn, J.; Michalek, F.; Tzschucke, C.C.; Bannwarth, W. Non-covalently solid-phase bound catalysts for organic synthesis. Top. Curr. Chem. 2004, 242, 43–75. [CrossRef][PubMed] 98. Köhler, K.; Pröckl, S.S.; Kleist, W. Supported palladium catalysts in Heck coupling reactions—Problems, potential and recent advances. Curr. Org. Chem. 2006, 10, 1585–1601. [CrossRef] 99. Polshettiwar, V.; Molnár, A. Silica-supported Pd catalysts for Heck coupling reactions. Tetrahedron 2007, 63, 6949–6976. [CrossRef] 100. Molnar, A. Efﬁcient, selective, and recyclable palladium catalysts in carbon-carbon coupling reactions. Chem. Rev. 2011, 111, 2251–2320. [CrossRef][PubMed] 101. Sheldon, R. Catalytic reactions in ionic liquids. Chem. Commun. 2001, 2399–2407. [CrossRef] 102. Singh, R.; Sharma, M.; Mamgain, R.; Rawat, D.S. Ionic liquids: A versatile medium for palladium-catalyzed reactions. J. Braz. Chem. Soc. 2008, 19, 357–379. [CrossRef] 103. Bellina, F.; Chiappe, C. The Heck reaction in ionic liquids: Progress and challenges. Molecules 2010, 15, 2211–2245. [CrossRef][PubMed] 104. Mastrorilli, P.; Monopoli, A.; Dell’Anna, M.M.; Latronico, M.; Cotugno, P.; Nacci, A. Ionic liquids in palladium-catalyzed cross-coupling reactions. Top. Organomet. Chem. 2013, 51, 237–285. [CrossRef] 105. Santos, C.I.; Barata, J.F.; Faustino, M.A.F.; Lodeiro, C.; Neves, M.G.P. Revisiting Heck–Mizoroki reactions in ionic liquids. RSC Adv. 2013, 3, 19219–19238. [CrossRef] 106. Limberger, J.; Leal, B.C.; Monteiro, A.L. Charge-tagged ligands: Useful tools for immobilising complexes and detecting reaction species during catalysis. Chem. Sci. 2015, 6, 77–94. [CrossRef][PubMed] 107. Bhanage, B.M.; Fujita, S.I.; Arai, M. Heck reactions with various types of palladium complex catalysts: Application of multiphase catalysis and supercritical carbon dioxide. J. Organomet. Chem. 2003, 687, 211–218. [CrossRef] 108. Skouta, R. Selective chemical reactions in supercritical carbon dioxide, water, and ionic liquids. Green Chem. Lett. Rev. 2009, 2, 121–156. [CrossRef] 109. Gürsel, I.V.; Noël, T.; Wang, Q.; Hessel, V. Separation/recycling methods of homogeneous transition metal catalysts in continuous ﬂow. Green Chem. 2015, 17, 2012–2026. [CrossRef]

© 2017 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).