catalysts

Review Microwave-Assisted Palladium-Catalyzed Cross-Coupling Reactions: Generation of Carbon–Carbon Bond

Kifah S. M. Salih 1,* and Younis Baqi 2,*

1 Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, P.O. Box 2713 Doha, Qatar 2 Department of Chemistry, College of Science, Sultan Qaboos University, P.O. Box 36, Muscat 123, Oman * Correspondence: [email protected] (K.S.M.S.); [email protected] (Y.B.); Tel.: +974-4403-7552 (K.S.M.S.); +968-2414-1473 (Y.B.)


Received: 1 November 2019; Accepted: 16 December 2019; Published: 18 December 2019


Abstract: Cross-coupling reactions furnishing carbon–carbon (C–C) bond is one of the most challenging tasks in organic syntheses. The early developed reaction protocols by Negishi, Heck, Kumada, Sonogashira, Stille, Suzuki, and Hiyama, utilizing palladium or its salts as catalysis have, for decades, attracted and inspired researchers affiliated with academia and industry. Tremendous efforts have been paid to develop and achieve more sustainable reaction conditions, such as the reduction in energy consumption by applying the microwave irradiation technique. Chemical reactions under controlled microwave conditions dramatically reduce the reaction time and therefore resulting in increase in the yield of the desired product by minimizing the formation of side products. In this review, we mainly focus on the recent advances and applications of palladium catalyzed cross-coupling carbon–carbon bond formation under microwave technology.

Keywords: cross-coupling reaction; C–C bond formation; Pd catalysts; microwave

1. Introduction The formation of carbon-carbon (C–C) bond through cross-coupling reactions represents as one of the most powerful tools in synthetic organic chemistry, therefore many attempts to develop new procedures featuring the C–C bind formation are listed in the literature. The early reaction attempts go back in the history, precisely to the mid of the ninetieth century, were Charles Adolphe Wurtz was testing the effects of sodium metal (Na) on C–C bond formation (Wurtz reaction, 1855), nine years later, this reaction was modified by Wilhelm Rudolph Fittig (Wurtz–Fittig reaction, 1864). In the beginning of the twentieth century, Fritz Ullmann was the first to report the use of transition metal element to form a C–C bond, Ullmann reaction 1901, followed by Cadiot–Chodkiewicz coupling in 1957, Castro–Stephens coupling in 1963, and Corey–House synthesis in 1967. All these reactions were performed in the presence of catalytic amount of cupper (Cu). In the 1970s a breakthrough was achieved when palladium (Pd) was introduced as one of the most powerful catalysts in the C–C bond formation. The developed reaction conditions were later on accredited and listed as named organic reactions, such as Kumada coupling (1972), Heck reaction (1972), Sonogashira coupling (1975), Negishi coupling (1977), Stille coupling (1978), Suzuki reaction (1979), Hiyama coupling (1988), and most recently Liebeskind–Srogl coupling (2000). Broad selections of ligands were tested and several catalyst systems have been invented, resulting in a large variety of new synthesized organic molecules. Additionally, many heterogenized palladium complexes and supported zerovalent palladium nanoparticles were frequently pursued for more sustainable recycling purposes [1,2]. Palladium-catalyzed cross-coupling reaction

Catalysts 2020, 10, 4; doi:10.3390/catal10010004 www.mdpi.com/journal/catalysts Catalysts 2020, 10, 4 2 of 35 becomes widely commonplace in synthesis of fine chemicals, complex and functionalized structures and pharmaceutical intermediates. In 2010, Nobel Prize in Chemistry was awarded to Heck, Negishi, and Suzuki for their fundamental achievements in organic chemistry utilizing palladium catalysts. Although cross-coupling reactions are routinely used in chemical synthesis, they display some limitations, which are mainly because of the high cost of palladium species, to some extend high cost of the ligand used, and the isolated products from cross-coupling reactions predominantly retain palladium. The cost issue will be ruled out in case of reducing the catalyst loading to 100 mol ppm, while reaching 10 mol ppm will eliminate the concern of toxicity [3]. The reactivity trend of aryl halides in cross-coupling reactions is as follows: aryl iodide > aryl bromide > aryl chloride > aryl fluoride. Thus, an efficient catalyst should transform the low-reactive substrates into products under mild reaction conditions. The use of microwave irradiation heating rather than conventional heating systems fulfils the requirement of green chemistry through reducing the time of slow thermal reactions from several hours and in some cases from days to less than one hour reaction time, which usually last for minutes with significant energy savings, in addition to boost up the yield and bring down the level of side reactions [4,5]. This paper highlights the recent advances and applications of palladium-catalyzed cross-coupling C–C bond formation under controlled microwave irradiation technology. It covers the most recent protocols, whereas some earlier examples can be found briefly in previous literatures [6–8]. Furthermore, priority is given to protocols bearing transformation of wide-range of substrates, emphasizing on their utility and restrictions to simplify the further development of this attractive area of research.

2. Palladium-Catalyzed Cross-Coupling Reactions under Microwave Irradiation

2.1. Heck Cross-Coupling Reaction In the early 1970s, both Heck [9] and Mizoroki [10] have separately reported the use of palladium to catalyze arylation reaction of olefins. Nowadays, this cross-coupling reaction is mostly recognized as the Heck reaction, which is considered as one of the most powerful method to substitute alkenes [11]. Usually, Heck reaction takes place through the generation of zerovalent palladium species as an active catalyst (Scheme1( a)). Oxidative addition step take place in which palladium(0) inserts itself in the aryl to halide bond, affording palladium(II) complex (b). Palladium consecutively forms a π complex with the alkene (c), insertion of alkene in the palladium–carbon bond (d), and then beta-hydride elimination leads to the formation of a new palladium-alkene π complex (e). Reductive elimination occurs as a final step giving the coupling product (f) and releasing the active Pd(0) catalyst, after abstracting the halohalide (HX). The reaction is highly stereoselective in nature and proceeds smoothly in the presence of a base. A large number of research and review articles, covering the arts in Heck reaction, have been recently published [12]. Catalysts 2020, 10, x FOR PEER REVIEW 3 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 3 of 35 Catalysts 2020, 10, x 4 FOR PEER REVIEW 3 of 35

Scheme 1. Overall catalytic cycle for the Heck olefination reaction. Scheme 1. Overall catalytic cycle for the Heck olefination reaction. Scheme 1. Overall catalytic cycle for the Heck olefination reaction. Scheme 1. Overall catalytic cycle for the Heck olefination reaction. Heck reactions could proceed via two different routes, neutral or cationic [13]: the cationic Heck reactions could proceed via two didifferentfferent routes,routes, neutral or cationiccationic [[13]:13]: the cationic pathwayHeck using reactions bidentate could phosphines proceed via and two 1,10- differentphenanthroline routes, derivativesneutral or cationicgives rise [13]: to α -arylationthe cationic of pathway using using bidentate bidentate phosphines phosphines and and 1,10- 1,10-phenanthrolinephenanthroline derivatives derivatives gives gives rise rise to toα-arylationα-arylation of terminalpathwayterminal usingolefinsolefins bidentate (internal(internal phosphines arylation)arylation) andunderunder 1,10- electronicallyelectronicallyphenanthroline controlledcontrolled derivatives coordination-insertioncoordination-insertion gives rise to α-arylation step,step, of of terminal olefins (internal arylation) under electronically controlled coordination-insertion step, Schemeterminal 2. olefins Microwave (internal heating arylation) was demonstrated under electronically to be beneficial controlled in activation coordination-insertion of aryl chlorides step, [14] Scheme2. Microwave heating was demonstrated to be beneficial in activation of aryl chlorides [ 14] or or triflates [15] toward highly regioselective internal Heck arylation, in the presence of Pd(OAc)2 as a orScheme triflates 2. Microwave[15] toward heatinghighly regioselective was demonstrated internal to Heckbe beneficial arylation, in inactivation the presence of aryl of Pd(OAc)chlorides2 as[14] a triflatesprecatalyst [15 ]with toward bidentate highly phosphine regioselective ligands internal (DPPF Heck or DPPP). arylation, Conversely, in the presence β-arylation of Pd(OAc) is promoted2 as a precatalystor triflates [15] with toward bidentate highly phosphine regioselective ligands internal (DPPF Heck or DPPP). arylation, Conversely, in the presence β-arylation of Pd(OAc) is promoted2 as a precatalyst with bidentate phosphine ligands (DPPF or DPPP). Conversely, β-arylation is promoted in inprecatalystin thethe neutralneutral with pathwaypathway bidentate conditionsconditions phosphine outout ligandsofof stericalsterical (DPPF reasons.reasons. or DPPP). Conversely, β-arylation is promoted the neutral pathway conditions out of sterical reasons. in the neutral pathway conditions out of sterical reasons.

Scheme 2. Possible products from Heck arylation of olefins. Scheme 2. PossiblePossible products products from from Heck arylation of olefins. olefins. Scheme 2. Possible products from Heck arylation of olefins. Larhed and coworkers have reported palladium-catalyzed selective terminal β-arylation of n-butyl Larhed and coworkers have reported palladium-catalyzed selective terminal β-arylation-arylation ofof n-- vinyl ether with a series of electronically and sterically different aryl chlorides. Almost moderate yields butylLarhed vinyl andether coworkers with a series have ofreported electronically palladium-catalyzed and sterically selective different terminal aryl chlorides. β-arylation Almost of n- were reached, when employing Herrmann’s palladacycle, monodentate [(t-Bu )PH]BF pre-ligand to moderatebutyl vinyl yields ether werewith areached, series ofwhen electronically employing and Herrmann’s sterically differentpalladacycle, aryl3 chlorides.monodentate4 Almost [(tt-- releaseBu3)PH]BF P(t-Bu)4 pre-ligand3 and Cy 2toNMe release as a P( baset-Bu) in3 aqueousand Cy2NMe DMF as or polyethylenea base in aqueous glycol DMF 200 (PEG-200)or polyethylene under Bumoderate3)PH]BF 4yields pre-ligand were toreached, release P(whent-Bu) 3 empland Cyoying2NMe Herrmann’s as a base in palladacycle, aqueous DMF monodentate or polyethylene [(t- microwaveglycol 200 (PEG-200) irradiation. under The selectivitymicrowave for irradiation. liner-product The in selectivity PEG-200 wasfor liner-product observed to be in slightly PEG-200 higher was glycolBu3)PH]BF 200 (PEG-200)4 pre-ligand under to release microwave P(t-Bu) irradiation.3 and Cy2NMe The selectivityas a base infor aqueous liner-product DMF orin PEG-200polyethylene was than in aqueous DMF, Scheme3[16]. observedglycol 200 to (PEG-200) be slightly under higher microwave than in aqueous irradiation. DMF, The Scheme selectivity 3 [16]. for liner-product in PEG-200 was observed to be slightly higher than in aqueous DMF, Scheme 3 [16].

Scheme 3. Microwave-promoted Heck olefinationolefination of aryl halides using Pd(OAc)Pd(OAc)22. Scheme 3. Microwave-promoted Heck olefination of aryl halides using Pd(OAc)2. Scheme 3. Microwave-promoted Heck olefination of aryl halides using Pd(OAc)2.

Catalysts 2020, 10, x FOR PEER REVIEW 4 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 4 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 4 of 35 CatalystsSeveral2020, 10 methodologies, 4 have been reported for Heck reaction under microwave conditions,4 such of 35 Several methodologies have been reported for Heck reaction under microwave conditions, such as theSeveral use of ionicmethodologies liquids, phosphine have been ligands reported [17], for supported Heck reaction catalysts under [18] microwave or Mg-Al conditions, layered double such as the use of ionic liquids, phosphine ligands [17], supported catalysts [18] or Mg-Al layered double hydroxidesas the use of (LDH) ionic liquids,[19]. The phosphine latter revealed ligands high [17], turnover supported numbers catalysts in [18]Heck or olefinationMg-Al layered of various double hydroxidesSeveral (LDH) methodologies [19]. The latter have revealed been reported high turnover for Heck numbers reaction in under Heck microwave olefination conditions,of various substitutedhydroxides (LDH)aryl chlorides [19]. The (Schemelatter revealed 4). This high acti turnovervity was numbers attributed in Heck that olefinationLDH stabilizes of various the substitutedsuch as the usearyl of chlorides ionic liquids, (Scheme phosphine 4). This ligands activity [17], was supported attributed catalysts that [18LDH] or Mg-Alstabilizes layered the nanopalladiumsubstituted aryl particles chlorides and (Scheme provides 4). adequateThis acti vityelectron was densityattributed to thethat anchoredLDH stabilizes zerovalent the nanopalladiumdouble hydroxides particles (LDH) and [19 ].provides The latter adequate revealed electron high turnover density numbers to the inanchored Heck olefination zerovalent of palladiumnanopalladium species, particles as a result, and enablingprovides the adequate oxidative electron addition density step of theto thedeactivated anchored electron-rich zerovalent palladiumvarious substituted species, as aryl a result, chlorides enabling (Scheme the4 oxidative). This activity addition was step attributed of the deactivated that LDH stabilizes electron-rich the chloroarenes.palladium species, as a result, enabling the oxidative addition step of the deactivated electron-rich chloroarenes.nanopalladium particles and provides adequate electron density to the anchored zerovalent palladium species,chloroarenes. as a result, enabling the oxidative addition step of the deactivated electron-rich chloroarenes.

Scheme 4. LDH-Pd catalyzed Heck olefination of chloroarenes. Scheme 4. LDH-PdLDH-Pd catalyzed catalyzed Heck Heck olefination olefination of chloroarenes. Scheme 4. LDH-Pd catalyzed Heck olefination of chloroarenes. The employment of ionic liquids, as nonvolatile solvent at room-temperature, has attracted The employment of ionic liquids,liquids, as nonvolatile solvent at room-temperature, has attracted considerableThe employment attention ofin ionicchemistry. liquid s,Ionic as nonvolatileliquids are solventpromptly at room-temperature,heated without any has substantial attracted considerable attention in chemistry. Ionic Ionic liquids liquids are are promptly promptly heated without any substantial pressureconsiderable build-up, attention as they in interactchemistry. very Ionic efficientl liquidsy with are thepromptly microwave heated [20]. without Xie et al.any have substantial used 1- pressure build-up, as as they they interact interact very very efficientl efficientlyy with with the the microwave microwave [20]. [20]. Xie Xie et etal. al. have have used used 1- octanyl-3-methylimidazoliumpressure build-up, as they interact tetrafluoroborate, very efficientl [OMIm]BFy with the 4microwave, in a solution [20]. ofXie aryl et al. halides, have used butyl 1- 1-octanyl-3-methylimidazoliumoctanyl-3-methylimidazolium tetrafluoroborate, tetrafluoroborate, [OMIm]BF [OMIm]BF4, 4in, ina asolution solution of of aryl aryl halides, halides, butyl acrylate,octanyl-3-methylimidazolium (n-Bu)3N and 3 mol% Pd/C.tetrafluoroborate, Aryl halides [OMIm]BFscreening 4re, vealedin a solution that aryl of iodide aryl halides,to proceed butyl in acrylate, ( (nn-Bu)-Bu)33NN and and 3 3mol% mol% Pd/C. Pd/C. Aryl Aryl halides halides screening screening re revealedvealed that that aryl aryl iodide iodide to toproceed proceed in higheracrylate, yield (n-Bu) compared3N and 3to mol% aryl-bromides Pd/C. Aryl or halides -chlorides, screening while rethevealed presence that ofaryl a substituentiodide to proceed in ortho in- higherin higher yield yield compared compared to aryl-bromides to aryl-bromides or -chl ororides, -chlorides, while while the presence the presence of a substituent of a substituent in ortho in- positionhigher yield to the compared halogen ledto aryl-bromidesto lower outcome, or -chl thisorides, is probably while duethe presenceto the ster ofic aeffect. substituent Aryl bromides in ortho- positionortho-position to the tohalogen the halogen led to lower led to outcome, lower outcome, this is probably this is probably due to the due ster toic the effect. steric Aryl eff bromidesect. Aryl bearingposition electron-withdrawing to the halogen led to lowergroups outcome, found to this be ismore probably reactive due and to thegave ster higheric effect. yields Aryl than bromides those bearingbromides electron-withdrawing bearing electron-withdrawing groups found groups tofound be more tobe reactive more reactive and gave and higher gave higheryields yieldsthan those than havingbearing an electron-withdrawing electron-donating groups, groups Scheme found 5to [21]. be more reactive and gave higher yields than those havingthose having an electron-donating an electron-donating groups, groups, Scheme Scheme 5 [21].5 [21]. having an electron-donating groups, Scheme 5 [21].

Scheme 5. Pd/C catalyzed Heck cross-coupling reaction. Scheme 5. Pd/CPd/C catalyzed catalyzed Heck cross-coupling reaction. Scheme 5. Pd/C catalyzed Heck cross-coupling reaction. Heck reaction was developed in several approaches including synthesis of natural products, Heck reaction was developed in several approaches including synthesis of natural products, heterocyclesHeck reaction and bioactivebioactive was developed molecules.molecules. in severalSelection approaches of biologicallybiologically including activeactive synthesis 4-aryl-3-alkenyl-substituted4-aryl-3-alkenyl-substituted of natural products, heterocycles and bioactive molecules. Selection of biologically active 4-aryl-3-alkenyl-substituted quinolin-2(1heterocyclesHH )-onesand)-ones bioactive have have been beenmolecules. synthesized synthesized Selection in Heck in reactionof Heck biologically usingreaction commercially active using 4-aryl-3-alkenyl-substituted commercially available intermediates. available quinolin-2(1H)-ones have been synthesized in Heck reaction using commercially available Theintermediates.quinolin-2(1 vinylationH )-ones ofThe 3-bromoquinolin-2(1 vinylati have onbeen of 3-bromoquinolin-2(1synthesizedH)-one derivatives in HeckH)-one with reaction ethylderivatives acrylateusing withcommercially was ethyl investigated acrylate available under was intermediates. The vinylation of 3-bromoquinolin-2(1H)-one derivatives with ethyl acrylate was microwaveinvestigatedintermediates. irradiation.under The microwave vinylati Theon irradiation.optimalof 3-bromoquinolin-2(1 reaction The opti conditionsmal reactionH)-one were derivativesconditions accomplished werewith accomplished ethyl using acrylate 3 mol% using was of investigated under microwave irradiation. The optimal reaction conditions were accomplished using tetrakis(triphenylphosphine)3investigated mol% of tetrakis(triphenylphosphine) under microwave palladium(0) irradiation. palladium(0) The and opti 3 equiv.mal and reaction of triethylamine3 equiv. conditions of triethylamine as were base inaccomplished DMF as base (Scheme in DMFusing6). 3 mol% of tetrakis(triphenylphosphine) palladium(0) and 3 equiv. of triethylamine as base in DMF Full(Scheme3 mol% conversions of6). tetrakis(triphenylphosphine) Full conversions to products to were products achieved palladium(0)were inachiev highed yieldsand in high3 equiv. within yields of 40–45 withintriethylamine min, 40–45 in min, lessas base thanin less in 5% DMFthan of (Scheme 6). Full conversions to products were achieved in high yields within 40–45 min, in less than debrominated5%(Scheme of debrominated 6). Full quinolinones conversions quinolinones being to products producedbeing produced were as achiev byproducts as edbyproducts in [high22]. yields [22]. within 40–45 min, in less than 5% of debrominated quinolinones being produced as byproducts [22]. 5% of debrominated quinolinones being produced as byproducts [22].

Scheme 6. Synthesis of 4-aryl-3-alkenyl-substituted quinolin-2(1H)-ones via Heck vinylation.

Catalysts 2020, 10, x FOR PEER REVIEW 5 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 5 of 35 Catalysts 2020, 10, 4 5 of 35 SchemeScheme 6.6. SynthesisSynthesis ofof 4-aryl-3-alkenyl-substituted4-aryl-3-alkenyl-substituted quinolin-2(1quinolin-2(1HH)-ones)-ones viavia HeckHeck vinylation.vinylation.

AA simplesimplesimple modification modificationmodification to to theto thethe classical classicalclassical Heck HeckHeck reaction reactionreaction under underunder microwave microwavemicrowave irradiation irradiationirradiation afforded affordedafforded valuable valuable conversions of aryl halides with terminal olefins using 0.05 mol% of palladium acetate valuableconversions conversions of aryl halides of aryl with halides terminal with olefins termin usingal olefins 0.05 mol%using of0.05 palladium mol% of acetatepalladium (Pd(OAc) acetate2). (Pd(OAc)2). The reaction mixture was adsorbed on neutral alumina and irradiated at 300 W for 20– (Pd(OAc)The reaction2). The mixture reaction was mixture adsorbed was on adsorbed neutral alumina on neutral and alumina irradiated and at irradiated 300 W for 20–25at 300 minW for under 20– 25solvent-25 minmin underunder and ligand-free solvent-solvent- andand conditions, ligand-freeligand-free Scheme conditions,conditions,7. Both SchemeScheme aryl bromides 7.7. BothBoth and arylaryl iodides bromidesbromides were andand converted iodidesiodides werewere into convertedhighconverted yields, intointo whereas highhigh yields,yields, the effi whereaswhereasciency of thethe aryl efficiencyefficiency chlorides ofof was arylaryl found chlorideschlorides to be waswas very foundfound low even toto bebe after veryvery applying lowlow eveneven a afterdoubleafter applyingapplying amount aa of doubledouble the catalyst. amountamount Moreover, ofof thethe catalyst.catalyst. electron-deficient MoMoreover,reover, electron-deficientelectron-deficient aryl halides were arylaryl more halideshalides reactive werewere than moremore the reactiveelectron-richreactive thanthan onesthethe electron-richelectron-rich [23]. onesones [23].[23].

Scheme 7. Microwave-promoted Heck olefination of aryl halides using Pd(OAc)2. Scheme 7. Microwave-promotedMicrowave-promoted Heck olefination olefination of aryl halides using Pd(OAc)2..

PalladiumPalladium nanoparticles nanoparticles supported supported on on graphene graphene (Pd/G) (Pd(Pd/G)/G) were were fabricated fabricated by by microwave-assisted microwave-assisted chemicalchemical reduction reduction of of the the aqueous aqueous mixturemixture ofof pallpall palladiumadiumadium nitratenitrate andand disperseddispersed graphitegraphite oxideoxide oxide sheets.sheets. sheets. TheThe developed developed heterogeneous heterogeneous Pd/G PdPd/G/G catalyst catalyst was was investigated investigated in in C–C C–C cross-coupling cross-coupling reactions reactions (Heck (Heck andand Suzuki). Suzuki). TheThe performanceperformance ofof Pd/GPd/G Pd/G demonstrateddemonstrated hi highhighgh catalytic catalytic activity activity in in opposite opposite to to the the widelywidely usedused palladium palladium supported supported on on charco charcoalcharcoalal (Pd/C) (Pd(Pd/C)/C) catalyst, catalyst, this this was was attributed attributed to to high high stability stability of of Pd Pd particlesparticles onon on thethe the supportedsupported supported graphenegraphene graphene... Pd/GPd/G Pd found/foundG found toto bebe to usefuluseful be useful heterogeneousheterogeneous heterogeneous catalystcatalyst catalyst forfor HeckHeck for cross-cross- Heck couplingcross-couplingcoupling reactionreaction reaction betweenbetween between arylaryl bromidebromide aryl bromide andand styrenestyrene and styrene dederivativesrivatives derivatives usingusing using 0.30.3 mol%mol% 0.3 mol% ofof thethe of catalystcatalyst the catalyst inin thethe in presencethepresence presence ofof potassiumpotassium of potassium carbonatecarbonate carbonate inin aqueous inaqueous aqueous ethanoethano ethanolll underunder under microwavemicrowave microwave heatingheating heating forfor for 1010 10 min,min, min, SchemeScheme Scheme 8.88.. WhileWhile aryl aryl chlorideschlorides werewere failedfailed toto bebe convertedconverted [[24].[24].24].

Scheme 8. Pd/G catalyzed Heck olefination of aryl bromides and styrenes. SchemeScheme 8.8. Pd/GPd/G catalyzedcatalyzed HeckHeck olefinationolefination ofof arylaryl bromidesbromides andand styrenes.styrenes. Recently, there has been a significant amount of research on the use of natural-based materials Recently, there has been a significant amount of research on the use of natural-based materials suchRecently, as cyclodextrins there has [25 ],been cellulose a significant [26] and amount cucurbit of [7 research] uril [27 ],on to the support use of Pd natural-based nanoparticles, materials for their suchsuch asas cyclodextrinscyclodextrins [25],[25], celluloscellulosee [26][26] andand cucurbitcucurbit [7][7] uriluril [27],[27], toto supportsupport PdPd nanoparticles,nanoparticles, forfor uniquetheir unique and potentially and potentially useful useful features. features. The Pd-loaded The Pd-loaded materials materials showed showed good conversion good conversion activity theirin Heck unique cross-coupling and potentially reactions useful under features. irradiation The Pd-loaded condition. materials Furthermore, showed monosaccharides good conversion are activityactivity inin HeckHeck cross-couplingcross-coupling reactionsreactions underunder irradiationirradiation condition.condition. Furthermore,Furthermore, monosaccharidesmonosaccharides widelyare widely available available biomolecules biomolecules and attempt and attempt to develop to develop greener andgreener economical and economical chemical reactions.chemical areMonosaccharides widely available are used biomolecules for its several and advantages, attempt to such develop as thecost-e greenerffectiveness, and economical for the coordination chemical reactions.reactions. MonosaccharidesMonosaccharides areare usedused forfor itsits severalseveral advantages,advantages, suchsuch asas thethe cost-effectiveness,cost-effectiveness, forfor thethe withcoordination metals,and with as metals, a reducing and agent as a forreducing the stabilization agent for ofthe the stabilization catalytically of active the catalytically nanoparticles active [28]. coordination with metals, and as a reducing agent for theD stabilization of the catalytically active Jain’snanoparticles group has [28]. studied Jain’s thegroup potential has studied for the the addition potential of for-glucosamine the addition to of Heck D-glucosamine coupling reactions, to Heck nanoparticlesexploring the possibility[28]. Jain’s ofgroup replacing has studied organophosphines. the potential After for the optimization addition of of D the-glucosamine reaction conditions, to Heck couplingcoupling reactions,reactions, exploringexploring thethe possibilitypossibility ofof replacingreplacing organophosphines.organophosphines. AfterAfter optimizationoptimization ofof the feasibilityreaction conditions, was assessed the feasibility for a selection was ofassessed aryl and for heteroaryl a selection iodides of aryl andand bromidesheteroaryl with iodides styrene. and theTherefore, reaction substituted conditions, trans-stilbenes the feasibility and was heteroaryl assessed for olefins a selection were obtained of aryl and in the heteroaryl presence iodides of 0.1 mol% and bromidesbromides withwith styrene.styrene. Therefore,Therefore, substitutedsubstituted trans-trans-stilbenesstilbenes andand heteroarylheteroaryl olefinsolefins werewere obtainedobtained inin of Pd(OAc)2, D-glucosamine (1 equiv.), and K2(CO3)2 (3 equiv.) in aqueous DMF under microwave the presence of 0.1 mol% of Pd(OAc)2, D-glucosamine (1 equiv.), and K2(CO3)2 (3 equiv.) in aqueous theheating presence for 60 of min.0.1 mol% As usual, of Pd(OAc) the yields2, D-glucosamine resulting from (1 conversionequiv.), and of K2 aryl(CO3 iodides)2 (3 equiv.) arehigher in aqueous than DMFDMF underunder microwavemicrowave heatingheating forfor 6060 min.min. AsAs usual,usual, thethe yieldsyields resultingresulting fromfrom conversionconversion ofof arylaryl aryliodides bromides. are higher Aryl than bearing aryl atbromides. 4-position Aryl electron-withdrawing bearing at 4-position groups electron-withdrawing is found to be more groups reactive is iodidescompared are with higher electron-donating than aryl bromides. functions, Aryl Scheme bearing9[ 29at ].4-position electron-withdrawing groups is foundfound toto bebe moremore reactivereactive comparedcompared withwith electron-donatingelectron-donating functifunctions,ons, SchemeScheme 99 [29].[29].

Catalysts 2020, 10, x FOR PEER REVIEW 6 of 35 Catalysts 2020, 10, 4 6 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 6 of 35

Scheme 9. Heck olefination of aryl halides using Pd(OAc)2 in the presence of D-glucosamine. Scheme 9. Heck olefination of aryl halides using Pd(OAc)2 in the presence of D-glucosamine. Scheme 9. Heck olefination of aryl halides using Pd(OAc)2 in the presence of D-glucosamine. Under controlled microwave process, Larhed Larhed and coworkers have explored the scope and Under controlled microwave process, Larhed and coworkers have explored the scope and2 limitationslimitations of of the base-free oxidative Heck reactionreaction with arylboronic acids, employing Pd(OAc) 2,, limitations of the base-free oxidative Heck reaction with arylboronic acids, employing Pd(OAc)2, dmphen (2,9-dimethyl-1,10-ph (2,9-dimethyl-1,10-phenanthroline)enanthroline) as the regio-controlling ligand and with p-quinone or air air dmphen (2,9-dimethyl-1,10-phenanthroline) as the regio-controlling ligand and with p-quinone or air as reoxidants of zerovalent palladium complex. The The oxidative couplings of arylboronic acids with as reoxidants of zerovalent palladium complex. The oxidative couplings of arylboronic acids with both electron-rich and electron-poor olefins olefins were conducted smoothly and regioselectively, giving both electron-rich and electron-poor olefins were conducted smoothly and regioselectively, giving high yields even even with with disubstitu disubstitutedted butyl butyl methacrylate, methacrylate, sensitive sensitive acrolein, acrolein, and and a a vinylboronate vinylboronate ester, ester, high yields even with disubstituted butyl methacrylate, sensitive acrolein, and a vinylboronate ester, Scheme 1010[ 30 ].[30]. Likewise, Likewise, palladium-catalyzed palladium-catalyzed decarboxylative decarboxylative Heck reaction Heck of 2,6-dimethoxybenzoic reaction of 2,6- Scheme 10 [30]. Likewise, palladium-catalyzed decarboxylative Heck reaction of 2,6- dimethoxybenzoicacid and methyl acrylate acid and was methyl recently acrylate reported was as recently a proof of reported principle as study a proof under of principle irradiation study condition under dimethoxybenzoic acid and methyl acrylate was recently reported as a proof of principle study under irradiationand using molecularcondition oxygenand using as themolecular oxidizing oxygen agent as [31 the]. oxidizing agent [31]. irradiation condition and using molecular oxygen as the oxidizing agent [31].

Scheme 10. Microwave-promoted Heck oxidative reaction of arylboronic acids with olefines. Scheme 10. Microwave-promoted Heck oxidative reaction of arylboronic acids with olefines. Scheme 10. Microwave-promoted Heck oxidative reaction of arylboronic acids with olefines. 2.2. Sonogashira Cross-Coupling Reaction 2.2. Sonogashira Cross-Coupling Reaction 2.2. SonogashiraSonogashira Cross-Coupling cross-coupling Reaction reaction has been developed in 1975 and since then proves to be as one ofSonogashira the very useful cross-coupling reaction implemented reaction has been successfully developed in a in wide 1975 variety and since of research then proves active to areas,be as Sonogashira cross-coupling reaction has been developed in 1975 and since then proves to be as oneincluding of the drugvery discoveryuseful reaction and development, implemented in successful the synthesisly in of a heterocycleswide variety and of research natural productsactive areas, [32]. one of the very useful reaction implemented successfully in a wide variety of research active areas, includingThis reaction drug involves discovery the couplingand development, between an in sp the2 carbon synthesis of an of aryl heterocycles or vinyl halide and (ornatural pseudohalide) products including drug discovery and development, in the synthesis2 of heterocycles and natural products [32].with aThis terminal reaction sp hybridized involves the carbon coupling from anbetween alkyne. an Although, sp carbon the reactionof an aryl mechanism or vinyl is halide fairly well(or [32]. This reaction involves the coupling between an sp2 carbon of an aryl or vinyl halide (or pseudohalide)established in thewith literature, a terminal it consists sp hybridized of two catalytic carbon cycles from and an researchers alkyne. mainlyAlthough, revolve the aroundreaction a pseudohalide) with a terminal sp hybridized carbon from an alkyne. Although, the reaction mechanismpalladium cycle. is fairly It iswell proposed established that thein the reaction literature, typically it consists goes of through two catalytic zerovalent cycles palladium and researchers species mechanism is fairly well established in the literature, it consists of two catalytic cycles and researchers mainlyas an active revolve catalyst. around In a the palladium oxidative cycle. addition It is step,proposed the insertion that the ofreaction palladium(0) typically into goes aryl through halide mainly revolve around a palladium cycle. It is proposed that the reaction typically goes through zerovalentbond delivers palladium the palladium(II) species as complex an active (b ).catalyst. A side cycleIn the supported oxidative byaddition copper step, as a co-catalystthe insertion (CuX) of zerovalent palladium species as an active catalyst. In the oxidative addition step, the insertion of palladium(0)develops the σinto-alkynylcopper(I) aryl halide bond organometallic delivers the palladium(II) reagent (g) for complex transmetalation (b). A side step cycle with supported complex byb. palladium(0) into aryl halide bond delivers the palladium(II) complex (b). A side cycle supported by copperThe σ-alkynylpalladium(II) as a co-catalyst (CuX) intermediate develops (hthe) is σ yielded-alkynylcopper(I) afterward alongorganometallic with the active reagent Cu species,(g) for copper as a co-catalyst (CuX) develops the σ-alkynylcopper(I) organometallic reagent (g) for transmetalationwhich involves withstep alkynewith complex substrate b and. The base σ-alkynylpalladium(II) in second reaction sequence intermediate (Cu-cycle). (h) is Reductive yielded transmetalation step with complex b. The σ-alkynylpalladium(II) intermediate (h) is yielded afterwardelimination along takes with place the eventually active Cu to species, afford thewhich coupling involves product with alkyne (i) and substrate to regenerate and thebase active in second Pd(0) afterward along with the active Cu species, which involves with alkyne substrate and base in second reactioncatalyst, Schemesequence 11 (Cu-cycle).[33,34]. Reductive elimination takes place eventually to afford the coupling productreaction (sequencei) and to regenerate (Cu-cycle). the Reductive active Pd(0) eliminatio catalyst,n takesScheme place 11 [33,34]. eventually to afford the coupling product (i) and to regenerate the active Pd(0) catalyst, Scheme 11 [33,34].

Catalysts 2020, 10, 4 7 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 7 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 7 of 35

Scheme 11. Overall mechanism for the Pd/Cu-catalyzed Sonogashira cross-coupling reaction. Scheme 11. Overall mechanism for the Pd/Cu-catalyze Pd/Cu-catalyzedd Sonogashira cross-coupling reaction.reaction.

InIn aa one-potone-pot one-pot synthesissynthesis synthesis ofof of indolesindoles indoles underunder under microwavmicrowav microwavee irradiation, irradiation, Larock’s Larock’s group group has hasreported reported the theinin situsitu in alkynylationalkynylation situ alkynylation ofof N-substituted/-substituted/ of N-substitutedN,,N-disubstituted-disubstituted/N,N-disubstituted 2-iodoaniline2-iodoaniline 2-iodoaniline inin typicaltypical in SonogashiraSonogashira typical Sonogashira couplingcoupling couplingconditions. conditions. The scope The of scopethe reactions of the reactions was demons was demonstratedtratedtrated byby electron-richelectron-rich by electron-rich arylaryl acetylenes,acetylenes, aryl acetylenes, usingusing PdCl2(PPh3)2, CuI and Et3N at 60 °C for 20–30 min [35]. 5-Iodo-4-methoxy-2-pyridone derivatives usingPdCl2(PPh PdCl3)22(PPh, CuI3 )and2, CuI Et3N and at Et603 N°C atfor 60 20–30◦C formin 20–30 [35]. min5-Iodo-4-methoxy-2-pyridone [35]. 5-Iodo-4-methoxy-2-pyridone derivatives derivativesreacted with reacted terminal with alkynes terminal under alkynes microwav under microwave-enhancede-enhanced Sonogashira Sonogashira conditions. conditions. The cross- The cross-couplingcoupling products products have haveundergone undergone sequential sequential demethylation demethylation and and furan furan annulation, annulation, furnishing furnishing 7- 7-arylfuro[3,2-arylfuro[3,2-c]pyridin-4(5]pyridin-4(5c]pyridin-4(5HH)-ones)-ones)-ones inin in aa aone-potone-pot one-pot reactionreaction reaction [36].[36]. [36]. OnOn On thethe the otherother other hand,hand, hand, arylaryl aryl bromidesbromides were were cross-coupled with terminal alkynes under mild conditions in the presence of PdCl2(PPh3)2, CuI and cross-coupled withwith terminalterminal alkynesalkynes underunder mildmild conditionsconditions inin thethe presencepresence of of PdCl PdCl22(PPh(PPh33))22, CuI andand Et3N under irradiation for 10 min (Scheme 12) [37]. Et33N under irradiation for 10 min (Scheme 1212))[ [37].37].

Scheme 12. One-pot synthesis of indoles under microwave irradiation. Scheme 12. One-pot synthesis of indoles under microwave irradiation. Pd-loaded multi-walled carbon nanotubes (Pd/MWCNT) have been used in alkynylation reactions Pd-loaded multi-walled carbon nanotubes (Pd/MWCNT) have been used in alkynylation in thePd-loaded absence of coppermulti-walled salts and carbon phosphine nanotubes ligands. (Pd/MWCNT) Under microwave have irradiation been used for 5in min alkynylation at 135–160 reactions in the absence of copper salts and phosphine ligands. Under microwave irradiation for 5 reactionsC, the reaction in the absence of iodoarenes of copper with salts 4-ethynyltoluene and phosphine in ligands. a mixture Under of ethanol-water microwave irradiation and potassium for 5 ◦min at 135–160 °C, the reaction of iodoarenes with 4-ethynyltoluene in a mixture of ethanol-water carbonatemin at 135–160 as base °C, a fftheorded reaction the cross-coupledof iodoarenes productswith 4-ethynyltoluene in good yields. in a Notably, mixture whenof ethanol-water piperidine and potassium carbonate as base afforded the cross-coupled products in good yields. Notably, when (pip) is used instead of K2CO3 in ethanol, much poorer yields were reached for the reactants with piperidine (pip) is used instead of K2CO3 in ethanol, much poorer yields were reached for the electron-donatingpiperidine (pip) is groups used instead on the iodoareneof K2CO3 moietiesin ethanol, (Scheme much 13poorer). The yields catalyst were revealed reached moderate for the reactants with electron-donating groups on the iodoarene moieties (Scheme 13). The catalyst revealed leachingreactants of with Pd (1.1%)electron-donating in the first use groups and is on mentioned the iodoarene in at least moieties five times (Scheme of recycling, 13). The catalyst though recyclingrevealed moderate leaching of Pd (1.1%) in the first use and is mentioned in at least five times of recycling, ismoderate not demonstrated leaching of [38 Pd]. (1.1%) Similarly, in the graphene-supported first use and is mentioned Pd nanoparticles in at least (Pd five/G) times were of reported recycling, for though recycling is not demonstrated [38]. Similarly, graphene-supported Pd nanoparticles (Pd/G) Sonogashirathough recycling reaction is not of conversiondemonstrated of few[38]. electron-rich Similarly, graphene-supported iodo-substrates with Pd phenylacetylene nanoparticles (Pd/G) under were reported for Sonogashira reaction of conversion of few electron-rich iodo-substrates with solvent-freewere reported microwave for Sonogashira irradiation reaction conditions of forconver 40 minsion [39 of]. few The substantialelectron-ric drawbackh iodo-substrates of using thesewith phenylacetylene under solvent-free microwave irradiation conditions for 40 min [39]. The substantial supportedphenylacetylene catalysts under (Pd solvent-free/MWCNT and microwave Pd/G) is irradi the conversionation conditions to the for desired 40 min products [39]. The is substantial limited to drawback of using these supported catalysts (Pd/MWCNT and Pd/G) is the conversion to the desired thedrawback aryl iodides. of using This these is probably supported due catalysts to the fact(Pd/MW that PdCNT nanoparticles and Pd/G) is might the conversion be mainly to buried the desired in the products is limited to the aryl iodides. This is probably due to the fact that Pd nanoparticles might be supportedproducts is frame. limited to the aryl iodides. This is probably due to the fact that Pd nanoparticles might be mainly buried in the supported frame.

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Scheme 13. Pd/MWCNT-catalyzedPd/MWCNT-catalyzed Sonogashira coupling reactions. Scheme 13. Pd/MWCNT-catalyzed Sonogashira coupling reactions. Sedelmeier etet al. al. have have reported reported the the application application of polyuria of polyuria microencapsulated microencapsulated palladium palladium catalyst Sedelmeier et al. have reported the application of polyuria microencapsulated palladium (PdEnCatcatalyst (PdEnCatTM TPP30)TM inTPP30) Sonogashira in Sonogashira cross-coupling cross-coupling reactions promotedreactions bypromoted microwave by microwave irradiation. catalyst (PdEnCatTM TPP30) in Sonogashira cross-coupling reactions promoted by microwave irradiation.Under the optimized Under the reaction optimized conditions, reaction onlyconditions, aryl bromides only aryl and bromides iodides reactedand iodides with reacted a wide varietywith a irradiation. Under the optimized reaction conditions, only aryl bromides and iodides reacted with a wideof terminal variety alkynes, of terminal giving alkynes, rise to thegiving corresponding rise to the couplingcorresponding products coupling in good products to excellent in good yields. to wide variety of terminal alkynes, giving rise to the corresponding coupling products in good to excellentBoth electron-rich yields. Both and electron-deficientelectron-rich and arylelectron-d halideseficient were coupled aryl halides under were copper coupled and inert under atmosphere copper excellent yields. Both electron-rich and electron-deficient aryl halides were coupled under copper andfree-conditions inert atmosphere in the presence free-conditions of DBU inin MeCNthe presen at 100–120ce of DBU◦C. The in MeCN reactions at 100–120 have demonstrated °C. The reactions a good and inert atmosphere free-conditions in the presence of DBU in MeCN at 100–120 °C. The reactions havelevel ofdemonstrated functional group a good tolerance level of toward functional acetyl, grou alcohol,p tolerance ester, chloro, toward amide, acetyl, nitrile, alcohol, and ester, nitro chloro, groups have demonstrated a good level of functional group tolerance toward acetyl, alcohol, ester, chloro, (Schemeamide, nitrile, 14). Additionally, and nitro groups a number (Scheme of functionalized 14). Additionally, enynes a number was also of generated functionalized in good enynes yields was by amide, nitrile, and nitro groups (Scheme 14). Additionally, a number of functionalized enynes was alsoconducting generated the in reaction good yields with abycis conducting/trans-mixture the of reactionβ-bromostyrene with a cis/ astrans a halide-mixture partner. of β-bromostyrene Recycling the also generated in good yields by conducting the reaction with a cis/trans-mixture of β-bromostyrene ascatalyst a halide after partner. simple filtrationRecycling was the investigated catalyst after in thesimple coupling filtration reaction was between investigated 4-bromoacetophenone in the coupling as a halide partner. Recycling the catalyst after simple filtration was investigated in the coupling reactionand phenylacetylene. between 4-bromoacetophenone A yield of 98% from and the phenylacet first use ofylene. the catalyst A yield was of dropped98% from down the first to 92%use of in the reaction between 4-bromoacetophenone and phenylacetylene. A yield of 98% from the first use of the catalystsixth cycle. was This dropped minor down loss in to the 92% catalytic in the activitysixth cycle. states This that minor the metal loss releasein the catalytic from the activity encapsulated states catalyst was dropped down to 92% in the sixth cycle. This minor loss in the catalytic activity states thatPd-species the metal is very release slow from [40]. the encapsulated Pd-species is very slow [40]. that the metal release from the encapsulated Pd-species is very slow [40].

Scheme 14. PdEnCatPdEnCat TPP30-catalyzed Sonogashira coupling reaction. Scheme 14. PdEnCat TPP30-catalyzed Sonogashira coupling reaction. Under solvent-free microwave irradiation conditio conditions,ns, Sonogashira reaction was described using Under solvent-free microwave irradiation conditions, Sonogashira reaction was described using palladium modified modified mesoporous materials and zeolites, such as Pd-MCM-41, Pd-Y, Pd-VSB-5, and palladium modified mesoporous materials and zeolites, such as Pd-MCM-41, Pd-Y, Pd-VSB-5, and Pd-SBA-15. ForFor instance,instance, various various phenyl phenyl iodides, iodides, bearing bearing bromo bromo or chloro or chloro functionality, functionality, were coupled were Pd-SBA-15. For instance, various phenyl iodides, bearing bromo or chloro functionality, were withcoupled phenylacetylene with phenylacetylene using Pd-MCM-41 using Pd-MCM-41 or Pd-Y in or the Pd-Y presence in the ofpresence DBU as of a DBU base atas 120a base◦C inat 40120 min °C coupled with phenylacetylene using Pd-MCM-41 or Pd-Y in the presence of DBU as a base at 120 °C (Schemein 40 min 15 (Scheme)[41]. 15) [41]. in 40 min (Scheme 15) [41].

Scheme 15. Pd-modified mesoporous materials catalyzed Sonogashira coupling reaction. Scheme 15. Pd-modifiedPd-modified mesoporous materials catalyzed Sonogashira coupling reaction.reaction. Bodke and coworkers have developed an access for the synthesis of 4-methyl-7- Bodke and and coworkers coworkers have have developed developed an access an accessfor the forsynthesis the of synthesis 4-methyl-7- of alkyl/aryl/heteroaryl alkynyl coumarins under microwave irradiation. In the presence of 4-methyl-7-alkylalkyl/aryl/heteroaryl/aryl /heteroarylalkynyl coumarins alkynyl coumarinsunder microwave under microwaveirradiation. irradiation.In the presence In theof presencePdCl2(PCy of3)2, PdCl TBAF2(PCy∙3H23O)2 ,and TBAF DMA3H2 Oas anda solvent, DMA asthe a solvent,cross-coupling the cross-coupling reaction of 4-methyl-7- reaction of PdCl2(PCy3)2, TBAF∙3H2O and DMA as a solvent, the cross-coupling reaction of 4-methyl-7- nonafluorobutylsulfonyloxy coumarin· with a selection of terminal alkynes was achieved (Scheme 4-methyl-7-nonafluorobutylsulfonyloxynonafluorobutylsulfonyloxy coumarin with coumarin a selection with aof selection terminal of alkynes terminal was alkynes achieved was achieved(Scheme 16). The products were obtained in high yields with electron rich acetylenes, while slightly lesser (Scheme16). The 16products). The products were obtained were obtained in high inyields high wi yieldsth electron with electron rich acetylenes, rich acetylenes, while slightly while slightly lesser yields were achieved with electron deficient alkynes in 18–33 min. Remarkably, nonaflates were yields were achieved with electron deficient alkynes in 18–33 min. Remarkably, nonaflates were

Catalysts 2020, 10, 4 9 of 35

Catalysts 2020, 10, x FOR PEER REVIEW 9 of 35 Catalystslesser yields 2020, 10 were, x FOR achieved PEER REVIEW with electron deficient alkynes in 18–33 min. Remarkably, nonaflates9 were of 35 showed to couple more efficiently than the analogous triflates, which generated the required product showed to couple more efficiently than the analogous triflates, which generated the required product along with competing detriflated- and hydrolyzed-side products [42]. along with competing detriflated- and hydrolyzed-side products [42].

Scheme 16. Synthesis of 4-methyl-7-alkyl/aryl/heteroaryl alkynyl coumarins. Scheme 16. Synthesis of 4-methyl-7-alkyl/aryl/heteroaryl alkynyl coumarins. A method for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene was recently developed using A method for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene was recently developed using copper and palladium-catalyzed coupling of trimethylsilylacetylene and aryl bromides or iodides. copper and palladium-catalyzed coupling of trimethylsilylacetylene and aryl bromides or iodides. Under microwave irradiation in acetonitrile and in the presence of triethylamine as a base. The desired Under microwave irradiation in acetonitrile and in the presence of triethylamine as a base. The products, bearing numerous functional groups, were obtained in good to excellent yields within 2–10 desired products, bearing numerous functional groups, were obtained in good to excellent yields min. Aryl halides substituted on position-2 were coupled in slightly lesser yields, whereas, good results within 2–10 min. Aryl halides substituted on position-2 were coupled in slightly lesser yields, were achieved for heterocyclic aryl halides or naphthalene halides under same reaction conditions whereas, good results were achieved for heterocyclic aryl halides or naphthalene halides under same (Scheme 17)[43]. reaction conditions (Scheme 17) [43].

Scheme 17. Sonogashira reaction of aryl- or heteroaryl-halides with trimethylsilylacetylene. Scheme 17. Sonogashira reaction of aryl- or heteroaryl-halides with trimethylsilylacetylene. Eventually, a limited number of homogenous palladium complexes [44,45] and supported Eventually, a limited number of homogenous palladium complexes [44,45] and supported palladium nanoparticles [46] were described for Sonogashira coupling reaction of aryl bromide and palladium nanoparticles [46] were described for Sonogashira coupling reaction of aryl bromide and iodide with phenylacetylene under microwave reaction condition. iodide with phenylacetylene under microwave reaction condition. It is worth mentioning that the mechanism of copper-free Sonogashira reaction was earlier It is worth mentioning that the mechanism of copper-free Sonogashira reaction was earlier proposed as a monometallic mechanism [47]. However, a catalytic cycle proceeds through a tandem proposed as a monometallic mechanism [47]. However, a catalytic cycle proceeds through a tandem Pd/Pd cycle comparable to the Pd/Cu tandem variant (Scheme 11) was quite recently revealed, Pd/Pd cycle comparable to the Pd/Cu tandem variant (Scheme 11) was quite recently revealed, supported by considerable experimental and computational scrutiny [48]. supported by considerable experimental and computational scrutiny [48]. 2.3. Suzuki Cross-Coupling Reaction 2.3. Suzuki Cross-Coupling Reaction The palladium-catalyzed Suzuki cross-coupling, developed in 1979, is by far one of the most The palladium-catalyzed Suzuki cross-coupling, developed in 1979, is by far one of the most explored reaction in organicorganic chemistrychemistry toto synthesizesynthesize unsymmetricalunsymmetrical biarylbiaryl derivatives.derivatives. It is also exploredknown in reaction numerous in publications organic chemistry by the name to synthesi Suzuki-Miyauraze unsymmetrical reaction. biaryl The reaction derivatives. employs It readilyis also known in numerous publications by the name Suzuki-Miyaura reaction. The reaction employs availablereadily available substrates, substrates, arylhalide arylhalide and organoboron and organoboron compounds, compounds, and tolerates and atolerates selection a of selection functional of readilygroups underavailable mild substrates, reaction conditions. arylhalide Theand stability organoboron of boronic compounds, acids to heat and and tolerates water, a in selection addition of to functional groups under mild reaction conditions. The stability of boronic acids to heat and water, in easeaddition of handling to ease andof handling separation an ofd separation by-products of from by-products the reaction from mixtures, the reaction makes mixtures, the reaction makes widely the additionapplicable to underease of homogeneous handling and andseparation heterogeneous of by-products conditions from [49 the]. reaction Typically, mixtures, the cross-coupling makes the reaction widely applicable under homogeneous and heterogeneous conditions [49]. Typically, the reactioncross-coupling proceeds reaction through proceeds the generation through the of generation zerovalent of palladium zerovalent species, palladium Scheme species, 18. Scheme The active 18. cross-couplingPd-catalyst (a) isreaction subjected proceeds to oxidative through addition the generation step by arylof zerovalent halide, aff palladiumording palladium(II) species, Scheme complex 18. The active Pd-catalyst (a) is subjected to oxidative addition step by aryl halide, affording (b). The coupling partner, boronic acid, undergoes a transmetallation in the presence of base, giving the palladium(II) complex (b). The coupling partner, boronic acid, undergoes a transmetallation in the diarylpalladium(II) intermediate (j). Finally, the reductive elimination proceeds to give the coupling presence of base, giving the diarylpalladium(II) intermediate (j). Finally, the reductive elimination proceeds to give the coupling biaryls product (k) and releasing the active Pd(0) catalyst. High catalyst loading is needed when aryl chlorides is used, because of the disfavored oxidative addition step raising from high C‒Cl bond strength compared with C‒Br and C‒I bonds [50]. Moreover, this overall

Catalysts 2020, 10, 4 10 of 35

Catalystsbiaryls 2020 product, 10, x FOR (k) PEER and releasingREVIEW the active Pd(0) catalyst. High catalyst loading is needed10 when of 35 Catalystsaryl chlorides 2020, 10, isx FOR used, PEER because REVIEW of the disfavored oxidative addition step raising from high C-Cl10 bond of 35 catalyticstrength cycle compared is almost with functional C-Br and in C-I Stille, bonds Negishi, [50]. Moreover, Hiyama, Kumada, this overall and catalytic decarboxylative cycle is almostcross- catalytic cycle is almost functional in Stille, Negishi, Hiyama, Kumada, and decarboxylative cross- couplingfunctional reactions in Stille, [51]. Negishi, Hiyama, Kumada, and decarboxylative cross-coupling reactions [51]. coupling reactions [51].

Scheme 18. Overall catalytic cycle for the Suzuki cross-coupling reaction. Scheme 18. OverallOverall catalytic catalytic cycle cycle for for the the Suzuki cross-coupling reaction. Schotten’s group has reported that palladium acetate catalyzes the cross-coupling reaction of Schotten’s group has reported that palladium acetate catalyzes the cross-coupling reaction of poly(ethylene glycol) (PEG) ester of bromo-, iodo-, and triflate-para-substituted triflate-para-substituted benzoates with aryl poly(ethylene glycol) (PEG) ester of bromo-, iodo-, and triflate-para-substituted benzoates with aryl boronic acids in water under microwave irradiation for 2–4 min (Scheme 19). Under ligand free boronic acids in water under microwavemicrowave irradiationirradiation for 2–42–4 minmin (Scheme(Scheme 1919).). Under ligand free condition, high conversion of starting materials was observed and the produced polymeric support condition, high conversion of starting material materialss was observed and the produced polymeric support remains more stable than the one prepared under conventional thermal conditions, that induced ester remains more stable than the one one prepared prepared under under co conventionalnventional thermal conditions, that induced ester bond cleavage [52]. Similarly, palladium acetate in low-loading (0.4 mol%) was used in cross- bond cleavagecleavage [52[52].]. Similarly, Similarly, palladium palladium acetate acetate in low-loading in low-loading (0.4 mol%)(0.4 mol%) was used was in used cross-coupling in cross- coupling reaction of aryl bromides with phenylboronic acid in water under microwave heating [53]. couplingreaction ofreaction aryl bromides of aryl bromides with phenylboronic with phenylbo acidronic in water acid under in water microwave under microwave heating [53 heating]. [53].

SchemeScheme 19. Palladium(II)Palladium(II) acetate acetate catalyzes catalyzes th thee Suzuki Suzuki cross-coupling cross-coupling reaction. Scheme 19. Palladium(II) acetate catalyzes the Suzuki cross-coupling reaction. The coupling of an arylboronic acid to a β-chloroalkyl/arylidene-chloroalkyl/arylidene malonate in in the presence of The coupling of an arylboronic acid to a β-chloroalkyl/arylidenet malonate in the presence of K22COCO33 andand 1 1 mol% of thethe air-stableair-stable palladiumpalladium catalyst,catalyst, [([(-Bu)t-Bu)22P(OH)]P(OH)]22PdCl2,, under under microwave K2CO3 and 1 mol% of the air-stable palladium catalyst, [(t-Bu)2P(OH)]2PdCl2, under microwave irradiationirradiation affaffordsords β -arylβ-aryl/alkylarylidene/alkylarylidene malonates, malonates, which werewhich synthesized were synthesized mainly upon mainly Knoevenagel upon irradiation affords β-aryl/alkylarylidene malonates, which were synthesized mainly upon Knoevenagel condensation. The mild reaction conditions allow a variety of arylboronic acids bearing Knoevenagel condensation. The mild reaction conditions allow a variety of arylboronic acids bearing electron-rich, electron-deficient, sterically demanding systems, amino and hydroxyl functionality to electron-rich, electron-deficient, sterically demanding systems, amino and hydroxyl functionality to afford the products in good yields, Scheme 20 [54]. afford the products in good yields, Scheme 20 [54].

Catalysts 2020, 10, 4 11 of 35 condensation. The mild reaction conditions allow a variety of arylboronic acids bearing electron-rich, electron-deficient,Catalysts 2020, 10, x FOR sterically PEER REVIEW demanding systems, amino and hydroxyl functionality to afford11 of the 35 productsCatalysts 2020 in, 10 good, x FOR yields, PEER SchemeREVIEW 20[54]. 11 of 35

Scheme 20. Suzuki coupling reaction of arylboronic acids with β-chloroalkyl/arylidene-chloroalkyl/arylidene malonates. Scheme 20. Suzuki coupling reaction of arylboronic acids with β-chloroalkyl/arylidene malonates. Zhu etet al.al. havehave introducedintroduced aromatic aromatic group group onto onto the the bromotriazole bromotriazole acyclonucleoside acyclonucleoside derivative derivative via Suzukivia SuzukiZhu coupling et al.coupling have reaction. introduced reaction. The 5-aryltriazole Thearomatic 5-aryltriazole group acyclonucleosides onto acyclonucleosides the bromotriazole featuring featuring numerous acyclonucleoside numerous aromatic derivative groupsaromatic on theviagroups triazoleSuzuki on ringthecoupling triazole were synthesizedreaction. ring were The using synthesized5-aryltriazole tetrakis(triphenylphosphine)palladium(0) using acyclonucleosides tetrakis(triphenylphosphine)palladium(0) featuring numerous in aqueous aromatic solution in undergroupsaqueous microwave on solution the triazole under irradiation. ringmicrowave were Remarkably, synthesized irradiation. the type Remausing of rkably, thetetrakis(triphenylphosphine)palladium(0) used the base type significantly of the used a ffbaseects significantly the reaction. in aqueous solution under microwave irradiation. Remarkably, the type of the used base significantly Goodaffects to the excellent reaction. yields Good were to achievedexcellent whenyields K were2CO3 achievedis employed when and K the2CO coupling3 is employed products and were the formedaffectscoupling the but products reaction. in favor were ofGood intra-molecular formed to excellent but in cyclization yieldsfavor wereof ofintra-molecular 5-bromoachieved triazole when cyclization derivatives.K2CO3 is ofemployed However,5-bromo andtriazole almost the coupling products were formed but in favor of intra-molecular cyclization of 5-bromo triazole aderivatives. quantitative However, yields of almost the coupling a quantitative products yields were achievedof the coupling when Liproducts2CO3 is utilized,were achieved suppressing when thederivatives.Li2CO cyclization3 is utilized, However, of thesuppressing starting almost material athe quantitative cyclization completely. yieldsof the The startingof the base coupling behaviormaterial products completely. was justified were The to achieved thebase formation behavior when ofLiwas2 aCO Lijustified3+ is-complex utilized, to the withsuppressing formation the side theof chain acycl Li of+ization-complex 5-bromotriazole of thewith starting the derivative, side material chain prohibiting completely.of 5-bromotriazole the The cyclization base derivative, behavior and + consolidatingwasprohibiting justified the to the cyclization the Suzuki formation coupling and ofconsolidating a reactions, Li -complex Scheme the withSuzuki 21 the[55 coupling ].side chain reactions, of 5-bromotriazole Scheme 21 [55]. derivative, prohibiting the cyclization and consolidating the Suzuki coupling reactions, Scheme 21 [55].

Scheme 21. Synthesis of 5-aryltriazole acyclonucl acyclonucleosideseosides via Suzuki coupling reactions. Scheme 21. Synthesis of 5-aryltriazole acyclonucleosides via Suzuki coupling reactions. Solvent-free conditions have been frequently revealed in syntheticsynthetic chemistry to reduce cost and amountSolvent-free ofof wastewaste generatedconditionsgenerated from fromhave side beenside reactions. reactions.frequently In In revealed non-solvent non-solvent in syntheti conditions, conditions,c chemistry the the conversions conversions to reduce of cost solidof solid and or liquidamountor liquid aryl of aryl waste halides halides generated with with various various from arylboronic si arylboronicde reactions. acids acid Ins to non-solventto cross-coupled cross-coupled conditions, products products the werewere conversions accomplishedaccomplished of solid in highor liquid yields,yields, aryl usingusing halides 1 1 mol% mol%with ofvarious of PEPPSI-iPr PEPPSI-iPr arylboronic (pyridine-enhanced (pyridine- acids toenhanced cross-coupled precatalyst precatalyst products preparation, preparation, were stabilization,accomplished stabilization, and in initiation)highand initiation) yields, and using threeand 1three equiv.mol% equiv. of KPEPPSI-iPr 2ofCO K32COat 1103 at(pyridine- ◦110C for °C 10forenhanced min 10 min under underprecatalyst microwave microwave preparation, irradiation irradiation stabilization, (Scheme (Scheme 22). Toand22). obtain Toinitiation) obtain full conversions, fulland conversions, three equiv. a good aof good homogenization K2CO homogenization3 at 110 °C of for all 10 solidof min all reactants solidunder reactants microwave in a mortar in a irradiationmortar is necessary is necessary (Scheme before charging22).before To chargingobtain them full into them conversions, the into microwave the microwave a good reaction homogenization reaction vial. This vial. rapid This of all rapid methodology solid methodology reactants works in aworks mortar smoothly smoothly is necessary with with aryl beforearyl bromides charging and them iodides, into the while microwave the presence reaction ofvial. electron-withdrawing This rapid methodology substituents works smoothly on the withless- arylreactive bromides aryl chlorides and iodides, is essentia whilel to the obtain presence full conversion of electron-withdrawing [56]. substituents on the less- reactive aryl chlorides is essential to obtain full conversion [56].

Catalysts 2020, 10, 4 12 of 35

bromides and iodides, while the presence of electron-withdrawing substituents on the less-reactive Catalysts 2020, 10, x FOR PEER REVIEW 12 of 35 Catalystsaryl chlorides 2020, 10, isx FOR essential PEER REVIEW to obtain full conversion [56]. 12 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 12 of 35

Scheme 22. Solvent-free PEPPSI-iPr-catalyzed Suzuki cross-coupling reactions. Scheme 22. Solvent-free PEPPSI-iPr-catalyzed Suzuki cross-coupling reactions. Scheme 22. Solvent-freeSolvent-free PEPPSI-iPr-catalyzedPEPPSI-iPr-catalyzed SuzukiSuzuki cross-couplingcross-coupling reactions.reactions. A range of aryl bromides bearing electron-donatingelectron-donating or electron-withdrawingelectron-withdrawing substituents such A range of aryl bromides bearing electron-donatinging oror electron-withdrawielectron-withdrawing substituents such as-Me, -NH 2,, -CO -CO2H,H, -NO -NO2, ,etc., etc., were were cross-coupled cross-coupled with with phenylboronic phenylboronic acid acid in in an open-vessel as-Me, -NH22, -CO22H, -NO2,2 etc., were cross-coupled with phenylboronic acid in an open-vessel as-Me, -NH2, -CO2H, -NO2, etc., were cross-coupled with phenylboronic acid in an open-vessel condition. One One mole mole scale scale of of reactants reactants was was used used with with 0.009 mol% of palladium stock solution and condition.condition. OneOne molemole scalescale ofof reactantsreactants waswas usedused withwith 0.0090.009 mol%mol% ofof palladiumpalladium stockstock solutionsolution andand Na2COCO3 inin aqueousaqueous ethanol ethanol under under microwave microwave irradiation, irradiation, affording affording the biphenyl the biphenyl products products in moderate in Na22CO33 in aqueous ethanol under microwave irradiation, affording the biphenyl products in Na2CO3 in aqueous ethanol under microwave irradiation, affording the biphenyl products in moderateto excellent to yields,excellent Scheme yields, 23 Scheme[57]. 23 [57]. moderate to excellent yields, Scheme 23 [57].

Scheme 23. Palladium-catalyzed Suzuki cross-coupling reactions. Scheme 23. Palladium-catalyzed Suzuki cross-coupling reactions. Scheme 23. Palladium-catalyzed Suzuki cross-coupling reactions. The use of recyclable solid catalyst under microwave irradiation condition condition offers offers a series of The use of recyclable solid catalyst under microwave irradiation condition offers a series of advantages, includingincluding the the direct direct recovery recovery of both of productboth product and catalyst. and catalyst. Hence, homogeneous Hence, homogeneous palladium advantages, including the direct recovery of both product and catalyst. Hence, homogeneous palladiumcatalysts or catalysts nanoparticles or nanoparticles were doped, were impregnated doped, impregnated [58], or immobilized [58], or immobilized [59] on various [59] supportson various to palladium catalysts or nanoparticles were doped, impregnated [58], or immobilized [59] on various supportsaddress the to address issues of the separation. issues of Solventlessseparation. microwave-assistedSolventless microwave-assisted Suzuki reaction Suzuki ofaryl reaction halides of aryl and supportssupports toto addressaddress thethe issuesissues ofof separation.separation. SolvenSolventlesstless microwave-assistedmicrowave-assisted SuzukiSuzuki reactionreaction ofof arylaryl halidesboronic and acids boronic on palladium-doped acids on palladium-doped KF/Al O was KF/Al first2O3 reported was first byreported Kabalka byet Kabalka al. [60]. et The al. [60]. reaction The halides and boronic acids on palladium-doped2 3 KF/Al2O3 was first reported by Kabalka et al. [60]. The halides and boronic acids on palladium-doped KF/Al2O3 was first reported by Kabalka et al. [60]. The reactionperformance performance was found was to found be insensitive to be insensitive to the substituents to the substituents on the boronic on the acidboronic and acid most and effi mostcient reactionreaction performanceperformance waswas foundfound toto bebe insensitiveinsensitive toto thethe substituentssubstituents onon thethe boronicboronic acidacid andand mostmost efficientwhen aryl when iodides aryl are iodides utilized are (Scheme utilized 24 (Scheme). Vinyl boronic24). Vinyl acid boronic or allylic acid halide or allylic were transformedhalide were efficientefficient whenwhen arylaryl iodidesiodides areare utilizedutilized (Scheme(Scheme 24).24). VinylVinyl boronicboronic acidacid oror allylicallylic halidehalide werewere transformedsmoothly to thesmoothly cross-coupled to the products,cross-coupled whereas produc no reactionsts, whereas were no observed reactions when were alkylboronic observed when acid, transformedtransformed smoothlysmoothly toto thethe cross-coupledcross-coupled producproducts,ts, whereaswhereas nono reactionsreactions werewere observedobserved whenwhen alkylboronicvinyl halide, oracid, alkyl vinyl halide halide, were involvedor alkyl ashalide reactants were [61 involved]. Although as thisreactants transformation [61]. Although represented this alkylboronic acid, vinyl halide, or alkyl halide were involved as reactants [61]. Although this transformationas a satisfactory represented work, the authors as a sa didtisfactory not mention work, the details authors on yield did andnot mention Pd leaching details after on subsequent yield and transformationtransformation representedrepresented asas aa sasatisfactorytisfactory work,work, thethe auauthorsthors diddid notnot mentionmention details on yield and Pdreuse leaching of the dopedafter subsequent catalyst. This reuse protocol of the encountering doped catalyst. two mainThis limitations,protocol encountering the first one two is that main the Pd leaching after subsequent reuse of the doped catalyst.catalyst. ThisThis protocolprotocol encounteringencountering twotwo mainmain limitations,cross-coupling the first does one not is proceed that the withcross-coupling aryl chloride, does and not theproceed second with limitation aryl chloride, is that and the the KF second/Al2O3 limitations,limitations, thethe firstfirst oneone isis thatthat thethe cross-couplingcross-coupling doesdoes notnot proceedproceed withwith arylaryl chloride,chloride, andand thethe secondsecond limitationsample needs is that to the beexposed KF/Al2O to3 sample ambient needs air for to be at leastexposed two to weeks ambient prior air to for use at andleast in two order weeks to obtain prior limitation is that the KF/Al2O3 sample needs to be exposed to ambient air for at least two weeks prior limitation is that the KF/Al2O3 sample needs to be exposed to ambient air for at least two weeks prior togood use yields.and in order This couldto obtain be rationalizedgood yields. thatThis thecould presence be rationalized of high levelthat the of moisturepresence of accelerates high level the of toto useuse andand inin orderorder toto obtainobtain goodgood yields.yields. ThisThis couldcould be rationalized that the presence of high level of moisturecross-coupling accelerates reactions. the cross-coupling reactions. moisture accelerates the cross-coupling reactions.

Scheme 24. Pd-doped KF/Al KF/Al2OO33 catalyzedcatalyzed Suzuki Suzuki coupling coupling reactions. reactions. Scheme 24. Pd-doped KF/Al2O3 catalyzed Suzuki coupling reactions. Scheme 24. Pd-doped KF/Al2O3 catalyzed Suzuki coupling reactions. The use of palladium on carbon (Pd/C) is considered as an attractive supporting material in The use of palladium on carbon (Pd/C) is considered as an attractive supporting material in microwave-assistedThe use of palladium organic on synthe carbonsis, (Pd/C) as carbon-support is considered asitself an attractivestrongly supportingabsorbs most material of the in microwave-assisted organic synthesis, as carbon-support itself strongly absorbs most of the microwavemicrowave-assisted energy [62]. organic Arvely synthe and Leadbeatersis, as carbon-support have studied cross-coupling itself strongly reaction absorbs of arylmost chlorides of the microwave energy [62]. Arvely and Leadbeater have studied cross-coupling reaction of aryl chlorides

Catalysts 2020, 10, 4 13 of 35

The use of palladium on carbon (Pd/C) is considered as an attractive supporting material Catalysts 2020, 10, x FOR PEER REVIEW 13 of 35 inCatalysts microwave-assisted 2020, 10, x FOR PEER organic REVIEW synthesis, as carbon-support itself strongly absorbs most of13 of the 35 microwave energy [62]. Arvely and Leadbeater have studied cross-coupling reaction of aryl chlorides with phenylboronic acid in water as a solvent, using Pd/C and under simultaneous microwave withwith phenylboronicphenylboronic acidacid inin waterwater asas aa solvent,solvent, usingusing PdPd/C/C andand underunder simultaneoussimultaneous microwavemicrowave heating/cooling system. The microwave has been noticed to prolong the lifetime of the aryl chloride heatingheating/cooling/cooling system.system. The microwave has beenbeen noticednoticed toto prolongprolong thethe lifetimelifetime ofof thethe arylaryl chloridechloride substrates (bearing electron-neutral or electron-donating substituents) and to yield the desired biaryl substratessubstrates (bearing(bearing electron-neutralelectron-neutral oror electron-donatingelectron-donating substituents)substituents) andand toto yieldyield thethe desireddesired biarylbiaryl accompanied with unreacted aryl chlorides [63]. accompaniedaccompanied withwith unreactedunreacted arylaryl chlorideschlorides [[63].63]. Ley and coworkers have described the application of palladium encapsulated catalyst LeyLey andand coworkers coworkers have have described described the application the applic of palladiumation of encapsulatedpalladium encapsulated catalyst (PdEnCat catalystTM) (PdEnCatTM) in Suzuki cross-coupling reactions in both conventional reflux and microwaves in(PdEnCat Suzuki cross-couplingTM) in Suzuki reactionscross-coupling in both reactions conventional in refluxboth conventional and microwaves reflux irradiation and microwaves conditions. irradiation conditions. The EnCat has displayed significant catalytic performance and offered a facile Theirradiation EnCathas conditions. displayed The significant EnCat has catalytic displayed performance significant and catalytic offered performance a facile workup and procedure. offered a facile The workup procedure. The heterogeneous palladium catalyst is simply recovered by filtration, through heterogeneousworkup procedure. palladium The heterogeneous catalyst is simply palladium recovered catalyst by is filtration, simply recovered through a by fritted filtration, sulfonic through acid a fritted sulfonic acid functionalized silica cartridge, and reused several times with less than 1% of functionalizeda fritted sulfonic silica acid cartridge, functionalized and reused silica several cartridge, times and with reused less than several 1% oftimes palladium with less leaching than 1% from of palladium leaching from the content of the encapsulated catalyst, detected by inductively coupled thepalladium content leaching of the encapsulated from the content catalyst, of the detected encaps byulated inductively catalyst, coupled detected plasma. by inductively With variety coupled of plasma. With variety of boronic acids and aryl halides, the cross-coupling reactions were boronicplasma. acidsWith and variety aryl halides, of boronic the cross-coupling acids and aryl reactions halides, were the demonstrated cross-coupling in high reactions yields usingwere demonstrated in high yields using EnCat and tetrabutylammonium acetate (n-Bu4NOAc) in EnCatdemonstrated and tetrabutylammonium in high yields using acetate EnCat (n-Bu andNOAc) tetrabutylammonium in acetonitrile or ethanol acetate for ( 15n-Bu min4NOAc) at 140 inC acetonitrile or ethanol for 15 min at 140 °C unde4r microwave condition (Scheme 25). The methodology◦ underacetonitrile microwave or ethanol condition for 15 min (Scheme at 140 25 °C). unde Ther methodology microwave condition has been (Scheme used for 25). the The preparation methodology of a has been used for the preparation of a library of biaryl derivatives through cross-coupling reaction libraryhas been of biarylused for derivatives the preparation through of cross-coupling a library of biaryl reaction derivatives between through aryl bromides cross-coupling and boronic reaction acids, between aryl bromides and boronic acids, whereas a single example with aryl chloride was whereasbetween aaryl single bromides example and with boronic aryl chloride acids, waswhereas successfully a single carried example out underwith aryl extended chloride reaction was successfully carried out under extended reaction time [64]. timesuccessfully [64]. carried out under extended reaction time [64].

Scheme 25. PdEnCatTM assisted Suzuki cross-coupling reactions of boronic acids and aryl halides. SchemeScheme 25.25. PdEnCatPdEnCatTM assistedassisted Suzuki cross-coupling reactions of boronic acids and aryl halides. In many cases, the use of ionic liquids as an alternative to conventional polar solvents is InIn manymany cases,cases, thethe useuse ofof ionicionic liquidsliquids asas anan alternativealternative toto conventionalconventional polarpolar solventssolvents isis advantageous in term of shorter reaction time, complete conversion of staring materials, facile product advantageousadvantageous inin termterm ofof shortershorter reactionreaction time,time, cocompletemplete conversionconversion ofof ststaringaring materials,materials, facilefacile separation, and high yields [65]. A number of guanidinium ionic liquids (GILs) have been reported productproduct separation,separation, andand highhigh yieldsyields [65].[65]. AA numbernumber ofof guanidiniumguanidinium ionicionic liquidsliquids (GILs)(GILs) havehave beenbeen to exhibit high catalytic activities and more stabilities of ligand-free metal catalyst under aqueous reportedreported toto exhibitexhibit highhigh catalyticcatalytic activitiesactivities andand momorere stabilitiesstabilities ofof ligand-freeligand-free metalmetal catalystcatalyst underunder aqueousconditions. conditions. A catalyst A systemcatalyst generated system generated in situ from in situ Pd(OAc) from2 Pd(OAc), base (K2,CO base3 or (K NBu2CO43 OH)or NBu and4OH) GIL aqueous conditions. A catalyst system generated in situ from Pd(OAc)2, base (K2CO3 or NBu4OH) in aqueous ethanol was reported to synthesize biaryls in moderate to excellent yields via Suzuki andand GILGIL inin aqueousaqueous ethanolethanol waswas reportedreported toto synthesisynthesizeze biarylsbiaryls inin moderatemoderate toto excellentexcellent yieldsyields viavia cross-coupling of aryl halides with aryl phenylboronic acid under focused microwave irradiating for SuzukiSuzuki cross-couplingcross-coupling ofof arylaryl halideshalides withwith arylaryl phenylboronicphenylboronic acidacid underunder focusedfocused microwavemicrowave 10–40 min in an inert atmosphere (Scheme 26). During the reaction, well-dispersed Pd(0) species irradiatingirradiating forfor 10–4010–40 minmin inin anan inertinert atmosphereatmosphere (Scheme(Scheme 26).26). DuringDuring thethe reaction,reaction, well-dispersedwell-dispersed is generated in nano-scale and stabilized by guanidinium salt affording Pd micelle/GIL, which is Pd(0)Pd(0) speciesspecies isis generatedgenerated inin nano-scalenano-scale andand stabilizedstabilized byby guanidiniumguanidinium saltsalt affordingaffording PdPd micelle/GIL,micelle/GIL, responsible for enhancing the activity. Notably, GILs bearing long alkyl chains have demonstrated whichwhich isis responsibleresponsible forfor enhancingenhancing thethe activity.activity. Notably,Notably, GILsGILs bearingbearing longlong alkylalkyl chainschains havehave superior performance in the catalytic reaction than those with short alkyl substituents [66]. demonstrateddemonstrated superiorsuperior performanceperformance inin thethe catalyticcatalytic reactionreaction thanthan thosethose withwith shortshort alkylalkyl substituentssubstituents [66].[66].

Scheme 26. Palladium-catalyzedPalladium-catalyzed cross-coupling reacti reactionsons in guanidinium ionic liquids (GIL). Scheme 26. Palladium-catalyzed cross-coupling reactions in guanidinium ionic liquids (GIL).

SimilarSimilar toto thethe abovementionedabovementioned protocol,protocol, glucosglucosee waswas usedused inin isopropanolisopropanol toto stabilizestabilize thethe generatedgenerated Pd(0)Pd(0) speciesspecies insteadinstead ofof GILGIL forfor Suzuki-MSuzuki-Miyauraiyaura cross-couplingcross-coupling reactions,reactions, butbut withwith limitedlimited examplesexamples ofof conversionconversion ofof arylaryl iodiiodidesdes withwith phenylphenyl boronicboronic acidacid [67].[67].

Catalysts 2020, 10, 4 14 of 35

Similar to the abovementioned protocol, glucose was used in isopropanol to stabilize the generated Pd(0) species instead of GIL for Suzuki-Miyaura cross-coupling reactions, but with limited examples Catalysts 2020, 10, x FOR PEER REVIEW 14 of 35 Catalystsof conversion 2020, 10, ofx FOR aryl PEER iodides REVIEW with phenyl boronic acid [67]. 14 of 35 Recently, coordinated Pd(II) complex to 2,2 -dipyridylamine was immobilized on acidic resin Recently, coordinated Pd(II) complex to 2,20′′-dipyridylamine-dipyridylamine waswas immobilizedimmobilized onon acidicacidic resinresin polymer from gum resin, and employed in Suzuki-Miyaura coupling reactions. The Pd-loaded polymer polymer from gum resin, and employed in Suzuki-Miyaura coupling reactions. The Pd-loaded was synthesized via nucleophilic substitution of 2-chloropyridine by 2-pyridylamine, affording polymer was synthesized via nucleophilic substitutiontion ofof 2-chloropyridi2-chloropyridine by 2-pyridylamine, 2,2 -dipyridylamine, which was reacted with acid chloride-functionalized polymer, and eventually affording0 2,2′′-dipyridylamine,-dipyridylamine, whichwhich waswas reactedreacted withwith acidacid chloride-functionalizedchloride-functionalized polymer,polymer, andand coordinated with Pd(OAc)2 to provide the precatalyst. This heterogenized precatalyst has displayed eventually coordinated with Pd(OAc)22 toto provideprovide thethe precatalyst.precatalyst. ThThisis heterogenizedheterogenized precatalystprecatalyst hashas high activity of coupling aryl halides and arylboronic acids under microwave irradiation. The presence displayed high activity of coupling aryl halides and arylboronic acids under microwave irradiation. of equimolar concentration of Na2CO3 is essential to afford moderate to excellent yields of the The presence of equimolar concentration of Na22CO33 isis essentialessential toto affordafford moderatemoderate toto excellentexcellent yieldsyields corresponding biaryls in aqueous ethanol at 120 C for 5 min (Scheme 27). The recyclability of the of the corresponding biaryls in aqueous ethanol at◦ 120 °C for 5 min (Scheme 27). The recyclability of catalyst exhibited very good yields over three cycles (99% to 93%). However, the yield dropped to 53% thethe catalystcatalyst exhibitedexhibited veryvery goodgood yieldsyields overover thrthree cycles (99% to 93%). However, the yield dropped in the sixth cycle [68]. toto 53%53% inin thethe sixthsixth cyclecycle [68].[68].

Scheme 27. Suzuki cross-coupling reactions through immobilize palladium-catalyst. Scheme 27. Suzuki cross-coupling reactions through immobilize palladium-catalyst. Natural halloysite nanotubes (HNT), a double-layered hollow cylinder of aluminosilicate mineral Natural halloysite nanotubes (HNT), a double-layered hollow cylinder of aluminosilicate structure, have been recently employed to immobilize palladium particles. The external surface mineral structure, have been recently employed toto immobilizeimmobilize palladiumpalladium particles.particles. TheThe externalexternal of the nanotubes was first embedded with 3-mercaptopropyl trimethoxysilane, followed by the surface of the nanotubes was first embedded with 3-mercaptopropyl trimethoxysilane, followed by reaction with vinylimidazolium ionic liquids and then treated with palladium particles [69]. The thethe reactionreaction withwith vinylimidazoliumvinylimidazolium ionicionic liquidsliquids andand thenthen treatedtreated withwith palladiumpalladium particlesparticles [69].[69]. TheThe immobilized pd-precatalyst (HNT-Pd) was administered in in 0.1 mol% or 1 mol% for Suzuki reaction immobilizedimmobilized pd-precatalystpd-precatalyst (HNT-Pd)(HNT-Pd) waswas administadministered in in 0.1 mol% or 1 mol% for Suzuki under microwave irradiation. The reaction of several types of aryl bromides and aryl iodides with reaction under microwave irradiation. The reaction of several types of aryl bromides and aryl iodides phenylboronic acid yielded biphenyl compounds in high yield when the reactions were performed in with phenylboronic acid yielded biphenyl compounds in high yield when the reactions were the presence of K2CO3 as base in water-ethanol at 120 ◦C for 10 min. However, the reaction displayed a performed in the presence of K22CO33 asas basebase inin water-ethanolwater-ethanol atat 120120 °C°C forfor 1010 min.min. However,However, thethe very less reactivity with aryl chlorides, its reactivity could be increased by either extending the reaction reaction displayed a very less reactivity with aryl chlorides,lorides, itsits reactivityreactivity couldcould bebe increasedincreased byby eithereither time or increasing the reaction temperature, Scheme 28[70]. extending the reaction time or increasing thethe reactionreaction temperature,temperature, SchemeScheme 2828 [70].[70].

Scheme 28. Suzuki cross-coupling reactions through immobilize palladium-catalyst. Scheme 28. Suzuki cross-coupling reactions through immobilize palladium-catalyst. The heterogeneous catalyst system demonstrated a good recyclability between phenylboronic acid andThe 3-bromoanisole.heterogeneous catalyst The catalyst system was demonstrated recovered after aa goodgood each recyclability runrecyclability by centrifugation, betweenbetween phenylboronicphenylboronic washed, dried, acidand reusedand 3-bromoanisole. again with freshly The catalyst added solvent, was recovered starting after materials, each run and by base. centrifugation, A conversion washed, of 90% dried, in the and reused again with freshly added solvent, starting materials, and base. A conversion of 90% in the cycle 1 was dropped to 88% in cycle 5, revealing a marginal lose in the performance of immobilized palladium-catalyst. In a similar manner, palladium supported on halloysite-triazolium salt was synthesized and reported recently for Suzuki cross-coupling reactions [71].

Catalysts 2020, 10, 4 15 of 35 cycle 1 was dropped to 88% in cycle 5, revealing a marginal lose in the performance of immobilized palladium-catalyst.Catalysts 2020, 10, x FOR PEER In a REVIEW similar manner, palladium supported on halloysite-triazolium salt15 wasof 35 synthesized and reported recently for Suzuki cross-coupling reactions [71]. The focus on employing biomaterial matrices to immobilize homogeneous palladium complexes received much attentionattention inin termterm ofof environmentallyenvironmentally friendlyfriendly catalysts.catalysts. For instance, chitosan is extensively studied as as a a catalyst catalyst support support material material fo forr having having high high affinity affinity fo forr metal metal ions. ions. Baran Baran et al. et al.synthesized synthesized chitosan chitosan supported supported Pd Pdcatalyst catalyst and and ex examinedamined its its catalytic catalytic activity activity in solvent-freesolvent-free microwave-assisted SuzukiSuzuki reactions. reactions. Briefly, Briefly, chitosan chitosan was was condensed condensed at reflux at reflux with mono-iminewith mono-imine Schiff Schiff base ligand and then with monochloroacetic acid at 60 °C for a week. The produced base ligand and then with monochloroacetic acid at 60 ◦C for a week. The produced macromolecule was macromolecule was further reacted with Na2PdCl4 in aqueous media, giving rise to yellow-green further reacted with Na2PdCl4 in aqueous media, giving rise to yellow-green biomaterial supported biomaterial supported Pd catalyst. This precatalyst was used in 0.01 mol% along with potassium Pd catalyst. This precatalyst was used in 0.01 mol% along with potassium carbonate at 50 ◦C for 4 mincarbonate in cross-coupling at 50 °C for reactions 4 min betweenin cross-coupling different aryl reactions halides withbetween phenylboronic different aryl acids. halides Depending with onphenylboronic the substituents acids. and Depending type of halides on the used, substitu biarylsents were and considerably type of halides formed used, in di ffbiarylserent yieldswere andconsiderably as usual, formed aryl chloride in different displayed yields a and poor as conversion usual, aryl withchloride phenylboronic displayed a acidpoor (Scheme conversion 29)[ with72]. Similarly,phenylboronic chitosan- acidUlva (Scheme(green alga)29) [72]. [73], Similarly, sporopollenin chitosan- microcapsuleUlva (green [74], andalga) chitosan [73], sporopollenin/cellulose [75] compositesmicrocapsule were [74], employed and chitosan/cellulose recently as a palladium[75] composites catalyst were support employed in Suzuki recently coupling as a palladium reactions undercatalyst microwave support in irradiation Suzuki coupling conditions. reactions under microwave irradiation conditions.

Scheme 29. Suzuki coupling reactions via chit chitosan-basedosan-based palladium catalyst.

A variety of furocoumarin-biaryl derivatives was synthesized under conventional heating and A variety of furocoumarin-biaryl derivatives was synthesized under conventional heating and microwave irradiation methods using water as solvent via Suzuki coupling reaction for evaluation microwave irradiation methods using water as solvent via Suzuki coupling reaction for evaluation of antimicrobial activity. As low conversion of starting materials was observed, the optimized of antimicrobial activity. As low conversion of starting materials was observed, the optimized reaction conditions include 10 mol% of Pd(PPh3)4 with Na2CO3 as a base in aqueous phase under reaction conditions include 10 mol% of Pd(PPh3)4 with Na2CO3 as a base in aqueous phase under microwave heating. Scheme 30 illustrates the coupling reactions of bromo-furocoumarin derivatives microwave heating. Scheme 30 illustrates the coupling reactions of bromo-furocoumarin derivatives with different arylboronic acids, affording the target products in high yields. Interestingly, part of with different arylboronic acids, affording the target products in high yields. Interestingly, part of the synthesized compounds demonstrated moderate to high antibacterial and antifungal activities the synthesized compounds demonstrated moderate to high antibacterial and antifungal activities compared to standard drugs Gatifloxacin and Clotrimazole, respectively [76]. compared to standard drugs Gatifloxacin and Clotrimazole, respectively [76].

Scheme 30. Synthesis of furocoumarin-biaryl derivatives via cross-coupling reactions.

Catalysts 2020, 10, x FOR PEER REVIEW 15 of 35

The focus on employing biomaterial matrices to immobilize homogeneous palladium complexes received much attention in term of environmentally friendly catalysts. For instance, chitosan is extensively studied as a catalyst support material for having high affinity for metal ions. Baran et al. synthesized chitosan supported Pd catalyst and examined its catalytic activity in solvent-free microwave-assisted Suzuki reactions. Briefly, chitosan was condensed at reflux with mono-imine Schiff base ligand and then with monochloroacetic acid at 60 °C for a week. The produced macromolecule was further reacted with Na2PdCl4 in aqueous media, giving rise to yellow-green biomaterial supported Pd catalyst. This precatalyst was used in 0.01 mol% along with potassium carbonate at 50 °C for 4 min in cross-coupling reactions between different aryl halides with phenylboronic acids. Depending on the substituents and type of halides used, biaryls were considerably formed in different yields and as usual, aryl chloride displayed a poor conversion with phenylboronic acid (Scheme 29) [72]. Similarly, chitosan-Ulva (green alga) [73], sporopollenin microcapsule [74], and chitosan/cellulose [75] composites were employed recently as a palladium catalyst support in Suzuki coupling reactions under microwave irradiation conditions.

Scheme 29. Suzuki coupling reactions via chitosan-based palladium catalyst.

A variety of furocoumarin-biaryl derivatives was synthesized under conventional heating and microwave irradiation methods using water as solvent via Suzuki coupling reaction for evaluation of antimicrobial activity. As low conversion of starting materials was observed, the optimized reaction conditions include 10 mol% of Pd(PPh3)4 with Na2CO3 as a base in aqueous phase under microwave heating. Scheme 30 illustrates the coupling reactions of bromo-furocoumarin derivatives with different arylboronic acids, affording the target products in high yields. Interestingly, part of

Catalyststhe synthesized2020, 10, 4 compounds demonstrated moderate to high antibacterial and antifungal activities16 of 35 compared to standard drugs Gatifloxacin and Clotrimazole, respectively [76].

Scheme 30. Synthesis of furocoumarin-biaryl derivatives via cross-coupling reactions. Catalysts 2020, Scheme10, x FOR 30. PEER Synthesis REVIEW of furocoumarin-biaryl derivatives via cross-coupling reactions. 16 of 35

Palladacyclic complexes [77] have been described lately in a number of cross-coupling reactions. Palladacyclic complexes [77] have been described lately in a number of cross-coupling reactions. The Suzuki-Miyaura reaction of chloro uracil analogue with potassium aryltrifluoroborates (ArBF3K), wasThe Suzuki-Miyaura recently reported reaction to be mediated of chloro in uracil water. analogue Good to with excellent potassium yields aryltrifluoroborates of arylated uracil derivatives (ArBF3K), werewas recently obtained reported under optimized to be mediated reaction in conditionswater. Good when to excellent 5 mol% yields of Xphos-Pd-G2 of arylated (second uracil derivatives generation were obtained under optimized reaction conditions when 5 mol% of Xphos-Pd-G2 (second XPhos precatalyst) was employed with three equiv. of cesium carbonate at 100 ◦C for an hour under generation XPhos precatalyst) was employed with three equiv. of cesium carbonate at 100 °C for an microwave irradiation (Scheme 31). The ArBF3K substrates have demonstrated excellent conversion hour under microwave irradiation (Scheme 31). The ArBF3K substrates have demonstrated excellent with electron rich uracil analogue to products rather than other boron sources, such as ArB(OH)2 conversion with electron rich uracil analogue to products rather than other boron sources, such as and ArB(OR)2. This is probably due to the presence of the boronic acid function, which might promoteArB(OH) side2 and reactions ArB(OR) such2. This as protodeboronation, is probably due to oxidative the presence homocoupling, of the boronic and/ oracid oxidative function, insertion. which Thus,might excesspromote use side of boronicreactions acid such is as needed protodeboron to directation, the reaction oxidative toward homocoupling, completion and/or [78]. Likewise,oxidative insertion. Thus, excess use of boronic acid is needed to direct the reaction toward completion [78]. a water-soluble Pd-imidate complex has been utilized for the Suzuki-Miyaura cross-coupling of Likewise, a water-soluble Pd-imidate complex has been utilized for the Suzuki-Miyaura cross- four different nucleosides with (hetero)arylboronic acids under microwave-assisted protocol [79]. coupling of four different nucleosides with (hetero)arylboronic acids under microwave-assisted Sodium tetraphenylborate was efficiently employed instead of ArB(OH)2, ArB(OR)2, or ArBF3K in the protocol [79]. Sodium tetraphenylborate was efficiently employed instead of ArB(OH)2, ArB(OR)2, or cross-coupling reaction with four-fold of aryl bromides in the presence of different palladium catalysts ArBF3K in the cross-coupling reaction with four-fold of aryl bromides in the presence of different under microwave heating, yielding a variety of biaryl derivatives [80,81]. palladium catalysts under microwave heating, yielding a variety of biaryl derivatives [80,81].

Scheme 31. Xphos-Pd-G2 catalyzed Suzuki-Miyaura cross-coupling reactions. Scheme 31. Xphos-Pd-G2 catalyzed Suzuki-Miyaura cross-coupling reactions. Lee et al. have examined the Suzuki coupling reactions of a broad selection of Lee et al. have examined the Suzuki coupling reactions of a broad selection of isomeric isomeric bromoimidazo[1,2-a]pyridines and substituted arylboronic acids. A range of arylated bromoimidazo[1,2-a]pyridines and substituted arylboronic acids. A range of arylated imidazo[1,2- imidazo[1,2-a]pyridines were synthesized for biological studies under microwave irradiation conditions a]pyridines were synthesized for biological studies under microwave irradiation conditions using 1 using 1 mol% of Pd(PPh3)4 and an equimolar concentration of Cs2CO3 in DMF at 130 ◦C for 40 min mol% of Pd(PPh3)4 and an equimolar concentration of Cs2CO3 in DMF at 130 °C for 40 min (Scheme (Scheme 32). In general, the presence of 2-substitutent on 3-bromoimidazo[1,2-a]pyridine did not 32). In general, the presence of 2-substitutent on 3-bromoimidazo[1,2-a]pyridine did not display display major steric effects with substituted arylboronic acids. Additionally, electron-donating or major steric effects with substituted arylboronic acids. Additionally, electron-donating or - -withdrawing group on arylboronic acids did not affect the reaction outcomes, the resulting products withdrawing group on arylboronic acids did not affect the reaction outcomes, the resulting products were achieved in moderate to high yields [82]. were achieved in moderate to high yields [82].

Scheme 32. Suzuki coupling reactions of bromoimidazo[1,2-a]pyridines and arylboronic acids.

A catalyst system designed and synthesized lately by dispersion of bimetallic Pd(II)-NiO nanoparticles over microporous zeolite-NaY was described for the Suzuki-Miyaura cross-coupling reaction of aryl chlorides with arylboronic acid derivatives. In aqueous ethanol and in the presence of base (K2CO3), a 30 mg of loaded catalyst (Pd = 2.62 mg/100 mg, ICP) was considered to be the most suitable amount to selectively produce the biaryls using multimode microwave reactor at 30 °C with 80% power (680 W) (Scheme 33). The outcome of microwave irradiation for this reaction was compared against conventional heating, revealing that the yields of the reactions was almost double

Catalysts 2020, 10, x FOR PEER REVIEW 16 of 35

Palladacyclic complexes [77] have been described lately in a number of cross-coupling reactions. The Suzuki-Miyaura reaction of chloro uracil analogue with potassium aryltrifluoroborates (ArBF3K), was recently reported to be mediated in water. Good to excellent yields of arylated uracil derivatives were obtained under optimized reaction conditions when 5 mol% of Xphos-Pd-G2 (second generation XPhos precatalyst) was employed with three equiv. of cesium carbonate at 100 °C for an hour under microwave irradiation (Scheme 31). The ArBF3K substrates have demonstrated excellent conversion with electron rich uracil analogue to products rather than other boron sources, such as ArB(OH)2 and ArB(OR)2. This is probably due to the presence of the boronic acid function, which might promote side reactions such as protodeboronation, oxidative homocoupling, and/or oxidative insertion. Thus, excess use of boronic acid is needed to direct the reaction toward completion [78]. Likewise, a water-soluble Pd-imidate complex has been utilized for the Suzuki-Miyaura cross- coupling of four different nucleosides with (hetero)arylboronic acids under microwave-assisted protocol [79]. Sodium tetraphenylborate was efficiently employed instead of ArB(OH)2, ArB(OR)2, or ArBF3K in the cross-coupling reaction with four-fold of aryl bromides in the presence of different palladium catalysts under microwave heating, yielding a variety of biaryl derivatives [80,81].

Scheme 31. Xphos-Pd-G2 catalyzed Suzuki-Miyaura cross-coupling reactions.

Lee et al. have examined the Suzuki coupling reactions of a broad selection of isomeric bromoimidazo[1,2-a]pyridines and substituted arylboronic acids. A range of arylated imidazo[1,2- a]pyridines were synthesized for biological studies under microwave irradiation conditions using 1 mol% of Pd(PPh3)4 and an equimolar concentration of Cs2CO3 in DMF at 130 °C for 40 min (Scheme 32). In general, the presence of 2-substitutent on 3-bromoimidazo[1,2-a]pyridine did not display major steric effects with substituted arylboronic acids. Additionally, electron-donating or - Catalystswithdrawing2020, 10 ,group 4 on arylboronic acids did not affect the reaction outcomes, the resulting products17 of 35 were achieved in moderate to high yields [82].

Scheme 32. Suzuki coupling reactions of bromoimidazo[1,2-a]pyridinesbromoimidazo[1,2-a]pyridines and arylboronic acids.acids.

A catalyst system designeddesigned and synthesizedsynthesized latelylately by dispersiondispersion ofof bimetallicbimetallic Pd(II)-NiOPd(II)-NiO nanoparticles over microporous zeolite-NaY was described for thethe Suzuki-MiyauraSuzuki-Miyaura cross-couplingcross-coupling reaction of arylaryl chlorideschlorides withwith arylboronicarylboronic acidacid derivatives.derivatives. In aqueous ethanol and in the presencepresence of base (K (K22COCO3),3), a a30 30 mg mg of of loaded loaded catalyst catalyst (Pd (Pd = 2.62= 2.62 mg/1 mg00/ 100mg, mg,ICP) ICP) was wasconsidered considered to be tothe be most the mostsuitable suitable amount amount to selectively to selectively produce produce the biaryls the biaryls using using multimode multimode microwave microwave reactor reactor at 30 at°C 30 with◦C with80% 80%power power (680 (680W) W)(Scheme (Scheme 33). 33 The). The outcome outcome of ofmicrowave microwave irradiation irradiation for for this this reaction was comparedCatalysts 2020 against, 10, x FOR conventional PEER REVIEW heating, revealing thatthat the yields of the reactions was almost double17 of 35 under irradiation conditions for 20 min and the biaryl products obtained in high yields. The Pd-NiO under irradiation conditions for 20 min and the biaryl products obtained in high yields. The Pd-NiO species were predicted as “true catalyst” by cyclic voltammetry study. Whereas, NiO represents as species were predicted as “true catalyst” by cyclic voltammetry study. Whereas, NiO represents as an active surface for redox reaction to in situ generated Pd(0), which represents the active species for an active surface for redox reaction to in situ generated Pd(0), which represents the active species for C-Cl bond activation step [83]. Though the reaction displayed high conversions of aryl chlorides, the C‒Cl bond activation step [83]. Though the reaction displayed high conversions of aryl chlorides, the generality of the reaction was demonstrated with a number of substrates. generality of the reaction was demonstrated with a number of substrates.

Scheme 33. Scheme 33. Suzuki coupling reactions via Pd-NiO nanocatalyst. In a same manner, Pd/CuO was described more recently for the cross-coupling of aryl boronic In a same manner, Pd/CuO was described more recently for the cross-coupling of aryl boronic acids with aryl halides (I, Br, and Cl) under irradiation conditions in aqueous ethanol, but with limited acids with aryl halides (I, Br, and Cl) under irradiation conditions in aqueous ethanol, but with substrate scope [84]. Lately, water-soluble benzimidazole-Pd complex is described for Suzuki reaction limited substrate scope [84]. Lately, water-soluble benzimidazole-Pd complex is described for Suzuki of less-reactive aryl chlorides. The catalyst was synthesized via reaction of bis-benzimidazolyl-pyridine reaction of less-reactive aryl chlorides. The catalyst was synthesized via reaction of bis- with 1,3-propanesulfonate, yielding the desired ligand which was subsequently coordinated with benzimidazolyl-pyridine with 1,3-propanesulfonate, yielding the desired ligand which was potassium tetrachloropalladate(II) (K2PdCl4) to give a yellow solid of Pd(II) complex. Aqueous subsequently coordinated with potassium tetrachloropalladate(II) (K2PdCl4) to give a yellow solid of solution of this catalyst was used in 0.1 mol% with K2CO3 in the coupling reaction between Pd(II) complex. Aqueous solution of this catalyst was used in 0.1 mol% with K2CO3 in the coupling chlorobenzenes and arylboronic acids under microwave irradiation for 15 min. Remarkably, the reaction between chlorobenzenes and arylboronic acids under microwave irradiation for 15 min. catalyst by itself showed moderate activity and increased by adding tetrabutylammonium bromide Remarkably, the catalyst by itself showed moderate activity and increased by adding (TBAB) or 1-butyl-3-methylimidazolium hexafluoro-phosphate (Bmim-PF ) as an additive to replace tetrabutylammonium bromide (TBAB) or 1-butyl-3-methylimidazolium6 hexafluoro-phosphate the ionic potassium and stabilize the active Pd(0) species. Thus, electron rich aryl chlorides and (Bmim-PF6) as an additive to replace the ionic potassium and stabilize the active Pd(0) species. Thus, sterically hindered substrates were smoothly transformed to biaryls in high yields, Scheme 34[ 85]. electron rich aryl chlorides and sterically hindered substrates were smoothly transformed to biaryls Furthermore, a few number of palladium(II) complexes bearing amine-based ligands was reported as in high yields, Scheme 34 [85]. Furthermore, a few number of palladium(II) complexes bearing amine- a homogeneous precatalyst for Suzuki-Miyaura cross-coupling reactions of boronic acids with mainly based ligands was reported as a homogeneous precatalyst for Suzuki-Miyaura cross-coupling aryl bromides under microwave irradiation conditions [86,87]. reactions of boronic acids with mainly aryl bromides under microwave irradiation conditions [86,87].

Scheme 34. Palladium-catalyzed Suzuki cross-coupling reactions.

Quite recently, an air and moisture stable starch-based Pd(II) catalyst was synthesized from functionalization of starch surface with 3-aminopropyl triethoxysilane. The formation of Schiff base was accomplished with 2-thiophenecarboxaldehyde in ethanol and the resulting ligand was eventually stirred with Na2PdCl4 in water. The Pd(II) catalyst was employed in Suzuki coupling reactions of aryl halides (Cl, Br, and I) with phenyl boronic acid in the presence of potassium carbonate and under microwave irradiation conditions. Moderate to excellent yields of biphenyls were obtained in short reaction time at 50 °C and high TONs and TOFs were achieved with very low catalyst loading. Moreover, the reusability of the catalyst was explored in 10 consecutive cycles, in which biphenyl yield decreased from 99 to 80%, with very low leaching of palladium ion (~1%) per catalytic cycle (Scheme 35) [88]. It is worth mentioning that a good reaction yield was achieved starting from aryl chlorides, which often gives very low yield and in some cases resulted in no

Catalysts 2020, 10, x FOR PEER REVIEW 17 of 35 under irradiation conditions for 20 min and the biaryl products obtained in high yields. The Pd-NiO species were predicted as “true catalyst” by cyclic voltammetry study. Whereas, NiO represents as an active surface for redox reaction to in situ generated Pd(0), which represents the active species for C‒Cl bond activation step [83]. Though the reaction displayed high conversions of aryl chlorides, the generality of the reaction was demonstrated with a number of substrates.

Scheme 33. Suzuki coupling reactions via Pd-NiO nanocatalyst.

In a same manner, Pd/CuO was described more recently for the cross-coupling of aryl boronic acids with aryl halides (I, Br, and Cl) under irradiation conditions in aqueous ethanol, but with limited substrate scope [84]. Lately, water-soluble benzimidazole-Pd complex is described for Suzuki reaction of less-reactive aryl chlorides. The catalyst was synthesized via reaction of bis- benzimidazolyl-pyridine with 1,3-propanesulfonate, yielding the desired ligand which was subsequently coordinated with potassium tetrachloropalladate(II) (K2PdCl4) to give a yellow solid of Pd(II) complex. Aqueous solution of this catalyst was used in 0.1 mol% with K2CO3 in the coupling reaction between chlorobenzenes and arylboronic acids under microwave irradiation for 15 min. Remarkably, the catalyst by itself showed moderate activity and increased by adding tetrabutylammonium bromide (TBAB) or 1-butyl-3-methylimidazolium hexafluoro-phosphate (Bmim-PF6) as an additive to replace the ionic potassium and stabilize the active Pd(0) species. Thus, electron rich aryl chlorides and sterically hindered substrates were smoothly transformed to biaryls in high yields, Scheme 34 [85]. Furthermore, a few number of palladium(II) complexes bearing amine- basedCatalysts ligands2020, 10, 4was reported as a homogeneous precatalyst for Suzuki-Miyaura cross-coupling18 of 35 reactions of boronic acids with mainly aryl bromides under microwave irradiation conditions [86,87].

Scheme 34. Palladium-catalyzed Suzuki cross-coupling reactions. Scheme 34. Palladium-catalyzed Suzuki cross-coupling reactions. Quite recently, an air and moisture stable starch-based Pd(II) catalyst was synthesized from Quite recently, an air and moisture stable starch-based Pd(II) catalyst was synthesized from functionalization of starch surface with 3-aminopropyl triethoxysilane. The formation of Schiff base functionalization of starch surface with 3-aminopropyl triethoxysilane. The formation of Schiff base was accomplished with 2-thiophenecarboxaldehyde in ethanol and the resulting ligand was eventually was accomplished with 2-thiophenecarboxaldehyde in ethanol and the resulting ligand was stirred with Na2PdCl4 in water. The Pd(II) catalyst was employed in Suzuki coupling reactions of aryl eventually stirred with Na2PdCl4 in water. The Pd(II) catalyst was employed in Suzuki coupling halides (Cl, Br, and I) with phenyl boronic acid in the presence of potassium carbonate and under reactions of aryl halides (Cl, Br, and I) with phenyl boronic acid in the presence of potassium microwave irradiation conditions. Moderate to excellent yields of biphenyls were obtained in short carbonate and under microwave irradiation conditions. Moderate to excellent yields of biphenyls reaction time at 50 ◦C and high TONs and TOFs were achieved with very low catalyst loading. Moreover, were obtained in short reaction time at 50 °C and high TONs and TOFs were achieved with very low the reusability of the catalyst was explored in 10 consecutive cycles, in which biphenyl yield decreased catalyst loading. Moreover, the reusability of the catalyst was explored in 10 consecutive cycles, in from 99 to 80%, with very low leaching of palladium ion (~1%) per catalytic cycle (Scheme 35)[88]. It which biphenyl yield decreased from 99 to 80%, with very low leaching of palladium ion (~1%) per is worth mentioning that a good reaction yield was achieved starting from aryl chlorides, which often Catalystscatalytic 2020 cycle, 10, x(Scheme FOR PEER 35)REVIEW [88]. It is worth mentioning that a good reaction yield was achieved18 of 35 gives very low yield and in some cases resulted in no reactions, indicating the high robustness of the starting from aryl chlorides, which often gives very low yield and in some cases resulted in no reactions,recently developed indicating starch-based the high robustness Pd-catalyst of the toward recently Suzuki developed cross-coupling starch-based reactions. Pd-catalyst toward Suzuki cross-coupling reactions.

Scheme 35. Starch-basedStarch-based Palladium-catalyzed Palladium-catalyzed cross-coupling cross-coupling reactions.

2.4. Stille Stille Cross-Coupling Cross-Coupling Reaction Reaction Stille cross-coupling reaction was firstfirst describeddescribed inin 1978.1978. It It involves involves a a reaction between organotin compounds (organostannanes) and and a variety of arylhalides or arylpseudohalides via Palladium-catalyzed coupling coupling reaction under almost base-free conditions.conditions. The The reaction proceeds throughthrough the generation of active zerovalent palladiumpalladium species in a conventionalconventional cross-coupling mechanism. Although Although the the reaction reaction is is very very stable stable to to oxygen oxygen and moisture and tolerates numerous functional groups, groups, it it raises raises the the environmental issue issue seriously seriously for for the the employment of of the toxic organostannanes [89]. [89]. Under Under microwave microwave irradiation, irradiation, nevertheless, nevertheless, the the reaction reaction has has been been widely employed in in polymerizations polymerizations [90] [90 ]and and few few protocol protocolss have have been been developed developed and and published published during during the lastthe lasttwo two decades. decades. Microwave-accelerated Microwave-accelerated one-po one-pott hydrostannylation/Stille hydrostannylation/Stille coupling coupling reaction reaction was reported for the conversion of 1-alkynes to 1,3-dien 1,3-dieneses or styrenes. To To achieve efficient efficient couplings, a mixture of 1 mol% of Pd(PPh ) , alkyne, Bu SnCl, aqueous KF, polymethylhydrosiloxane (PMHS), mixture of 1 mol% of Pd(PPh33)4, alkyne, Bu33SnCl, aqueous KF, polymethylhydrosiloxane (PMHS), and catalytic TBAF was irradiated using a domestic microwave. After 3 min, the reaction vessel was cooled and and charged charged with with the the electrophile electrophile and and anothe anotherr 1 1mol% mol% of of Pd Pd catalyst catalyst (once (once or or twice twice within within 5 min, depending on the reaction progress). The benefit of portion addition of palladium precursor was anticipated to thermal decomposition of the palladium catalyst and the reduction of electrophile was often accompanied Stille products. Alkynes with trisubstituted at the propargylic position, phenyl acetylene, and methyl propiolate were highly biased toward the formation of the E-Stille products in high yields. However, less hindered alkynes typically afford isomeric mixtures in rather lower yields, likely because of postproduction isomerization, Scheme 36 [91].

Scheme 36. Palladium-catalyzed one-pot hydrostannylation/Stille coupling reactions.

Likewise, Pd(PPh3)4 was reported as a rapid synthesis of biaryls in one-pot stannylation/Stille reaction of two aryl and/or heteroaryl bromides or iodide. Moderate to excellent yields were achieved in the presence of various functional groups such as: F, Ac, CHO, CF3, CN, CO2Et, CO2H, OH, OMe, and NO2 under microwave heating in water at 100 °C (Scheme 37). Although the one-pot approach comprises the elimination of the isolation/purification steps of the aryl stannanes, it should bypass the production of undesirable homocoupling resulting from stannylation reaction [92].

Catalysts 2020, 10, x FOR PEER REVIEW 18 of 35 reactions, indicating the high robustness of the recently developed starch-based Pd-catalyst toward Suzuki cross-coupling reactions.

Scheme 35. Starch-based Palladium-catalyzed cross-coupling reactions.

2.4. Stille Cross-Coupling Reaction Stille cross-coupling reaction was first described in 1978. It involves a reaction between organotin compounds (organostannanes) and a variety of arylhalides or arylpseudohalides via Palladium-catalyzed coupling reaction under almost base-free conditions. The reaction proceeds through the generation of active zerovalent palladium species in a conventional cross-coupling mechanism. Although the reaction is very stable to oxygen and moisture and tolerates numerous functional groups, it raises the environmental issue seriously for the employment of the toxic organostannanes [89]. Under microwave irradiation, nevertheless, the reaction has been widely employed in polymerizations [90] and few protocols have been developed and published during the last two decades. Microwave-accelerated one-pot hydrostannylation/Stille coupling reaction was reported for the conversion of 1-alkynes to 1,3-dienes or styrenes. To achieve efficient couplings, a Catalystsmixture2020 of ,110 mol%, 4 of Pd(PPh3)4, alkyne, Bu3SnCl, aqueous KF, polymethylhydrosiloxane (PMHS),19 of 35 and catalytic TBAF was irradiated using a domestic microwave. After 3 min, the reaction vessel was cooled and charged with the electrophile and another 1 mol% of Pd catalyst (once or twice within 5 min,5 min, depending depending on on the the reaction reaction progress). progress). The The benefit benefit of portion of portion addition addition of palladium of palladium precursor precursor was wasanticipated anticipated to thermal to thermal decomposition decomposition of the of palladium the palladium catalyst catalyst and the and reduction the reduction of electrophile of electrophile was wasoften often accompanied accompanied Stille Stille products. products. Alkynes Alkynes with with trisubstituted trisubstituted atat the the prop propargylicargylic position, position, phenyl acetylene, and methyl propiolate were hi highlyghly biased toward the formation of the E-Stille products in high yields. However, However, less hindered hindered alkynes alkynes typicall typicallyy afford afford isomeric mixtures in rather rather lower lower yields, yields, likely because of postproduction isomerization,isomerization, SchemeScheme 3636[ 91[91].].

Scheme 36. Palladium-catalyzedPalladium-catalyzed one-pot one-pot hydrostannylation/Stille hydrostannylation/Stille coupling reactions.

Likewise, Pd(PPh 3))44 waswas reported reported as as a a rapid synthesis of biaryls in one-pot stannylationstannylation/Stille/Stille reaction of two aryl and/or and/or hetero heteroarylaryl bromides or iodide. Moderate to excellent yields were achieved in the presence of various functionalfunctional groups suchsuch as:as: F, Ac,Ac, CHO,CHO, CFCF33, CN,CN, COCO22Et, CO 2H,H, OH, OH, OMe, OMe, and NO2 under microwave heating in water at 100 ◦°CC (Scheme 3737).). Although the one-pot approach comprises thethe eliminationelimination ofof the the isolation isolation/purificati/purificationon steps steps of of the the aryl aryl stannanes, stannanes, it should it should bypass bypass the Catalystsproductionthe production 2020, of10, undesirablex ofFOR undesirable PEER REVIEW homocoupling homocoupling resulting resulting from from stannylation stannylation reaction reaction [92]. [92]. 19 of 35

Scheme 37. Palladium-catalyzedPalladium-catalyzed one-pot one-pot hydrostannylation/Stille hydrostannylation/Stille coupling reactions.

Van der Eycken and coworkers have described thatthat Stille coupling reactions of few substrates were eefficientlyfficiently proceeded underunder microwavemicrowave irradiationirradiation inin moderatemoderate yieldsyields usingusing Pd(PPhPd(PPh33)4,, rather than underunder conventional conventional heating heating condition. condition. No improvement No improvement was observed was when observed the abovementioned when the abovementionedcatalyst is replaced catalyst with moreis replaced active with ones more like Pd(dppf)Cl active ones2 likeor Pd Pd(dppf)Cl2(dba)3 and2 or even Pd2(dba) in the3 and presence even in of thebulky presence phosphine of bulky ligands phosphine [93]. ligands [93]. Stille cross-coupling reaction of 3,5-dibromo-1-methyl-1H-1,2,4-triazole-1,2,4-triazole with with a a selection of organotin derivatives derivatives was was revealed revealed for for building building polyheteroaryl polyheteroaryl systems systems bearing bearing a 1,2,4-triazole a 1,2,4-triazole unit. Cebriánunit. Cebri et al.án found et al. found that PdCl that2(PPh PdCl32)(PPh2/LiCl3) 2or/LiCl PdCl or2(PPh PdCl3)22(PPh/CuI3 catalyzed)2/CuI catalyzed the coupling the coupling partners partners under microwaveunder microwave at 110 °C at 110in solvent-free◦C in solvent-free conditions conditions for 15 formin 15 to min produce to produce the 5-monosubstituted the 5-monosubstituted 1,2,4- 1,2,4-triazolestriazoles as the as main the mainor exclusive or exclusive product product in good in goodyields. yields. This suggest This suggest that the that 5-position the 5-position of 1,2,4- of 1,2,4-triazolestriazoles has the has higher the higher reactivity. reactivity. However, However, when whenthe reactive the reactive 2-thienyltin 2-thienyltin precursor precursor had been had used, been aused, 3-substituted a 3-substituted product product was accomplished was accomplished in small in small amount. amount. LiCl LiCl was wasobserved observed to be to the be theadditive additive of choiceof choice for for five-membered five-membered heterocycles heterocycles and and aryl aryl stannanes, stannanes, while while for for six-membered six-membered heterocycles, stannanes favorfavor thethe presencepresence of of CuI CuI in in order order to to give give higher higher yields yields of of the the products products and and to accelerateto accelerate the thecoupling coupling reactions reactions (Scheme (Scheme 38). 38).

Scheme 38. Synthesis of polyheteroaryl systems via Stille coupling reactions.

The monosubstituted products were subjected to another coupling reaction, furnishing symmetric or asymmetric disubstituted 1,2,4-triazole derivatives. On the other hand, 1-phenyl-4- (tributylstannyl)-1H-1,2,3-triazole was reacted with different aryl or heteroaryl halides under microwave irradiation at 150 °C for 15 min, affording the 1,2,3-triazole derivatives in moderate to high yields (Scheme 39) [94].

Scheme 39. PdCl2(PPh3)2/LiCl mediated Stille coupling reactions.

Susanto et al. developed a light fluorous, thermally stable oxime-based palladacycle precatalyst for Stille reaction. The scope of the reaction was established with a variety of organostannanes and aryl halides in the presence of palladacycle (0.005 mol% Pd) and TBAB in water and under microwave irradiation for short reaction time at 100 °C for 5 min (Scheme 40). The recyclability of the catalyst

Catalysts 2020, 10, x FOR PEER REVIEW 19 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 19 of 35

Scheme 37. Palladium-catalyzed one-pot hydrostannylation/Stille coupling reactions. Scheme 37. Palladium-catalyzed one-pot hydrostannylation/Stille coupling reactions. Van der Eycken and coworkers have described that Stille coupling reactions of few substrates Van der Eycken and coworkers have described that Stille coupling reactions of few substrates were efficiently proceeded under microwave irradiation in moderate yields using Pd(PPh3)4, rather thanwere efficientlyunder conventional proceeded underheating microwave condition. irradiation No improvement in moderate yieldswas usingobserved Pd(PPh when3)4, rather the than under conventional heating condition. No improvement was observed when the abovementioned catalyst is replaced with more active ones like Pd(dppf)Cl2 or Pd2(dba)3 and even in theabovementioned presence of bulky catalyst phosphine is replaced ligands with [93]. more active ones like Pd(dppf)Cl2 or Pd2(dba)3 and even in the presenceStille cross-coupling of bulky phosphine reaction ligands of 3,5-dibromo-1-methyl-1 [93]. H-1,2,4-triazole with a selection of organotinStille derivativescross-coupling was revealedreaction forof building3,5-dibromo-1-methyl-1 polyheteroaryl Hsystems-1,2,4-triazole bearing witha 1,2,4-triazole a selection unit. of organotin derivatives was revealed for building polyheteroaryl systems bearing a 1,2,4-triazole unit. Cebrián et al. found that PdCl2(PPh3)2/LiCl or PdCl2(PPh3)2/CuI catalyzed the coupling partners under microwaveCebrián et al. at found 110 °C that in PdClsolvent-free2(PPh3)2 /LiClconditions or PdCl for2(PPh 15 min3)2/CuI to producecatalyzed the the 5-monosubstituted coupling partners under1,2,4- triazolesmicrowave as atthe 110 main °C orin solvent-freeexclusive product conditions in good for yields.15 min Thisto produce suggest the that 5-monosubstituted the 5-position of 1,2,4- triazoles hasas the the main higher or reactivity. exclusive However,product in when good the yields. reactive This 2-thienyltin suggest that precursor the 5-position had been of used,1,2,4- atriazoles 3-substituted has the product higher reactivity.was accomplished However, in when small the amount. reactive LiCl 2-thienyltin was observed precursor to be hadthe additivebeen used, of choicea 3-substituted for five-membered product was heterocycles accomplished and in arylsmall stannanes, amount. LiClwhile wa fors observed six-membered to be the heterocycles, additive of stannaneschoice for favorfive-membered the presence heterocycles of CuI in order and arylto give stannanes, higher yields while of for the six-membered products and heterocycles,to accelerate Catalysts 2020, 10, 4 20 of 35 thestannanes coupling favor reactions the presence (Scheme of 38). CuI in order to give higher yields of the products and to accelerate the coupling reactions (Scheme 38).

Scheme 38. SynthesisSynthesis of polyheteroaryl systems via Stille coupling reactions. Scheme 38. Synthesis of polyheteroaryl systems via Stille coupling reactions. The monosubstituted products were subjectedsubjected to anotheranother couplingcoupling reaction,reaction, furnishing The monosubstituted products were subjected to another coupling reaction, furnishing symmetric or or asymmetric asymmetric disubsti disubstitutedtuted 1,2,4-triazole 1,2,4-triazole derivatives. derivatives. On the other On hand, the other 1-phenyl-4- hand, symmetric or asymmetric disubstituted 1,2,4-triazole derivatives. On the other hand, 1-phenyl-4- 1-phenyl-4-(tributylstannyl)-1(tributylstannyl)-1H-1,2,3-triazoleH-1,2,3-triazole was reacted was with reacted different with diarylfferent or heteroaryl aryl or heteroaryl halides halidesunder (tributylstannyl)-1H-1,2,3-triazole was reacted with different aryl or heteroaryl halides under microwaveunder microwave irradiation irradiation at 150 at°C 150 for◦ C15 for min, 15 min,affording affording the 1,2,3-triazole the 1,2,3-triazole derivatives derivatives in moderate in moderate to microwave irradiation at 150 °C for 15 min, affording the 1,2,3-triazole derivatives in moderate to highto high yields yields (Scheme (Scheme 39) 39 [94].)[94 ]. high yields (Scheme 39) [94].

Scheme 39. PdCl2(PPh3)2/LiCl mediated Stille coupling reactions. Scheme 39. PdCl2(PPh3)2/LiCl mediated Stille coupling reactions. Catalysts 2020, 10, x FOR PEERScheme REVIEW 39. PdCl 2(PPh3)2/LiCl mediated Stille coupling reactions. 20 of 35 Susanto et al. developed a light fluorous, thermally stable oxime-based palladacycle precatalyst Susanto et al. developed a light fluorous, thermally stable oxime-based palladacycle precatalyst forwas Stille examined reaction. for Thethe scopecoupling of thereaction reaction of wastributyl(phenyl)stannane established with a variety with ofiodobenzene organostannanes under for StilleSusanto reaction. et al. Thedeveloped scope ofa lightthe reaction fluorous, was therma establishedlly stable with oxime-based a variety ofpalladacycle organostannanes precatalyst and andoptimized aryl halides conditions, in the stating presence that ofthe palladacycle yields over fi (0.005ve runs mol% were Pd) quantitative, and TBAB as in palladium water and leaching under arylfor Stille halides reaction. in the presenceThe scope of ofpalladacycle the reaction (0.005 was mol%established Pd) and with TBAB a variety in water of andorganostannanes under microwave and microwavewas very low. irradiation Remarkably, for short this reaction palladacycle time at 100complexC for 5was min demonstrated (Scheme 40). Theunder recyclability microwave of irradiationaryl halides for in theshort presence reaction of timepalladacycle at 100 °C (0.005 for 5 mol% min◦ (SchemePd) and TBAB 40). The in water recyclability and under of themicrowave catalyst theirradiation catalyst asfor was a short very examined reactionefficient for timeand the versatile couplingat 100 °C precatalyst reactionfor 5 min of (Schemefor tributyl(phenyl)stannane a wide 40). range The ofrecyclability cross-coupling with of iodobenzene the reactions, catalyst underincluding: optimized Suzuki-Miyaura, conditions, Sonogashira, stating that the Heck, yields Gl overaser-type, five runs and wereKumada quantitative, in either as aqueous palladium or leachingorganic medium was very [95]. low. Remarkably, this palladacycle complex was demonstrated under microwave irradiationSimilarly, as a an very air e andfficient moisture and versatile stable palladacycle precatalyst for catalyst, a wide [Pd{C range6H of4(CH cross-coupling2N(CH2Ph)2)}( reactions,μ-Br)]2, including:was explored Suzuki-Miyaura, in the cross-coupling Sonogashira, reaction Heck, of several Glaser-type, aryl halides and Kumada with phenyltributyltin in either aqueous derivatives or organic mediumunder microwave [95]. irradiation in DMF at 100 °C, generating biaryls in high yield in 2–20 min [96].

Scheme 40. Paladacycle-catalyzed Stille coupling reactions.

Similarly,Palladium an nanoparticles air and moisture generated stable in palladacycle situ from PdCl catalyst,2–PEG400 [Pd{C in6H the4(CH presence2N(CH 2ofPh) DMAP2)}(µ-Br)] was2, wasrevealed explored recently in the for cross-coupling the production reaction of a variety of several of functionalized aryl halides biaryls. with phenyltributyltin The cross-coupling derivatives reaction underof one microwaveequiv. of tetraphenylstannane irradiation in DMF with at 100 4 ◦equiC, generatingv. of aryl halides biaryls inwas high conducted yield in 2–20under min microwave [96]. heatingPalladium to afford nanoparticles the corresponding generated biaryls in situ fromin high PdCl yields.2–PEG400 In general, in the presence electron-withdrawing of DMAP was revealedsubstituents recently on the for thearyl production halides furnished of a variety higher of functionalized yields than biaryls.aryl halides The cross-coupling with electron-donating reaction of onesubstituents; equiv. of tetraphenylstannanebiphenyl was produced with in 4 equiv.few exampl of aryles halides as the was only conducted byproduct under from microwave homocoupling heating of totetraphenyltin afford the corresponding (Scheme 41). biaryls The reusability in high yields. of the In catalyst general, was electron-withdrawing verified in the coupling substituents of SnPh on4 with the aryl1-bromo-4-chlorobenzene. halides furnished higher After yields extraction than aryl halidesof organic with electron-donatingmaterial by diethy substituents;l ether, the biphenyl remaining was PEG400 and Pd nanoparticles were subjected to the next run. A yield of 94% was dropped to 81% from the fourth reuse of the catalyst even when the reaction time was prolonged to 40 min. Though this protocol is considered as an atom-efficient approach, the commercial availability of a variety of tin-precursors (tetraorganotin compounds) is highly limited [97].

Scheme 41. In situ generated Pd nanoparticles mediated Stille coupling reactions.

2.5. Negishi Cross-Coupling Reaction Negishi cross-coupling reaction was developed in 1977. It is frequently employed in industrial application processes for coupling organic halides or triflates with organozinc compounds using palladium(0) or palladium(II) species. Öhberg and Westman have reported the first Negishi coupling of 4-bromobenzaldehyde with 2-cyanophenylzinc-bromide under microwave condition. The biaryl was formed in 90% yield after 1 min at 160 °C, Scheme 42 [98].

Catalysts 2020, 10, x FOR PEER REVIEW 20 of 35 was examined for the coupling reaction of tributyl(phenyl)stannane with iodobenzene under optimized conditions, stating that the yields over five runs were quantitative, as palladium leaching was very low. Remarkably, this palladacycle complex was demonstrated under microwave irradiation as a very efficient and versatile precatalyst for a wide range of cross-coupling reactions, including: Suzuki-Miyaura, Sonogashira, Heck, Glaser-type, and Kumada in either aqueous or organic medium [95]. Similarly, an air and moisture stable palladacycle catalyst, [Pd{C6H4(CH2N(CH2Ph)2)}(μ-Br)]2, was explored in the cross-coupling reaction of several aryl halides with phenyltributyltin derivatives under microwave irradiation in DMF at 100 °C, generating biaryls in high yield in 2–20 min [96].

Scheme 40. Paladacycle-catalyzed Stille coupling reactions.

Palladium nanoparticles generated in situ from PdCl2–PEG400 in the presence of DMAP was revealed recently for the production of a variety of functionalized biaryls. The cross-coupling reaction Catalystsof one equiv.2020, 10 ,of 4 tetraphenylstannane with 4 equiv. of aryl halides was conducted under microwave21 of 35 heating to afford the corresponding biaryls in high yields. In general, electron-withdrawing substituents on the aryl halides furnished higher yields than aryl halides with electron-donating produced in few examples as the only byproduct from homocoupling of tetraphenyltin (Scheme 41). substituents; biphenyl was produced in few examples as the only byproduct from homocoupling of The reusability of the catalyst was verified in the coupling of SnPh4 with 1-bromo-4-chlorobenzene. tetraphenyltin (Scheme 41). The reusability of the catalyst was verified in the coupling of SnPh4 with After extraction of organic material by diethyl ether, the remaining PEG400 and Pd nanoparticles 1-bromo-4-chlorobenzene. After extraction of organic material by diethyl ether, the remaining were subjected to the next run. A yield of 94% was dropped to 81% from the fourth reuse of the PEG400 and Pd nanoparticles were subjected to the next run. A yield of 94% was dropped to 81% catalyst even when the reaction time was prolonged to 40 min. Though this protocol is considered as from the fourth reuse of the catalyst even when the reaction time was prolonged to 40 min. Though an atom-efficient approach, the commercial availability of a variety of tin-precursors (tetraorganotin this protocol is considered as an atom-efficient approach, the commercial availability of a variety of compounds) is highly limited [97]. tin-precursors (tetraorganotin compounds) is highly limited [97].

Scheme 41. In situ generated Pd nanoparticles mediated Stille coupling reactions. Scheme 41. In situ generated Pd nanoparticles mediated Stille coupling reactions. 2.5. Negishi Cross-Coupling Reaction 2.5. Negishi Cross-Coupling Reaction Negishi cross-coupling reaction was developed in 1977. It is frequently employed in industrial applicationNegishi processes cross-coupling for coupling reaction organic was developed halides orin triflates1977. It is with frequently organozinc employed compounds in industrial using palladium(0)application processes or palladium(II) for coupling species. organic Öhberg halides and Westman or triflates have with reported organozinc the first compounds Negishi coupling using palladium(0)of 4-bromobenzaldehyde or palladium(II) with species. 2-cyanophenylzinc-bromide Öhberg and Westman underhave reported microwave the first condition. Negishi The coupling biaryl CatalystsCatalysts 2020 2020, ,10 10, ,x x FOR FOR PEER PEER REVIEW REVIEW 2121 of of 35 35 wasof 4-bromobenzaldehyde formed in 90% yield afterwith 1 2-cyanophenylzinc-bromide min at 160 ◦C, Scheme 42[98 ].under microwave condition. The biaryl was formed in 90% yield after 1 min at 160 °C, Scheme 42 [98].

Scheme 42. Pd-catalyzed Negishi cross-coupling reaction. SchemeScheme 42.42. Pd-catalyzedPd-catalyzed NegishiNegishi cross-couplingcross-coupling reaction.reaction. However, the cross-coupling reaction of 2,4-dichloropyrimidine with organozinc reagents prepared However,However, thethe cross-couplingcross-coupling reactionreaction ofof 2,4-2,4-dichloropyrimidinedichloropyrimidine withwith organozincorganozinc reagentsreagents from 2-fluoro-4-iodopyridine was investigated under microwave heating. The Pd(PPh3)4 allowed preparedepreparedfficient access fromfrom to 2-fluoro-4-iodopyridine2-fluoro-4-iodopyridinemono-coupled compound waswas in inve 90%investigated yield,stigated in under additionunder microwavemicrowave to di-coupled heating.heating. compound TheThe Pd(PPhPd(PPh (4%) and33))44 allowedtracesallowed of homoefficientefficient coupling accessaccess product toto monomono (Scheme-coupled-coupled 43 )[compoundcompound99]. inin 90%90% yield,yield, inin additionaddition toto didi-coupled-coupled compoundcompound (4%)(4%) andand tracestraces ofof homohomo couplingcoupling productproduct (Scheme(Scheme 43)43) [99].[99].

SchemeSchemeScheme 43.43. Pd-catalyzedPd-catalyzed Negishi Negishi cross-coupling cross-coupling reaction. reaction.reaction.

Microwave-assisted Negishi coupling was developed using the Pd2(dba)3/t-Bu3P HBF4 system. Microwave-assistedMicrowave-assisted NegishiNegishi couplingcoupling waswas developeddeveloped usingusing thethe PdPd22(dba)(dba)33//tt-Bu-Bu33PP∙·∙HBFHBF44 system.system. The optimized reaction conditions were conducted using aryl zinc chlorides with electron-deficient TheThe optimizedoptimized reactionreaction conditionsconditions werewere conductedconducted usingusing arylaryl zinczinc chlorideschlorides withwith electron-deficientelectron-deficient and electron-rich aryl chlorides as coupling partners at 175 C for 10 min, giving the corresponding andand electron-richelectron-rich arylaryl chlorideschlorides asas couplingcoupling partnerspartners atat 175175 °C◦°C forfor 1010 min,min, givinggiving thethe correspondingcorresponding products in good to high yields. Notably, the 4-nitrophenyl chloride was cross-coupled successfully productsproducts inin goodgood toto highhigh yields.yields. Notably,Notably, thethe 4-nitrophenyl4-nitrophenyl chloridechloride waswas cross-coupledcross-coupled successfullysuccessfully with n-butyl zinc chloride within 30 min in 84% (Scheme 44)[100]. withwith nn-butyl-butyl zinczinc chloridechloride withinwithin 3030 minmin inin 84%84% (Scheme(Scheme 44)44) [100].[100].

SchemeScheme 44.44. Palladium-catalyzedPalladium-catalyzed NegishiNegishi couplingcoupling reactions.reactions.

AnAn efficientefficient approachapproach toto obtainobtain arylzincarylzinc cocompoundsmpounds forfor NegishiNegishi reactionreaction isis handlinghandling arylaryl chlorideschlorides oror arylaryl bromidesbromides withwith magnesiummagnesium turningsturnings underunder microwavemicrowave irradiation.irradiation. AA consequentconsequent transmetalationtransmetalation withwith ZnClZnCl22-TMEDA-TMEDA generatedgenerated thethe arylzincarylzinc species,species, whichwhich waswas directlydirectly introducedintroduced intointo aa couplingcoupling reactionreaction withwith arylaryl bromidebromide derivativesderivatives usingusing Pd(PPhPd(PPh33))22ClCl22 asas aa precatalyst.precatalyst. TheThe cross-cross- couplingcoupling reaction reaction was was completed completed after after irradiation irradiation at at 80 80 or or 120 120 °C °C in in THF THF or or THF-DMF THF-DMF mixture mixture within within aa shortshort time,time, dependingdepending onon thethe substratessubstrates used.used. FoForr instance,instance, arylaryl chlorideschlorides diddid notnot reactreact underunder thethe aforementionedaforementioned conditions,conditions, while,while, thethe couplingcoupling rereactionaction betweenbetween 4-bromophenylzinc4-bromophenylzinc chloridechloride andand bromobenzaldehydebromobenzaldehyde occurredoccurred atat roomroom temperature.temperature. TheThe chemoselectivitychemoselectivity ofof thethe reactionreaction waswas obviousobvious whenwhen 2-chloro-bromobe2-chloro-bromobenzenenzene isis employed,employed, inin whichwhich thethe cross-couplingcross-coupling tooktook placeplace selectivelyselectively viavia bromide,bromide, affordingaffording thethe correspondingcorresponding biarylbiaryl (Scheme(Scheme 45)45) [101].[101].

SchemeScheme 45.45. SynthesisSynthesis ofof biarylsbiaryls viavia three-stepthree-step reaction.reaction.

Catalysts 2020, 10, x FOR PEER REVIEW 21 of 35

Scheme 42. Pd-catalyzed Negishi cross-coupling reaction.

However, the cross-coupling reaction of 2,4-dichloropyrimidine with organozinc reagents prepared from 2-fluoro-4-iodopyridine was investigated under microwave heating. The Pd(PPh3)4 allowed efficient access to mono-coupled compound in 90% yield, in addition to di-coupled compound (4%) and traces of homo coupling product (Scheme 43) [99].

Scheme 43. Pd-catalyzed Negishi cross-coupling reaction.

Microwave-assisted Negishi coupling was developed using the Pd2(dba)3/t-Bu3P∙HBF4 system. The optimized reaction conditions were conducted using aryl zinc chlorides with electron-deficient and electron-rich aryl chlorides as coupling partners at 175 °C for 10 min, giving the corresponding Catalysts 2020, 10, 4 22 of 35 products in good to high yields. Notably, the 4-nitrophenyl chloride was cross-coupled successfully with n-butyl zinc chloride within 30 min in 84% (Scheme 44) [100].

Scheme 44. Palladium-catalyzed Negishi coupling reactions. Scheme 44. Palladium-catalyzed Negishi coupling reactions. An efficient approach to obtain arylzinc compounds for Negishi reaction is handling aryl chlorides An efficient approach to obtain arylzinc compounds for Negishi reaction is handling aryl or aryl bromides with magnesium turnings under microwave irradiation. A consequent transmetalation chlorides or aryl bromides with magnesium turnings under microwave irradiation. A consequent with ZnCl2-TMEDA generated the arylzinc species, which was directly introduced into a coupling transmetalation with ZnCl2-TMEDA generated the arylzinc species, which was directly introduced reaction with aryl bromide derivatives using Pd(PPh3)2Cl2 as a precatalyst. The cross-coupling into a coupling reaction with aryl bromide derivatives using Pd(PPh3)2Cl2 as a precatalyst. The cross- reaction was completed after irradiation at 80 or 120 ◦C in THF or THF-DMF mixture within a coupling reaction was completed after irradiation at 80 or 120 °C in THF or THF-DMF mixture within short time, depending on the substrates used. For instance, aryl chlorides did not react under the a short time, depending on the substrates used. For instance, aryl chlorides did not react under the aforementioned conditions, while, the coupling reaction between 4-bromophenylzinc chloride and aforementioned conditions, while, the coupling reaction between 4-bromophenylzinc chloride and bromobenzaldehyde occurred at room temperature. The chemoselectivity of the reaction was obvious bromobenzaldehyde occurred at room temperature. The chemoselectivity of the reaction was when 2-chloro-bromobenzene is employed, in which the cross-coupling took place selectively via obvious when 2-chloro-bromobenzene is employed, in which the cross-coupling took place bromide, affording the corresponding biaryl (Scheme 45)[101]. selectively via bromide, affording the corresponding biaryl (Scheme 45) [101].

Catalysts 2020, 10, x FOR PEER REVIEW 22 of 35 Scheme 45. Synthesis of biaryls via three-step reaction. Scheme 45. Synthesis of biaryls via three-step reaction. Espinet’s group has disclosed a protocol for the synthesis of sterically hindered chiral Espinet’s group has disclosed a protocol for the synthesis of sterically hindered chiral binaphthalene derivatives. The enantioselective cross-coupling reactions were conducted between binaphthalene derivatives. The enantioselective cross-coupling reactions were conducted between naphthylbromides and bis(naphthalen-1-yl)zinc compounds using Pd2dba3‧CHCl3 and a chiral naphthylbromides and bis(naphthalen-1-yl)zinc compounds using Pd2dba3 CHCl3 and a chiral ligand, ligand, (R,Sp)-(2-diphenylphosphinoferrocenyl)ethyl-dimethylamine (L, Scheme· 46). The coupling (R,Sp)-(2-diphenylphosphinoferrocenyl)ethyl-dimethylamine (L, Scheme 46). The coupling proceeded proceeded smoothly even with sterically demanding substrate (R1 = R2 = Me) in THF at 100 °C within smoothly even with sterically demanding substrate (R1 = R2 = Me) in THF at 100 ◦C within 45 min 45 min under an inert atmosphere. Alternatively, the authors have performed the same syntheses under an inert atmosphere. Alternatively, the authors have performed the same syntheses under under Suzuki reaction conditions (using 1-naphthaleneboronic acids instead of bis(naphthalen-1- Suzuki reaction conditions (using 1-naphthaleneboronic acids instead of bis(naphthalen-1-yl)zinc yl)zinc derivatives) achieving slightly better outcomes than the Negishi protocol [102]. derivatives) achieving slightly better outcomes than the Negishi protocol [102].

Scheme 46. Synthesis of chiral binaphthalene derivatives via Negishi cross-coupling reaction. Scheme 46. Synthesis of chiral binaphthalene derivatives via Negishi cross-coupling reaction. Recently, Motwani and Larhed have developed palladium-catalyzed carbonylative Negishi cross-couplingsRecently, Motwani for aryl iodides and Larhed and aryl have bromides developed with benzylzinc palladium-catalyzed bromide under carbonylative controlled microwave Negishi irradiation.cross-couplings The carbonylativefor aryl iodides cross-coupling and aryl brom involvesides thewith introduction benzylzinc ofbromide CO between under the controlled coupling partners,microwave using irradiation. molybdenum The carbonylative hexacarbonyl cross-co as a solidupling in situ involves source ofthe CO. introduction As depicted of inCO Scheme between 47, the reactioncoupling conditions partners, using were optimizedmolybdenum depending hexacarbonyl on the as aryl a solid halide in used,situ source to give of a CO. set of As diarylated depicted ethanones,in Scheme 47, a common the reaction pharmacophore, conditions were in moderate optimized to highdepending yields [on103 the]. aryl halide used, to give a set of diarylated ethanones, a common pharmacophore, in moderate to high yields [103].

Scheme 47. Synthesis of biaryls via three-step reaction.

2.6. Hiyama Cross-Coupling Reaction Hiyama cross-coupling reaction was first reported in 1988. In it, the C–C bond formation takes place in the cross-coupled between organosilanes with aryl, vinyl, or alkyl halides or pseudohalides. The coupling reaction is analogous to the Suzuki reaction and an activating agent such as fluoride ion or a base is required to activate the organosilane reagent, via the formation of a pentavalent silicon center. This intermediate is unstable and permits facile breaking of a C–Si bond in the transmetalation step [104]. The first microwave irradiation protocol was described within few minutes for Hiyama coupling reaction of aryl halides with aryl- or vinyl-siloxane derivatives. The reaction was activated using TBAF in THF, while the active catalyst species was generated in situ from [Pd(allyl)Cl]2 and N- dicyclohexylphosphino-N-methylpiperazine (Cy2P-N-MePip). Aryl bromide and activated aryl chlorides were proceeded smoothly, furnishing the desired products with high yields. However,

Catalysts 2020, 10, x FOR PEER REVIEW 22 of 35

Espinet’s group has disclosed a protocol for the synthesis of sterically hindered chiral binaphthalene derivatives. The enantioselective cross-coupling reactions were conducted between naphthylbromides and bis(naphthalen-1-yl)zinc compounds using Pd2dba3‧CHCl3 and a chiral ligand, (R,Sp)-(2-diphenylphosphinoferrocenyl)ethyl-dimethylamine (L, Scheme 46). The coupling proceeded smoothly even with sterically demanding substrate (R1 = R2 = Me) in THF at 100 °C within 45 min under an inert atmosphere. Alternatively, the authors have performed the same syntheses under Suzuki reaction conditions (using 1-naphthaleneboronic acids instead of bis(naphthalen-1- yl)zinc derivatives) achieving slightly better outcomes than the Negishi protocol [102].

Scheme 46. Synthesis of chiral binaphthalene derivatives via Negishi cross-coupling reaction.

Recently, Motwani and Larhed have developed palladium-catalyzed carbonylative Negishi cross-couplings for aryl iodides and aryl bromides with benzylzinc bromide under controlled microwave irradiation. The carbonylative cross-coupling involves the introduction of CO between the coupling partners, using molybdenum hexacarbonyl as a solid in situ source of CO. As depicted Catalystsin Scheme2020 ,47,10, 4the reaction conditions were optimized depending on the aryl halide used, to 23give of 35a set of diarylated ethanones, a common pharmacophore, in moderate to high yields [103].

Scheme 47. Synthesis of biaryls via three-step reaction. Scheme 47. Synthesis of biaryls via three-step reaction. 2.6. Hiyama Cross-Coupling Reaction 2.6. Hiyama Cross-Coupling Reaction Hiyama cross-coupling reaction was first reported in 1988. In it, the C–C bond formation takes placeHiyama in the cross-coupled cross-coupling between reaction organosilanes was first reported with aryl, in 1988. vinyl, In orit, alkylthe C–C halides bond or formation pseudohalides. takes Theplace coupling in the cross-coupled reaction is analogous between toorganosilanes the Suzuki reaction with aryl, and vinyl, an activating or alkyl halides agent such or pseudohalides. as fluoride ion orThe a basecoupling is required reaction to is activate analogous the organosilaneto the Suzuki reagent,reaction via and the an formation activating of agent a pentavalent such as fluoride silicon center.ion or aThis base intermediate is required to is activa unstablete the and organosilane permits facile reagent, breaking via th ofe a formation C–Si bond of in a thepentavalent transmetalation silicon stepcenter. [104 This]. intermediate is unstable and permits facile breaking of a C–Si bond in the transmetalation step [104].The first microwave irradiation protocol was described within few minutes for Hiyama coupling reactionThe offirst aryl microwave halides with irradiation aryl- or protocol vinyl-siloxane was described derivatives. within Thefew reactionminutes for was Hiyama activated coupling using reaction of aryl halides with aryl- or vinyl-siloxane derivatives. The reaction was activated using TBAF in THF, while the active catalyst species was generated in situ from [Pd(allyl)Cl]2 and TBAF in THF, while the active catalyst species was generated in situ from [Pd(allyl)Cl]2 and N- NCatalysts-dicyclohexylphosphino- 2020, 10, x FOR PEER REVIEWN-methylpiperazine (Cy2P-N-MePip). Aryl bromide and activated23 arylof 35 chloridesdicyclohexylphosphino- were proceededN-methylpiperazine smoothly, furnishing (Cy the2P-N-MePip). desired products Aryl bromide with high and yields. activated However, aryl chlorides were proceeded smoothly, furnishing the desired products with high yields. However, deactivated arylaryl chlorides chlorides such such as 4-chlorotoluene,as 4-chlorotoluen withe, with phenylsiloxane phenylsiloxane was transformed was transformed into a mixture into a of mixture aromatic of aromatic compounds compounds along with along a trace with of a thetrace desired of the product,desired product, Scheme 48 Scheme[105]. 48 [105].

Scheme 48. Palladium-catalyzed Hiyama coupling reactions.

A precatalyst precatalyst based based on NHC-ligand on NHC-ligand prepared prepared in situ from in situpalladium from acetate palladium with 1-benzyl-3-(2- acetate with 1-benzyl-3-(2-hydroxy-2-phenylethyl)-1hydroxy-2-phenylethyl)-1H-imidazoliumH -imidazoliumchloride was described chloride wasas a describedfluorine-free as aHiyama fluorine-free cross- Hiyamacoupling cross-couplingreactions of a reactionsrange of aryl of a rangebromides of aryl with bromides trimethoxy(phenyl)silane. with trimethoxy(phenyl)silane. The coupling was The couplingperformed was in the performed presence in of the 50% presence aqueous of NaOH, 50% aqueous both activated NaOH, bothand deactivated activated and aryl deactivated bromides arylafforded bromides the corresponding afforded the correspondingbiaryls in good biaryls to high in yields. good Whereas, to high yields. the use Whereas, of TBAB the in usethe coupling of TBAB inof heteroaryl the coupling bromides of heteroaryl and chloroarens bromides is andnecessar chloroarensy to improve is necessary the yield toof the improve outcomes, the yieldsince ofTBAB the outcomes,stabilizes the since colloidal TBAB stabilizespalladium the nanoparticles. colloidal palladium Other silicon-based nanoparticles. reagents Other silicon-basedwere conducted reagents with werearyl bromides conducted under with arylthe bromidesoptimized under conditions the optimized to afford conditions the biaryls, to abutfford in the lower biaryls, yields but than in lower the yieldstrimethoxy(phenyl)silane than the trimethoxy(phenyl)silane (Scheme 49) [106]. (Scheme 49)[106].

Scheme 49. Palladacycle-catalyzed Hiyama coupling reactions.

Hajipour and Rafiee have reported a thermally stable and oxygen insensitive monomeric palladacycle precatalyst for the synthesis of substituted biaryls. Under the optimized reaction conditions in DMF as the solvent and TBAF as the promoter, a selection of biaryls were produced in high yields when bromo- and iodoarens are employed. In contrast, good yields were achieved with chloroarens bearing electron-donating or electron-withdrawing substituents in short reaction time under microwave heating (Scheme 50) [107]. The same authors have revealed another protocol for Hiyama reaction of just about the same substrate scope, using palladium salt of 1-benzyl-4-aza-1- azoniabicyclo-[2.2.2]octane chloride and KF as an activator under microwave irradiation [108].

Scheme 50. Palladacycle-catalyzed Hiyama coupling reactions.

1-Methyl-2-aminoalkylimidazole derivative was reported as an efficient ligand for Hiyama reaction under solvent-free conditions in the presence of Pd(OAc)2. Aryl bromides with a range of electron-donating and electron-withdrawing substituents were cross-coupled with aryl(trimethoxy)silane, afforded the correspondent biaryls in good to high yields under irradiation conditions. The congested 2-bromotoluene yielded the coupling product in 85%, while the 2- bromophenol coupled with 40% yield. This was rationalized for the poor reactivity, as the 2- bromophenol could deactivate the catalyst by coordination to the metal center. The reaction with heteroaryl halides and aryl chlorides was in general less effective (Scheme 51). Moreover, a variety

CatalystsCatalysts 2020 2020, ,10 10, ,x x FOR FOR PEER PEER REVIEW REVIEW 2323 of of 35 35 deactivateddeactivated arylaryl chlorideschlorides suchsuch asas 4-chlorotoluen4-chlorotoluene,e, withwith phenylsiloxanephenylsiloxane waswas transformedtransformed intointo aa mixturemixture of of aromatic aromatic compounds compounds along along with with a a trace trace of of the the desired desired product, product, Scheme Scheme 48 48 [105]. [105].

SchemeScheme 48. 48. Palladium-catalyzed Palladium-catalyzed Hiyama Hiyama coupling coupling reactions. reactions.

AA precatalyst precatalyst based based on on NHC-ligand NHC-ligand prepared prepared in in situ situ from from palladium palladium acetate acetate with with 1-benzyl-3-(2- 1-benzyl-3-(2- hydroxy-2-phenylethyl)-1hydroxy-2-phenylethyl)-1HH-imidazolium-imidazolium chloridechloride waswas describeddescribed asas aa fluorine-freefluorine-free HiyamaHiyama cross-cross- couplingcoupling reactionsreactions ofof aa rangerange ofof arylaryl bromidesbromides withwith trimethoxy(phenyl)silane.trimethoxy(phenyl)silane. TheThe couplingcoupling waswas performedperformed inin thethe presencepresence ofof 50%50% aqueousaqueous NaOH,NaOH, bothboth activatedactivated andand deactivateddeactivated arylaryl bromidesbromides affordedafforded the the corresponding corresponding biaryls biaryls in in good good to to high high yields. yields. Whereas, Whereas, the the use use of of TBAB TBAB in in the the coupling coupling ofof heteroaryl heteroaryl bromides bromides and and chloroarens chloroarens is is necessar necessaryy to to improve improve the the yield yield of of the the outcomes, outcomes, since since TBAB TBAB stabilizesstabilizes thethe colloidalcolloidal palladiumpalladium nanoparticles.nanoparticles. OtherOther silicon-basedsilicon-based reagentsreagents werewere conductedconducted withwith Catalysts 2020, 10, 4 24 of 35 arylaryl bromidesbromides underunder thethe optimizedoptimized conditionsconditions toto aaffordfford thethe biaryls,biaryls, butbut inin lowerlower yieldsyields thanthan thethe trimethoxy(phenyl)silanetrimethoxy(phenyl)silane (Scheme (Scheme 49) 49) [106]. [106].

SchemeScheme 49. 49. Palladacycle-catalyzed Palladacycle-catalyzed Hiyama Hiyama coupling coupling reactions. reactions. Hajipour and Rafiee have reported a thermally stable and oxygen insensitive monomeric HajipourHajipour andand RafieeRafiee havehave reportedreported aa thermallythermally stablestable andand oxygenoxygen insensitiveinsensitive monomericmonomeric palladacycle precatalyst for the synthesis of substituted biaryls. Under the optimized reaction conditions palladacyclepalladacycle precatalystprecatalyst forfor thethe synthesissynthesis ofof susubstitutedbstituted biaryls.biaryls. UnderUnder thethe optimizedoptimized reactionreaction in DMF as the solvent and TBAF as the promoter, a selection of biaryls were produced in high yields conditionsconditions in in DMF DMF as as the the solvent solvent and and TBAF TBAF as as the the promoter, promoter, a a selection selection of of biaryls biaryls were were produced produced in in when bromo- and iodoarens are employed. In contrast, good yields were achieved with chloroarens highhigh yieldsyields whenwhen bromo-bromo- andand iodoarensiodoarens areare employedemployed. . InIn contrast,contrast, goodgood yieldsyields werewere achievedachieved withwith bearing electron-donating or electron-withdrawing substituents in short reaction time under microwave chloroarenschloroarens bearingbearing electron-donatingelectron-donating oror electron-welectron-withdrawingithdrawing substituentssubstituents inin shortshort reactionreaction timetime heating (Scheme 50)[107]. The same authors have revealed another protocol for Hiyama reaction of just underunder microwavemicrowave heatingheating (Scheme(Scheme 50)50) [107].[107]. TheThe sasameme authorsauthors havehave revealedrevealed anotheranother protocolprotocol forfor about the same substrate scope, using palladium salt of 1-benzyl-4-aza-1-azoniabicyclo-[2.2.2]octane HiyamaHiyama reactionreaction ofof justjust aboutabout thethe samesame substratesubstrate scope,scope, usingusing palladiumpalladium saltsalt ofof 1-benzyl-4-aza-1-1-benzyl-4-aza-1- chloride and KF as an activator under microwave irradiation [108]. azoniabicyclo-[2.2.2]octaneazoniabicyclo-[2.2.2]octane chloride chloride and and KF KF as as an an activator activator under under microwave microwave irradiation irradiation [108]. [108].

Scheme 50. Palladacycle-catalyzed Hiyama coupling reactions. SchemeScheme 50. 50. Palladacycle-catalyzed Palladacycle-catalyzed Hiyama Hiyama coupling coupling reactions. reactions. 1-Methyl-2-aminoalkylimidazole derivative was reported as an efficient ligand for Hiyama 1-Methyl-2-aminoalkylimidazole1-Methyl-2-aminoalkylimidazole derivativederivative waswas rereportedported asas anan efficientefficient ligandligand forfor HiyamaHiyama reaction under solvent-free conditions in the presence of Pd(OAc)2. Aryl bromides with reactionareaction range underunder of electron-donating solvent-freesolvent-free conditionsconditions and electron-withdrawing inin thethe presencepresence ofof Pd(OAc)Pd(OAc) substituents22. . ArylAryl bromideswerebromides cross-coupled withwith aa rangerange with ofof electron-donatingaryl(trimethoxy)silane,electron-donating andand a ff ordedelectron-withdrawingelectron-withdrawing the correspondent biarylssubstituentssubstituents in good towerewere high yieldscross-coupledcross-coupled under irradiation withwith aryl(trimethoxy)silane,conditions.aryl(trimethoxy)silane, The congested affordedafforded 2-bromotoluene thethe correspondentcorrespondent yielded biarylsbiaryls the inin coupling goodgood toto highhigh product yieldsyields in underunder 85%, irradiationirradiation while the conditions. The congested 2-bromotoluene yielded the coupling product in 85%, while the 2- 2-bromophenolconditions. The coupledcongested with 2-bromotoluene 40% yield. Thisyielded was the rationalized coupling forproduct the poorin 85%, reactivity, while asthe the 2- bromophenol coupled with 40% yield. This was rationalized for the poor reactivity, as the 2- Catalysts2-bromophenolbromophenol 2020, 10, xcoupled FOR could PEER deactivatewith REVIEW 40% theyield. catalyst This was by coordination rationalized tofor the the metal poor center.reactivity, The as reaction 24the of 352- bromophenol could deactivate the catalyst by coordination to the metal center. The reaction with withbromophenol heteroaryl could halides deactivate and aryl the chlorides catalyst wasby coor in generaldination less to the effective metal (Scheme center. The51). reaction Moreover, with a heteroaryl halides and aryl chlorides was in general less effective (Scheme 51). Moreover, a variety ofvarietyheteroaryl hydroxy- of hydroxy- halides and amino-functionalizedand and aryl amino-functionalized chlorides was imidazoles in general imidazoles lesswere effective were evaluated evaluated (Scheme as asefficient 51). effi cientMoreover, ligands ligands afor variety for the the palladium-catalyzedpalladium-catalyzed Hiyama reaction [109]. [109].

SchemeScheme 51. 51. Palladacycle-catalyzedPalladacycle-catalyzed Hiyama Hiyama coupling coupling reactions. reactions. On the other hand, the catalytic activity of the Pd-PVP nanoparticles toward the coupling reaction On the other hand, the catalytic activity of the Pd-PVP nanoparticles toward the coupling between phenyltrimethoxysilane and aryl halides was demonstrated with many examples of aryl reaction between phenyltrimethoxysilane and aryl halides was demonstrated with many examples bromides, and only two example of aryl chlorides. The reactions were performed in water using of aryl bromides, and only two example of aryl chlorides. The reactions were performed in water sodium hydroxide as the activator at 110 C for 6–9 min under microwave heating (Scheme 52). Despite using sodium hydroxide as the activator◦ at 110 °C for 6–9 min under microwave heating (Scheme 52). the achievement of high yields using low catalyst-loading, the scope of the reaction was limited Despite the achievement of high yields using low catalyst-loading, the scope of the reaction was mainly to activated aryl halides. The reusability of the catalyst was evaluated in four consecutive runs limited mainly to activated aryl halides. The reusability of the catalyst was evaluated in four displaying marginal decrease in the catalytic activity [110]. consecutive runs displaying marginal decrease in the catalytic activity [110].

Scheme 52. Hiyama reactions of phenyltrimethoxysilane with aryl halides.

2.7. Liebeskind-Srogl Cross-Coupling Reaction The Liebeskind-Srogl reaction was recently developed in 2000 [111]. It represents a powerful method developed lately for the construction of C‒C bonds through the palladium-catalyzed cross- coupling of thio-organic compounds with various electrophilic reagents, such as boronic acids and organostannanes, in the presence of stoichiometric amount of copper salt [112,113]. For example, direct microwave-assisted Pd(PPh3)4-catalyzed desulfurative cross-coupling of thiourea compounds (3,4-dihydropyrimidine-2-thiones) and boronic acids were conducted in the presence of copper(I) thiophene-2-carboxylate (CuTC)-mediated conditions, leading to 2-aryl-1,4- dihydropyrimidines. Within few substrates the products were obtained in moderate to high yields, though this protocol represents the first direct coupling of thioureas under Liebeskind-Srogl conditions [114]. On the other hand, the cross-coupling reaction of substituted-pyrimidine-5- carboxylic acid thiol esters with aryl boronic acid gave the corresponding ketones in good yields in general. The reaction was proved to tolerate different substitutions on the pyrimidine scaffold and both electron-poor and electron-rich boronic acids as coupling partners in the presence of relatively inexpensive Pd(OAc)2 as a precatalyst, PPh3 as a ligand and CuTC as a co-catalyst under irradiation conditions for 1 h (Scheme 53) [115,116]. Similarly, arylation of functionalized 2- methylthiopyrimidine [117] and 4-phenylthiopyrimidine [118] derivatives with boronic acids were reported recently under microwave irradiation conditions.

CatalystsCatalysts 20202020,, 1010,, xx FORFOR PEERPEER REVIEWREVIEW 2424 ofof 3535 ofof hydroxy-hydroxy- andand amino-functionalizedamino-functionalized imidazolesimidazoles werewere evaluatedevaluated asas efficientefficient ligandsligands forfor thethe palladium-catalyzedpalladium-catalyzed HiyamaHiyama reactionreaction [109].[109].

SchemeScheme 51.51. Palladacycle-catalyzedPalladacycle-catalyzed HiyamaHiyama couplingcoupling reactions.reactions.

OnOn thethe otherother hand,hand, thethe catalyticcatalytic activityactivity ofof thethe Pd-PVPPd-PVP nanoparticlesnanoparticles towardtoward thethe couplingcoupling reactionreaction betweenbetween phenyltrimethoxysilanephenyltrimethoxysilane andand arylaryl halideshalides waswas demonstrateddemonstrated withwith manymany examplesexamples ofof arylaryl bromides,bromides, andand onlyonly twotwo exexampleample ofof arylaryl chlorides.chlorides. TheThe reactionsreactions werewere performedperformed inin waterwater usingusing sodiumsodium hydroxidehydroxide asas thethe activatoractivator atat 110110 °C°C forfor 6–96–9 minmin underunder microwavemicrowave heatingheating (Scheme(Scheme 52).52). DespiteDespite thethe achievementachievement ofof highhigh yieldsyields usingusing lowlow catalyst-loading,catalyst-loading, thethe scopescope ofof thethe reactionreaction waswas limitedCatalystslimited 2020 mainlymainly, 10, 4 toto activatedactivated arylaryl halides.halides. TheThe reusabilityreusability ofof thethe catalystcatalyst waswas evaluatedevaluated inin25 fourfour of 35 consecutiveconsecutive runsruns displayingdisplaying marginalmarginal decreasedecrease inin thethe catalyticcatalytic activityactivity [110].[110].

SchemeScheme 52. 52. HiyamaHiyama reactions reactions of of phenyltrimethoxysilane phenyltrimethoxysilane with with aryl aryl halides. halides. 2.7. Liebeskind-Srogl Cross-Coupling Reaction 2.7.2.7. Liebeskind-SroglLiebeskind-Srogl Cross-CouplingCross-Coupling ReactionReaction The Liebeskind-Srogl reaction was recently developed in 2000 [111]. It represents a powerful TheThe Liebeskind-SroglLiebeskind-Srogl reactionreaction waswas recentlyrecently develodevelopedped inin 20002000 [111].[111]. ItIt representsrepresents aa powerfulpowerful method developed lately for the construction of C-C bonds through the palladium-catalyzed methodmethod developeddeveloped latelylately forfor thethe constructionconstruction ofof CC‒‒CC bondsbonds throughthrough thethe palladium-catalyzedpalladium-catalyzed cross-cross- cross-coupling of thio-organic compounds with various electrophilic reagents, such as boronic acids couplingcoupling ofof thio-organicthio-organic compoundscompounds withwith variousvarious elelectrophilicectrophilic reagents,reagents, suchsuch asas boronicboronic acidsacids andand and organostannanes, in the presence of stoichiometric amount of copper salt [112,113]. organostannanes,organostannanes, inin thethe presencepresence ofof stoichiostoichiometricmetric amountamount ofof coppercopper saltsalt [112,113].[112,113]. For example, direct microwave-assisted Pd(PPh3)4-catalyzed desulfurative cross-coupling ForFor example,example, directdirect mimicrowave-assistedcrowave-assisted Pd(PPhPd(PPh33))44-catalyzed-catalyzed desulfurativedesulfurative cross-couplingcross-coupling ofof of thiourea compounds (3,4-dihydropyrimidine-2-thiones) and boronic acids were conducted thioureathiourea compoundscompounds (3,4-dihydro(3,4-dihydropyrimidine-2-thiones)pyrimidine-2-thiones) andand boroniboronicc acidsacids werewere conductedconducted inin thethe in the presence of copper(I) thiophene-2-carboxylate (CuTC)-mediated conditions, leading to presencepresence ofof copper(I)copper(I) thiophene-2-carboxylatethiophene-2-carboxylate (C(CuTC)-mediateduTC)-mediated conditions,conditions, leadingleading toto 2-aryl-1,4-2-aryl-1,4- 2-aryl-1,4-dihydropyrimidines. Within few substrates the products were obtained in moderate to high dihydropyrimidines.dihydropyrimidines. WithinWithin fewfew substratessubstrates thethe producproductsts werewere obtainedobtained inin moderatemoderate toto highhigh yields,yields, yields, though this protocol represents the first direct coupling of thioureas under Liebeskind-Srogl thoughthough thisthis protocolprotocol representsrepresents thethe firstfirst directdirect couplingcoupling ofof thioureasthioureas underunder Liebeskind-SroglLiebeskind-Srogl conditions [114]. On the other hand, the cross-coupling reaction of substituted-pyrimidine-5-carboxylic conditionsconditions [114].[114]. OnOn thethe otherother hand,hand, thethe cross-couplingcross-coupling reactionreaction ofof substituted-pyrimidine-5-substituted-pyrimidine-5- acid thiol esters with aryl boronic acid gave the corresponding ketones in good yields in general. The carboxyliccarboxylic acidacid thiolthiol estersesters withwith arylaryl boronicboronic acidacid gavegave thethe correspondingcorresponding ketonesketones inin goodgood yieldsyields inin reaction was proved to tolerate different substitutions on the pyrimidine scaffold and both electron-poor general.general. TheThe reactionreaction waswas provedproved toto toleratetolerate diffdifferenterent substitutionssubstitutions onon thethe pyrimidinepyrimidine scaffoldscaffold andand and electron-rich boronic acids as coupling partners in the presence of relatively inexpensive Pd(OAc) bothboth electron-poorelectron-poor andand electron-richelectron-rich boronicboronic acidsacids asas couplingcoupling partnerspartners inin thethe presencepresence ofof relativelyrelatively2 as a precatalyst, PPh3 as a ligand and CuTC as a co-catalyst under irradiation conditions for 1 h inexpensiveinexpensive Pd(OAc)Pd(OAc)22 asas aa precatalyst,precatalyst, PPhPPh33 asas aa ligandligand andand CuTCCuTC asas aa co-catalystco-catalyst underunder irradiationirradiation (Scheme 53)[115,116]. Similarly, arylation of functionalized 2-methylthiopyrimidine [117] and conditionsconditions forfor 11 hh (Scheme(Scheme 53)53) [115,116].[115,116]. Similarly,Similarly, arylationarylation ofof functionalizedfunctionalized 2-2- 4-phenylthiopyrimidine [118] derivatives with boronic acids were reported recently under microwave methylthiopyrimidinemethylthiopyrimidine [117][117] andand 4-phenylthiopyrimi4-phenylthiopyrimidinedine [118][118] derivativesderivatives withwith boronicboronic acidsacids werewere irradiation conditions. reportedreported recentlyrecently underunder microwavemicrowave irradiationirradiation conditions.conditions.

Scheme 53. Palladium-catalyzed Liebeskind-Srogl ketone synthesis.

Van der Eycken and coworkers have disclosed for the first time the Liebeskind–Sonogashira-type cross-coupling reaction between 5-chloro-3-(phenylsulfanyl) pyrazin-2(1H)-ones and terminal alkynes. The corresponding products, 5-chloro-3-alkynylpyrazinones, were obtained in moderate to high yields (Scheme 54). This transformation was performed satisfactorily when alkylthio substituent was present in the C3-position instead of a phenylthio substituent upon irradiation for 60 min. The scope of the protocol was further extended to solid-phase-linked pyrazinones, oxazinones, pyrazines, and phenyl thioesters [119]. The same authors have reported thereafter an improved route toward pyrazine-containing nucleoside analogues under standard Liebiskind-Srogl conditions. When pyrazines bearing S-4-methoxybenzyl substituent reacted with boronic acids in the presence of Pd(PPh3)4 and CuTC in THF, the cross-coupled products were formed in good to high yields under irradiation conditions at 120 ◦C for an hour [120]. Catalysts 2020, 10, x FOR PEER REVIEW 25 of 35 Catalysts 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 25 of 35

Scheme 53. Palladium-catalyzed Liebeskind-Srogl ketone synthesis. Scheme 53. Palladium-catalyzed Liebeskind-Srogl-Srogl ketoneketone synthesis.synthesis. Van der Eycken and coworkers have disclosed for the first time the Liebeskind–Sonogashira- Van der Eycken and coworkers have disclosed for the first time the Liebeskind–Sonogashira- type cross-coupling reaction between 5-chloro-3-(phenylsulfanyl) pyrazin-2(1H)-ones and terminal typetype cross-couplingcross-coupling reactionreaction betweenbetween 5-chloro-3-(phenylsulfanyl)5-chloro-3-(phenylsulfanyl) pyrazin-2(pyrazin-2(1H)-ones)-ones andand terminalterminal alkynes. The corresponding products, 5-chloro-3-alkynylpyrazinones, were obtained in moderate to alkynes. The corresponding products, 5-chloro-3-alkynylpyrazinones, were obtained in moderate to high yields (Scheme 54). This transformation was performed satisfactorily when alkylthio substituent high yields (Scheme 54). This transformation was performed satisfactorily when alkylthio substituent was present in the C3-position instead of a phenylthio substituent upon irradiation for 60 min. The was present in the C3-position instead of a phenylthioio substituentsubstituent uponupon irradiationirradiation forfor 6060 min.min. TheThe scope of the protocol was further extended to solid-phase-linked pyrazinones, oxazinones, pyrazines, scope of the protocol was further extended to solid-phase-linked pyrazinones, oxazinones,oxazinones, pyrazines,pyrazines, and phenyl thioesters [119]. The same authors have reported thereafter an improved route toward and phenyl thioesters [119]. The same authors have reported thereafter an improved route toward pyrazine-containing nucleoside analogues under standard Liebiskind-Srogl conditions. When pyrazine-containing nucleoside analogues under standard Liebiskind-Srogl conditions. When pyrazines bearing S-4-methoxybenzyl substituent reacted with boronic acids in the presence of pyrazines bearing S-4-methoxybenzyl-4-methoxybenzyl substituentsubstituent reactedreacted wiwithth boronicboronic acidsacids inin thethe presencepresence ofof Pd(PPh3)4 and CuTC in THF, the cross-coupled products were formed in good to high yields under CatalystsPd(PPh20203)4 and, 10, 4CuTC in THF, the cross-coupled products were formed in good to high yields 26under of 35 irradiation conditions at 120 °C for an hour [120]. irradiationirradiation conditionsconditions atat 120120 °C°C forfor anan hourhour [120].[120]. R R2 Pd(PPh ) Cl R2 R2 Pd(PPh3))2Cl2 R2 R N O CuI, Cs 3CO2 2 R N O R1 N O CuI, Cs2CO3 R1 N O 1 + R3 2 3 1 + R3 MW, DMF, 95 °C, 45 min Ph MW, DMF, 95 °C, 45 min Cl N S Ph Cl N Cl N S R1 =H,Me,Bn,4-MeOC6H4 Cl N R1 =H,Me,Bn,4-MeOC6H4 R R2 =4-MeOBn,CH2Cy, (CH2)3Ph R3 R2 =4-MeOBn,CH2Cy, (CH2)3Ph 3 R3 = hexyl, Cy, Ph, 2-MeC6H4, 3-thienyl, etc 69-88% R3 = hexyl, Cy, Ph, 2-MeC6H4, 3-thienyl, etc 69-88% Scheme 54. Liebeskind–Sonogashira-type cross-coupling reactions. Scheme 54. Liebeskind–Sonogashira-type cross-coupling reactions. On the other hand, a diversitydiversity ofof heteroarylheteroaryl methylthioethersmethylthioethers was cross-coupled with terminal On the other hand, a diversity of heteroaryl methylthioethersthylthioethers waswas cross-coupledcross-coupled withwith terminalterminal alkynes. The full conversion of starting materials under microwave irradiation was not enough using alkynes. The full conversion of starting materials under microwave irradiation was not enough using CuI (0.2 equiv.), Pd(dppf)ClPd(dppf)Cl22 (0.1 equiv.), andand Et3N (2 equiv.), equiv.), unless another amounts of the catalysts CuI (0.2 equiv.), Pd(dppf)Cl2 (0.1 equiv.), and Et3N (2 equiv.), unless another amounts of the catalysts and base were in need to be added freshly to the reaction mixture after half reaction time (overall 20 and base were in need to be added freshly to the reaction mixture after half reaction time (overall 20 mol% Pd). The limited conversion of starting mate materialsrials was attributed to the catalyst, which could mol% Pd). The limited conversion of starting materials was attributed to the catalyst, which could decompose under the applied reaction conditionsconditions (Scheme(Scheme 5555))[ [121].121]. decompose under the applied reaction conditionsconditions (Scheme(Scheme 55)55) [121].[121].

Scheme 55. Sonogashira-type reaction of aryl methyl-thioethersmethyl-thioethers with terminal alkynes. Scheme 55. Sonogashira-type reaction of aryl methyl-thioethersthyl-thioethers withwith terminalterminal alkynes.alkynes.

Prieur et et al. al. have havedescribed described a selective a selectivestrategy strategyfor the arylation for the of arylation 4-chloro-2- of Prieur et al. have described a selective strategy for the arylation of 4-chloro-2- 4-chloro-2-(methylthio)pyrrolo[3,2-(methylthio)pyrrolo[3,2-d]pyrimidined]pyrimidine derivatives under derivatives Suzuki-Miyaura under and Suzuki-MiyauraLiebeskind-Srog (methylthio)pyrrolo[3,2-(methylthio)pyrrolo[3,2-d]pyrimidine]pyrimidine derivativesderivatives underunder Suzuki-MiyauraSuzuki-Miyaura andand Liebeskind-SrogLiebeskind-Srog andconditions Liebeskind-Srog subsequently. conditions The later subsequently.was performed between The later 4-aryl-2-(methylthio)pyrrolo[3,2- was performed between conditions subsequently. The laterter waswas performedperformed betweenbetween 4-aryl-2-(methylthio)pyrrolo[3,2-4-aryl-2-(methylthio)pyrrolo[3,2- 4-aryl-2-(methylthio)pyrrolo[3,2-d]pyrimidines and boronic acids usingd]pyrimidines Pd(PPh3)4 andand copper(I) boronic acids 3-methylsalicylate using Pd(PPh (CuMeSal)3)4 and copper(I) in THF d]pyrimidines and boronic acids using Pd(PPh3)4 and copper(I) 3-methylsalicylate (CuMeSal) in THF 3-methylsalicylateat 100 °C for 1 h (Scheme (CuMeSal) 56). The in desulfurative THF at 100 reacC fortion 1 proceeded h (Scheme smoothly56). The in desulfurative the presence of reaction either at 100 °C for 1 h (Scheme 56). The desulfurative◦ reactiontion proceededproceeded smoothlysmoothly inin thethe presencepresence ofof eithereither proceededelectron-donating, smoothly electron-withdrawing, in the presence of either or electron-donating, heterocyclic substituents electron-withdrawing, on the arylboronic or heterocyclic acids, electron-donating, electron-withdrawing, or heterocyclic substituents on the arylboronic acids, substituentsleading to the on products the arylboronic in high acids,yields leading[122]. to the products in high yields [122]. leadingleading toto thethe productsproducts inin highhigh yieldsyields [122].[122].

Scheme 56. Palladium-catalyzed desulfurative cross-coupling reactions.

The Liebeskind–Srogl reaction was further employed as the key step to combine the two fragments together in a multi-step synthesis of cholesterol analogues [123], and in the synthesis of cannabinergic ligands, namely C1’-azacycloalkyl hexahydrocannabinols [124]. Moreover, the Soai-type aldehydes were obtained in a single-step synthesis from dehydrosulfurative coupling of terminal alkynes with 2-mercapto-1,3-pyrimidine-5-carbaldehyde under base-free conditions in low to high yields, Scheme 57[125,126]. Catalysts 2020, 10, x FOR PEER REVIEW 26 of 35 Catalysts 2020, 10, x FOR PEER REVIEW 26 of 35 Scheme 56. Palladium-catalyzed desulfurative cross-coupling reactions. Scheme 56. Palladium-catalyzed desulfurative cross-coupling reactions. The Liebeskind–Srogl reaction was further employed as the key step to combine the two The Liebeskind–Srogl reaction was further employed as the key step to combine the two fragmentsThe Liebeskind–Srogl together in a multi-step reaction synthesis was further of ch olesterolemployed analogues as the key [123], step and to incombine the synthesis the two of fragments together in a multi-step synthesis of cholesterol analogues [123], and in the synthesis of cannabinergicfragments together ligands, in a namely multi-step C1’-azacycloalkyl synthesis of ch hexahydrocannabinolsolesterol analogues [123], [124]. and Moreover, in the synthesis the Soai- of cannabinergic ligands, namely C1’-azacycloalkyl hexahydrocannabinols [124]. Moreover, the Soai- typecannabinergic aldehydes ligands, were obtainednamely C1’-azacycloalkyl in a single-step hexahydrocannabinolssynthesis from dehydrosulfurative [124]. Moreover, coupling the Soai- of type aldehydes were obtained in a single-step synthesis from dehydrosulfurative coupling of terminaltype aldehydes alkynes werewith 2-mercapto-1,3-pyrimidine-obtained in a single-step 5-carbaldehydesynthesis from underdehydrosulfurative base-free conditions coupling in low of Catalyststerminal2020 alkynes, 10, 4 with 2-mercapto-1,3-pyrimidine-5-carbaldehyde under base-free conditions in27 oflow 35 terminalto high yields, alkynes Scheme with 2-mercapto-1,3-pyrimidine-57 [125,126]. 5-carbaldehyde under base-free conditions in low to high yields, Scheme 57 [125,126].

Scheme 57. SynthesisSynthesis of of Soai-type Soai-type aldehydes fr fromom dehydrosulfurative reactions. Scheme 57. Synthesis of Soai-type aldehydes from dehydrosulfurative reactions. 2.8. Other Other Cross-Coupling Cross-Coupling Reaction 2.8. Other Cross-Coupling Reaction Although therethere are are a numbera number of cross-couplingof cross-couplin protocolsg protocols developed developed during during the past the few past decades, few Although there are a number of cross-coupling protocols developed during the past few decades,the fascinationAlthough the fascination bythere the scientificare by a thenumber communityscientific of cross-couplincommuni is far lessty comparing isg farprotocols less comparing with developed the aforementioned with during the aforementioned the approaches. past few decades, the fascination by the scientific community is far less comparing with the aforementioned Thedecades,approaches. Kumada the Thefascination reaction Kumada is by onereaction the of scientific these is one protocols communi of these reported typrotocols is far scarcelyless reported comparing in scarcely the peer-reviewedwith in the the aforementioned peer-reviewed literature, approaches. The Kumada reaction is one of these protocols reported scarcely in the peer-reviewed particularlyliterature,approaches. particularly underThe Kumada microwave under reaction conditions, microwave is one becauseof these conditions, ofprotocols the sensitivity becausereported of thescarcelyof organomagnesiumthe insensitivity the peer-reviewed of halides the literature, particularly under microwave conditions, because of the sensitivity of the (Grignardorganomagnesiumliterature, reagents)particularly halides as couplingunder (Grignard partners.microwave reagents) Within asconditions, coupling single example, partners.because thisWithin of type the single of sensitivity cross-coupling example, thisof type wasthe organomagnesium halides (Grignard reagents) as coupling partners. Within single example, this type oforganomagnesiumdescribed cross-coupling as a proof halideswas of conceptdescribed (Grignard under as reagents) microwavea proof as couplingof conditionsconcept partners. under [100]. Within Nevertheless,microwave single example,conditions the synthesized this [100]. type of cross-coupling was described as a proof of concept under microwave conditions [100]. Nevertheless,ofoxime-based cross-coupling palladacyclethe synthesized was described precatalyst oxime-based as (seea proof Schemepalladac of 40ycleconcept) was precatalyst employed under (seemicrowave in Scheme very low 40)conditions catalyst was employed loading [100]. Nevertheless, the synthesized oxime-based palladacycle precatalyst (see Scheme 40) was employed (0.05inNevertheless, very mol%) low catalyst in the coupling synthesized loading reaction (0.05 oxime-based mol%) between in coupling palladac different reactionycle combinations precatalyst between (seeof different alkyl Scheme halides combinations 40) was and employed Grignard of alkyl in very low catalyst loading (0.05 mol%) in coupling reaction between different combinations of alkyl halidesinreagents, very lowand leading catalyst Grignard to highloading reagents, yields (0.05 of leading mol%) the anticipated into couplinghigh productyields reaction of (Scheme the between anticipated 58). different The product recyclability combinations (Scheme of the 58). of catalyst alkyl The halides and Grignard reagents, leading to high yields of the anticipated product (Scheme 58). The wasrecyclabilityhalides carried and outGrignardof the using catalyst phenylmagnesiumreagents, was leadingcarried toout bromide high using yields andphenylmagnesium bromobenzeneof the anticipated underbromide product the and optimized (Scheme bromobenzene 58). reaction The recyclability of the catalyst was carried out using phenylmagnesium bromide and bromobenzene underrecyclabilityconditions. the optimized A of yield the ofcatalyst 91%reaction was was droppedconditions. carried to out 63%A usingyield in the phenylmagnesiumof fourth 91% runwas becausedropped bromide of to Pd 63% leaching, and in bromobenzenethe observed fourth asrun a under the optimized reaction conditions. A yield of 91% was dropped to 63% in the fourth run becauseunderblack precipitatedthe of Pdoptimized leaching, formed reaction observed during conditions. as the a reactionblack A pr yield [ecipitated95]. of 91% formed was duringdropped the to reaction 63% in [95]. the fourth run because of Pd leaching, observed as a black precipitated formed during the reaction [95].

Scheme 58. Paladacycle-catalyzed Kumada coupling reactions. Scheme 58. Paladacycle-catalyzed Kumada coupling reactions. Finze’s groupgroup has has reported reported on theon Kumada-typethe Kumada-type cross-coupling cross-coupling reaction reaction of mono of- and monodi-iodinated- and di- Finze’s group has reported on the Kumada-type cross-coupling reaction of mono- and di- iodinatedcarba-Finze’scloso carba--dodecaborate groupcloso has-dodecaborate reported anions with on anions various the Kuma with Grignard da-typevarious reagents. Grignardcross-coupling The reagents. coupling reaction The products couplingof mono were -products obtainedand di- iodinated carba-closo-dodecaborate anions with various Grignard reagents. The coupling products wereunder obtained microwave under conditions microwave in high conditions yields and shorterin high reaction yields timesand shorter using PdCl reaction2P(Ph 3times)2 in THFusing at were obtained under microwave conditions in high yields and shorter reaction times using PdClabout2P(Ph 60 ◦C3)2 (Scheme in THF at59 about)[127]. 60 °C (Scheme 59) [127]. PdCl2P(Ph3)2 in THF at about 60 °C (Scheme 59) [127].

Scheme 59. Microwave-assisted Kumada-type cross-coupling reactions.

Recently, decarboxylative cross-coupling reactions were found to be an appealing source for the generation of C–C bond. In this type of reaction, the relatively inexpensive carboxylic acid salt reacts with an organic halide or pseudohalides to form biaryls with the loss of CO2 [128]. Gooßen and coworkers have developed a palladium-catalyzed synthesis of biaryls derivatives from the decarboxylative cross-coupling of carboxylic acid salts with aryl bromides in the presence of CuI Catalysts 2020, 10, x FOR PEER REVIEW 27 of 35 Catalysts 2020,, 10,, xx FORFOR PEERPEER REVIEWREVIEW 27 of 35

Scheme 59. Microwave-assisted Kumada-type cross-coupling reactions. Scheme 59. Microwave-assisted Kumada-type cross-coupling reactions.

Recently, decarboxylative cross-coupling reactions were found to be an appealing source for the Recently, decarboxylative cross-coupling reactions were found to be an appealing source for the generation of C–C bond. In this type of reaction, the relatively inexpensive carboxylic acid salt reacts generation of C–C bond. In this type of reaction, the relatively inexpensive carboxylic acid salt reacts with an organic halide or pseudohalides to form biaryls with the loss of CO2 [128]. Gooßen and withCatalysts an2020 organic, 10, 4 halide or pseudohalides to form biaryls with the loss of CO2 [128]. Gooßen28 and of 35 coworkers have developed a palladium-catalyzed synthesis of biaryls derivatives from the coworkers have developed a palladium-catalyzed synthesis of biaryls derivatives from the decarboxylative cross-coupling of carboxylic acid salts with aryl bromides in the presence of CuI as decarboxylative cross-coupling of carboxylic acid salts with aryl bromides in the presence of CuI as a cocatalyst under microwave conditions. The reaction has proceeded smoothly with potassium 2- aas cocatalyst a cocatalyst under under microwave microwave conditions. conditions. The The reaction reaction has has proceeded proceeded smoothly smoothly with with potassium potassium 2- nitrobenzoate and numerous electron-rich and electron-poor aryl bromides in moderate to high nitrobenzoate2-nitrobenzoate and and numerous numerous electron-rich electron-rich and and elec electron-poortron-poor aryl aryl bromides bromides in in moderate moderate to to high yields in 5 min. However, the 4-bromotoluene was converted to the corresponding products (31– yields inin 55 min.min. However,However, the the 4-bromotoluene 4-bromotoluene was was converted converted to theto the corresponding corresponding products products (31–87%) (31– 87%) when conducted with a range of arenecarboxylic acid salts (Scheme 60). Under similar 87%)when when conducted conducted with a with range a of range arenecarboxylic of arenecarboxylic acid salts acid (Scheme salts 60 (Scheme). Under 60). similar Under conditions, similar conditions, few examples of aryl ketones were achieved from the couplingα of α-oxocarboxylates with conditions,few examples few ofexamples aryl ketones of aryl were ketones achieved were achieved from the from coupling the coupling of -oxocarboxylates of α-oxocarboxylates with with aryl aryl bromides [129]. The same group has also disclosed another protocol for the decarboxylative arylbromides bromides [129]. [129]. The sameThe same group group has also has disclosed also disclosed another another protocol protocol for the decarboxylative for the decarboxylative coupling coupling of aryl tosylates with aromatic carboxylate salts. In this approach, biaryl derivatives were couplingof aryl tosylates of aryl withtosylates aromatic with carboxylatearomatic carboxylate salts. In this salts. approach, In this approach, biaryl derivatives biaryl derivatives were obtained were obtainedin good yields in good using yields Pd(acac) using2 /Pd(acac)XPhos as2/XPhos a catalyst as a and catalyst CuO /1,10-phenanthrolineand CuO/1,10-phenanthroline as a co-catalyst as a co- to obtained in good yields using Pd(acac)2/XPhos as a catalyst and CuO/1,10-phenanthroline as a co- catalyst to facilitate the decarboxylative step under microwave irradiation for 2–5 min [130]. catalystfacilitate to the facilitate decarboxylative the decarboxylative step under step microwave under microwave irradiation irradiation for 2–5 min for [130 2–5]. min [130].

Scheme 60. Palladium-catalyzedPalladium-catalyzed decarboxylative cross-coupling reactions. Scheme 60. Palladium-catalyzed decarboxylative cross-coupling reactions.

Behrends et et al. al. has has described described the the desulfinative desulfinative cros cross-couplings-coupling of aryl of sulfinates aryl sulfinates and nitriles and nitriles using Behrends et al. has described the desulfinative cross-coupling of aryl sulfinates and nitriles using Pd(Ousing2CCF Pd(O3)22CCF and3 6-methyl-2,2)2 and 6-methyl-2,2′-bipyridyl0-bipyridyl (MBP) as (MBP) a catalytic as a catalytic system systemand trifluoroacetic and trifluoroacetic acid (TFA) acid Pd(O2CCF3)2 and 6-methyl-2,2′′-bipyridyl (MBP) as a catalytic system and trifluoroacetic acid (TFA) (TFA)as additive as additive in water-TH in water-THF.F. The Thescope scope of the of the microwave microwave protoc protocolol was was investigated investigated with with diverse as additive in water-THF. The scope of the microwave protocol was investigated with diverse sulfinatessulfinates and a range of nitriles bearing electron-richelectron-rich and electron-deficientelectron-deficient substituents, leading to sulfinates and a range of nitriles bearing electron-rich and electron-deficient substituents, leading to the arylaryl ketonesketones relativelyrelatively in in good good to to high high yields yields in in addition addition to theto the corresponding corresponding amides, amides, resulting resulting as a the aryl ketones relatively in good to high yields in addition to the corresponding amides, resulting asbyproduct a byproduct from thefrom hydration the hydration of the organicof the organic nitriles (Schemenitriles (Scheme61). Remarkably, 61). Remarkably, few selected few substrates selected as a byproduct from the hydration of the organic nitriles (Scheme 61). Remarkably, few selected weresubstrates performed were performed using a heating using block, a heating giving block, relatively giving lower relatively yields lower [131 ].yields [131]. substrates were performed using a heating block, giving relatively lower yields [131].

Scheme 61. Palladium-catalyzed desulfinative cross-coupling reactions. Scheme 61. Palladium-catalyzedPalladium-catalyzed desulfinative desulfinative cross-coupling reactions.

Allylic substitutionsubstitution has has been been scarcely scarcely reported reported in the in literature, the literature, although although it is useful it is in useful the syntheses in the Allylic substitution has been scarcely reported in the literature, although it is useful in the synthesesof valuable of chemical valuable structures. chemical structures. The coupling The reaction coupling of reaction diacetate of diene diacetate substrate diene with substrate a number withof a syntheses of valuable chemical structures. The coupling reaction of diacetate diene substrate with a numbernucleophiles, of nucleophiles, include carbon include nucleophiles carbon anucleophilefforded for thes afforded most part for the the expected most part di-substituted the expected dienyl di- number of nucleophiles, include carbon nucleophiles afforded for the most part the expected di- substitutedderivatives indienyl low yieldsderivatives under irradiationin low yields condition under for irradiation 20 min, using condition Pd(OAc) for2/PPh 203 asmin, a catalyst using substituted dienyl derivatives in low yields under irradiation condition for 20 min, using precursorPd(OAc)2/PPh in aqueous3 as a catalyst ethanol precursor (Scheme in62 aq)[132ueous]. ethanol (Scheme 62) [132]. Pd(OAc)2/PPh3 as a catalyst precursor in aqueous ethanol (Scheme 62) [132].

Scheme 62. Pd-catalyzed allylic substitution reactions.

3. Conclusions Palladium-catalyzed cross-coupling to generate C–C bond, such as Negishi, Heck, Kumada, Sonogashira, Stille, Suzuki, and Hiyama, under microwave condition has proved to be safe in Catalysts 2020, 10, 4 29 of 35 handling and cost effectiveness. It is well-known that the use of microwave technology to heat reactions would shorten the reaction time, but, in some cases, it was crucial for obtaining the desired products and to improve the yield of the products. It is worth mentioning that before developing and investigating cross-coupling reaction, the use of aqua regia to clean stirring bars and glassware are highly recommended, since palladium contamination down to level 50 ppb will be accountable for the generation of coupling product [133]. Moreover, the main advantage of solid support is the consecutive use of the materials (recycling of the catalyst). Finally, we hope that this review will inspire scientists for further exploration of the microwave irradiation in organic synthesis and to make this technology widely available soon.

Author Contributions: Both authors contributed equally to this work. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by Arab-German Young Academy of Sciences and Humanities (AGYA) grants (TP_2018_29 & TP_2019_04). Acknowledgments: The publication of this article was funded by the Qatar National Library. Conflicts of Interest: The authors declare no conflict of interest.

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