Bulky-Yet-Flexible Carbene Ligands and Their Use in Palladium Cross-Coupling

inorganics

Review Bulky-Yet-Flexible Carbene Ligands and Their Use in Palladium Cross-Coupling

Soﬁe M. P. Vanden Broeck , Fady Nahra † and Catherine S. J. Cazin * Centre for Sustainable Chemistry, Department of Chemistry, Ghent University, Krijgslaan 281-S3, B-9000 Gent, Belgium; [email protected] (S.M.P.V.B.); [email protected] (F.N.) * Correspondence: [email protected] Current address: VITO (Flemish Institute for Technological Research), Separation and Conversion Technology, † Boeretang 200, B-2400 Mol, Belgium.

Received: 10 May 2019; Accepted: 15 June 2019; Published: 21 June 2019

Abstract: In recent years, several classes of new N-heterocyclic carbene (NHC) ligands were developed around the concept of “ﬂexible steric bulk”. The steric hindrance of these ligands brings stability to the active species, while ligand ﬂexibility still allows for the approach of the substrate. In this review, the synthesis of several types of new classes, such as IBiox, cyclic alkyl amino carbenes (CAAC), ITent, and IPr* are discussed, as well as how they move the state-of-the-art in palladium catalyzed cross-coupling forward.

Keywords: N-heterocyclic carbenes; ﬂexible sterics; palladium; cross-coupling

1. Introduction In recent years, interest on N-heterocyclic carbenes (NHCs) has been growing rapidly due to their excellent stability, diversity and a possible tunability of steric and electronic properties [1–13]. Fine-tuning the steric hindrance led to major breakthroughs and improvements in catalysis [14–17]. Bulkier ligands stabilize the active species and disfavor bimolecular decomposition and other routes of deactivation [18–21]. However, steric bulk disfavors the approach of the substrate, which might diminish catalytic activity. Therefore, a delicate balance between skeletal flexibility and steric bulk is required to enhance catalytic efficacy [18–22]. The focus of this review is on three different classes of bulky ligands: IBiox [23], cyclic alkyl amino carbenes (CAAC)[24] and N,N’-bis(aryl)imidazolylidenes (such as the ITent-, IPr*- and SICyoctNap series) [25–29]. Their synthesis is discussed, as well as their role in palladium-catalyzed cross-coupling reactions.

2. IBiox Glorius was the first to report on the concept of “flexible steric bulk” with his work on bisoxazoline-derived N-heterocyclic carbene ligands (IBiox)[23,30]. The rigidity of these ligands comes from their tricyclic backbone. These ligands can be easily prepared, starting from their corresponding bisoxazolines [15,23,30] and tuning of steric bulk, flexibility, and chirality can be achieved by judicious substitutions [31,32] (Scheme1).

Inorganics 2019, 7, 78; doi:10.3390/inorganics7060078 www.mdpi.com/journal/inorganics InorganicsInorganicsInorganics 2019 20192019,, ,7 77,, ,x 78x FOR FOR PEER PEER REVIEW REVIEW 2 2 2 of of 15 14 15 Inorganics 2019, 7, x FOR PEER REVIEW 2 of 15 OHOH 1)1) DiethylDiethyl oxalateoxalate OO OO OO OO 2)2) SOCl SOCl2 ClCHClCH2OPivOPiv HH22NN 1) Diethyl2 oxalate 2 RR O O RR OH RR O N NO RR NN N N 3)2)3) NaOH,SOClNaOH, EtOH EtOH N N AgOTfAgOTf H RN R 2 ClCH2OPiv RR RR R2 R RRR RRR R NOTfOTf N R 3) NaOH, EtOH N N AgOTf R R R R R R OO OO OO OO OO OO OO OTf OO

ONN N NO ONN N NO ONN N NO ONN N NO RR RR N N N N N N N N n n IBioxMeIBioxMe n n R R nn == 1, 1, IBiox5IBiox5 RR = = Bn, Bn, IBiox[Bn] IBiox[Bn] n n IBioxMe n = 2, IBiox6 n = 2,1, IBiox6IBiox5 RR = = Ph, Bn,Ph, IBiox[Ph] IBiox[Bn]IBiox[Ph] IBiox[(-)-menthyl]IBiox[(-)-menthyl] nn == 3, 3, IBiox7 IBiox7 RR = = iPr,iPr, IBiox[ IBiox[iPr]iPr] n = 2, IBiox6 R = Ph, IBiox[Ph] IBiox[(-)-menthyl] n = 4, IBiox8 R =t tBu, IBiox[ttBu] n = 4,3, IBiox8IBiox7 R = iBu,Pr, IBiox[IBiox[iPr]Bu] n = 8, IBiox12 n = 8,4, IBiox12IBiox8 R = tBu, IBiox[tBu] n = 8, IBiox12 SchemeScheme 1. 1. Synthesis Synthesis of of the the IBiox IBiox ligand ligand series series [23,30,32–34]. [23,30,32–34]. Scheme 1. SynthesisSynthesis of of the the IBioxIBiox ligandligand series series [23,30,32–34]. [23,30,32–34]. TheThe flexibilityflexibility ofof thethe stericsteric hindrancehindrance ofof thesethese ligandsligands cancan bebe demonstrateddemonstrated byby thethe equilibriumequilibrium betweenbetweenThe variousflexibility ﬂexibilityvarious conformers conformers of the steric of of IBiox6IBiox6hindrance (Scheme (Scheme of these 2)2) [30]. [30].ligands can be demonstrated by the equilibrium between various conformers of IBiox6 (Scheme 22))[ [30].30].

OO OO OO OO OO OO

ONN N NO ONN N NO ONN N NO N N N N N N aa b b cc a b c SchemeSchemeScheme 2. 2. Equilibrium2. Equilibrium Equilibrium between between between conformations conformations conformations of of IBiox6of IBiox6 IBiox6(a –[30]. [30].c)[30 ]. Scheme 2. Equilibrium between conformations of IBiox6 [30]. 2.1.2.1.2.1. Suzuki–Miyaura Suzuki–Miyaura Cross-Coupling Cross-Coupling 2.1. Suzuki–MiyauraTheTheThe steric steric flexibility flexibilityflexibility Cross-Coupling of ofof the thethe IBiox IBioxIBiox series seriesseries proved provedproved to toto be bebe an anan important importantimportant factor factorfactor in inin enabling enablingenabling challenging challengingchallenging cross-coupling reactions, such as the formation of ortho-substituted biaryls via a Suzuki–Miyaura cross-couplingcross-couplingThe steric flexibility reactions,reactions, of suchsuch the asIBioxas thethe series formationformation proved ofof to orthoortho be an-substituted-substituted important biaryls biarylsfactor in via via enabling a a Suzuki–Miyaura Suzuki–Miyaura challenging coupling [15,23,30]. Screening of a series of IBiox ligands with cycloalkyl substituents showed that couplingcross-couplingcoupling [15,23,30].[15,23,30]. reactions, ScreeningScreening such ofofas a a the seriesseries formation ofof IBioxIBiox of ligandsligands ortho-substituted withwith cycloalkylcycloalkyl biaryls substituentssubstituents via a Suzuki–Miyaura showedshowed thatthat the formation of highly hindered tetra-ortho-substituted biaryls requires increased steric hindrance thecouplingthe formationformation [15,23,30]. ofof highlyhighly Screening hinderedhindered of a tetra- tetra-seriesorthoortho of -substitutedIBiox-substituted ligands biarylsbiaryls with cycloalkyl requiresrequires increasedincreased substituents stericsteric showed hindrancehindrance that about the NHC ligand [23]. In that context, IBiox12 emerged as the desired catalyst for this reaction abouttheabout formation thethe NHCNHC of ligandligand highly [23].[23]. hindered InIn thatthat tetra- context,context,ortho IBiox12IBiox12-substituted emergedemerged biaryls asas thetherequires desireddesired increased catalystcatalyst steric forfor thisthis hindrance reactionreaction (Scheme3)[23]. (Schemeabout(Scheme the 3) 3) NHC [23]. [23]. ligand [23]. In that context, IBiox12 emerged as the desired catalyst for this reaction (Scheme 3) [23]. IBiox12IBiox12 (3.6 (3.6 mol%), mol%), Pd(OAc) Pd(OAc)22 (3 (3 mol%) mol%) ClCl ++ (HO)(HO)BB 22 tt oo KOIBiox12KOBu,Bu, THF/toluene, THF/toluene,(3.6 mol%), Pd(OAc)110 110 C,C, 16 216 (3 h hmol%) RRnn R'R'nn RRnn R'R'nn Cl + (HO)2B KOtBu, THF/toluene, 110 oC, 16 h Rn R'n EtEt Rn OMeOMe R'n Et OMe MeOMeO MeO EtEt Et 96%96% 75%75% 47%47% 96% 75% 47% SchemeScheme 3. 3.3. Selected Selected examples examples of of Suzuki–Miyaura Suzuki–Miyaura cross-coupling cross-coupling using usingusing IBiox12 IBiox12IBiox12 [23]. [[23].23]. Scheme 3. Selected examples of Suzuki–Miyaura cross-coupling using IBiox12 [23]. WhileWhileWhile this this this system system is is produced produced in in situ, situ, the the the well-defined well-defined well-defined IBiox12IBiox12IBiox12-based-based-based dimer dimer dimer µ [PdCl(µ-Cl)(IBiox12)][PdCl([PdCl(µ-Cl)(IBiox12)]While-Cl)(IBiox12)] this system22 was waswas subsequently subsequently issubsequently produced isolated. isolated. isolated. in situ, The The The latter latter the latter showed showed well-defined showed comparable comparable comparable IBiox12 results results-based results to to its its in dimerin to situ situ its counterpart[PdCl(µ-Cl)(IBiox12)]incounterpart situ counterpart in in cross-couplingcross-coupling in cross-coupling2 was subsequently reactions reactions reactions [23]. [23]. isolated. [23]. The latter showed comparable results to its in situ counterpart in cross-coupling reactions [23]. 2.2.2.2.2.2. Alkyl Alkyl Sonogashira Sonogashira Cross-Coupling Cross-Coupling 2.2. AlkylTheTheThe Sonogashira SonogashiraSonogashira Cross-Couplingcross-coupling cross-coupling [14,35,36] [[14,35,36]14,35,36] of ofof alkynes alkynesalkynes with withwith organic organic halides halideshalides is is an an efficient eefficientfficient method methodmethod of obtaining functionalized alkynes. However, aromatic halides are typically used. Coupling of ofof obtaining obtainingThe Sonogashira functionalized functionalized cross-coupling alkynes. alkynes. [14,35,36] However, However, of aromaticalkynes aromatic with halides halides organic are are halides typically typically is an used. used. efficient Coupling Coupling method of of non-activated alkyl halides was always elusive due to problematic oxidative addition steps and non-activatedofnon-activated obtaining functionalized alkyl alkyl halides halides was alkynes.was always always However, elusive elusive aromatic due due to to problematic problematic halides are oxidative oxidative typically addition additionused. Coupling steps steps and and of side-reactions such as β-hydride elimination. The first successful example of this reaction [37] was the side-reactionsnon-activatedside-reactions such alkylsuch asas halides β-hydrideβ-hydride was elimination. alwayselimination. elusive TheThe due firstfirst to successfulsuccessful problematic exampleexample oxidative ofof thisthis addition reactionreaction steps [37][37] was andwas side-reactions such as β-hydride elimination. The first successful example of this reaction [37] was

Inorganics 2019, 7, x FOR PEER REVIEW 3 of 15 InorganicsInorganics 2019, 7, x 78 FOR PEER REVIEW 33 of of 1514 the palladium-catalyzed coupling of primary alkyl halides with terminal alkynes by Fu and co-workers.palladium-catalyzed Later, the coupling first Sonogashira of primary alkyl coupling halides of with secondary terminal bromides alkynes by with Fu and 1-octyne co-workers. was developed by Glorius and co-workers [38], using the well-defined [PdCl(µ-Cl)(IBiox7)]2 pre-catalyst developedLater, the ﬁrst by Glorius Sonogashira and co-workers coupling of [38], secondary using the bromides well-defined with 1-octyne [PdCl(µ-Cl)(IBiox7)] was developed2 pre-catalyst by Glorius (Schemeand co-workers 4). [38], using the well-deﬁned [PdCl(µ-Cl)(IBiox7)]2 pre-catalyst (Scheme4).

O O [PdCl(m-Cl)(IBiox7)]2 (2 mol%) O O [PdCl(m-Cl)(IBiox7)]2 (2 mol%) CuI (8 mol%) n CuI (8 mol%) n N N Alk Br + nHex Alk nHex N N Alk Br + Hex o Alk Hex Cl Cs2CO3, DMF/DME, 60 oC, 16-18 h Cl Cs2CO3, DMF/DME, 60 C, 16-18 h Pd Pd Cl Cl Cl Pd Cl EtO2C Cl EtO2C N N O nHex nHex nHex nHex nHex nHex O O 62% 76% 57% O O [PdCl(m-Cl)(IBiox7)]2 2 Scheme 4. SelectedSelected examples examples of of Sonogashira Sonogashira coupling coupling using using a well-defined well-deﬁned Pd- IBiox complex [38]. [38].

3. CAAC CAAC Series Series Bertrand and and co-workers co-workers recognized recognized the concept the concept of sterically of sterically ﬂexible ligands flexible in their ligands development in their developmentof the novel class of theof cyclic novel (alkyl)(amino)carbenes class of cyclic (alkyl)(amino)carbenes (CAACs)[24,39,40]. (CAACs These electron-rich) [24,39,40]. ligands These electron-richare pyrrolidine-based ligands are and pyrrolidine-based bear two quaternary and carbons. bear two They quaternary are prepared carbons. from They the corresponding are prepared fromimines the [24 corresponding] and after deprotonation imines [24] of the and CAAC after HOTf, deprotonation under harsh of the conditions, CAAC·HOTf, using LDA under (lithium harsh from the corresponding imines [24] and after · deprotonation of the CAAC·HOTf, under harsh conditions,diisopropylamide), using LDA addition (lithium of palladium diisopropylamide), allyl chloride addition dimer leadsof palladium to the formation allyl chloride of the well-deﬁneddimer leads η3 3 to[PdCl( the formation-allyl)(CAAC)] of the well-definedcomplex (Scheme [PdCl(η5).3-allyl)(CAAC)] complex (Scheme 5).

1) LDA O R R 2) O R Ar N R 2) Ar N R R R R 1) LDA R R Ar N N Ar N R 3 Pd Ar N R 3) Tf2O R 2) [PdCl(m-Cl)(h3-allyl)]2 Pd Ar R 3) Tf2O 2) [PdCl(m-Cl)(h -allyl)]2 OTf Cl CAAC·HOTf 3 CAAC·HOTf [PdCl(h3-allyl)(CAAC)]

i i i iPr iPr iPr i Pr Pr Pr iPr N N N i i i iPr iPr iPr Pd Pd Pd Cl Cl Me Cl Cl Cl Me 3 3 3 [PdCl(h3-allyl)(CAACa)] [PdCl(h3-allyl)(CAACb)] [PdCl(h3-allyl)(CAACc)] [PdCl(h -allyl)(CAACa)] [PdCl(h -allyl)(CAACb)] [PdCl(h -allyl)(CAACc)] Scheme 5. SynthesisSynthesis of of the the CAAC CAAC ligand ligand series [24]. [24].

η3 α The reactivity of these [PdCl(η[PdCl( 3-allyl)(CAAC)]-allyl)(CAAC)] complexes was tested in the α-arylation-arylation of aryl chlorides with with phenylethylketone phenylethylketone [24 [24].]. It was It was found found that the that most the sterically most sterically demanding demanding ligand (CAAC ligandc) (wasCAAC thec) most was the effective most wheneffective using when an using unsubstituted an unsubstituted aryl chloride, aryl chloride, whereas whereas the flexibility the flexibility of CAAC of (CAACc) was the most effective when using an unsubstituted aryl chloride, whereas the flexibility ofb CAACled to higherb led to yields higher with yields more with sterically more sterically hindered hindered aryl chlorides. aryl chlorides. CAACb led to higher yields with more sterically hindered aryl chlorides. 4. ITent 4. ITent Recent studies showed that up to a certain point, there is a proportional relationship between Recent studies showed that up to a certain point, there is a proportional relationship between the increase in the NHC steric bulk and the increase in catalytic activity [5,41]. This phenomenon the increase in the NHC steric bulk and the increase in catalytic activity [5,41]. This phenomenon led led to the implementation of flexible bulk into the design of one of the most commonly used NHCs: to the implementation of flexible bulk into the design of one of the most commonly used NHCs: IPr IPr (N,N’-bis-[2,6-(di-iso-propyl)phenyl]imidazol-2-ylidene). This new series is known as ITent (after (N,N’-bis-[2,6-(di-iso-propyl)phenyl]imidazol-2-ylidene). This new series is known as ITent (after its its tentacular structure) and the synthesis of these IPr-mimicking ligands was described by Nolan tentacular structure) and the synthesis of these IPr-mimicking ligands was described by Nolan and and co-workers (Scheme6a) [ 42]. Analogues of these ligands with a chloro-substituted backbone co-workers (Scheme 6a) [42]. Analogues of these ligands with a chloro-substituted backbone were were described by Organ and co-workers in their PEPPSI (Pyridine-Enhanced Precatalyst Preparation described by Organ and co-workers in their PEPPSI (Pyridine-Enhanced Precatalyst Preparation

Inorganics 2019,, 7,, 78x FOR PEER REVIEW 44 of of 1415 Inorganics 2019, 7, x FOR PEER REVIEW 4 of 15 Stabilization and Initiation) series [43] (Scheme 6b), and more recently, Liu and co-workers Stabilizationdescribed the and andsynthesis Initiation) Initiation) of the series acenaphthyl-substituted series [43 ] [43] (Scheme (Scheme6b), and 6b), backbone more and recently, more analogue recently, Liu and IPent co-workers LiuAn (Scheme and co-workers described 6c) [44]. An thedescribed synthesis the ofsynthesis the acenaphthyl-substituted of the acenaphthyl-substituted backbone analoguebackboneIPent analogue(Scheme IPentAn6 c)(Scheme [44]. 6c) [44]. (a) (b)

(a)NO2 (b) i) CCl4/dioxane (1:1) Cl Cl R R 8 Steps R R 80 oC, 2.5 h R R NO2 R N N R N N i) CCl4/dioxane (1:1) ClN NCl R R R R ii) HCl,o 0.5 h R R 8 Steps 80 C, 2.5 h Cl R N N R R N N R R N N R ii) HCl, 0.5 h R R ClCl R R R NHC R RNHC ·HClR R ITent familyR Cl R R NHC NHC ·HCl IPent, R = Me ITent family IHept, R = Et IPent, R = Me INon, R = nPr IHept, R = Et (c) INon, R = nPr (c)

1) AlMe3 EtOCH2Cl NH2 N N N N 1) AlMe3 EtOCH2Cl NH2 2) N N NCl N 2) Cl O O IPentAn·HCl O O An Scheme 6. Synthetic access to ITent ligands (a–c) [42–44].IPent ·HCl Scheme 6. SyntheticSynthetic access to ITentITent ligands (a–c)[) [42–44].42–44]. The Nolan group used this ITent series for the synthesis of their “custom-made” pre-catalysts [PdCl(ηThe3 -cin)(ITent)] Nolan group (cin used = thiscinnamyl) ITent series seriesand [PdCl(acac)(ITent)] forfor thethe synthesissynthesis ofof (acac theirtheir “custom-made”=“custom-made” acetylacetonate) pre-catalystspre-catalysts [42], while 3 [PdCl([PdCl(ηOrgan ηused3-cin)(ITent)] them to further (cin(cin == optimizecinnamyl) the and PEPPSI [PdCl(acac)(ITent)] series [16,27]. (acac(acac == acetylacetonate)acetylacetonate) [[42],42], whilewhile Organ used them to further optimize thethe PEPPSIPEPPSI seriesseries [[16,27].16,27]. 4.1. Suzuki–Miyaura Cross-Coupling 4.1. Suzuki–Miyaura Cross-Coupling 4.1. Suzuki–MiyauraThe synthesis of Cross-Coupling tetra-ortho-substituted biaryls under mild conditions remains a challenge in the Suzuki–MiyauraThe synthesis reaction. of tetra- Asortho shown-substituted above, the biaryls use underof ligands mild with conditions flexible remainsbulk proved a challenge to be critical, in the Suzuki–Miyauraand the first example reaction. using As NHC shown ligands above, was the describeduse of ligands ligands by Glorius with with flexible flexible in 2004 bulk [23]. proved proved Organ to was be be critical, critical,able to andfurther the firstfirst optimize example the using reaction NHC usingligands the was ITent described series. by Glorius More in specifically, 2004 [[23].23]. Organ the well-defined was able to furtherPEPPSI-IPent optimize optimize pre-catalyst the the reaction reaction was using used using the toITent achieve the series.ITent a wider More series. scope specifically, than More previous specifically, the well-defined reports the [27]. PEPPSI-IPent well-defined pre-catalystPEPPSI-IPentThe Nolan was pre-catalyst used group to used achieve was the used a well-definedwider to achieve scope thana[PdCl(η wider previous scope3-cin)(ITent)] reportsthan previous [ 27 pre-catalyst]. reports series [27]. to further 3 η 3 advanceThe Nolanthe Nolan state-of-the-art group group used used the [42]. thewell-defined Of well-defined particular[PdCl( interest,[PdCl(η-cin)(ITent)] [PdCl(η3-cin)(ITent)]pre-catalyst-cin)(IPent)] pre-catalyst series was toable series further to toefficiently advance further η3 theadvancecatalyze state-of-the-art the state-of-the-art cross-coupling [42]. Of particular [42]. of highly Of particular interest, hindered[PdCl( interest, aryl chlorides-cin)(IPent)] [PdCl(η with3-cin)(IPent)]was boronic able to was acids efficiently able at lowto catalyze efficiently catalysts the cross-couplingcatalyzeloading (Scheme the cross-coupling of 7). highly hindered of highly aryl chlorides hindered with aryl boronic chlorides acids with at low boronic catalysts acids loading at low (Scheme catalysts7). loading (Scheme 7). [PdCl(h3-cin)(IPent)] (0.5-1 mol%) Cl + (HO)2B t 3 o Rn Rn' [PdCl(KOhBu,-cin)(IPent)] toluene, 65 (0.5-1 C, 22 mol%) h Rn Rn' Cl + (HO)2B t o Rn Rn' KO Bu, toluene, 65 C, 22 h Rn Rn'

MeO MeO

90% (0.5 mol%) 92% (0.5 mol%) 85% (1 mol%) 90% (0.5 mol%) 92% (0.5 mol%) 85% (1 mol%) Scheme 7. Selected examples of the Suzuki–Miyaura coupling using [PdCl([PdCl(ηη33-cin)(IPent)] [42].[42]. Scheme 7. Selected examples of the Suzuki–Miyaura coupling using [PdCl(η3-cin)(IPent)] [42]. Organ and and co-workers co-workers also also used used the [Pd-PEPPSI-IPent] the [Pd-PEPPSI-IPent]pre-catalyst pre-catalyst for the challenging for the challenging coupling ofcoupling allylboronicOrgan of andallylboronic acid co-workers with di acidﬀerent alsowith aryl useddifferent halides the [ 45aryl[Pd-PEPPSI-IPent]]. In halides this context, [45]. (hetero)arylIn pre-catalystthis context, halides for(hetero)aryl were the successfullychallenging halides α coupledcouplingwere successfully with of allylboronic high coupled selectivity acid with for with high the different selectivity-product aryl (Schemefor halides the α-product8). [45]. In (Scheme this context, 8). (hetero)aryl halides were successfully coupled with high selectivity for the α-product (Scheme 8).

Inorganics 2019, 7, 78 5 of 14 InorganicsInorganics 2019 2019, ,7 7, ,x x FOR FOR PEER PEER REVIEW REVIEW 5 5 of of 15 15

X X [Pd-PEPPSI-IPent][Pd-PEPPSI-IPent] (2 (2 mol%) mol%) ++ ++ PinBPinB 55 M M KOH, KOH, THF,THF, reflux, reflux, 24 24 h h RR RR RR NN N N XX = = Cl, Cl, Br Br aa-product-product gg-product-product ClCl PdPd ClCl N OMeOMe N

ClCl tButBu MeOMeO NN NN [Pd-PEPPSI-IPent][Pd-PEPPSI-IPent]

XX = = Br, Br, 81% 81% XX = = Br, Br, 96% 96% XX = = Br, Br, 83% 83% XX = = Cl, Cl, 47%47% a/ga/g = = 97/3 97/3 a/ga/g = = >99/1 >99/1 a/ga/g = = >99/1 >99/1 a/g = >99/1 a/g = >99/1 SchemeSchemeScheme 8.8. 8. Examples Examples of of the the Suzuki–Miyaura Suzuki–Miyaura coupling coupling usingusing using allylboronicallylboronic allylboronic estersesters esters andand and arylaryl aryl halideshalides halides [[45]. 45[45].].

Recently,Recently,Recently, Liu LiuLiu and andand co-workers co-workersco-workers showed showedshowed that thatthat the thethe [Pd-PEPPSI-IPent [Pd-PEPPSI-IPent[Pd-PEPPSI-IPentAnAnAn]]] precatalyst precatalystprecatalyst is is is eefficientefficientﬃcient in in in thethethe the thethe Suzuki-Miyaura Suzuki-MiyauraSuzuki-Miyaura couplingcouplingcoupling ofofof a aa wide widewide range rangerange of ofof hindered hinderedhindered arylboronic arylboronicarylboronic acids acidsacids and andand hindered hinderedhindered aryl arylaryl chlorideschlorideschlorides atat at 8080 80 ◦°C C°C usingusing using aa a 11 1 molmol mol %% % PdPd Pd loadingloading loading [[44]. 44[44].].

4.2.4.2.4.2. NegishiNegishi Cross-Coupling Cross-Coupling AfterAfterAfter thethethe firstfirstfirst NegishiNegishiNegishi couplingcouplingcoupling withwithwith thethethe well-definedwell-definedwell-defined [Pd-PEPPSI-IPr] [Pd-PEPPSI-IPr][Pd-PEPPSI-IPr] pre-catalyst pre-catalyst pre-catalyst [ [46],46 [46],], the the the OrganOrganOrgan group groupgroup showed showedshowed that thatthat the thethe[Pd-PEPPSI-IPent] [Pd-PEPPSI-IPent][Pd-PEPPSI-IPent]pre-catalyst pre-catalystpre-catalyst was waswas even eveneven more moremore active, active,active, especially especiallyespecially in the inin synthesisthethe synthesissynthesis of tetra- ofof tetra-tetra-orthoortho-substitutedortho-substituted-substituted biaryls biarylsbiaryls [47,48 [47,48].[47,48].]. The same TheThe samesame palladium palladiumpalladium pre-catalyst pre-catalystpre-catalyst also proved alsoalso provedproved to be highlytoto be be highly e highlyfficient efficient efficient in the coupling in in the the coupling of coupling secondary of of secondary secondaryalkylzincsubstrates alkylzinc alkylzinc to substrates substrates aryl halides to to [ aryl49 aryl]. The halides halides flexible [49]. [49]. steric The The bulkflexibleflexible of the steric stericIPent bulk bulkligand of of reduced the the IPentIPent the ligand ligandβ-hydride reduced reduced elimination the the β-hydride β-hydride/migratory elimination/migratory elimination/migratory insertion considerably, insertion insertionlimiting theconsiderably,considerably, formation of limiting limiting the isomeric the the formation formationby-product. of of Later, the the isomeric Organisomeric and by-product. by-product. co-workers Later, Later,improved Organ Organ this and andselectivity co-workers co-workers even Cl furtherimprovedimproved by usingthis this selectivity selectivity[Pd-PEPPSI-IPent even even further further] (Scheme byby using using9 )[[Pd-PEPPSI-IPent [Pd-PEPPSI-IPent43]. ClCl]] (Scheme (Scheme 9) 9) [43]. [43].

R'R' R'R' ZnBrZnBr [Pd-PEPPSI-IPent[Pd-PEPPSI-IPentClCl]] (1 (1 mol%) mol%) XX ++ ++ R'R' R"R" THF/toluene, r.t. RR THF/toluene, r.t. RR RR R"R" R"R" XX = = Cl, Cl, Br, Br, OTf OTf productproduct (n) (n) by-productby-product (i) (i)

BocBoc OO NN OHCOHC OO OO BocNBocN

XX = = Br, Br, 99%99% XX = = Cl, Cl, 68% 68% XX = = OTf, OTf, 96% 96% (n/i(n/i = = 99/1) 99/1) (n/i(n/i = = 17/1) 17/1) (n/i(n/i = = 99/1) 99/1)

SchemeSchemeScheme 9.9. 9. Selected Selected examples examples for for the the Negishi Negishi cross-couplingcross-coupling cross-coupling ofof of secondarysecondary secondary alkylzincalkylzinc alkylzinc substratessubstrates substrates [[43]. 43[43].].

Recently, Organ and co-workers described a silica-supported pre-catalyst, Recently,Recently, Organ Organ and and co-workers co-workers described described a a silica-supported silica-supported pre-catalyst, pre-catalyst, [Pd-PEPPSI-IPent-SiO2], and evaluated its activity in challenging Negishi cross-coupling [Pd-PEPPSI-IPent-SiO[Pd-PEPPSI-IPent-SiO22]], , andand evaluatedevaluated itsits activityactivity inin challengingchallenging NegishiNegishi cross-couplingcross-coupling reactionsreactions reactions under ﬂow conditions [50]. The catalyst material was used in a packed-bed reactor at room underunder flow flow conditions conditions [50]. [50]. The The catalyst catalyst material material was was used used in in a a packed-bed packed-bed reactor reactor at at room room temperature and small residence times (10 min or less) were enough to obtain high conversions. temperaturetemperature and and small small residence residence times times (10 (10 min min or or less) less) were were enough enough to to obtain obtain high high conversions. conversions. 4.3. Stille Coupling 4.3.4.3. Stille Stille Coupling Coupling In 2010, Organ and co-workers reported a Stille coupling using [Pd-PEPPSI-IPent] (Scheme 10)[51]. InIn 2010, 2010, Organ Organ and and co-workers co-workers reported reported a a Stille Stille coupling coupling using using [Pd-PEPPSI-IPent] [Pd-PEPPSI-IPent] (Scheme (Scheme 10) 10) While the method can be used for aryls and heteroaryl substrates, at relatively mild temperatures [51].[51]. While While the the method method can can be be used used for for aryls aryls and and heteroaryl heteroaryl substrates, substrates, at at relatively relatively mild mild (60–80 ◦C), high catalyst loadings are needed in all cases (4–8 mol %). temperaturestemperatures (60–80 (60–80 °C), °C), high high catalyst catalyst loadings loadings are are needed needed in in all all cases cases (4–8 (4–8 mol mol %). %).

Inorganics 2019, 7, 78 6 of 14 InorganicsInorganics 20192019,, 77,, xx FORFOR PEERPEER REVIEWREVIEW 6 6 of of 15 15

[Pd-PEPPSI-IPent] (4-8 mol%) Ar/Het SnBu [Pd-PEPPSI-IPent] (4-8 mol%) Ar/Het SnBu33 ++ XX Ar'/Het' Ar'/Het' Het/ArHet/Ar Ar'/Het'Ar'/Het' CsF,CsF, 1,4-dioxane 1,4-dioxane 4Å4Å MS, MS, 60-8060-80 °C,°C, 16-2416-24 hh

OMe N(Boc) OMe N(Boc)22 NN N N NN NO N N NN NO22 NN O SS O SS 62%62% 92%92% 75%75% 90%90% (4(4 mol%mol% Pd)Pd) (4(4 mol%mol% Pd)Pd) (8(8 mol%mol% Pd)Pd) (8(8 mol%mol% Pd)Pd) X = Br X = Cl X = Cl XX == ClCl X = Br X = Cl X = Cl SchemeScheme 10.10. ExamplesExamples ofof thethe StilleStille couplingcoupling catalyzedcatalyzed byby [Pd-PEPPSI-IPent][Pd-PEPPSI-IPent] [[51].[51].51].

4.4. Buchwald-Hartwig Cross-Coupling 4.4.4.4. Buchwald-HartwigBuchwald-Hartwig Cross-CouplingCross-Coupling AfterAfter thethethe first firstfirst report reportreport of ofof the thethe use useuse of ofof palladium-NHC palladium-NHCpalladium-NHC systems systemssystems for for thefor the aminationthe aminationamination reaction reactionreaction by Nolan byby NolanNolan [52], the[52],[52], concept thethe conceptconcept of ligands ofof ligandsligands with with “flexiblewith “flexible“flexible bulk” bulk”bulk” advanced advancedadvanced the state-of-the-art. thethe state-of-the-art.state-of-the-art. Organ OrganOrgan reported reportedreported the usethethe [Pd-PEPPSI-IPent] [Pd-PEPPSI-IPr] ofuseuse ofof [Pd-PEPPSI-IPent][Pd-PEPPSI-IPent][53 ] [53][53] under underunder milder mildermilder conditions conditionsconditions than thanthan the thethe ones onesones used usedused with withwith the thethe [Pd-PEPPSI-IPr][Pd-PEPPSI-IPr] IPent analogue,analogue, allowing allowing allowing for for for a greater a a greater greater tolerance tolerance tolerance of functional of of functional functional groups. groups. groups. The The The derivativeIPentIPent derivative derivative was even was was capable even even IPr ofcapablecapable catalyzing ofof catalyzingcatalyzing some reactions somesome reactionsreactions that were thatthat previously werewere previouslypreviously unattainable unattainableunattainable using usingusing the thethe-based IPrIPr-based-based catalyst catalystcatalyst [54]. However,[54].[54]. However,However, it must itit must bemust noted bebe notednoted that high thatthatcatalyst highhigh catalystcatalyst loadings loadingsloadings (4 mol (4(4 %) molmol were %)%) necessary werewere necessarynecessary to achieve toto achieveachieve good results. goodgood Moreresults.results. recently, MoreMore recently,recently, the same thethe group samesame successfully groupgroup successfullysuccessfully achieved achievedachieved the coupling thethe couplingcoupling of various ofof amides variousvarious with amidesamides aryl withwith and 3 Cl [Pd(η -cin)Cl(DiMeIHept3 )] Cl heteroarylarylaryl and and chlorides heteroaryl heteroaryl using chlorides chlorides using using [Pd(η[Pd(η3-cin)Cl(DiMeIHept-cin)Cl(DiMeIHeptas catalyst, assistedCl)])] as as by catalyst, catalyst, boron-derived assisted assisted Lewis by by acidsboron-derivedboron-derived [55]. LewisLewis acidsacids [55].[55]. TheThe Nolan Nolan Nolan group group group was was was able able able to reduce to to reduce reduce the catalyst the the catalyst catalyst loading loadingby loading using by[PdCl(acac)(ITent)] by using using [PdCl(acac)(ITent)][PdCl(acac)(ITent)]complexes (Schemecomplexescomplexes 11 )[ (Scheme(Scheme42]. More 11)11) specifically, [42].[42]. MoreMore the specifically,specifically, use of the theIHeptthe useuseligand ofof thethe permitted IHeptIHept ligandligand to lower permittedpermitted the catalyst toto lowerlower loading thethe tocatalystcatalyst 0.1–0.2 loadingloading mol %. toto This 0.1–0.20.1–0.2 system molmol allows %.%. ThisThis for systemsystem the use allowsallows of otherwise forfor thethe diuseuseffi cultofof otherwiseotherwise coupling difficult partners,difficult couplingcoupling such as electron-poorpartners,partners, suchsuch anilines. asas electron-poorelectron-poor anilines.anilines.

R'R' H ClCl H [PdCl(acac)(IHept)][PdCl(acac)(IHept)] (0.1-0.2(0.1-0.2 mol%)mol%) NN + N R RR + N t R RR R'R' KOKOtBu,Bu, DME,DME, 8080 °C,°C, 2-42-4 hh RR

OMeOMe OO BuBu HH HH HH NN CFCF3 NN NN N 3 BuBu N NN MeOMeO MeOMeO OMeOMe 90%90% 68% 68% 96% 78% 90% 96% 78% 90% SchemeScheme 11.11. ExamplesExamples ofof the the Buchwald-HartwigBuchwald-Hartwig couplingcoupling catalyzedcatalyzed byby [PdCl(acac)(IHept)][PdCl(acac)(IHept)] [[42].[42].42].

TheThe Organ Organ group group investigated investigated investigated the the coupling coupling coupling of of of 2-aminopyridine 2-aminopyridine 2-aminopyridine derivatives derivatives using using Cl [Pd-PEPPSI-IPent[Pd-PEPPSI-IPentClCl]] [56].[[56].56]. SuchSuch Such catalystscatalysts werewere successful successful in in the the coupling coupling ofof suchsuchsuch aminopyridinesaminopyridinesaminopyridines withwith variousvarious arylaryl chlorides,chlorides, butbut itit mustmust bebe mentionedmentioned thatthat catalystcatalyst poisoningpoisoning occurredoccurred duedue toto metalmetal coordinationcoordination ofof thethe aminopyridine.aminopyridine. An Recently,Recently, LiuLiuLiu andandand co-workersco-workersco-workers showedshowedshowed thatthatthat [Pd-PEPPSI-IPent [Pd-PEPPSI-IPent[Pd-PEPPSI-IPentAnAn]] waswas an an efficient eefficientfficient pre-catalystpre-catalyst inin thethe aminationamination ofof (hetero)aryl(hetero)aryl chlorideschlorideschlorides underunderunder aerobicaerobicaerobic conditions conditionsconditions [ [57].57[57].]. 5. N-Naphthyl-Based NHCs 5.5. NN-Naphthyl-Based-Naphthyl-Based NHCsNHCs Another class of NHC ligands with naphthyl groups on the nitrogen atoms was synthesized AnotherAnother classclass ofof NHCNHC ligandsligands withwith naphthylnaphthyl groupsgroups onon thethe nitrogennitrogen atomsatoms waswas synthesizedsynthesized byby by Dorta and co-workers and used to prepare well-defined palladium pre-catalysts [29,58–60]. DortaDorta and and co-workers co-workers and and used used to to prepare prepare well-defined well-defined palladium palladium pre-catalysts pre-catalysts [29,58–60]. [29,58–60]. [PdCl(η3-cin){anti-(2,7)-SICyoctNap}], one of the most important complexes of the series, was the first [PdCl(η[PdCl(η33-cin){-cin){antianti-(2,7)-SICyoctNap}]-(2,7)-SICyoctNap}],, oneone ofof thethe mostmost importantimportant complexescomplexes ofof thethe series,series, waswas thethe well-defined complex to promote the coupling of tetra-ortho-substituted biaryls via a Suzuki–Miyaura firstfirst well-definedwell-defined complexcomplex toto promotepromote thethe couplingcoupling ofof tetra-tetra-orthoortho-substituted-substituted biarylsbiaryls viavia aa Suzuki–Suzuki– MiyauraMiyaura reactionreaction atat roomroom temperaturetemperature (Scheme(Scheme 12)12) [29,60].[29,60]. ItIt showedshowed thatthat thethe successsuccess ofof thisthis ligandligand

Inorganics 2019, 7, 78 7 of 14 InorganicsInorganics 2019 2019, ,7 7, ,x x FOR FOR PEER PEER REVIEW REVIEW 7 7 of of 15 15 liedreactionlied with with at the roomthe NHC NHC temperature being being twisted twisted (Scheme around around 12)[29 the the,60 ]. metal metal It showed center center that with with the two twosuccess bulky bulky of this faces faces ligand and and lied two two with less less hinderedthehindered NHC faces. beingfaces. twisted around the metal center with two bulky faces and two less hindered faces.

[PdCl( 3-cin){3 anti-(2,7)-SICyoctNap}] X B(OH) [PdCl(hh -cin){anti-(2,7)-SICyoctNap}] R'R' X B(OH)22 R" (0.2(0.2 - -2 2 mol%) mol%) R" ++ R"R" RR R'R' t t N N KOKOBu,Bu, toluene, toluene, r.t. r.t. - -65 65 °C °C RR N N R"R" XX = = Cl, Cl, Br Br R"R" PdPd Cl OO Cl PhPh

NN R" = cyclooctyl O R" = cyclooctyl O NN

X = Br, 96% X = Br, 88% X = Cl, 86% X = Cl, 72% X = Br, 96% X = Br, 88% X = Cl, 86% X = Cl, 72% 3 SchemeScheme 12. 12. Selected Selected examples examples using using [PdCl(η [PdCl([PdCl(ηη3-cin){-cin){3-cin){antianti-(2,7)-SICyoctNap}]-(2,7)-SICyoctNap}]-(2,7)-SICyoctNap}] [[29]. 29[29].].

6.6.6. IPr* IPr*IPr* and andand Related RelatedRelated NHCs NHCsNHCs TheTheThe IPr* IPr*IPr* ligand ligand proved proved optimal optimal for for thethe balance balance between between sterics sterics andand ﬂexibility.flexibility.flexibility. This ThisThis hindered hinderedhindered ligand,ligand,ligand, which which was was ﬁrstfirst first synthesizedsynthesized synthesized byby by Mark Markó Markóó and and and co-workers co-workers co-workers [ 28[28], [28],], triggered triggered triggered interest interest interest and and and a numbera a number number of ofcongenersof congeners congeners were were were developed developed developed [61 –[61–64]. [61–64].64]. Other Other Other manipulations manipulations manipulations of the of of IPrthe the frameworkIPr IPr framework framework were were were investigated, investigated, investigated, such +C suchassuch the as asIPr the the IPr IPrseries+C+C series series by Holland by by Holland Holland and co-workersand and co-workers co-workers [65] and[65] [65] theand and substitution the the substitution substitution of the of of NHC the the NHC NHC backbone backbone backbone with withlongwith long alkyllong alkyl chainsalkyl chains chains by Glorius by by Glorius Glorius and co-workersand and co-workers co-workers [66] (Figure[66] [66] (Figure (Figure1). 1). 1).

ArAr ArAr ArAr ArAr NN N N NN N N RR RR RR RR ArAr ArAr RR RR ArAr Ar Ar NN N N Ar = Ph, R = Me IPr* Ar = Ph, R = Me IPr* R = CPh IPr+CPh3+CPh3 R = CPh33 IPr TolTol ArAr = = p p-Tol,-Tol, R R = = Me Me IPr*IPr* +C(4-Me-Ph)3 RR = = C(4-Me-Ph) C(4-Me-Ph)3 IPr IPr+C(4-Me-Ph)3 R = C H IPrC11H23C11H23 3 R = C1111H2323 IPr OMeOMe ArAr = = Ph, Ph, R R = = OMe OMe IPr*IPr* t +C(4-tBu-Ph)3 RR = = C(4- C(4-Bu-Ph)tBu-Ph)3 IPr IPr+C(4-tBu-Ph)3 R = C H IPrC7H15C7H15 3 R = C77H1515 IPr t t ArAr = = p p--Bu-Ph,Bu-Ph, R R = = Me Me IPr**IPr** +Ad RR = = 1-adamantyl 1-adamantyl IPr IPr+Ad (2-Np) ArAr = = 2-Naphthyl, 2-Naphthyl, R R = = Me Me IPr*IPr*(2-Np)

+C CxHy FigureFigureFigure 1. 1. 1.Structure Structure Structure ofof of thethe theIPr* IPr* IPr*,,IPr ,IPr IPr+C+C andand and IPrIPr IPrCxHyCxHy ligands ligandsligands [28,61–64]. [28,61–64]. [28,61–64 ]. 6.1. Suzuki Miyaura Cross-Coupling 6.1.6.1. Suzuki Suzuki Miyaura Miyaura Cross-Coupling Cross-Coupling The [PdCl(η3-cin)(IPr*)] pre-catalyst proved to be efficient in the preparation of TheThe [PdCl(η[PdCl(η3-cin)(IPr*)]3-cin)(IPr*)] pre-catalyst pre-catalyst proved proved to to be be efficient efficient in in the the preparation preparation of of tetra-ortho-substituted biaryls via Suzuki–Miyaura coupling at room temperature using 1 mol % tetra-tetra-orthoortho-substituted-substituted biaryls biaryls via via Suzuki–Miyaura Suzuki–Miyaura coupling coupling at at room room temperature temperature using using 1 1 mol mol % % Pd Pd Pd loading [67]. loadingloading [67]. [67]. Holland and co-workers reported the [PdCl(η3-cin)(IPr+C)] series in Suzuki–Miyaura coupling of HollandHolland and and co-workers co-workers reported reported the the [PdCl(η [PdCl(η3-cin)(IPr3-cin)(IPr+C+C)])] series series in in Suzuki–Miyaura Suzuki–Miyaura coupling coupling 4-chloro(trifluoromethyl)benzene and phenylboronic acid [65]. When compared with the IPr analogue, ofof 4-chloro(trifluoromethyl)benzene 4-chloro(trifluoromethyl)benzene and and phenylboronic phenylboronic acid acid [65]. [65]. When When compared compared with with the the IPrIPr all complexes were found more active with a trend of increase in steric bulk directly proportional to analogue,analogue, all all complexes complexes were were found found more more active active with with a a trend trend of of increase increase in in steric steric bulk bulk directly directly increase of activity up to a certain tipping point; this is where flexibility is compromised because of a proportionalproportional to to increase increase of of activity activity up up to to a a certain certain tipping tipping point; point; this this is is where where flexibility flexibility is is too large steric hindrance (Table1). compromisedcompromised because because of of a a too too large large steric steric hindrance hindrance (Table (Table 1). 1).

Inorganics 2019, 7, 78x FOR PEER REVIEW 88 of of 1514 Inorganics 2019, 7, x FOR PEER REVIEW 8 of 15 Table 1. Investigation of the [PdCl(η3-cin)(IPr+C)] series in Suzuki–Miyaura coupling [65]. TableTable 1. 1.Investigation Investigation of of the the[PdCl( [PdCl(ηη3-cin)(IPr3-cin)(IPr++CC)])] seriesseries in in Suzuki–Miyaura Suzuki–Miyaura coupling coupling [65]. [65].

CF3 CF3 B(OH) 3 C+ CF 2 [PdCl(h -cin)(IPr )] (0.02 mol%) CF3 3+ B(OH)2 [PdCl(h3-cin)(IPrC+)] (0.02 mol%) + iPrOH /THF (9:1), 60 °C, 15 h Cl i Cl PrOH /THF (9:1), 60 °C, 15 h

3 +C Entry [PdCl(3 η -cin)(IPr+C )] GC Conversion (%) Entry [PdCl(η 3-cin)(IPr +C)] GC Conversion (%) Entry [PdCl(η -cin)(IPr3 )] GC Conversion (%) 1 1 [PdCl(η[PdCl(3-cin)(IPr)]η -cin)(IPr)] 55%55% 1 [PdCl(η3-cin)(IPr)]η3 +CPh3 55% 2 2 [PdCl(η[PdCl(3-cin)(IPr-cin)(IPr+CPh3)] )] 87%87% 2 3 [PdCl(η[PdCl(3-cin)(IPrη3-cin)(IPr+CPh3+C(4-Me-Ph)3)] )] 86%87% 3 [PdCl(η3-cin)(IPr+C(4-Me-Ph)3)] 86% 3 4 [PdCl(η[PdCl(3-cin)(IPrη3-cin){IPr+C(4-Me-Ph)3+C(4-)]tBu-Ph)3 )] 85% 86% 4 [PdCl(η3-cin){IPr3+C(4-tBu-Ph)3+)]Ad 85% 4 5 [PdCl(η3-cin){IPr[PdCl(η -cin)(IPr+C(4-tBu-Ph)3)] )] 69% 85% 5 [PdCl(η3-cin)(IPr+Ad)] 69% 5 [PdCl(η3-cin)(IPr+Ad)] 69%

Recently, Qian and co-workers reported a polymer analogue to the IPr ligand (Figure2, left) for Recently,Recently, Qian Qian and and co-workers co-workers reported reported aa polymerpolymer analogue to the IPr ligandligand (Figure(Figure 2,2, left) left) for for useuse as as a a recoverable recoverable catalyst catalyst [[68].68[68].]. ThisThis catalystcatalyst was was testedtested in the cross-coupling involving activated activated arylaryl bromides bromides and and chlorides. chlorides. Reusability ReusabilityReusability of ofof the the catalyst catalyst was was shown shown over over 6 6 runs—however, runs—however, no no kinetic kinetic datadata was was provided—thusprovided—thus provided—thus thethe the possibilitypossibility possibility of ofof the thethe system systemsystem acting acting as as a reservoira reservoir of ofof active activeactive species speciesspecies cannot cannotcannot be beruledbe ruled ruled out. out. out. AnAn alternative alternative approach approach to to catalystcatalyst separationseparation using using membranes was undertaken byby Ormerod Ormerod andand co-workers co-workers on on IPr IPr and and related related ligands.ligands. While While earlyearly studies studies were were carried carried outout out onon on IPrIPr IPr ligandligand ligand [69],[69], [69], modificationmodiﬁcationmodification of of the the latter latter by by appending appending long long chains chains at at the parapara-position-position ofof of thethe the phenylphenyl phenyl ringring ring (Figure(Figure (Figure 2, 22,, right)right) proved proved judicious judicious for for catalyst catalyst recovery recovery throughthrough nanoﬁltration.nanofiltration.nanofiltration. This allowedallowed thethe cross-couplingcross-coupling reactionreaction in in a a semicontinuous semicontinuous mode mode inin aa membrane-assistedmembrane-assisted reactorreactor [[70].70].

R =

H 2CH 2CH 2COCO OO 2 2 2 OO NN N N CC H2CH2CH22COCO HH ClCl PdPdClCl 22 NN N FF FF FF RR R FF FF FF NN ClCl H CH CH COCO 2 2 22 FF FFFF FF FF FF FF ClCl nn H2CH2CH22COCO

FigureFigure 2. 2.Polymer-modiﬁed 2. Polymer-modifiedPolymer-modified IPr-complex IPr-complex IPr-complex (left )[ (left)68 (left)] and [68] [68]para -tailed and para IPr ligands-tailed ( IPr IPrright ligands ligands) for semicontinuous (right) (right) for for semicontinuousreactionssemicontinuous [70]. reactions reactions [70]. [70]. 6.2. Buchwald Hartwig Cross-Coupling 6.2.6.2. Buchwald Buchwald Hartwig Hartwig Cross-Coupling Cross-Coupling The Nolan group investigated the use of [PdCl(η3-cin)(IPr*)] and [Pd-PEPPSI-IPr*] in the TheThe Nolan Nolan group group investigated investigated the the use use of of [PdCl(η[PdCl(η33-cin)(IPr*)] and and [Pd-PEPPSI-IPr*][Pd-PEPPSI-IPr*] in in the the Buchwald-Hartwig reaction [71–73] and found that they were the most active pre-catalysts for this Buchwald-HartwigBuchwald-Hartwig reaction reaction [71–73] [71–73] andand foundfound thatthat theythey were the most active pre-catalystspre-catalysts forfor thisthis reactionreaction to to date. date. Both Both complexes complexes showed showed similar similar activity, activity, which which indicates indicates that that the the active active species species is theis reaction to date. Both complexes3 showed similar activity, which indicates that the active species is same in both cases. The [PdCl(η -cin)(IPr*)]3 pre-catalyst was also used in a solvent-free amination thethe same same in in both both cases. cases. The The [PdCl(η[PdCl(η3-cin)(IPr*)]-cin)(IPr*)] pre-catalyst pre-catalyst was also also used used in in a a solvent-free solvent-free using 1 mol % of the complex in neat condition [74]. This allowed for the use of primary amines at aminationamination using using 1 1 mol mol % % of of the the complexcomplex inin neatneat conditioncondition [74]. This allowed forfor thethe useuse ofof primaryprimary room temperature, which was previously not possible. aminesamines at at room room temperature, temperature, which which was was previouslypreviously notnot possible. The very easily prepared [PdCl(acac)(IPr*)] pre-catalyst was shown to be active in the same TheThe very very easily easily prepared prepared [PdCl(acac)(IPr*)][PdCl(acac)(IPr*)] pre-catalystpre-catalyst was shown to to bebe activeactive in in the the same same reactionreaction [71 [71]] and andshowed showed chemoselective chemoselective arylamination arylamination of various of dihalides various resulting dihalides in mono-aminated resulting in reaction [71] and showedOMe chemoselective arylamination of various dihalides resulting in products. [PdCl(acac)(IPr* )] was also testedOMe and proved to be even more active, allowing for the mono-aminatedmono-aminated products. products. [PdCl(acac)(IPr* [PdCl(acac)(IPr*OMe)])] waswas alsoalso testedtested and proved toto bebe eveneven moremore active,active, couplingallowing of for challenging the coupling electron-poor of challenging anilines electron-poor (Scheme anilines13)[62]. (Scheme 13) [62]. allowing for the coupling of challenging electron-poor anilines (Scheme 13) [62].

Inorganics 2019, 7, 78 9 of 14 Inorganics 2019, 7, x FOR PEER REVIEW 9 of 15 Inorganics 2019, 7, x FOR PEER REVIEW 9 of 15 R' R' X R' [PdCl(acac)(NHC*)] N X R' N R + H N [PdCl(acac)(NHC*)] R R + H N LiHMDS or KOtAm, 1,4-dioxane, 110 °C R R R t R R LiHMDS or KO Am, 1,4-dioxane, 110 °C X = Cl, Br, I X = Cl, Br, I 0.4 mol% Pd 0.05 mol% Pd 0.4 mol% Pd 0.05 mol% Pd H O O O O NH N H N N N HN N N Cl Cl MeO Cl Cl MeO X = I; IPr*, 71% X = Br; IPr*, 65% X = Cl; IPr*OMe (GC Conv. >99%) X = Cl; IPr*OMe (GC Conv. >99%) X = I; IPr*, 71% X = Br; IPr*, 65% X = Cl; IPr*OMe (GC Conv. >99%) X = Cl; IPr*OMe (GC Conv. >99%) X = Cl; IPr* (GC Conv. 0%) X = Cl; IPr* (GC Conv. 15%) X = Cl; IPr* (GC Conv. 0%) X = Cl; IPr* (GC Conv. 15%) Scheme 13. Examples of the Buchwald-Hartwig coupling using [PdCl(acac)(IPr*)] or SchemeScheme 13. 13. ExamplesExamples of of the the Buchwald-Hartwig Buchwald-Hartwig coupling coupling using using [PdCl(acac)(IPr*)][PdCl(acac)(IPr*)] oror OMe t [PdCl(acac)(IPr*[PdCl(acac)(IPr*[PdCl(acac)(IPr*OMeOMe)])])] asasas pre-catalystspre-catalysts pre-catalysts [62,71]. [62,71]. (KO (KOtAmtAm == = potassiumpotassiumpotassium tert terttert-amylate).-amylate).-amylate).

GloriusGlorius and andand co-workers co-workersco-workers used used their their series series of of long-carbon-chain-based long-carbon-chain-based palladium palladiumpalladium complexes complexes complexes in thein in 3 3 C11H23C11H23 Buchwald-Hartwigthethe Buchwald-Hartwig Buchwald-Hartwig amination aminationamination [66]. [66]. Of this Of this series, series,[PdCl( [PdCl(η[PdCl(ηη -allyl)(IPr3-allyl)(IPr-allyl)(IPrC11H23)])](see)] (see (see Figure Figure Figure1) 1) proved 1) proved proved to betoto be thebe the the most most most active activeactive (0.1 (0.1(0.1 mol molmol % Pd %% Pd loading, loading, 75 75◦C). °C).°C).

6.3.6.3. OtherOther Palladium-CatalyzedPalladium-Catalyzed ReactionsReactions TheThe IPr* IPr*IPr* ligandligandligand andandand itsitsits analoguesanaloguesanalogues werewere alsoalsoalso usedused in in the the cross-coupling cross-coupling of ofof Grignard GrignardGrignard reagents reagentsreagents leadingleadingleading to toto the thethe formation formationformation ofofof tetra-tetra-tetra-orthoortho-substituted-substituted compounds compounds [75] [[75]75] in in high highhigh yields. yields.yields. Finally, Finally, the thethe same samesame ligandligandligand family family family was was was shown shown shown to to to lead lead lead to active to active catalysts catalysts in the in in formation the the formation formation of C–S of of bonds C–S C–S bonds bonds(Scheme (Scheme (Scheme 14)[76 14), 77 14) ]. [76,77].[76,77]. BrMgBrMg Het/ArHet/Ar [PdCl(m-Cl)(IPr*)]-Cl)(IPr*)]22 (0.1(0.1 mol%)mol%) Het/ArHet/Ar X X ++ R RR R 1,4-dioxane, 6060 ooC,C, 16 16 hh 2222 examples examples 73-98%73-98% yield yield

XX RSRS [PdCl(h3-cin)(IPr*-cin)(IPr*OMeOMe)])] (0.1-2.5(0.1-2.5 mol%) mol%) RSRS H H ++ R' R' KOttBu, 1,4-dioxane, 110110 ooC,C, 12 12 hh R' 3737 examples examples 69-98%69-98% yield yield

OO S O XX 33 S O [PdCl(h -cin)(IPr*)]-cin)(IPr*)] (5(5 mol%)mol%) R ++ R R' SS R' KOttAm, 1,4-dioxane, 110110 ooC,C, 2020 h h R' RR 2222 examples examples 34-82%34-82% yield yield HetHet == HeteroarylHeteroaryl Ar = Aryl Ar = Aryl OMe SchemeSchemeScheme 14. 14.14. Other OtherOther palladium-catalyzed palladium-catalyzedpalladium-catalyzed cross-couplingscross-couplings using usingusing IPr* IPr*IPr* and and IPr* IPr*OMeOMe ligands ligandsligands [75–77]. [75–77]. [75–77 ].

7.7. ConclusionsConclusions andand OutlookOutlook “Bulky“Bulky yetyet flexible”flexible”flexible” ligandsligandsligands werewere recentlyrecently investigated,investigated, greatly greatly advancing advancingadvancing the the state-of-the-art, state-of-the-art, particularlyparticularlyparticularly ininin reactionsreactionsreactions involvinginvolvinginvolving stericallysterically congestedcongested couplingcoupling partners. partners. The The correlation correlationcorrelation between betweenbetween flexibleflexibleflexible stericsteric steric bulkbulkbulk andand catalyticcatalytic activity is not alwaysalways straightforward, straightforward, as as is is proven proven by by the the failure failure of ofof somesomesome extremelyextremely extremely large largelarge ligands.ligands.ligands. Advancements in this field not only benefited palladium chemistry but were also successfully Advancements in this fieldfield notnot onlyonly benefitedbenefited palladiumpalladium chemistrychemistry but werewere alsoalso successfullysuccessfully applied to other research areas and related metals such as nickel. Various reports on the design and applied to other researchresearch areasareas andand relatedrelated metalsmetals suchsuch asas nickel.nickel. Various reportsreports on thethe designdesign andand applications of IPr- and IPr*-based (among other related derivatives) nickel catalysts by Nolan [78– applications ofofIPr IPr-- and andIPr* IPr*-based-based (among (among other other related related derivatives) derivatives) nickel nickel catalysts catalysts by Nolanby Nolan [78 –[78–81], 81], Nakamura [82], Ackermann [83], Sun [84], Cramer [85], Newman [86], and Matsubara [87] 81], Nakamura [82], Ackermann [83], Sun [84], Cramer [85], Newman [86], and Matsubara [87]

Inorganics 2019, 7, 78 10 of 14

Nakamura [82], Ackermann [83], Sun [84], Cramer [85], Newman [86], and Matsubara [87] pioneered the transfer of the “bulky yet flexible” concept from palladium to nickel-based coupling reactions. The combination of nickel with other “bulky yet flexible” ligands such as CAACs [88,89] and abnormal NHCs [90] also saw some success. Moreover, Montgomery [91], Louie [92] and Johnson [93] used this concept to further investigate and consequently advance the synthesis and catalytic application of styrene-based nickel complexes, thus building upon the work of Belderrain and Nicasio [94]. Future advances, in particular through mechanistic studies, will provide insights into the exact role of electronic and steric parameters of NHC ligands on catalyst activity, thus guiding further catalyst design efforts across the periodic table. Nonetheless, these “bulky yet flexible” NHCs have already pushed the limits of highly hindered cross-coupling reactions, and hold great promise for combined high activity and catalyst recycling for numerous other metal systems.

Funding: Part of this work was funded by a Research Foundation—Flanders (FWO) grant (180327/1S99819N). Acknowledgments: The authors greatly acknowledge the Research Foundation—Flanders (FWO) for financial support. Conflicts of Interest: The authors declare no conflict of interest.

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