catalysts

Review Acenaphthene-Based N-Heterocyclic Carbene Metal Complexes: Synthesis and Application in Catalysis

Paulina Baczewska 1,†, Katarzyna Sniady´ 1,†, Wioletta Ko´snik 2 and Michał Michalak 1,*

1 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; [email protected] (P.B.); [email protected] (K.S.)´ 2 NanoVelos S.A., Rakowiecka 36, 02-532 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-22-343-2018 † Contributed equally.

Abstract: N-Heterocyclic carbene (NHC) ligands have become a privileged structural motif in modern homogenous and heterogeneous catalysis. The last two decades have brought a plethora of structurally and electronically diversified carbene ligands, enabling the development of cutting-edge transformations, especially in the area of carbon-carbon bond formation. Although most of these were accomplished with common imidazolylidene and imidazolinylidene ligands, the most challenging ones were only accessible with the acenaphthylene-derived N-heterocyclic carbene ligands bearing a π-extended system. Their superior σ-donor capabilities with simultaneous ease of modification of the rigid backbone enhance the catalytic activity and stability of their transition metal complexes, which makes BIAN-NHC (BIAN—bis(imino)acenaphthene) ligands an attractive tool for the development of challenging reactions. The present review summarizes synthetic efforts towards BIAN-NHC metal


complexes bearing acenaphthylene subunits and their applications in modern catalysis, with special
 emphasis put on recently developed enantioselective processes. Citation: Baczewska, P.; Sniady,´ K.; Ko´snik,W.; Michalak, M. Keywords: N-heterocyclic carbene; acenaphthylene; NHC-BIAN metal complexes; transition metal Acenaphthene-Based N-Heterocyclic catalysis Carbene Metal Complexes: Synthesis and Application in Catalysis. Catalysts 2021, 11, 972. https:// doi.org/10.3390/catal11080972 1. Introduction N-Heterocyclic carbene ligands (NHC), since first being isolated in a stable form Academic Editor: Sónia Carabineiro by Arduengo [1] in 1991, have revolutionized the field of modern metal catalysis [2–9], as well as organocatalysis [10–14]. The unique stereoelectronic characteristics (strong Received: 22 July 2021 σ-donor and weak π-acceptor properties) are mainly responsible for the formation of Accepted: 13 August 2021 Published: 14 August 2021 well-defined, thermally stable metal complexes, and hence, widespread application for the development of new efficient catalytic processes. To date, many structurally diversified

Publisher’s Note: MDPI stays neutral NHC ligands have been developed, varying in ring size, aryl or alkyl substituents attached with regard to jurisdictional claims in to the nitrogen atom, the heteroatom incorporated in the ring core, or cyclic and acyclic published maps and institutional affil- backbone (for selected examples, see Figure1). All these structural modifications allow for iations. straightforward tuning of steric and electronic properties of a given ligand, critical for the development of new catalytic processes or the further improvement of existing ones. The control of the activity of the catalytic pocket by modulating the electronic and steric properties is easily achieved in the case of NHC ligands. Although much research is limited to the classical imidazolium or imidazolinium ligands, further structural tuning of Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the imidazole core has brought a breakthrough for catalysis [15,16]. In this respect, NHC- π This article is an open access article BIAN-type ligands [BIAN–bis(imino)acenaphthene] bearing a -extended system have distributed under the terms and found tremendous applications in the area of C-C or C-heteroatom bond formation, as well conditions of the Creative Commons as in enantioselective catalysis in the last decade. Their key structural feature arises from Attribution (CC BY) license (https:// the perfect combination of the electronic and steric properties of NHC-BIAN type carbenes. creativecommons.org/licenses/by/ Regarding electronic properties, the π-extended polyaromatic system slightly increases 4.0/). σ-donor properties with respect to the classical imidazolium and imidazolium ligands.

Catalysts 2021, 11, 972. https://doi.org/10.3390/catal11080972 https://www.mdpi.com/journal/catalysts Catalysts 2021, 11, 972 2 of 45

Catalysts 2021, 11, 972 2 of 44

Plenio and co-workers [17] have investigated the electron donor ability of NHC-BIAN- Rh complexes by infrared spectroscopy and electrochemical methods (Figure2). It was

found that CO stretching frequencies (average value) of the respective NHC-Rh(CO)2Cl Figurecomplexes 1. The structure are very of similarcommonly to commonused NHC SIMes and BIAN-NHC or IMes carbene ligands. ligands. Due to the small −1 difference in νav value (around 4 cm ), it is difficult to estimate and directly compare The control of the activity of the catalytic pocket by modulating the electronic and the electronic character of NHC-BIAN-type ligands with others [18]. However, one can steric properties is easily achieved in the case of NHC ligands. Although much research assume that NHC-BIAN ligands are slightly stronger donors than commonly used SIMes oris limited IMes, on to thethe basisclassical of infraredimidazolium spectroscopic or imidazolinium data. Furthermore, ligands, further the structural electrochemical tuning of the imidazole core has brought a breakthrough for catalysis [15,16]. In this respect, Catalysts 2021, 11, 972 studies confirmed that the redox potential is slightly lower (in comparison with SIMes2 of or45 IMes),NHC-BIAN-type also indicating ligands a slightly [BIAN–bis(imino)acenaphthene] stronger donor ability (Figure bearing2). a π-extended system have found tremendous applications in the area of C-C or C-heteroatom bond formation, as well as in enantioselective catalysis in the last decade. Their key structural feature arises from the perfect combination of the electronic and steric properties of NHC-BIAN type carbenes. Regarding electronic properties, the π-extended polyaromatic system slightly increases σ-donor properties with respect to the classical imidazolium and imidazolium ligands. Plenio and co-workers [17] have investigated the electron donor ability of NHC- BIAN-Rh complexes by infrared spectroscopy and electrochemical methods (Figure 2). It was found that CO stretching frequencies (average value) of the respective NHC- Rh(CO)2Cl complexes are very similar to common SIMes or IMes carbene ligands. Due to the small difference in νav value (around 4 cm−1), it is difficult to estimate and directly compare the electronic character of NHC-BIAN-type ligands with others [18]. However, one can assume that NHC-BIAN ligands are slightly stronger donors than commonly used SIMes or IMes, on the basis of infrared spectroscopic data. Furthermore, the electrochemical studies confirmed that the redox potential is slightly lower (in comparison Figure 1. The structure of commonly used NHC and BIAN-NHC ligands. Figurewith 1. The SIMes structure or IMes), of commonly also indicating used NHC a sl andightly BIAN-NHC stronger ligands.donor ability (Figure 2). The control of the activity of the catalytic pocket by modulating the electronic and steric properties is easily achieved in the case of NHC ligands. Although much research is limited to the classical imidazolium or imidazolinium ligands, further structural tuning of the imidazole core has brought a breakthrough for catalysis [15,16]. In this respect, NHC-BIAN-type ligands [BIAN–bis(imino)acenaphthene] bearing a π-extended system have found tremendous applications in the area of C-C or C-heteroatom bond formation, as well as in enantioselective catalysis in the last decade. Their key structural feature arises from the perfect combination of the electronic and steric properties of NHC-BIAN type carbenes. Regarding electronic properties, the π-extended polyaromatic system slightly increases σ-donor properties with respect to the classical imidazolium and imidazolium ligands. Plenio and co-workers [17] have investigated the electron donor ability of NHC- BIAN-Rh complexes by infrared spectroscopy and electrochemical methods (Figure 2). It was found that CO stretching frequencies (average value) of the respective NHC- Figure 2. Comparison of the electronic properties of NHC ligands with NHC-BIAN-type one. Rh(CO)Figure 2.2ClComparison complexes of are the very electronic similar properties to common of NHC SIMes ligands or withIMes NHC-BIAN-type carbene ligands. one. Due to the small difference in νav value (around 4 cm−1), it is difficult to estimate and directly ApartApart from from the the electronic electronic properties, properties, steric steric effects effects seem toseem add toto the add excellent to the reactivityexcellent compare the electronic character of NHC-BIAN-type ligands with others [18]. However, ofreactivity NHC-BIAN-type of NHC-BIAN-type ligands in catalysis. ligands This in couldcatalysis. be attributed This could to the be “buttressing attributed effect”to the one can assume that NHC-BIAN ligands are slightly stronger donors than commonly used of“buttressing the acenaphthylene effect” of backbone the acenaphthylene [19]. The close backbone proximity [19]. of The the rigidclose polyaromatic proximity of skeletonthe rigid SIMes or IMes, on the basis of infrared spectroscopic data. Furthermore, the wouldpolyaromatic seem to skeleton push the would N-aryl seem substituent to push closerthe N-aryl to the substituent metallic center, closer enabling to the metallic better electrochemical studies confirmed that the redox potential is slightly lower (in comparison controlcenter, ofenabling the catalytic better pocketcontrol underof the homogenous catalytic pocket conditions. under homogenous Unfortunately, conditions. careful with SIMes or IMes), also indicating a slightly stronger donor ability (Figure 2). analysisUnfortunately, of the availablecareful analysis crystallographic of the available data of the crystallographic metal complexes data did of not the confirm metal this assumption. Rather surprisingly (Figure3), the angles between N-aryl substituents of NHC-BIAN-IPrAgCl [20] and NHC-BIAN-IPrAuCl [20] are higher (155◦, and 149◦, respectively) in comparison to their congeners possessing structurally identical N-wingtip substituents, such IPrAgCl [21] (137◦) and IPrAuCl [22] (138◦) derivatives.

Figure 2. Comparison of the electronic properties of NHC ligands with NHC-BIAN-type one.

Apart from the electronic properties, steric effects seem to add to the excellent reactivity of NHC-BIAN-type ligands in catalysis. This could be attributed to the “buttressing effect” of the acenaphthylene backbone [19]. The close proximity of the rigid polyaromatic skeleton would seem to push the N-aryl substituent closer to the metallic center, enabling better control of the catalytic pocket under homogenous conditions. Unfortunately, careful analysis of the available crystallographic data of the metal

Catalysts 2021, 11, 972 3 of 45

complexes did not confirm this assumption. Rather surprisingly (Figure 3), the angles between N-aryl substituents of NHC-BIAN-IPrAgCl [20] and NHC-BIAN-IPrAuCl [20] are higher (155°, and 149°, respectively) in comparison to their congeners possessing structurally identical N-wingtip substituents, such IPrAgCl [21] (137°) and IPrAuCl [22] (138°) derivatives. Furthermore, the %Vbur parameter (describing the steric properties of NHC ligands [23,24]), estimated on the basis of X-ray data, has indicated much the same steric hindrance of NHC-BIAN-type ligands as for other ligands commonly used in catalysis. Catalysts 2021, 11, 972 Unfortunately, the real situation under homogenous conditions in solution is unknown,3 of 44 and further evidence is required to understand the unique reactivity of NHC-BIAN metal complexes.

Figure 3. 3. AngleAngle between between N-wingtip N-wingtip substituents substituents and the and selected the selected bond distance, bond distance, based on basedcrystallographic on crystallographic data. IPracnAgCl data. [20],IPracn IPrAgClAgCl [20 [21],], IPrAgCl IPracnAuCl [21], [20], IPracn IPrAuClAuCl [20 [22].], IPrAuCl [22].

TheFurthermore, aim of the the present %Vbur articleparameter is to (describing provide a thecomprehensive steric properties overview of NHC of ligands the methods [23,24]), forestimated the synthesis on thebasis of NHC-BIAN-type of X-ray data, has ligands indicated and much their the metal same complexes, steric hindrance with of special NHC- emphasisBIAN-type on ligands the practical as for other aspects ligands (such commonly as accessibility used in of catalysis. the substrate, Unfortunately, scalability, the etc.). real Tosituation the best under of our homogenous knowledge, conditionsno similar inrevi solutionew has isbeen unknown, published and to furtherdate. The evidence catalytic is propertiesrequired to of understand NHC-BIAN the type unique complexes reactivity will of NHC-BIAN also be briefly metal discussed, complexes. since an excellent reviewThe on aim the of catalytic the present applications article is to of provide NHC-BIAN-type a comprehensive complexes overview has ofrecently the methods been publishedfor the synthesis by Szostak of NHC-BIAN-typeand co-workers [19]. ligands and their metal complexes, with special emphasis on the practical aspects (such as accessibility of the substrate, scalability, etc.). 2.To Synthetic the best of Routes our knowledge, to BIAN-Type no similar NHC reviewPrecursors has been published to date. The catalytic propertiesN-Heterocyclic of NHC-BIAN carbene type precursors complexes contai will alsoning be an briefly acenaphthylene discussed, since element an excellent (NHC- BIAN)review have on the found catalytic widespread applications application of NHC-BIAN-type in the synthesis of complexes many metal has complexes, recently been and hencepublished allowed by Szostak for the and development co-workers [19of]. many catalytic reactions due to the unique electronic2. Synthetic and, Routes even more to BIAN-Type so, steric properties NHC Precursors. In the present chapter, the synthetic efforts towards NHC precursors will be discussed to provide a comprehensive overview of the N-Heterocyclic carbene precursors containing an acenaphthylene element (NHC- most common synthetic approaches in a comparative fashion. The structure of the present BIAN) have found widespread application in the synthesis of many metal complexes, chapter is governed by the symmetry of NHC-BIAN-type ligands, including chiral NHC- and hence allowed for the development of many catalytic reactions due to the unique BIAN-type ligands, which will also be presented in the final part. electronic and, even more so, steric properties. In the present chapter, the synthetic efforts towards NHC precursors will be discussed to provide a comprehensive overview of the 2.1. Synthesis of Monodentate Carbene Precursors most common synthetic approaches in a comparative fashion. The structure of the present chapterMonodentate is governed precursors by the symmetry of N-heterocyclic of NHC-BIAN-type carbenes constitute ligands, including the most chiral numerous NHC- groupBIAN-type among ligands, all salts which possessing will also acenaphthylene be presented in theelements final part. in their structure. In this chapter, the presented synthetic methods are classified in terms of ligand symmetry, and C2.1.2-symmetric Synthesis ofachiral Monodentate ligands Carbene will be Precursorsdiscussed first, followed by C1-symmetric ones. NMonodentate-Heterocyclic precursors carbene precursors of N-heterocyclic with low carbenes steric congestion constitute theare mosteasily numerous accessed followinggroup among a two-step all salts pathway possessing (Scheme acenaphthylene 1). The first elements step leads in to their the structure.formation Inof thisthe correspondingchapter, the presented bisimine synthetic 3, by methods the condensation are classified inof termsaniline of ligandderivative symmetry, 1 with and C2-symmetric achiral ligands will be discussed first, followed by C1-symmetric ones. N-Heterocyclic carbene precursors with low steric congestion are easily accessed following a two-step pathway (Scheme1). The first step leads to the formation of the corresponding bisimine 3, by the condensation of aniline derivative 1 with acenaphtho- quinone (2) in the presence of a Lewis acid, usually ZnCl2, and AcOH as the solvent. In some cases, bisimine 3 formation could be accomplished without Lewis acid in AcOH, or in a mixture of MeCN and AcOH [17,25–38]. An interesting “green” alternative to the classical condensation leading to 3n, w, x has been proposed by Garcia [26,39]. The authors have proved that effective formation of bisimine 3n, w, x could be attained under mechanochemical conditions (in a ball mill). Catalysts 2021, 11, 972 4 of 45

Catalysts 2021, 11, 972 4 of 44 acenaphthoquinone (2) in the presence of a Lewis acid, usually ZnCl2, and AcOH as the solvent. In some cases,

NH2 Cl 6 2 R R 2 O O 6 2 5 R R 3 6 2 R R R5 R R R3 5 3 R R N N N N R4 R4 R4 R4 R4 R2 R6 R2 R6 1 R3 R5 R3 R5 3 4 Methods for bisimine formation Methods for ring closure Method A1 Method A2 Method A3 1. ZnCl2,AcOH,reflux 1. ZnCl2,AcOH,reflux 1. ZnCl2,AcOH Method H Method I 2. Na2C2O4, H2O,DCM 2. K2CO3, H2O,DCM toluene, reflux EtOCH2Cl MeOCH2Cl 2. Na C O K C O 90–100 °C 100 °C, 16 h 2 2 4, 2 2 4 16–24 h Method A4 Method A5 H2O,DCM 1. ZnCl2,AcOH,reflux 1. ZnCl2, neat, 170 °C 2. K2C2O4, H2O,DCM 2. K2CO3, H2O, reflux

Method B Method C Method D 1. AcOH, MeCN, reflux 1. AcOH, Na2SO4 1. AcOH, reflux 2. -30 °C, 16 h (CF3CO)2O, ball mill, 30 Hz 2. K2CO3,H2O, reflux Method E Method F Method G AcOH, 70 °C, 16 h AcOH, MeCN, reflux AcOH, reflux

Examples of bisimine

3a 3b 3c 3d iPr iPr N N N N N N N N

iPr iPr

70% (met. A2)ref. 35 85% (met. B)ref. 30 85% (met. A3)ref. 26 70% (met. A2)ref. 33 71% (met. A2)ref. 33 77% (met. A2)ref. 32 85% (met. F)ref. 34 80% (met. A4)ref. 28 37% (met. A1)ref. 27 72% (met. A2)ref. 35 90% (met. F)ref. 35 97% (met. A4)ref. 37 -a (met. A2)ref. 36 70% (met. A2)ref. 27 84% (met. G)ref. 37 71% (met. A5)ref. 37 89% (met. A4)ref. 28 PIB = H 18

3e 3f 3g 3i

N N N N N N N N

R PIB BIP

53% (met. A4)ref. 28 98% (met. A3)ref. 29 90% (met. A1)ref. 25 89% (met. E)ref. 38 92% (met. A5)ref. 37 64% (met. A4)ref. 28 73% (met. A3)ref. 26

3j 3k 3l 3m

Cl Cl N N N N N N N N C6H11 C6H11 Cl Cl

72% (met. D)ref. 31 87% (met. F)ref. 17 66% (met. F)ref. 17 70% (met. A3)ref. 29

3n 3o 3p 3q

O2N NO2 N N N N N N N N Br Br O2N NO2 NC CN

O2N NO2

64% (met. C)ref. 39 61% (met. A3)ref. 26 70% (met. A3)ref. 29 70% (met. A3)ref. 29 63% (met. A1)ref. 27 85% (met. A3)ref. 29

3r 3s 3t 3u

CF3 N N N N N N N N MeO2C CO2Me F F CF3 CF3

CF3

46% (met. A1)ref. 27 65% (met. A2)ref. 33 58% (met. A2)ref. 33 85% (met. A3)ref. 29 73% (met. A3)ref. 29

Scheme 1. Cont.

Catalysts 2021, 11, 972 5 of 44 Catalysts 2021, 11, 972 5 of 45

a SchemeScheme 1.1. StructureStructure ofof bisiminebisimine 33 andand NHCNHC precursorsprecursors4 4bearing bearing anan acenaphthyleneacenaphthylene subunit.subunit. a TheThe yieldyield ofof bisiminebisimine 3a3a formation was not provided. formation was not provided.

Tobisimine complete 3 formation NHC skeleton could be formation, accomplished bisimines without3 are Lewis subjected acid in to AcOH, a cyclization or in a reaction,mixture of usually MeCN performed and AcOH with [17,25–38]. chloromethyl An inte methylresting ether“green” (MOMCl) alternative or its to lessthe classical volatile homolog,condensation ethyl leading chloromethyl to 3n, w ether, x has (EOMCl), been proposed as the source by Garcia of the [26,39]. precarbenic The authors carbon atom.have Itproved should that be noted effective that theformation strong alkylating of bisimine agents 3n (MOMCl, w, x orcould EOMCl) be areattained usually under used asmechanochemical the solvents in the conditio ring closurens (in a step, ball affordingmill). imdazolium salts 4 with excellent yields. All examplesTo complete of bisimines NHC skeleton3 and NHC formation, precursors bisimines4 described 3 are in subjected the literature to a are cyclization depicted inreaction, Scheme usually1. As it performed was shown, with significantly chloromethyl more methyl examples ether of bisimine(MOMCl)3 orformation its less volatile could behomolog, found inethyl the chloromethyl literature data ether than (EOMCl), for the related as the NHC source precursor of the precarbenic4. This results carbon from atom. the factIt should that bisimines be noted 3thatpossessing the strong an alkylating acenaphthylene agentssubunit (MOMCl serve or EOMCl) as superior are usuallyN,N-ligands used foras the metal solvents complexes, in the beyondring closur thee main step, subjectaffording of thisimdazolium review, NHC-BIAN-type salts 4 with excellent complexes. yields. All examplesSterically of more bisimines hindered 3 and NHC NHC precursors precursors6 4containing described in benzhydryl the literature substituents are depicted at positionsin Scheme 2 1. and As 6it relativewas shown, to the significantly aniline nitrogen more couldexamples also of be bisimine obtained 3 byformation the pathway could describedbe found in above the literature using similar data reactionthan for conditionsthe related (SchemeNHC precursor2). However, 4. This bisimine results from5 forma- the tionfact that step bisimines required the3 possessing presence ofan Lewis acenaphthylene acids, such subunit as ZnCl serve2 or AlMe as superior3 (TMA) N, [N40-ligands–44]. It shouldfor metal be complexes, noted that bisiminebeyond the formation main subject could of be this conducted review, NHC-BIAN-type on a large scale. Bisiminecomplexes.5i was synthesizedSterically more on 100 hindered g scale NHC in 75% precursors yield. All bisimines6 containing5 bearing benzhydryl benzhydryl substituents subunits at andpositions individual 2 and salts 6 relative6 are presentedto the aniline in Scheme nitrogen2. could also be obtained by the pathway described above using similar reaction conditions (Scheme 2). However, bisimine 5 formation step required the presence of Lewis acids, such as ZnCl2 or AlMe3 (TMA) [40–

Catalysts 2021, 11, 972 6 of 45

Catalysts 2021, 11, 972 44]. It should be noted that bisimine formation could be conducted on a large 6scale. of 44 Bisimine 5i was synthesized on 100 g scale in 75% yield. All bisimines 5 bearing benzhydryl subunits and individual salts 6 are presented in Scheme 2.

6 2 R NH2 R Cl

2 6 2 R6 R2 O O R R R6 R2 R6 R2 R6 R2 N N N N 4 R4 R4 4 4 R R2 R6 R R2 R6 R 1 R2 5 R6 R2 6 R6 Methods for bisimine formation Methods for ring closure Method A Method J Method H Method I 1. ZnCl2,AcOH,reflux AlMe , toluene 3 EtOCH Cl MeOCH Cl 2. K2C2O4, H2O,DCM 100 °C 2 2 90–100 °C 100 °C, 16 h 16–24 h

Examples of bisimine

R R R R R R R R R R R R R R R R

N N N N N N N N MeO OMe Cl Cl tBu tBu R R R R R R R R R R R R R R R R

ref. 40 ref. 41 ref. 41 ,R=4-CH C H ,60%(met.A)ref. 41 5a,R=C6H5, 10% (met. J) 5h,R=C6H5, 86% (met. A) 5k,R=4-CH3C6H4,74% (met. A) 5m 3 6 4 ref. 41 ref. 41* ref. 41 5b,R=4-CH3C6H4, 68% (met. A) 5i,R=4-CH3C6H4, 82% (met. A) 5l,R=4-CH3OC6H4,61%(met.A) ref. 44 t ref. 41 5c,R=4-CH3C6H4, 48% (met. A) 5j,R=4-BuC6H4, 83% (met. A) ref. 41 * 100g scale 75% 5d,R=4-CH3OC6H4, 72% (met. A) t ref. 41 5e,R=4-BuC6H4, 70% (met. A) ref. 41 5f,R=4-FC6H4, 20% (met. A) R ref. 41 R R R 5g,R=4-PhC6H4, 80% (met. A) R R

N N N N

R R R R R R

ref. 42 5n, R = Me, 50% (met. J)ref. 43 5o,R=C6H5, 67% (met. A) ref. 42 5p,R=(3,5-OCH3)C6H3,59%(met.A)

Examples of NHC precursor

Cl Cl Cl Cl

R R R R R R R R R R R R R R R R

N N N N N N N N MeO OMe Cl Cl R R R R R R R R R R R R R R R R

ref. 41 ref. 41 ref. 41 ref. 43 6a,R=4-CH3C6H4, 74% (met. I) 6b,R=4-CH3C6H4, 90% (met. I) 6c,R=4-CH3C6H4, 65% (met. I) 6d, R = Me, 70% (met. H) Scheme 2. Synthesis of bisimines 5 and NHC precursors 6 from anilines bearing benzhydryl subunits. Scheme 2. Synthesis of bisimines 5 and NHC precursors 6 from anilines bearing benzhydryl subunits. Acenaphthoquinone (1) could also be used as the platform for the synthesis of Acenaphthoquinone (1) could also be used as the platform for the synthesis of unsym- unsymmetrical NHC precursors 9 [44–46]. The synthetic pathway commenced with the metrical NHC precursors 9 [44–46]. The synthetic pathway commenced with the addition ofaddition one molar of one equivalent molar equivalent of aniline of1 anilineto form 1 monoimineto form monoimine7 under 7 acidic under conditions acidic conditions (AcOH or(AcOHp-TSA or had p-TSA to behad used, to be Scheme used,3 Scheme). The incorporation 3). The incorporation of the second of the aniline second subunit aniline needssubunit the needs strongly the strongly acidic p -TSAacidic in p-TSA boiling in boiling toluene toluene to reach to bisimine reach bisimine8 in the 8 yieldin the range yield 31–81%.range 31–81%. The final The ring fina closurel ring closure was performed was performed with chloromethyl with chloromethyl ethyl ether ethyl to ether afford to NHCafford precursor NHC precursor9 in excellent 9 in excellent yield, usually yield, above usually 80%. abov It shoulde 80%. beIt should noted that be noted sequential that formationsequential offormation bisimine of (via bisimine initial formation (via initial of formation keto imine) of was keto also imine) applied was foralso the applied synthesis for ofthe symmetric synthesis of salts symmetric9a,b with salts excellent 9a,b with results excellent [46]. results [46].

Catalysts 2021, 11, 972 7 of 44 Catalysts 2021, 11, 972 7 of 45

SchemeScheme 3. 3.Synthesis Synthesis of of C C11-symmetric-symmetric NHCNHC precursorsprecursors bearing bearing an an acenaphthylene acenaphthylene subunit. subunit.

AmongAmong the the sterically sterically hindered hindered NHC NHC precursors, precursors, special special attention attention was given was to given pentip- to ticenepentipticene derivatives. derivatives. Plenio andPlenio co-workers and co-worke [47] havers [47] developed have developed a scalable a syntheticscalable synthetic route to thoseroute derivativesto those derivatives bearing a uniquebearing rigid a unique skeleton rigid (Scheme skeleton4). The(Scheme resulting 4). The salt resulting13 could salt be easily13 could accessed be easily via bisimine accessed formation via bisimine starting formation from aminophenol starting 10from(available aminophenol via double 10 cycloaddition(available via ofdouble hydroquinone cycloaddition and anthraceneof hydroquinone on a multigram and anthracene scale), andon a subsequent multigram O-alkylationscale), and subsequent and ring closure, O-alkylation performed and ring in the closure, usual performed manner. It in should the usual be noted manner. that It should be noted that bisimine 11 plays a dual role—a protecting group for the amine

Catalysts 2021, 11, 972 8 of 44

Catalysts 2021, 11, 972 8 of 45

bisimine 11 plays a dual role—a protecting group for the amine function in the O-alkylation stepfunction and a directin the O-alkylation structural element step and fora direct the constructionstructural element of the for imidazole the construction ring. of the imidazole ring.

SchemeScheme 4. The 4. The synthesis synthesis of of NHC NHC precursorsprecursors bearing bearing a apentiptycene pentiptycene subunit. subunit.

2.2.2.2. Synthesis Synthesis of of Polidentate Polidentate CarbeneCarbene Precursors Precursors Polyfunctional carbene ligands are particularly attractive due to their potential for Polyfunctional carbene ligands are particularly attractive due to their potential for use use in catalysis, as they lead to metal complexes [48] often exhibiting higher catalytic in catalysis,activity compared as they leadto their to monofunctional metal complexes analogues [48] often [49]. exhibiting higher catalytic activity comparedMethods to their for monofunctionalthe preparation of analogues polyfunctional [49]. precursors of N-heterocyclic carbenes areMethods identical forto those the preparation applied for ofthe polyfunctional synthesis of their precursors monofunctional of N-heterocyclic counterparts. carbenes A areprecursor identical of to this those type applied was first for described the synthesis by Cowley of their and monofunctionalco-workers [50]. The counterparts. authors A precursorused mesityl of this amine type to was convert first describedtetraketopyracene by Cowley 14 into and tetraimine co-workers 16a [in50 the]. The presence authors of used mesitylZnCl2 amine. Unfortunately, to convert isolation tetraketopyracene of free tetraimine14 into 16a tetraimine required16a decomplexationin the presence using of ZnCl 2. Unfortunately,potassium oxalate. isolation A few of freeyears tetraimine later, Alcarazo16a required and co-workers decomplexation [51] synthesized using NHC potassium oxalate.precursor A few based years on later, 2,6-diisopropylamine Alcarazo and co-workers (DIPP). [This51] synthesizedtime, the condensation NHC precursor was based onperformed 2,6-diisopropylamine in a mixture of (DIPP). AcOH Thisand MeCN time, thewithout condensation any Lewis wasacid performedadditive to provide in a mixture of AcOHtetraimine and 16b MeCN with withoutan excellent any 90% Lewis yield. acid The additive final cyclization to provide with tetraimine MOMCl afforded16b with an NHC precursor 17 in good yield (Scheme 5). Some applications of polyfunctional NHC excellent 90% yield. The final cyclization with MOMCl afforded NHC precursor 17 in good ligands for catalytic processes are discussed in Section 3.1.5. yield (Scheme5). Some applications of polyfunctional NHC ligands for catalytic processes are discussed in Section 3.1.5.

2.3. Synthesis of Chiral Carbene Precursors Rather rare, but very promising from the point of view of enantioselective catalysis are chiral salts of N-heterocyclic carbenes based on the acenaphthylene framework. The rigidity of the polyaromatic skeleton could directly influence the N-wingtip substituent, creating a chiral pocket around the metallic centre more efficiently than simple imidazolium or imidazolinium ligands.

Catalysts 2021, 11, 972 9 of 44 Catalysts 2021, 11, 972 9 of 45

Scheme 5. Synthetic pathways leading to bisacenaphthylene derivatives. Scheme 5. Synthetic pathways leading to bisacenaphthylene derivatives.

2.3. Synthesis of ChiralIn 2018, Carbene Cramer Precursors and co-workers [52] obtained a series of chiral NHC precursors Ratherbearing rare, but C2 verysymmetry promising (Scheme from6 ).the The po synthesisint of view of of salts enantioselective20 commenced catalysis with the addition are chiral saltsof aniline of N-heterocyclic18 to acenaphthoquinone carbenes based (1), on followed the acenaphthylene by cyclization framework. with EOMCl The (Scheme 6). It rigidity of theshould polyaromatic be noted that skeleton the substitution could directly of the influence methyl substituentthe N-wingtip in the substituent,para position relative creating a tochiral the amino pocket group around with athe sterically metallic hindered centre tertmore-butyl efficiently group (Table than1 , entrysimple 2) afforded imidazoliumbisimine or imidazolinium19b and the ligands. chiral precursor NHC 20b in low yields. Similarly, the introduction In 2018,of aCramer xylyl group and (3,5-dimethylbenzyl),co-workers [52] obtained possessing a series two of electron-donating chiral NHC precursors methyl groups, in bearing C2 placesymmetry of the (Scheme phenyl substituent 6). The synthesis in the side-arm, of salts 20 led commenced to the chiral with salt 20cthe inaddition higher yield after of aniline 18two to stepsacenaphthoquinone (Table1, entry 3). (1), Further followed attempts by cyclization to introduce with substituentsEOMCl (Scheme with 6). higher steric It should behindrance, noted that namely, the substituti the 3,5-di-tert-butylphenylon of the methyl groupsubstituent (Table 1in, entrythe para 4), led position to a significantly Catalysts 2021, 11, 972 decreased yield. It should be emphasized that bisimine 19d was prepared10 of 45 under slightly relative to the amino group with a sterically hindered tert-butyl group (Table 1, entry 2) afforded bisiminedifferent 19b conditions and the where chiral the precursor use of strongly NHC 20b acidic in plow-TSA yields. in place Similarly, of ZnCl 2thewas required. introduction of a xylyl group (3,5-dimethylbenzyl), possessing two electron-donating methyl groups, in place of the phenyl substituent in the side-arm, led to the chiral salt 20c in higher yield after two steps (Table 1, entry 3). Further attempts to introduce substituents with higher steric hindrance, namely, the 3,5-di-tert-butylphenyl group (Table 1, entry 4), led to a significantly decreased yield. It should be emphasized that bisimine 19d was prepared under slightly different conditions where the use of strongly acidic p-TSA in place of ZnCl2 was required.

Scheme 6. Synthetic pathway to chiral C2-symmetric NHC precursor 20. Scheme 6. Synthetic pathway to chiral C2-symmetric NHC precursor 20. Table 1. Preparation of salts 20.

Entry Ar R Conditions 19 (%) 20 (%) 1 Ph Me A 70 (19a) 40 (20a) 2 Ph tBu A 60 (19b) 17 (20b) 3 3,5−(CH3)2C6H3 Me A 54 (19c) 52 (20c) 4 3,5−(tBu)2C6H3 Me B 23 (19d) 10 (20d)

Further research of Shi and co-workers [53] has proved that the yield of bisimine formation could be greatly improved by the exclusion of Lewis or Brönsted acids (Scheme 7). Condensation of aniline 18a with acenaphthoquinone (1) conducted in a mixture of MeCN and AcOH afforded cleanly product 19a in higher 88% yield (in comparison to 70%, reported by Cramer [52], Schemes 6 and 7). Rather surprisingly, increasing the reaction temperature to 100 °C and extension the cyclization time to 24 h afforded salt 20a with a two-fold better yield than that in Cramer’s work.

Scheme 7. Improved synthetic pathway to chiral C2-symmetric NHC precursor.

Chiral NHC salts described above appear to be excellent ligands for metal-catalyzed enantioselective formation of indole [54], pyrrole [54], and pyridone derivatives [52] (vide infra), often found in drugs and natural products. A key structural element for their successful application were readily available chiral anilines, originally reported by Gawley and co-workers, and accessible via the resolution of the complicated mixture on chiral preparative HPLC (Scheme 8) [55]. Further research by Gawley and Pfaltz has revealed that chiral aniline 18 could be easily accessed by the initial formation of bis- styrene derivative 23, and subsequent enantioselective hydrogenation of 1,1-diaryl- substituted alkene [56]. Finally, aniline 18b was obtained on a 5 g scale with excellent selectivity (98:0.2:1.8, mixture of R,R:S,S:meso product).

Catalysts 2021, 11, 972 10 of 45

Catalysts 2021, 11, 972 10 of 44

Scheme 6. Synthetic pathway to chiral C2-symmetric NHC precursor 20.

Table 1. PreparationTable 1.of Preparationsalts 20. of salts 20.

Entry Entry Ar Ar R Conditions R Conditions 19 (%) 19 20 (%) (%) 20 (%) 1 1Ph PhMe MeA A70 (19a) 7040 (19a (20a)) 40 (20a) 2 2Ph Ph tBu tBuA 60A (19b) 6017 (19b (20b)) 17 (20b) 3 3,5−(CH ) C H Me A 54 (19c) 52 (20c) 3 2 6 3 3 2 6 3 3 3,5−(CH ) C H t Me A 54 (19c) 52 (20c) 4 3,5−( Bu)2C6H3 Me B 23 (19d) 10 (20d) 4 3,5−(tBu)2C6H3 Me B 23 (19d) 10 (20d)

Further researchFurther of Shi research and co-workers of Shi and co-workers[53] has proved [53] has that proved the yield that of the bisimine yield of bisimine for- formation couldmation be greatly could improved be greatly by improved the exclusion by the of exclusion Lewis or of Brönsted Lewis or acids Brönsted (Scheme acids (Scheme7) . 7). CondensationCondensation of aniline of18a aniline with 18aacenaphthoquinonewith acenaphthoquinone (1) conducted (1) conducted in a mixture in a mixture of of MeCN MeCN and AcOHand AcOH afforded afforded cleanly cleanly product product 19a in19a higherin higher 88% yield 88% yield(in comparison (in comparison to to 70%, re- 70%, reportedported by Cramer by Cramer [52], [Schemes52], Schemes 6 and6 and7). 7Rather). Rather surprisingly, surprisingly, increasing increasing the the reaction ◦ reaction temperaturetemperature to 100 to °C 100 andC extension and extension the cyclization the cyclization time to time 24 h to afforded 24 h afforded salt 20a salt 20a with a with a two-foldtwo-fold better yield better than yield that than in thatCramer’s in Cramer’s work. work.

Scheme 7. Improved synthetic pathway to chiral C2-symmetric NHC precursor. Scheme 7. Improved synthetic pathway to chiral C2-symmetric NHC precursor.

Chiral NHC saltsChiral described NHC salts above described appear aboveto be excellent appear to ligands be excellent for metal-catalyzed ligands for metal-catalyzed enantioselectiveenantioselective formation of indole formation [54], of pyrrole indole [54], [54], and pyrrole pyridone [54], and derivatives pyridone [52] derivatives (vide [52](vide infra), often foundinfra), in often drugs found and in natural drugs products. and natural A products.key structural A key element structural for their element for their successful applicationsuccessful applicationwere readily were available readily availablechiral anilines, chiral anilines, originally originally reported reported by by Gawley Gawley and co-workers,and co-workers, and accessible and accessible via th viae resolution the resolution of the ofcomplicated the complicated mixture mixture on on chiral chiral preparativepreparative HPLC HPLC (Scheme (Scheme 8) [55].8)[ 55Further]. Further research research by byGawley Gawley and and Pfaltz Pfaltz has revealed that revealed that chiralchiral aniline aniline18 18could could be be easily easily accessed accessed by theby the initial initial formation formation of bis-styrene of bis- derivative styrene derivative23, and 23 subsequent, and subsequent enantioselective enantioselective hydrogenation hydrogenation of 1,1-diaryl-substituted of 1,1-diaryl- alkene [56]. substituted alkeneFinally, [56]. aniline Finally,18b wasaniline obtained 18b was ona obtained 5 g scale withon a excellent5 g scale selectivity with excellent (98:0.2:1.8, mixture selectivity (98:0.2:1.8,of R,R:S ,mixtureS:meso product). of R,R:S,S:meso product). In 2018, Cramer and co-workers [52] implemented Gawley and Pfaltz’s protocol based on enantioselective reduction for the preparation of anilines 18b,c bearing more bulky aryl substituents. The authors also proposed synthetic routes to bisalkenyl aniline derivative 23. In the first step, terminal alkyne 21 was converted to vinyl borate 24 through hydroboration catalyzed by nickel-bisphosphine complex (Scheme8). The respective vinyl borate 24 was subjected to Suzuki coupling with 2,6-dibromoaniline to furnish the desired alkenylaniline 23. It should be mentioned that an increase in the steric hindrance of aryl substituent (23a vs. 23b) decreased the yield of the enantioselective reduction (Scheme8).

Catalysts 2021, 11, 972 11 of 44 Catalysts 2021, 11, 972 11 of 45

Gawley, Pfaltz 2013

NH2 NH2 5 mol% Rh(nbd)2BF4 NH2 7 mol% DuanPhos P tBu montmorillonite KSF Ph Ph H2 (45 bar) Ph Ph + H H Ph DCM/MeOH 1/7 t 140 °C, 12 h P Bu rt, 48 h tBu tBu 98% tBu

21a 22 23a 18a (1R,1'R,2S,2'S)-DuanPhos

Cramer 2018

3 mol% Ni(dppp)Cl2,DIBAL THF,0°Ctort,2h MeOB(pin) NH2 THF, rt to 80 °C, 24 h Br Br + Ar Ar B(pin) Ar = 3,5-(CH3)2C6H3, 91% (24a) t Ar = 3,5-( Bu)2C6H3,82%(24b) 21 24

5 mol% PEPPSI-iPr KOH THF, 70 °C, 24 h

Ar = 3,5-(CH3)2C6H3, R = Me, 73% (23a) t Ar = 3,5-( Bu)2C6H3,R=Me,96%(23b)

5 mol% Rh(nbd)2BF4 7 mol% DuanPhos NH2 NH2 H2 (45 bar) Ar Ar DCM/MeOH, rt, 48 h Ar Ar

Ar = 3,5-(CH3)2C6H3,R=Me,98%(18b) Ar = 3,5-(tBu) C H , R = Me, 62% (18c) R 2 6 3 R 18 23

Scheme 8. Synthetic pathway leading to chiral C2-symmetric anilines via enantioselective reduction. Scheme 8. Synthetic pathway leading to chiral C2-symmetric anilines via enantioselective reduction.

3. PreparationIn 2018, Cramer of Metal and Complexes co-workers and [52] Their implemented Application Gawley in Catalysis and Pfaltz’s protocol based3.1. Synthesis on enantioselective of Palladium Complexesreduction andfor Theirthe preparation Applications of anilines 18b,c bearing more bulky aryl substituents. The authors also proposed synthetic routes to bisalkenyl aniline Palladium complexes constitute the most abundant group among metal complexes derivative 23. In the first step, terminal alkyne 21 was converted to vinyl borate 24 through based on the acenaphthylene skeleton. To provide a systematic overview of the synthesis hydroboration catalyzed by nickel-bisphosphine complex (Scheme 8). The respective and applications of palladium complexes, methods for their preparation were divided into vinyl borate 24 was subjected to Suzuki coupling with 2,6-dibromoaniline to furnish the a few categories, including symmetry of BIAN-NHC ligands, their structural modifications, desired alkenylaniline 23. It should be mentioned that an increase in the steric hindrance and the character of the ligand coordinated to the palladium center. In the first subsection, of aryl substituent (23a vs. 23b) decreased the yield of the enantioselective reduction the methods for PEPPSI complexes preparation as well as modifications of NHC ligands (Scheme 8). and ligands coordinated to palladium (including chelating ones) will be discussed. In the final part of the subsection, the application of complexes with a π-extended NHC- 3. Preparation of Metal Complexes and Their Application in Catalysis backbone will be briefly presented, and the possibility of using palladium complexes under 3.1.heterogeneous Synthesis of Palladium conditions Co willmplexes be commented and Their Applications on as well. Palladium complexes constitute the most abundant group among metal complexes based3.1.1. on NHC-BIAN-PEPPSI-Type the acenaphthylene skeleton. Complexes To provide a systematic overview of the synthesis and applicationsPEPPSI-type of complexes palladium (Pyridine-Enhanced complexes, methods Precatalyst for their Preparation preparation Stabilization were divided, and Ini- intotiation a )few were categories, first described including in 2006 symmetry by Organ and of co-workersBIAN-NHC [ 16ligands,,57,58], whotheir proved structural their modifications,utility in cross-coupling and the character reactions of duethe ligand to excellent coordinated catalytic to activity the palladium and stability. center. The In the key firststructural subsection, element, the namelymethods pyridine for PEPPSI or its comp substitutedlexes preparation analogues (usuallyas well as 3-chloropyridine) modifications ofcoordinated NHC ligands to palladiumand ligands could coordinated be easily to introduced palladium by (including the treatment chelating of palladium ones) will com- be discussed.plexes with In an the excess final of part ligand of atthe elevated subsec temperature.tion, the application Organ’s methodof complexes appeared with suitable a π- extendedfor a plethora NHC-backbone of C2-symmetric will be BIAN-NHC-PdCl briefly presented,2Py and complexes, the possibility and their of using synthesis palladium could complexesbe conducted under on aheterogeneous few hundred milligram conditions scale, will highlightingbe commented the on practical as well. aspect for further applications in catalysis (Scheme9). 3.1.1. NHC-BIAN-PEPPSI-Type Complexes PEPPSI-type complexes (Pyridine-Enhanced Precatalyst Preparation Stabilization, and Initiation) were first described in 2006 by Organ and co-workers [16,57,58], who proved

Catalysts 2021, 11, 972 12 of 45

their utility in cross-coupling reactions due to excellent catalytic activity and stability. The key structural element, namely pyridine or its substituted analogues (usually 3- chloropyridine) coordinated to palladium could be easily introduced by the treatment of palladium complexes with an excess of ligand at elevated temperature. Organ’s method appeared suitable for a plethora of C2-symmetric BIAN-NHC-PdCl2Py complexes, and their synthesis could be conducted on a few hundred milligram scale, highlighting the practical aspect for further applications in catalysis (Scheme 9). A significant number of palladium(II) complexes bearing C2 symmetry have been synthesized by the Tu and Liu research groups, independently (Scheme 9). First, complexes possessing only simple alkyl substituents in the ortho position of the aniline, such as mesityl or DIPP derivatives (25a–c [35,59–61], 25d–g [62] and 25h–i [43,63]) were obtained in a moderate 48–68% yield. Further research in this area resulted in the synthesis of the highly sterically hindered palladium(II) complexes 25j–n [46] and 25n [41], containing benzhydryl substituents, in comparable yields. Finally, Liu and co-workers synthesized interesting examples of C2-symmetric complexes 37 [64] with diverse Catalysts 2021, 11, 972substituents in the ortho position of the aniline ring. The synthesis of all mentioned 12 of 44 PEPPSI-Pd complexes appeared to be easily scalable, delivering 100 milligram quantities of the respective metal complexes for further catalytic applications.

Scheme 9. Synthetic efforts towards C2-symmetric PEPPSI-type palladium complexes. Scheme 9. Synthetic efforts towards C2-symmetric PEPPSI-type palladium complexes.

A significant number of palladium(II) complexes bearing C2 symmetry have been synthesized by the Tu and Liu research groups, independently (Scheme9). First, complexes possessing only simple alkyl substituents in the ortho position of the aniline, such as mesityl or DIPP derivatives (25a–c [35,59–61], 25d–g [62] and 25h–i [43,63]) were obtained in a moderate 48–68% yield. Further research in this area resulted in the synthesis of the highly sterically hindered palladium(II) complexes 25j–n [46] and 25n [41], containing benzhydryl substituents, in comparable yields. Finally, Liu and co-workers synthesized interesting examples of C2-symmetric complexes 37 [64] with diverse substituents in the ortho position of the aniline ring. The synthesis of all mentioned PEPPSI-Pd complexes appeared to be easily scalable, delivering 100 milligram quantities of the respective metal complexes for further catalytic applications. Bearing in mind that the catalytic activity of palladium(II) complexes strictly depends on even small structural changes in the ligand, Liu has developed a series of C1-symmetric complexes 26 (Scheme 10) exhibiting remarkable reactivity in cross-coupling reactions (see, vide infra)[45]. It should be noted that this is one of the very rare examples of successful synthesis of N-heterocyclic carbene precursors and metal complexes bearing an electron-withdrawing substituent [65–67], in this particular case a fluorine. The syntheses of complexes of general structure 26 were conducted on a large scale, providing easy access to more than 0.5 g of the metal complex in each case. Catalysts 2021, 11, 972 13 of 45

Bearing in mind that the catalytic activity of palladium(II) complexes strictly depends on even small structural changes in the ligand, Liu has developed a series of C1-symmetric complexes 26 (Scheme 10) exhibiting remarkable reactivity in cross-coupling reactions (see, vide infra) [45]. It should be noted that this is one of the very rare examples of successful synthesis of N-heterocyclic carbene precursors and metal complexes bearing an Catalysts 2021, 11, 972 electron-withdrawing substituent [65–67], in this particular case a fluorine. The syntheses13 of 44 of complexes of general structure 26 were conducted on a large scale, providing easy access to more than 0.5 g of the metal complex in each case.

Scheme 10. Synthetic efforts towards C11-symmetric PEPPSI-type palladium complexes.

NHC-BIAN-Pd palladiumpalladium complexes complexes have have proved proved to be to the be most the prevalent most prevalent in catalysis in amongcatalysis metal among complexes metal complexes possessing possessing an acenaphthylene an acenaphthylene structural subunit structural and subunit have found and widespreadhave found widespread applications applications in cross-coupling in cross-coupling reactions. Amongreactions. cross-coupling Among cross-coupling reactions, Suzukireactions, and Suzuki Buchwald-Hartwig and Buchwald-Hartwig reactions are reactions the most are explored the most ones explored with PEPPSI-type ones with palladiumPEPPSI-type complexes. palladium complexes. One of the early examples of the Suzuki re reactionaction was described by Tu and co-workers in 20122012 (Scheme(Scheme 11 11))[ 35[35].]. Authors Authors proved proved the the usefulness usefulness of of complex complex25a 25afor for the the coupling coupling of boronicof boronic acids acids with with a wide a wide array array of aryl of aryl bromides bromides and and more more challenging challenging aryl aryl chlorides. chlorides. The respectiveThe respective products products were isolated were isolated with excellent with yields,excellent also yields, in the casealso of in heteroaromatic the case of t components,heteroaromatic using components, 0.5 mol% ofusing25a and0.5 KOmol%Bu of as base.25a and Further KOtBu improvement as base. Further for the Suzukiimprovement reaction forhas the Suzuki been achieved reaction byhas the been Liu achieved group by [68 the]. The Liu group authors [68]. decorated The authors the acenaphthylenedecorated the acenaphthylene backbone with backbone the bulky withtert-Bu the group bulky (in tertanti-orientation-Bu group (in) byanti-orientation the addition) reactionby the addition with tert -BuLi.reaction The with respective tert-BuLi. complex The 27arespectiveappeared complex to be extremely 27a appeared activefor to thebe couplingextremely of active low reactive for the aryl coupling chloride of without low reactive inert gas aryl atmosphere. chloride Thewithout most importantinert gas feature of Liu’s protocol is the use of weakly basic conditions (K PO instead of KOtBu) Catalysts 2021, 11, 972 atmosphere. The most important feature of Liu’s protocol is the3 use4 of weakly14 of 45 basic and low catalyst loading, in the range 0.05–0.1 mol%. conditions (K3PO4 instead of KOtBu) and low catalyst loading, in the range 0.05–0.1 mol%. Further investigations of Liu and co-workers furnished complexes 25h–i and 25o–s, catalytically active in the Suzuki reaction under aerobic conditions. Sterically hindered PEPPSI-IPent-Pd complex 25i proved to be very effective for the synthesis of sterically hindered biaryls, including 2,6,2′,6′-tetrasubstituted ones from a wide range of aryl and especially heteroaryl chlorides and boronic acids [43]. Comparable reactivity of complex 25i has been reported in reactions catalyzed by complex 25q [64]. The most significant advantage of the developed protocol is a further decrease in catalyst loading, being as low as 0.025 mol%. Moreover, the application of K2CO3 as the base furnished heterobiaryls and polyheteroarenes with excellent functional group tolerance from a variety of heterocycle building blocks, including pyridine, furan, and thiophene derivatives, as well as much more challenging thiazoles and pyrazines (usually effecting deactivation of the palladium catalyst).

SchemeScheme 11. 11.Application Application of of Pd-PEPPSI-typePd-PEPPSI-type complexes complexes for for Suzuki Suzuki coupling. coupling.

FurtherAs an alternative investigations to the ofSuzuki Liu andreaction, co-workers biaryl systems furnished can be complexes efficiently accessed25h–i and via 25o–s, catalyticallythe Negishi active reaction, in theespecially Suzuki when reaction boronic under acids aerobic (or their conditions. analogues) are Sterically difficult hindered to PEPPSI-IPent-Pdprepare. Tu and complexco-workers25i haveproved developed to be verythe coupling effective of for aromatic the synthesis and aliphatic of sterically organozinc compounds with both aryl chlorides and bromides at room temperature hindered biaryls, including 2,6,20,60-tetrasubstituted ones from a wide range of aryl and (Scheme 12) [60]. The respective products 30 were obtained with excellent yield, even for especiallysecondary heteroaryl organozinc chlorides compounds, and prone boronic to undergo acids [43 β].-elimination. Comparable It reactivityshould be noted of complex 25ithathas 0.25 been mol% reported of complex in reactions 25a was catalyzedneeded to achieve by complex the high25q yield,[64]. also The in mostthe case significant of advantageheteroaromatic of the compounds, developed protocolincluding is thiophene, a further decreasefuran, as inwell catalyst as pyridine loading, and being as lowpyridazine as 0.025 derivatives. mol%. Moreover, the application of K2CO3 as the base furnished hetero- biaryls and polyheteroarenes with excellent functional group tolerance from a variety of

Scheme 12. Application of Pd-PEPPSI-type complexes for Negishi coupling.

Another efficient protocol for the synthesis of biaryl compounds was developed by Organ, Feringa, and co-workers in 2019 [69]. The authors achieved for the first time the Murahashi coupling of an organolithium reagent with aryl bromide (Scheme 13) at low temperature (−62 °C). The coupling reaction proved to be highly chemoselective towards aryl bromide in the presence of chloride, making sequential selective Br/Cl coupling possible. A wide range of aryl and alkyl lithium reagents 31 were successfully coupled with bromides, including heteroaromatic ones. Unfortunately, the reaction requires high catalyst loading (5.0 mol% of 25t) to maintain the high yields.

Catalysts 2021, 11, 972 14 of 45

Catalysts 2021, 11, 972 14 of 44

heterocycle building blocks, including pyridine, furan, and thiophene derivatives, as well Scheme 11. Application of Pd-PEPPSI-type complexes for Suzuki coupling. as much more challenging thiazoles and pyrazines (usually effecting deactivation of the palladium catalyst). As an alternative to the Suzuki reaction, biaryl systems can be efficiently accessed via As an alternative to the Suzuki reaction, biaryl systems can be efficiently accessed via the Negishi reaction, especially when boronic acids (or their analogues) are difficult to the Negishi reaction, especially when boronic acids (or their analogues) are difficult to pre- prepare. Tu and co-workers have developed the coupling of aromatic and aliphatic pare. Tu and co-workers have developed the coupling of aromatic and aliphatic organozinc organozinc compounds with both aryl chlorides and bromides at room temperature compounds with both aryl chlorides and bromides at room temperature (Scheme 12)[60]. (Scheme 12) [60]. The respective products 30 were obtained with excellent yield, even for The respective products 30 were obtained with excellent yield, even for secondary organoz- secondary organozinc compounds, prone to undergo β-elimination. It should be noted inc compounds, prone to undergo β-elimination. It should be noted that 0.25 mol% of that 0.25 mol% of complex 25a was needed to achieve the high yield, also in the case of complex 25a was needed to achieve the high yield, also in the case of heteroaromatic heteroaromatic compounds, including thiophene, furan, as well as pyridine and compounds, including thiophene, furan, as well as pyridine and pyridazine derivatives. pyridazine derivatives.

SchemeScheme 12. Application 12. Application of Pd-PEPPSI-type of Pd-PEPPSI-type complexes complexes for Negishi for Negishicoupling. coupling.

Another efficientAnother protocol efficient for protocol the synthesi for thes of synthesis biaryl compounds of biaryl compounds was developed was by developed by Organ, Feringa,Organ, and Feringa, co-workers and co-workersin 2019 [69]. in The 2019 authors [69]. The achieved authors for achieved the first fortime the the first time the Murahashi couplingMurahashi of couplingan organolithium of an organolithium reagent with reagent aryl bromide with aryl (Scheme bromide 13) (Scheme at low 13) at low temperaturetemperature (−62 °C). The (− coupling62 ◦C). The reaction coupling proved reaction to be proved highly tochemoselective be highly chemoselective towards towards aryl bromidearyl in bromidethe presence in the of presence chloride, of making chloride, sequential making sequentialselective Br/Cl selective coupling Br/Cl coupling possible. A possible.wide range A wideof aryl range and ofalkyl aryl lithium and alkyl reagents lithium 31 reagentswere successfully31 were successfully coupled coupled Catalysts 2021, 11, 972with bromides,with including bromides, heteroaromatic including heteroaromatic ones. Unfortunately, ones. Unfortunately, the reaction the requires reaction high requires 15high of 45 catalyst loadingcatalyst (5.0 loadingmol% of (5.0 25t mol%) to maintain of 25t) tothe maintain high yields. the high yields.

SchemeScheme 13.13.Application Application ofof Pd-PEPPSIPd-PEPPSI typetype complexescomplexes forfor MurahashiMurahashi coupling.coupling.

TheThe secondsecond extensively extensively investigated investigated group group of reactionsof reactions catalyzed catalyzed by palladium by palladium com- plexes,complexes, besides besides the formationthe formation of biaryls,of biaryls, is theis the Buchwald-Hartwig Buchwald-Hartwig amination. amination. Indeed,Indeed, PEPPSI-PdPEPPSI-Pd typetype complexescomplexes havehave shownshown remarkable remarkable activity activity for for C-N C-N bond bond formation. formation. The The firstfirst literatureliterature reportreport camecame fromfrom thethe TuTu group group [ 59[59]] and and concerned concerned the the use use of of complex complex25a 25a forfor thethe synthesissynthesis ofof secondarysecondary andand tertiarytertiary aminesamines fromfrom low-reactivitylow-reactivity aryl aryl chlorides chlorides with with virtuallyvirtually quantitativequantitative yieldsyields (Scheme(Scheme 1414).). FurtherFurther researchresearch ofof thethe samesame groupgroup hashas ledled toto thethe developmentdevelopment of of complexescomplexes26c 26cbearing bearingC C11 symmetry,symmetry,which whichdrastically drastically influenced influenced the the reactivityreactivity [[45].45]. TuTu andand co-workersco-workers havehave demonstrateddemonstrated theirtheir remarkableremarkable activityactivity forfor thethe couplingcoupling ofofortho ortho- and- and more more sterically sterically hindered hinderedbis-ortho-substituted bis-ortho-substituted chlorides chlorides with with pri- maryprimary and and secondary secondary amines. amines. Importantly, Importantly, complex complex26c exhibits26c exhibits perfect perfect stability stability under under the reactionthe reaction conditions, conditions, and anand inert an atmosphereinert atmosp washere not was required not required for high for efficiency. high efficiency. Similar Similar catalytic activity and scope of applicability were reported for the more sterically hindered complexes 25h [63] and 25m [46]. It should be noted that the evaluation of the catalytic activity of complexes presented in Scheme 14 was performed on model Buchwald-Hartwig reactions with slightly structurally different substrate and conditions, preventing a direct comparison. Furthermore, no data are available for comparison with other PEPPSI-type complexes, in particular with IPr or IMes derivatives.

Scheme 14. Buchwald-Hartwig coupling catalyzed by Pd-PEPPSI-type complexes.

Palladium complexes based on the acenaphthylene scaffold were also applied in the Sonogashira reaction (Scheme 15) [70]. Here, the combination of two carbene complexes, namely palladium complex 25a and IPrCuCl (35a) enabled the reaction between terminal alkynes and aromatic bromides. Regrettably, the reaction requires a relatively high temperature of 120 °C. However, it could be performed with very low palladium catalyst loading 25a, as little as 0.01 mol%.

Catalysts 2021, 11, 972 15 of 45

Scheme 13. Application of Pd-PEPPSI type complexes for Murahashi coupling.

The second extensively investigated group of reactions catalyzed by palladium complexes, besides the formation of biaryls, is the Buchwald-Hartwig amination. Indeed, PEPPSI-Pd type complexes have shown remarkable activity for C-N bond formation. The first literature report came from the Tu group [59] and concerned the use of complex 25a for the synthesis of secondary and tertiary amines from low-reactivity aryl chlorides with virtually quantitative yields (Scheme 14). Further research of the same group has led to the development of complexes 26c bearing C1 symmetry, which drastically influenced the reactivity [45]. Tu and co-workers have demonstrated their remarkable activity for the Catalysts 2021, 11, 972 15 of 44 coupling of ortho- and more sterically hindered bis-ortho-substituted chlorides with primary and secondary amines. Importantly, complex 26c exhibits perfect stability under the reaction conditions, and an inert atmosphere was not required for high efficiency. Similarcatalytic catalytic activity andactivity scope and of scope applicability of applicab wereility reported were reported for the more for stericallythe more hinderedsterically hinderedcomplexes complexes25h [63] and 25h25m [63] [and46]. 25m It should [46]. It be should noted thatbe noted the evaluation that the evaluation of the catalytic of the catalyticactivity of activity complexes of presentedcomplexes in Schemepresente 14d wasin Scheme performed 14 onwas model performed Buchwald-Hartwig on model Buchwald-Hartwigreactions with slightly reactions structurally with slightly different structurally substrate and different conditions, substrate preventing and conditions, a direct preventingcomparison. a Furthermore,direct comparison. no data Furthermore, are available no for data comparison are available with for other comparison PEPPSI-type with othercomplexes, PEPPSI-type in particular complexes, with IPr in orparticular IMes derivatives. with IPr or IMes derivatives.

Scheme 14. Buchwald-Hartwig coupling catalyzed by Pd-PEPPSI-typePd-PEPPSI-type complexes.complexes.

Palladium complexes based on the acenaphthylene scaffold were also applied in thethe Sonogashira reaction (Scheme 15)15)[ [70].70]. Here, the combination of two carbene complexes, namely palladium complex 25a and IPrCuCl (35a) enabled the reaction betweenbetween terminalterminal alkynes andand aromatic aromatic bromides. bromides. Regrettably, Regrettably, the reactionthe reaction requires requires a relatively a relatively high temper- high Catalysts 2021, 11, 972 ature of 120 ◦C. However, it could be performed with very low palladium catalyst loading16 of 45 temperature of 120 °C. However, it could be performed with very low palladium catalyst loading25a, as little 25a, asas 0.01little mol%. as 0.01 mol%.

SchemeScheme 15. 15.Sonogashira Sonogashira coupling coupling catalyzed catalyzed by by Pd-PEPPSI-type Pd-PEPPSI-type complexes. complexes.

TheThe modified-PEPPSI-Pd modified-PEPPSI-Pd complexescomplexes were also successfully successfully applied applied in in azole azole arylation aryla- tion[62]. [62 The]. The sequential sequential C-H C-H activation/arylation activation/arylation was wasdescribed described by Liu by Liuand and co-workers co-workers with withcomplex complex 25g25g. The. The key key to tosuccessful successful coupling coupling was was the the introductionintroduction ofof aa benzhydryl benzhydryl substituentsubstituent into into the the aniline aniline subunit subunit of of complex complex25g 25g, increasing, increasing the theσ -donorσ-donor properties properties of of NHCNHC ligand, ligand, and and hence hence facilitating facilitating the oxidative the oxidative addition addition step. This step. structural This modifica-structural tionmodification enabled highly enabled regioselective highly regioselective coupling of co aupling wide range of a wide of azoles, range including of azoles, imidazole, including imidazole, triazole, oxazole, and thiazole derivatives under aerobic conditions at very low catalyst loading of complex 25g, in the range 0.05–0.5 mol% (Scheme 16).

Scheme 16. Azole arylation catalyzed by Pd-PEPPSI-type complexes.

3.1.2. π-Allyl NHC-BIAN-Pd Complexes Palladium π-allyl complexes are usually extremely active in many catalytic transformations, but less stable than the respective NHCPdCl2 derivatives (or their congeners). Taking into account the excellent activity, it is rather surprising that palladium π-allyl complexes bearing acenaphthylene backbone were marginally reported [71–73]. Their preparation directly from an NHC-BIAN-type precursor required a palladium dimer and a strong base (38a, Scheme 17) [72]. It should be noted that the introduction of a phenyl-substituted π-allyl moiety (38b) was achieved at elevated temperatures with rather moderate yields.

Catalysts 2021, 11, 972 16 of 45

Scheme 15. Sonogashira coupling catalyzed by Pd-PEPPSI-type complexes.

The modified-PEPPSI-Pd complexes were also successfully applied in azole arylation [62]. The sequential C-H activation/arylation was described by Liu and co-workers with Catalysts 2021, 11, 972 complex 25g. The key to successful coupling was the introduction of a benzhydryl16 of 44 substituent into the aniline subunit of complex 25g, increasing the σ-donor properties of NHC ligand, and hence facilitating the oxidative addition step. This structural modification enabled highly regioselective coupling of a wide range of azoles, including triazole,imidazole, oxazole, triazole, and oxazole, thiazole and derivatives thiazole derivatives under aerobic under conditions aerobic conditions at very low at very catalyst low 25g loadingcatalyst ofloading complex of complex, in the 25g range, in the 0.05–0.5 range mol%0.05–0.5 (Scheme mol% 16(Scheme). 16).

SchemeScheme 16.16.Azole Azole arylationarylation catalyzedcatalyzed byby Pd-PEPPSI-typePd-PEPPSI-type complexes.complexes.

3.1.2.3.1.2. ππ-Allyl-Allyl NHC-BIAN-PdNHC-BIAN-Pd Complexes Complexes PalladiumPalladiumπ -allylπ-allyl complexes complexes are usuallyare usually extremely extremely active in active many catalyticin many transforma- catalytic tions,transformations, but less stable but than less the stable respective than NHCPdCl the respective2 derivatives NHCPdCl (or their2 derivatives congeners). (or Taking their intocongeners). account theTaking excellent into activity,account it isthe rather excellent surprising activity, that palladiumit is ratherπ -allylsurprising complexes that bearingpalladium acenaphthylene π-allyl complexes backbone bearing were acenaphthylene marginally reported backbone [71 were–73]. marginally Their preparation reported directly[71–73]. from Their an NHC-BIAN-typepreparation directly precursor from requiredan NHC-BIAN-type a palladium dimer precursor and a strongrequired base a Catalysts 2021, 11, 972 (38a, Scheme 17)[72]. It should be noted that the introduction of a phenyl-substituted17 of 45 palladium dimer and a strong base (38a, Scheme 17) [72]. It should be noted that the πintroduction-allyl moiety of (38b a )phenyl-substituted was achieved at elevated π-allyl temperatures moiety (38b with) was rather achieved moderate at elevated yields. temperatures with rather moderate yields.

Scheme 17. Synthesis of π-allyl-allyl palladiumpalladium complexes.complexes.

The above-mentioned π-allyl-allyl complexescomplexes 38b were firstfirst appliedapplied asas catalystscatalysts inin thethe aminocarbonylation reactionreaction of of iodoarenes iodoarenes (Scheme (Scheme 18)[ 7218)]. Tu[72]. and Tu co-workers and co-workers demon- strateddemonstrated that the that reaction the reaction can be can carried be carrie outd with out carbonwith carbon monoxide monoxide under under relatively relatively low pressurelow pressure of the of gasthe gas (1 atm.). (1 atm.). The The developed developed procedure procedure was was applied applied to to a a wide wide rangerange ofof primary and secondary amines, and finallyfinally forfor thethe synthesissynthesis ofof tamiboratenetamiboratene onon aa gramgram scale. Similar conditions have been successfully used for the aminocarbonylation of ortho- diiodoarenes, providingproviding accessaccess toto imidesimides [[73].73]. InIn this case, slightly higher temperature andand DABCO as base were needed.needed.

Scheme 18. Aminocarbonylation catalyzed by π-allyl palladium complexes.

An interesting application of a π-allyl BIAN-NHC palladium complex was also reported by the Tu group who described for the first time the sulfonation of boronic acids [72]. The authors developed a unique method for the preparation of aryl-alkyl sulfones from boronic acids and α-bromoesters. The sulfone formation was efficiently catalyzed by a cinnamyl derivative of palladium complex 38b where potassium metabisulfite (K2S2O5) served as the source of the sulfone group. Moreover, the authors proposed, based on several control experiments, a reaction catalytic cycle comprising transmetalation, SO2 insertion, and final alkylation (Scheme 19). They gave particular attention to the role of TBAF in the alkylation step of the dimeric palladium compound, most likely facilitating the sulfinate formation.

Catalysts 2021, 11, 972 17 of 45

Scheme 17. Synthesis of π-allyl palladium complexes.

The above-mentioned π-allyl complexes 38b were first applied as catalysts in the aminocarbonylation reaction of iodoarenes (Scheme 18) [72]. Tu and co-workers demonstrated that the reaction can be carried out with carbon monoxide under relatively low pressure of the gas (1 atm.). The developed procedure was applied to a wide range of primary and secondary amines, and finally for the synthesis of tamiboratene on a gram Catalysts 2021, 11, 972scale. Similar conditions have been successfully used for the aminocarbonylation of ortho- 17 of 44 diiodoarenes, providing access to imides [73]. In this case, slightly higher temperature and DABCO as base were needed.

Scheme 18.Scheme Aminocarbonylation 18. Aminocarbonylation catalyzed catalyzed by π-allyl by palladiumπ-allyl palladium complexes. complexes.

An interestingAn application interesting applicationof a π-allyl of BIAN-NHC a π-allyl BIAN-NHC palladium palladium complex was complex also was also re- reported by theported Tu group by the who Tu group described whodescribed for the first for time the firstthe sulfonation time the sulfonation of boronic of acids boronic acids [72]. [72]. The authorsThe authors developed developed a unique a uniquemethod method for the forpreparation the preparation of aryl-alkyl of aryl-alkyl sulfones sulfones from from boronicboronic acids and acids α-bromoesters. and α-bromoesters. The sulfone The formatio sulfonen formation was efficiently was efficientlycatalyzed by catalyzed by a a cinnamyl derivativecinnamyl of derivative palladium of complex palladium 38b complex where potassium38b where metabisulfite potassium metabisulfite (K2S2O5) (K2S2O5) served as theserved source as of the the source sulfone of thegroup. sulfone Moreover, group. the Moreover, authors theproposed, authors based proposed, on based on several controlseveral experiments, control experiments, a reaction cata a reactionlytic cycle catalytic comprising cycle comprisingtransmetalation, transmetalation, SO2 SO2 insertion, andinsertion, final alkylation and final (Scheme alkylation 19). (Scheme They gave 19). particular They gave attention particular to the attention role of to the role of Catalysts 2021, 11, 972 18 of 45 TBAF in the TBAFalkylation in the step alkylation of the dimeric step of palladium the dimeric compound, palladium most compound, likely facilitating most likely facilitating the sulfinate theformation. sulfinate formation.

SchemeScheme 19. 19.Sulfonation Sulfonation of boronicof boronic acids acids catalyzed catalyzed by π-allyl by π palladium-allyl palladium complexes. complexes.

3.1.3.3.1.3. Chelate Chelate Complexes Complexes An interesting equilibrium between the catalytic activity and stability of the palladium An interesting equilibrium between the catalytic activity and stability of the complex was presented by Tu and co-workers [74]. Conducting studies on the coupling of palladium complex was presented by Tu and co-workers [74]. Conducting studies on the coupling of amines and heteroaryl chlorides, the authors demonstrated that palladacycle 38b exhibits much better activity in comparison to standard PEPPSI-Pd complexes. In this manner, a number of secondary and tertiary amines were obtained from challenging chloropyridines with excellent yields. The corresponding series of palladacycles 38 were synthesized from the carbene precursor 44 in the usual manner, in the presence of K2CO3. Moreover, the coordination between palladium and the amine was unambiguously confirmed by X-ray crystallography (Scheme 20).

Scheme 20. Synthesis of palladium complexes bearing a chelating arm.

3.1.4. Skeleton Modifications of NHC-BIAN-Pd Complexes and Their Catalytic Activity Further research in the area of palladium catalysis has led to the development of PEPPSI-type complexes with a modified acenaphthylene structural element. Liu and co- workers have synthetized carbene precursors 45 possessing two tert-butyl groups in an

Catalysts 2021, 11, 972 18 of 45

Catalysts 2021, 11, 972 Scheme 19. Sulfonation of boronic acids catalyzed by π-allyl palladium complexes. 18 of 44

3.1.3. Chelate Complexes An interesting equilibrium between the catalytic activity and stability of the aminespalladium and complex heteroaryl was chlorides,presented by the Tu authors and co-workers demonstrated [74]. Conducting that palladacycle studies on38b theexhibits muchcoupling better of amines activity and in heteroaryl comparison chlorides, to standard the authors PEPPSI-Pd demonstrated complexes. that palladacycle In this manner, a number38b exhibits of secondary much better and activity tertiary in comparison amines were to standard obtained PEPPSI-Pd from challenging complexes. chloropyridines In this withmanner, excellent a number yields. of Thesecondary corresponding and tertiary series amines of palladacycles were obtained38 fromwere challenging synthesized from chloropyridines with excellent yields. The corresponding series of palladacycles 38 were the carbene precursor 44 in the usual manner, in the presence of K2CO3. Moreover, the coordinationsynthesized from between the carbene palladium precursor and 44 the in aminethe usual was manner, unambiguously in the presence confirmed of K2CO3 by. X-ray Moreover, the coordination between palladium and the amine was unambiguously crystallography (Scheme 20). confirmed by X-ray crystallography (Scheme 20).

SchemeScheme 20.20. Synthesis of of palladium palladium complexes complexes bearing bearing a chelating a chelating arm. arm.

3.1.4.3.1.4. SkeletonSkeleton Modifications Modifications of ofNHC-BIAN NHC-BIAN-Pd-Pd Complexes Complexes and Their and TheirCatalytic Catalytic Activity Activity Catalysts 2021, 11, 972 Further research in the area of palladium catalysis has led to the development of 19 of 45 Further research in the area of palladium catalysis has led to the development of PEPPSI-typePEPPSI-type complexes complexes with with a modified a modified acenap acenaphthylenehthylene structural structural element. element. Liu and Liuco- and co- workers have synthetized carbene precursors 45 possessing two tert-butyl groups in an workers have synthetized carbene precursors 45 possessing two tert-butyl groups in an anti-relationshipanti-relationship (Scheme 2121))[ [68].68]. TheseThese saltssalts werewere usedused forfor thethe synthesissynthesis ofof palladiumpalladium complexescomplexes27 27 usingusing PdClPdCl22 and pyridine asas the solvent. The catalytic activity waswas evaluatedevaluated inin thethe SuzukiSuzuki reactionreaction (for(for details,details, seesee SchemeScheme 1111).).

SchemeScheme 21.21. SyntheticSynthetic approachapproach toto NHC-BIAN-PdNHC-BIAN-Pd complexescomplexes withwith modifiedmodified backbone.backbone.

3.1.5.3.1.5. Polyfunctional NHC-BIAN-PdNHC-BIAN-Pd ComplexesComplexes AsAs mentionedmentioned earlier earlier (Scheme (Scheme5), polyfunctional 5), polyfunctional metal complexesmetal complexes based on based polyaro- on maticpolyaromatic systems systems usually exhibitusually different exhibit catalyticdifferent properties.catalytic properties. To date, a singleTo date, example a single of polyfunctionalexample of polyfunctional palladium complexes palladium has complexes been described has been by Peris described and co-workers by Peris [ 49and]. The co- catalyticworkers [49]. activity The of catalytic the respective activity bispalladiumof the respective complexes bispalladium49, bearing complexes acenaphthylene 49, bearing scaffold,acenaphthylene was studied scaffold, in the was acylation studied of arylin the chloride acylation and theof aryl Suzuki chloride coupling and(Scheme the Suzuki 22). Unfortunately,coupling (Scheme bispalladium 22). Unfortunately,49 shows bispalladium similar catalytic 49 shows activity similar in comparison catalytic activity to mono- in functionalcomparison complexes. to monofunctional complexes.

Scheme 22. Application of polyfunctional NHC-BIAN-Pd complexes for the acylation of aldehydes and Sonogashira coupling.

Catalysts 2021, 11, 972 19 of 45

anti-relationship (Scheme 21) [68]. These salts were used for the synthesis of palladium complexes 27 using PdCl2 and pyridine as the solvent. The catalytic activity was evaluated in the Suzuki reaction (for details, see Scheme 11).

Scheme 21. Synthetic approach to NHC-BIAN-Pd complexes with modified backbone.

3.1.5. Polyfunctional NHC-BIAN-Pd Complexes As mentioned earlier (Scheme 5), polyfunctional metal complexes based on polyaromatic systems usually exhibit different catalytic properties. To date, a single example of polyfunctional palladium complexes has been described by Peris and co- workers [49]. The catalytic activity of the respective bispalladium complexes 49, bearing Catalysts 2021, 11, 972 acenaphthylene scaffold, was studied in the acylation of aryl chloride and the Suzuki19 of 44 coupling (Scheme 22). Unfortunately, bispalladium 49 shows similar catalytic activity in comparison to monofunctional complexes.

SchemeScheme 22.22. Application ofof polyfunctionalpolyfunctional NHC-BIAN-PdNHC-BIAN-Pd complexescomplexes forfor thethe acylationacylation ofof aldehydesaldehydes andand SonogashiraSonogashira coupling.coupling.

3.1.6. Heterogenization of NHC-BIAN-Pd Complexes The methods discussed so far have concerned only homogeneous palladium catalysis. Unfortunately, there are many drawbacks associated with homogeneous catalysis, espe- cially on an industrial scale. Catalytic homogeneous processes yield large amounts of waste, contributing to environmental pollution. In addition, low atom economy and difficult catalyst recovery are common drawbacks. Thus, heterogenization of homogenous catalysts on solid support proved useful in many processes to date, allowing for the straightforward recovery of the usually expensive metal complex. The first example of heterogenization of BIAN-NHC-Pd complexes was given by Bazzi and co-workers [38]. The authors synthetized PEPPSI-Pd-type complexes covalently bonded to a polymeric support via long nonpolar chains containing 18 isobutylene units. Pleasingly, the polyisobutylene polymer (PIB) attached to complex 50 increased its solubility in a nonpolar solvent. This allowed for easy separation of amines from the palladium catalyst by polar solvent extraction, without the need for time-consuming and expensive column chromatography and, accordingly, enabled the efficient recovery of the catalyst. The respective palladium complex 50 was obtained under standard conditions (PdCl2 and K2CO3) from NHC precursor 4f with moderate 68% yield (Scheme 23), and its catalytic activity was investigated using the Buchwald-Hartwig amination. The authors observed remarkably high catalytic activity in non-polar media, such as n-heptane, for the coupling of aryl halides with secondary amines and anilines. Catalysts 2021, 11, 972 20 of 45

3.1.6. Heterogenization of NHC-BIAN-Pd Complexes The methods discussed so far have concerned only homogeneous palladium catalysis. Unfortunately, there are many drawbacks associated with homogeneous catalysis, especially on an industrial scale. Catalytic homogeneous processes yield large amounts of waste, contributing to environmental pollution. In addition, low atom economy and difficult catalyst recovery are common drawbacks. Thus, heterogenization of homogenous catalysts on solid support proved useful in many processes to date, allowing for the straightforward recovery of the usually expensive metal complex. The first example of heterogenization of BIAN-NHC-Pd complexes was given by Bazzi and co-workers [38]. The authors synthetized PEPPSI-Pd-type complexes covalently bonded to a polymeric support via long nonpolar chains containing 18 isobutylene units. Pleasingly, the polyisobutylene polymer (PIB) attached to complex 50 increased its solubility in a nonpolar solvent. This allowed for easy separation of amines from the palladium catalyst by polar solvent extraction, without the need for time-consuming and expensive column chromatography and, accordingly, enabled the efficient recovery of the catalyst. The respective palladium complex 50 was obtained under standard conditions (PdCl2 and K2CO3) from NHC precursor 4f with moderate 68% yield (Scheme 23), and its Catalysts 2021, 11, 972catalytic activity was investigated using the Buchwald-Hartwig amination. The authors 20 of 44 observed remarkably high catalytic activity in non-polar media, such as n-heptane, for the coupling of aryl halides with secondary amines and anilines.

Scheme 23. SchemeSynthesis 23. of Pd-PEPPSISynthesis of complexes Pd-PEPPSI bearing complexes polymer bearing subunits polymer and application subunits forand the application Buchwald-Hartwig for the reaction. Buchwald-Hartwig reaction. Considering the drawbacks associated with the recovery of the catalyst under homoge- Consideringnous the conditions, drawbacks Tu andassociated co-workers with described the recovery the heterogenization of the catalyst of BIAN-NHC-Pdunder com- homogenous conditions,plexes on magnetic Tu and nanoparticles, co-workers described easily sparable the heterogenization by external magnetic of BIAN- field [75]. The immo- NHC-Pd complexesbilization on magnetic of palladium nanoparticles, complex 54 easilywas achieved sparable via by aexternal two-step magnetic protocol. field First, palladacycle [75]. The immobilization54 was synthesized of palladium by the complex reaction 54 of was salt achieved4g with silanevia a two-step53 and PdCl protocol.2 in the presence of First, palladacycleK2CO 543. was Then, synthesized palladacycle by54 the, possessing reaction of a long-chainsalt 4g with triethylsilyl silane 53 and tail wasPdCl anchored2 on the in the presencesurface of K2CO of a3. magneticThen, palladacycle nanoparticle 54, coated possessing with silicaa long-chain (SMNPs) triethylsilyl by silyl ether tail formation. The Catalysts 2021, 11,was 972 anchored immobilizedon the surface catalyst of a magnetic55 proved nanoparticle its high catalytic coated activity with in silica the Suzuki-Miyaury(SMNPs) by reaction21 of of 45 silyl ether formation.9-chloroacridine The immobilized (51) with catalyst phenylboronic 55 proved acid its (48 high) (Scheme catalytic 24). activity in the Suzuki-Miyaury reaction of 9-chloroacridine (51) with phenylboronic acid (48) (Scheme 24).

SchemeScheme 24. 24.Immobilization Immobilization of palladium of palladium complexes complexes on magnetic on nanoparticlesmagnetic nanoparticles and their application and their inapplication the Suzuki-Miyaura in the Suzuki-Miyaura coupling of chloroacridines. coupling of chloroacridines.

Apart from the palladium complexes immobilized on solid support, other unconventional approaches to reactions under heterogeneous conditions have been described. An interesting option for carrying out palladium-catalyzed reactions under mechanochemical conditions was presented by Browne (Scheme 25) [76]. Mechanochemistry is a relatively new field of organic synthesis, in which the energy required for the reaction is supplied by collisions, and the chemical reactions are usually carried out in ball mills. The major advantages of this innovative approach, in comparison to the conventional reaction in solution, are higher reaction rates, greater selectivity, and reduced usage of organic solvents, which are not environmentally neutral. The first examples of a cross-coupling reaction under mechanochemical conditions was described by Browne’s group in 2018 (Scheme 25) [76]. The respective Negishi coupling of a zinc compound with bromobenzene was efficiently catalyzed by PEPPSI- type complex 25a, previously reported by Tu and co-workers [60] (Scheme 9). It should be mentioned that organozinc compound 57 was also generated in situ, providing ester 58 with 64% yield after two steps (Scheme 25). Further utility of palladium catalyst 25a under mechanochemical conditions was exemplified also by Browne and co-workers [77] in the Buchwald-Hartwig reaction of chlorobenzene 29a with morpholine 32b. The reaction was carried out in ball mills with sand as the grinding medium, in the presence of strong KOtBu base, providing tertiary amines with low yield. Notably, the above- described reactions under mechanochemical conditions do not require anhydrous conditions or inert gas atmosphere, providing a practical alternative to classical, strictly anhydrous conditions.

Catalysts 2021, 11, 972 21 of 44

Apart from the palladium complexes immobilized on solid support, other unconven- tional approaches to reactions under heterogeneous conditions have been described. An interesting option for carrying out palladium-catalyzed reactions under mechanochemical conditions was presented by Browne (Scheme 25)[76]. Mechanochemistry is a relatively new field of organic synthesis, in which the energy required for the reaction is supplied by collisions, and the chemical reactions are usually carried out in ball mills. The major advantages of this innovative approach, in comparison to the conventional reaction in Catalysts 2021, 11, 972 solution, are higher reaction rates, greater selectivity, and reduced usage of organic solvents,22 of 45 which are not environmentally neutral.

SchemeScheme 25. 25.Application Application of of Pd-PEPPSI Pd-PEPPSI complexes complexes under under mechanochemical mechanochemical conditions. conditions.

3.2. TheNHC-BIAN-Ni first examples Complexes of a cross-coupling in Catalysis reaction under mechanochemical conditions was describedNHC-Ni by complexes Browne’s have group found in 2018 many (Scheme applicat 25)[ions76]. in The catalysis respective and Negishi can be viewed coupling as ofan a inexpensive zinc compound replacement with bromobenzene for palladium. was Currently, efficiently catalyzedNHC-Ni-catalyzed by PEPPSI-type transformations complex 25aare, previouslythe subject reported of growing by Tu intensive and co-workers research, [60 ]including (Scheme9 ).NHC-BIAN-Ni It should be mentioned catalysis. that The organozincfollowing compoundsubsection 57coveringwas also NHC-BIAN-Ni generated in situ, catalysis providing was divided ester 58 withinto 64%two subgroups, yield after tworegarding steps (Scheme the structure 25). Further of NHC utility precursors of palladium for catalystthe formation25a under of mechanochemicalachiral and chiral conditionscompounds. was exemplified also by Browne and co-workers [77] in the Buchwald-Hartwig reactionUsually, of chlorobenzene nickel complexes29a with are generated morpholine in situ32b. due The to reaction their inherent was carried instability. out inTo t balldate, mills there with is only sand one as theexample grinding of the medium, synthesis in theof an presence N-heterocyclic of strong nickel KO Bu complex base, providingbearing an tertiary acenaphthylene amines with backbone low yield. in isolable Notably, form. the above-described In 2018, Cramer reactions and co-workers under mechanochemical[52] synthesized conditionsthis type of do complex not require following anhydrous the conditionsprocedureor previously inert gasatmosphere, reported by providingNolan [78]. a practical Therefore, alternative NHC precursor to classical, 20a strictly wasanhydrous reacted with conditions. nickelocene 59 under 3.2.microwave NHC-BIAN-Ni conditions Complexes for 16 inh at Catalysis 75 °C, affording nickel complex 60 in high yield (Scheme 26). NHC-Ni complexes have found many applications in catalysis and can be viewed as an inexpensive replacement for palladium. Currently, NHC-Ni-catalyzed transformations are the subject of growing intensive research, including NHC-BIAN-Ni catalysis. The following subsection covering NHC-BIAN-Ni catalysis was divided into two subgroups, regarding the structure of NHC precursors for the formation of achiral and chiral compounds.

Scheme 26. Synthetic approach to chiral nickelocenes bearing acenaphthylene backbone.

Regarding the catalytic applications, the majority of the NHC-BIAN-Ni-catalyzed reactions include transformations where the active nickel complex is generated in situ, as mentioned. The first example of a Ni-catalyzed transformation was reported by Newman’s group [79] and concerns amide bond formation in the presence of Ni(COD)2 and salt 4g. In this approach, methyl benzoate (61) underwent a reaction with aniline 39a

Catalysts 2021, 11, 972 22 of 45

Scheme 25. Application of Pd-PEPPSI complexes under mechanochemical conditions.

3.2. NHC-BIAN-Ni Complexes in Catalysis NHC-Ni complexes have found many applications in catalysis and can be viewed as an inexpensive replacement for palladium. Currently, NHC-Ni-catalyzed transformations are the subject of growing intensive research, including NHC-BIAN-Ni catalysis. The Catalysts 2021, 11, 972 following subsection covering NHC-BIAN-Ni catalysis was divided into two subgroups,22 of 44 regarding the structure of NHC precursors for the formation of achiral and chiral compounds. Usually, nickel complexes are generated in situ due to their inherent instability. To date,Usually, there is nickelonly one complexes example are of generated the synthesis in situ of due an toN-heterocyclic their inherent nickel instability. complex To date,bearing there an is acenaphthylene only one example backbone of the synthesis in isolable of an form.N-heterocyclic In 2018, Cramer nickel complexand co-workers bearing an[52] acenaphthylene synthesized this backbone type of incomplex isolable following form. In 2018,the procedure Cramer and previously co-workers reported [52] syn- by thesizedNolan [78]. this typeTherefore, of complex NHC following precursor the 20a procedure was reacted previously with reportednickelocene by Nolan 59 under [78]. Therefore,microwave NHC conditions precursor for 1620a h atwas 75 reacted°C, affording with nickelocenenickel complex59 under 60 in high microwave yield (Scheme condi- ◦ tions26). for 16 h at 75 C, affording nickel complex 60 in high yield (Scheme 26).

SchemeScheme 26.26. Synthetic approach toto chiralchiral nickelocenesnickelocenes bearingbearing acenaphthyleneacenaphthylene backbone.backbone.

RegardingRegarding thethe catalyticcatalytic applications,applications, thethe majoritymajority ofof thethe NHC-BIAN-Ni-catalyzedNHC-BIAN-Ni-catalyzed reactionsreactions includeinclude transformationstransformations wherewhere thethe activeactive nickelnickel complexcomplex isis generatedgenerated inin situ,situ, asas Catalysts 2021, 11, 972 23 of 45 mentioned.mentioned. TheThe first first example example of a Ni-catalyzedof a Ni-catalyzed transformation transformation was reported was byreported Newman’s by groupNewman’s [79] and group concerns [79] and amide concerns bond formationamide bond in theformation presence in of the Ni(COD) presence2 and of saltNi(COD)4g. In2 thisand approach,salt 4g. In methylthis approach, benzoate methyl (61) underwent benzoatea (61 reaction) underwent with aniline a reaction39a in with the presenceaniline 39a of in the presence of strong KOtBu base to give benzanilide 39a, although in low yield strong KOtBu base to give benzanilide 39a, although in low yield (Scheme 27). It should be (Scheme 27). It should be noted that NHC precursor 4g was the only one examined during notedthe optimization that NHC process. precursor 4g was the only one examined during the optimization process.

SchemeScheme 27. 27. ApplicationApplication of ofNHC-BIAN-Ni NHC-BIAN-Ni complexes complexes for the for amidation the amidation of esters. of esters.

The following following year, year, Sun Sun and co-workers and co-workers [80] presented [80] presented the reductive the coupling reductive of coupling1,2- of diphenylacetylene (63a) with imine 62a in the presence of Ni(COD)2 catalyst and NHC 1,2-diphenylacetylene (63a) with imine 62a in the presence of Ni(COD)2 catalyst and NHC precursor 4c with low steric hindrance. In the coupling reaction, i-PrOH was used as a precursor 4c with low steric hindrance. In the coupling reaction, i-PrOH was used as a hydrogen source for the hydrogen transfer reduction. More sterically hindered salt 4g hydrogen source for the hydrogen transfer reduction. More sterically hindered salt 4g with with isopropyl groups afforded allyl amines 64a in much higher yields than the less active isopropylNHC precursor groups 4c bearing afforded methyl allyl aminesgroups (Scheme64a in much 28). higher yields than the less active NHC precursor 4c bearing methyl groups (Scheme 28).

Scheme 28. Nickel-catalyzed addition of imines to internal alkynes.

Further research by Tu’s group [61] proved that palladium could be efficiently replaced by nickel for Buchwald-Hartwig-type amination. The authors applied the catalytic system composed of NiCl2-(DME) and NHC precursor 4g for the coupling reaction of 2-naphthyl p-toluenesulfonate (65) with morpholine (51), in the presence of phenylboronic acid pinacol ester. The reaction afforded tertiary amines in varying yields, depending on the base and solvent used (Scheme 29).

Scheme 29. Nickel-catalyzed Buchwald-Hartwig amination of tosylate.

Catalysts 2021, 11Catalysts, 972 2021, 11, 972 23 of 45 23 of 45

in the presencein the of presencestrong KO oft Bustrong base KO to tBugive base benzanilide to give benzanilide39a, although 39a in, although low yield in low yield (Scheme 27).(Scheme It should 27). be Itnoted should that be NHC noted precursor that NHC 4g precursor was the only 4g was one the examined only one during examined during the optimizationthe optimization process. process.

Scheme 27. ApplicationScheme 27. of Application NHC-BIAN-Ni of NHC-BIAN-Ni complexes for complexes the amidation for the of amidationesters. of esters.

The followingThe year, following Sun and year, co-workers Sun and [80]co-workers presented [80] the presented reductive the coupling reductive of coupling1,2- of 1,2- diphenylacetylenediphenylacetylene (63a) with imine(63a) with62a in imine the presence 62a in the of presenceNi(COD) of2 catalyst Ni(COD) and2 catalyst NHC and NHC precursor 4cprecursor with low 4c steric with hindrance. low steric Inhindrance. the coupling In the reaction, coupling i-PrOH reaction, was i- usedPrOH as was a used as a Catalysts 2021, 11, 972 hydrogen sourcehydrogen for thesource hydrogen for the transfer hydrogen reduction. transfer Morereduction. sterically More hindered sterically salt hindered 4g salt23 of 4g 44 with isopropylwith groups isopropyl afforded groups allyl afforded amines allyl 64a inamines much 64a higher in much yields higher than theyields less than active the less active NHC precursorNHC 4c precursor bearing methyl 4c bearing groups methyl (Scheme groups 28). (Scheme 28).

Scheme 28. Nickel-catalyzedScheme 28. Nickel-catalyzed addition of imines addition to internal of imines alkynes. to internal alkynes.

Further researchFurther by researchresearch Tu’s group by by Tu’s Tu’s[61] group groupprov [61ed] [61] provedthat prov palladium thated palladiumthat couldpalladium could be efficiently becould efficiently be efficiently replaced replaced byreplacedby nickel nickel for forby Buchwald-Hartwig-typeBuchwald-Hartwig-typenickel for Buchwald-Hartwig-type amination.amination. The amination.The authors authors applied The applied authors the catalyticthe applied system the catalytic systemcatalyticcomposed composed system of NiCl ofcomposed2-(DME) NiCl2-(DME) and of NHCNiCl and2 precursor-(DME) NHC precursorand4g forNHC the 4g couplingprecursor for the reaction coupling4g for ofthe 2-naphthyl coupling reaction of 2-naphthylreactionp-toluenesulfonate of p2-naphthyl-toluenesulfonate (65) withp-toluenesulfonate morpholine (65) with ( 51morpholine (),65 in) thewith presence morpholine(51), in of the phenylboronic (presence51), in the of acidpresence pinacol of phenylboronicphenylboronicester. acid The pinacol reaction acid ester. afforded pinacol The reaction ester. tertiary The afforded amines reaction intertiary varyingafforded amines yields, tertiary in dependingvarying amines yields, in on varying the base yields, and depending ondependingsolvent the base used andon (Scheme the solvent base 29 andused). solvent (Scheme used 29). (Scheme 29).

Scheme 29.Scheme Nickel-catalyzedScheme 29. 29.Nickel-catalyzed Nickel-catalyzed Buchwald-Hartwig Buchwald-Hartwig Buchwald-Hartwig amination aminationof aminationtosylate. of tosylate.of tosylate.

The last example of an achiral transformation, proving the usefulness of NHC nickel complexes for [3+2] cross-dimerization, was developed by Huang and Ho in 2020 [81]. The authors described the unique reactivity of unactivated olefins 67 and methylenecy- clopropanes 66, leading to cyclopentanes bearing exocyclic double bonds (Scheme 30). The method exhibited high chemoselectivity and regioselectivity. The nickel complexes

used in the studies were prepared in situ by the reaction of Ni(COD)2 and allyl chloride with the corresponding NHC, also generated in situ through the treatment of the NHC salt with KHMDS. Thus, the authors obtained [Ni(allyl)]Cl (70a) and [Ni(Phallyl)]Cl (70b) complexes in high yields, 82% and 71%, respectively. The highest reaction yields and selectivity of cross-dimerization reaction towards alkene insertion were obtained when the less hindered Ni-complex 70a was used. The authors created a vast scope of cyclopentenes 68, including spiro and fused ring systems. The next subsection highlights enantioselective transformations affording chiral com- pounds, which are often a structural element found in biologically active compounds. Enantioselectivity of the reaction is achieved by the design of a chiral space in the catalyst area, which determines the orientation of the substrate during the catalyst-substrate bond- ing. In the examples discussed herein, such an effect could be achieved by modifying the steric crowding around the nickel atom by NHC. The acenaphthylene-based ligand allowed for subtle structural changes to create a chiral pocket, providing excellent performance in enantioselective Ni-catalyzed reactions. In 2018, Cramer and co-workers [52] reported the enantioselective cyclization of 2- pyridone and its isomer 4-pyridone. In the first example, 2-pyridone 71 was subjected to cyclization catalyzed by NHC-Ni(COD)2 complex in the presence of a Lewis acid—MAD (Scheme 31). Notably, substitution of the methyl group in NHC ligand 20 by the tert- butyl group (20c) significantly decreased the yield and enantioselectivity of product 72. Replacement of the phenyl groups with 3,5-xylyl substituent in the side chains attached to the aromatic rings (20b) led to product 72 with higher enantiomeric excess and yield (Scheme 31). Further attempts to introduce more crowded substituents did not provide improved results. Catalysts 2021, 11, 972 24 of 45

The last example of an achiral transformation, proving the usefulness of NHC nickel complexes for [3+2] cross-dimerization, was developed by Huang and Ho in 2020 [81]. The authors described the unique reactivity of unactivated olefins 67 and methylenecyclopropanes 66, leading to cyclopentanes bearing exocyclic double bonds (Scheme 30). The method exhibited high chemoselectivity and regioselectivity. The nickel complexes used in the studies were prepared in situ by the reaction of Ni(COD)2 and allyl chloride with the corresponding NHC, also generated in situ through the treatment of the NHC salt with KHMDS. Thus, the authors obtained [Ni(allyl)]Cl (70a) and [Ni(Phallyl)]Cl (70b) complexes in high yields, 82% and 71%, respectively. The highest reaction yields and selectivity of cross-dimerization reaction towards alkene insertion were obtained Catalysts 2021, 11, 972 24 of 44 when the less hindered Ni-complex 70a was used. The authors created a vast scope of cyclopentenes 68, including spiro and fused ring systems.

Catalysts 2021, 11, 972 25 of 45

SchemeScheme 30. 30. Nickel-catalyzedNickel-catalyzed cross-dimerization cross-dimerization of of methylidene methylidene cyclopropanes cyclopropanes with with alkenes. alkenes.

The next subsection highlights enantioselective transformations affording chiral compounds, which are often a structural element found in biologically active compounds. Enantioselectivity of the reaction is achieved by the design of a chiral space in the catalyst area, which determines the orientation of the substrate during the catalyst-substrate bonding. In the examples discussed herein, such an effect could be achieved by modifying the steric crowding around the nickel atom by NHC. The acenaphthylene-based ligand allowed for subtle structural changes to create a chiral pocket, providing excellent performance in enantioselective Ni-catalyzed reactions. In 2018, Cramer and co-workers [52] reported the enantioselective cyclization of 2- pyridone and its isomer 4-pyridone. In the first example, 2-pyridone 71 was subjected to cyclization catalyzed by NHC-Ni(COD)2 complex in the presence of a Lewis acid—MAD (Scheme 31). Notably, substitution of the methyl group in NHC ligand 20 by the tert-butyl group (20c) significantly decreased the yield and enantioselectivity of product 72. Replacement of the phenyl groups with 3,5-xylyl substituent in the side chains attached to the aromatic rings (20b) led to product 72 with higher enantiomeric excess and yield (Scheme 31). Further attempts to introduce more crowded substituents did not provide improved results.

SchemeScheme 31.31. EnantioselectiveEnantioselective C-HC-H activationactivation ofof pyridinonespyridinonesand andindoles. indoles.

Moreover,Moreover, thethe cyclizationcyclization reactionreaction ofof 2-pyridone2-pyridone derivativederivative73 73bearing bearingtrisubstituted trisubstituted alkenes,alkenes, catalyzedcatalyzed by th thee N-heterocyclic N-heterocyclic carbene carbene 20d20d withwith a anickel nickel complex, complex, allowed allowed to toextend extend the the scope scope of of chiral chiral quinolizidines quinolizidines 74. The correspondingcorresponding reactionreaction conditionsconditions appearedappeared toto bebe effectiveeffective forfor 4-pyridone4-pyridone derivativesderivatives 7676 asas well,well, leadingleading toto aa productproduct withwith highhigh efficiency.efficiency. InIn thethe followingfollowing year,year, Cramer’sCramer’s groupgroup [[54]54] carriedcarried outout thethe enantioselectiveenantioselective cyclizationcyclization ofof indoleindole77 77catalyzed catalyzedby by NHC-Ni(COD) NHC-Ni(COD)22 complexcomplex 20c20c(generated (generated inin situ). situ). AlthoughAlthough thethe cyclizationcyclization reactionreaction waswas performedperformed underunder relativelyrelatively mildmild conditions,conditions, indoleindole derivativederivative78 78 waswas obtainedobtained in in 25% 25% yield yield and and with with very very low lo enantiomericw enantiomeric excess, excess, namely namely 4% (Scheme4% (Scheme 32). 32). In 2019, Shi and co-workers [82] reported the first example of enantioselective cyclization of alkenylpyridine 79, resulting in the formation of a chiral isoquinoline derivative 80 (Scheme 32). Direct activation of the C-H bond of the pyridine ring in positions 3 and 4 was accomplished by a chiral N-heterocyclic carbene ligand with diverse steric crowding, leading to product 80 in high yield and with high enantiomeric excess. Here, the pyridine derivative 79 was cyclized in the presence of Ni(COD)2 and the N- heterocyclic carbene, with MAD in cyclopropyl methyl ether (CPME) (Scheme 32). It should be mentioned that the replacement of the methyl or benzyl groups with 3,5-xylyl group (20b) in the wingtip substituent of the NHC ligand led to the product with higher enantiomeric excess, up to 86%.

Scheme 32. Enantioselective cyclization of alkenylpyridines.

Catalysts 2021, 11, 972 25 of 45

Scheme 31. Enantioselective C-H activation of pyridinones and indoles.

Moreover, the cyclization reaction of 2-pyridone derivative 73 bearing trisubstituted alkenes, catalyzed by the N-heterocyclic carbene 20d with a nickel complex, allowed to extend the scope of chiral quinolizidines 74. The corresponding reaction conditions appeared to be effective for 4-pyridone derivatives 76 as well, leading to a product with high efficiency. In the following year, Cramer’s group [54] carried out the enantioselective cyclization of indole 77 catalyzed by NHC-Ni(COD)2 complex 20c (generated in situ). Although the cyclization reaction was performed under relatively mild conditions, indole derivative 78 was obtained in 25% yield and with very low enantiomeric excess, namely 4% (Scheme 32). In 2019, Shi and co-workers [82] reported the first example of enantioselective cyclization of alkenylpyridine 79, resulting in the formation of a chiral isoquinoline derivative 80 (Scheme 32). Direct activation of the C-H bond of the pyridine ring in positions 3 and 4 was accomplished by a chiral N-heterocyclic carbene ligand with diverse steric crowding, leading to product 80 in high yield and with high enantiomeric excess. Here, the pyridine derivative 79 was cyclized in the presence of Ni(COD)2 and the N- heterocyclic carbene, with MAD in cyclopropyl methyl ether (CPME) (Scheme 32). It Catalysts 2021, 11, 972should be mentioned that the replacement of the methyl or benzyl groups with 3,5-xylyl 25 of 44 group (20b) in the wingtip substituent of the NHC ligand led to the product with higher enantiomeric excess, up to 86%.

Scheme 32. EnantioselectiveScheme 32. cyclizationEnantioselective of alkenylpyridines. cyclization of alkenylpyridines.

In 2019, Shi and co-workers [82] reported the first example of enantioselective cycliza- tion of alkenylpyridine 79, resulting in the formation of a chiral isoquinoline derivative 80 (Scheme 32). Direct activation of the C-H bond of the pyridine ring in positions 3 and 4

was accomplished by a chiral N-heterocyclic carbene ligand with diverse steric crowding, leading to product 80 in high yield and with high enantiomeric excess. Here, the pyridine derivative 79 was cyclized in the presence of Ni(COD)2 and the N-heterocyclic carbene, Catalysts 2021, 11, 972 26 of 45 with MAD in cyclopropyl methyl ether (CPME) (Scheme 32). It should be mentioned that the replacement of the methyl or benzyl groups with 3,5-xylyl group (20b) in the wingtip substituent of the NHC ligand led to the product with higher enantiomeric excess, up to 86%. Sun and co-workers [80] have developed an enantioselective reductive coupling reactionSun of and 1,2-diphenylacetylene co-workers [80] have (63a developed) with tosyl an enantioselectivehydrazones 62b reductive (Scheme coupling33). The reactionauthors ofinvestigated 1,2-diphenylacetylene a variety (63aof )NHC with tosylliga hydrazonesnd structures62b featuring(Scheme 33 diverse). The authors steric investigatedhindrance. All a varietythe NHC-BIAN of NHC ligandligands structures afforded allylic featuring sulfonamides diverse steric 64b hindrance.in good yields All thewith NHC-BIAN S absolute ligands configuration afforded, confirmed allylic sulfonamides by X-ray 64bstructurin goodal analysis. yields with Notably,S absolute the configurationauthors observed, confirmed very high by X-rayenantiomeric structural exce analysis.ss in all Notably, cases, theirrespective authors observedof the ligand very highstructure. enantiomeric excess in all cases, irrespective of the ligand structure.

Scheme 33. Enantioselective addition of imine to disubstituted alkynes.

Further synthetic potential of chiral NHC-BIANNHC-BIAN type ligands was explored by ShiShi and co-workers (Scheme 3434).). The authors proved the excellent performance of ligand 20c for the arylationarylation of ketonesketones 81 withwith speciallyspecially designeddesigned boronicboronic esterester 8282 (Bneo)(Bneo) [[83].83]. TheThe developed Ni-catalyzed protocol appeared to be applicable for a broad range of aromatic and heteroaromatic ketones, providingproviding easyeasy accessaccess toto aa varietyvariety ofof tertiary alcohols 8383 with excellent enantioselectivity and perfect tolerancetolerance of functional groups.groups. The same research group havehave developed developed a Ni-catalyzeda Ni-catalyzed protocol protocol for thefor synthesis the synthesis of chiral of N-arylatedchiral N-arylated amines 85aminesand unprotected85 and unprotected amines amines86. A series86. A ofseries chiral of tetrahydroquinolineschiral tetrahydroquinolines85 and 8586 andwere 86 synthesizedwere synthesized via kinetic via kinetic Buchwald-Hartwig Buchwald-Hartwig coupling coupling with aryl with chloride. aryl chloride. The key The to highlykey to enantioselectivehighly enantioselective kinetic resolutionkinetic resolution was a low-temperature was a low-temperature procedure, procedure, allowing allowing for excellent for controlexcellent of control stereoselectivity. of stereoselectivity.

Scheme 34. Enantioselective synthesis of tertiary alcohols through the arylation of ketones and tetrahydroquinolines via kinetic Buchwald-Hartwig coupling.

Catalysts 2021, 11, 972 26 of 45

Sun and co-workers [80] have developed an enantioselective reductive coupling reaction of 1,2-diphenylacetylene (63a) with tosyl hydrazones 62b (Scheme 33). The authors investigated a variety of NHC ligand structures featuring diverse steric hindrance. All the NHC-BIAN ligands afforded allylic sulfonamides 64b in good yields with S absolute configuration, confirmed by X-ray structural analysis. Notably, the authors observed very high enantiomeric excess in all cases, irrespective of the ligand structure.

Scheme 33. Enantioselective addition of imine to disubstituted alkynes.

Further synthetic potential of chiral NHC-BIAN type ligands was explored by Shi and co-workers (Scheme 34). The authors proved the excellent performance of ligand 20c for the arylation of ketones 81 with specially designed boronic ester 82 (Bneo) [83]. The developed Ni-catalyzed protocol appeared to be applicable for a broad range of aromatic and heteroaromatic ketones, providing easy access to a variety of tertiary alcohols 83 with excellent enantioselectivity and perfect tolerance of functional groups. The same research group have developed a Ni-catalyzed protocol for the synthesis of chiral N-arylated amines 85 and unprotected amines 86. A series of chiral tetrahydroquinolines 85 and 86 Catalysts 2021, 11, 972were synthesized via kinetic Buchwald-Hartwig coupling with aryl chloride. The key to 26 of 44 highly enantioselective kinetic resolution was a low-temperature procedure, allowing for excellent control of stereoselectivity.

Scheme 34. EnantioselectiveScheme 34. Enantioselective synthesis of tertiary synthesis alcohols of tertiary through alco thehols arylation through of the ketones arylation and tetrahydroquinolinesof ketones and via kinetic Buchwald-Hartwigtetrahydroquinolines coupling. via kinetic Buchwald-Hartwig coupling.

3.3. NHC-BIAN-Ru Complexes One of the most important applications of N-heterocyclic carbene ruthenium com- plexes as catalysts is the olefin metathesis reaction. The utility of this reaction in biologically active structure synthesis has proven to be invaluable, therefore it is a trending subject in organometallic catalysis [84]. This subsection covers the synthesis of second generation Hoveyda-type ruthenium complexes containing an acenaphthylene-based N-heterocyclic carbene ligand. Applications of the corresponding complexes in ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROMP) are also highlighted. Merino and co-workers [30] obtained, for the first time, an N-heterocyclic ruthenium complex 92 with acenaphthylene-containing structure. The two-step synthetic pathway in- volved deprotonation of 4c salt with a strong base (KOtAmyl) in n-hexane, and subsequent exchange of the phosphine ligand for the NHC ligand in first generation Hoveyda-type ruthenium complex 91. The reaction was carried out in the presence of CuCl as a phosphine scavenger, resulting in the corresponding ruthenium complex 92 in 76% yield. The ruthe- nium complex 92 exhibits high catalytic activity in RCM of model reagents (Scheme 35), leading to formation of cyclopentene 88 and dihydropyrrole 90 derivatives. Shortly after, Bazzi and co-workers reported the synthesis of an N-heterocyclic ruthe- nium complex attached to polyisobutene (17 isobutylene units) [85]. The respective ruthe- nium complex 95 was synthesized by the initial deprotonation of salt 4f with KOtBu, and the resulting free carbene was further reacted with first generation Hoveyda-type complex 95 to give ruthenium complex 95 in moderate yield (Scheme 36). The catalytic activity of complex 95 was investigated in ring-closing metathesis reaction (RCM) of N,N0- diallyl-4-methylbenzenesulfonamide (89), yielding tosyl-protected pyrrolidine (90) and ring-opening metathesis polymerization (ROMP) of norbornene derivatives (93). It should be mentioned that the RCM reactions were performed in n-heptane, allowing for easy separation of the respective products by simple filtration. The respective mother liquor containing the active catalyst was reused for up to eight cycles, affording pyrrolidine derivatives 90 without a decrease in yield. Catalysts 2021, 11, 972 27 of 45

3.3. NHC-BIAN-Ru Complexes One of the most important applications of N-heterocyclic carbene ruthenium complexes as catalysts is the olefin metathesis reaction. The utility of this reaction in biologically active structure synthesis has proven to be invaluable, therefore it is a trending subject in organometallic catalysis [84]. This subsection covers the synthesis of second generation Hoveyda-type ruthenium complexes containing an acenaphthylene- based N-heterocyclic carbene ligand. Applications of the corresponding complexes in ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROMP) are also highlighted. Merino and co-workers [30] obtained, for the first time, an N-heterocyclic ruthenium complex 92 with acenaphthylene-containing structure. The two-step synthetic pathway involved deprotonation of 4c salt with a strong base (KOtAmyl) in n-hexane, and subsequent exchange of the phosphine ligand for the NHC ligand in first generation Hoveyda-type ruthenium complex 91. The reaction was carried out in the presence of CuCl as a phosphine scavenger, resulting in the corresponding ruthenium complex 92 in Catalysts 2021, 11, 972 76% yield. The ruthenium complex 92 exhibits high catalytic activity in RCM of 27model of 44 reagents (Scheme 35), leading to formation of cyclopentene 88 and dihydropyrrole 90 derivatives.

Catalysts 2021, 11, 972 28 of 45 SchemeScheme 35. 35.Ring-closing Ring-closing metathesismetathesis catalyzed catalyzed by by NHC-BIAN NHC-BIAN Hoveyda-type Hoveyda-type complexes. complexes.

Shortly after, Bazzi and co-workers reported the synthesis of an N-heterocyclic ruthenium complex attached to polyisobutene (17 isobutylene units) [85]. The respective ruthenium complex 95 was synthesized by the initial deprotonation of salt 4f with KOtBu, and the resulting free carbene was further reacted with first generation Hoveyda-type complex 95 to give ruthenium complex 95 in moderate yield (Scheme 36). The catalytic activity of complex 95 was investigated in ring-closing metathesis reaction (RCM) of N,N′- diallyl-4-methylbenzenesulfonamide (89), yielding tosyl-protected pyrrolidine (90) and ring-opening metathesis polymerization (ROMP) of norbornene derivatives (93). It should be mentioned that the RCM reactions were performed in n-heptane, allowing for easy separation of the respective products by simple filtration. The respective mother liquor containing the active catalyst was reused for up to eight cycles, affording pyrrolidine derivatives 90 without a decrease in yield.

SchemeScheme 36. 36. ApplicationApplication of NHC-BIAN-Ru of NHC-BIAN-Ru complexes complexes for alkene for metathesis alkene metathesis reactions. reactions.

3.4. NHC-BIAN-Au3.4. NHC-BIAN-Au Complexes Complexes N-Heterocyclic carbene gold(I) complexes are a relatively numerous group of N-Heterocyclic carbene gold(I) complexes are a relatively numerous group of carbene carbene metal complexes. For this reason, the material reported herein has been divided into two sectionsmetal describing complexes. the Forsynthesis this reason, and application the material of the reportedcomplexes herein in catalysis. has been divided into The first sectiontwo sectionsis focused describing on the synthetic the synthesismethods reported and application in the literature of the [17,20,47,86– complexes in catalysis. The 89]. Notably,first not section all complexes is focused have on proven the synthetic catalytic methodsactivity, although reported the in theauthors literature did [17,20,47,86–89]. not exclude the possibility of their application in catalysis [17,47]. In 2016, Plenio and co-workers reported the synthesis of bulky gold(I) complex 96, pentiptycene derivatives, and complexes 97 with less steric hindrance (Scheme 37) [24,31]. The preparation procedure involves the reaction between NHC precursor (13 or 4) and AuCl•Me2S, in the presence of an excess (3–7 equiv) of K2CO3 in acetone as the solvent. This method was independently developed by the groups of Gimeno [90] and Nolan [91].

Catalysts 2021, 11, 972 28 of 44

Notably, not all complexes have proven catalytic activity, although the authors did not exclude the possibility of their application in catalysis [17,47]. In 2016, Plenio and co-workers reported the synthesis of bulky gold(I) complex 96, pentiptycene derivatives, and complexes 97 with less steric hindrance (Scheme 37)[24,31]. Catalysts 2021, 11, 972 The preparation procedure involves the reaction between NHC precursor (13 or 294) of and 45

Catalysts 2021, 11, 972 AuCl•Me2S, in the presence of an excess (3–7 equiv) of K2CO3 in acetone as the solvent.29 of 45

This method was independently developed by the groups of Gimeno [90] and Nolan [91].

Scheme 37. Synthesis of gold(I) complexes bearing sterically hindered N-wingtip substituents. SchemeScheme 37. 37.Synthesis Synthesis of of gold(I) gold(I) complexes complexes bearing bearing sterically sterically hindered hinderedN N-wingtip-wingtip substituents. substituents. In contrast to Plenio’s results, Cowley and co-workers [20,86] have reported the indirectInIn contrastsynthesiscontrast to toof Plenio’s gold(I)Plenio’s complexes results,results, CowleyCowley from NHC andand precursors co-workersco-workers (Scheme [20[20,86],86] have38).have This reportedreported approach thethe indirect synthesis of gold(I) complexes from NHC precursors (Scheme 38). This approach commencedindirect synthesis with silver(I) of gold(I) complex complexes (98a) from formation NHC byprecursors the reaction (Scheme of salt 38). 4g Thiswith approach Ag2O in thecommencedcommenced mixture of withwith DCM silver(I)silver(I) and THF. complexcomplex Subsequent (98a) formation transmetalation by by the the reaction reaction of silver(I) of of salt saltcomplex 4g4g withwith 98a Ag Ag with2O2O in (AuCl•tht)inthe the mixture mixture allowed of ofDCM DCM to and isolate and THF. THF. gold(I) Subsequent Subsequent complex transmetalation transmetalation99a in high of80% silver(I) of yield, silver(I) complex after complex two 98a steps with98a • with(Scheme(AuCl•tht) (AuCl 38). tht)allowed Apart allowed fromto isolate to isolatethe gold(I)catalytic gold(I) complex activity, complex 99a gold(I)99a inin high high complexes 80% 80% yield, yield, described afterafter twotwo above, stepssteps (Schemeincluding(Scheme 38 gold(I)38).). Apart Apart complex from from the 99a catalyticthe, have catalytic activity,proven activity, gold(I)antifungal complexesgold(I) and complexesantibacterial described described above, properties including above, [86– 99a 88].gold(I)including complex gold(I) complex, have proven 99a, have antifungal proven and antifungal antibacterial and antibacterial properties [86 properties–88]. [86– 88].

Scheme 38. Synthetic approach to NHC-BIAN-Au complex via transmetalation. Scheme 38. Synthetic approach to NHC-BIAN-Au complex via transmetalation. Belpassi’s group group [89] [89] shortened shortened the the two-step two-step synthetic synthetic route, route, previously previously proposed proposed by Cowley,by Cowley,Belpassi’s to one to one step group step by [89]eliminating by eliminatingshortened transm the transmetalation two-stepetalation synthetic (Scheme (Scheme 37).route, The37 previously). gold(I) The gold(I) complex proposed complex (99a by) (was99aCowley, )obtained was to obtained one directly step directly by after eliminating after the thereaction transm reaction ofetalation the of the NHC NHC (Scheme precursor precursor 37). The4g4g and gold(I)and AuCl•tht AuCl complex•tht in in ( 99a the ) was obtained directly after the reaction of the NHC precursor 4g and AuCl•tht in the presence of KHCO3 (Scheme(Scheme 39).39). Although Although the the reaction reaction time time increased increased from from 12 12 h h to to 72 h, thispresence method of afforded KHCO3 (Scheme gold(I) complex 39). Although 99a in the higher reaction yield, time compared increased toto Cowley’sCowley’s from 12 h methodmethod to 72 h, (Schemethis method 3838))[ [20]. 20afforded]. gold(I) complex 99a in higher yield, compared to Cowley’s method (Scheme 38) [20].

Scheme 39. Synthesis of NHC-BIAN-Au complexes directly from NHC precursors. Scheme 39. Synthesis of NHC-BIAN-Au complexes directly from NHC precursors.

Catalysts 2021, 11, 972 29 of 45

Scheme 37. Synthesis of gold(I) complexes bearing sterically hindered N-wingtip substituents.

In contrast to Plenio’s results, Cowley and co-workers [20,86] have reported the indirect synthesis of gold(I) complexes from NHC precursors (Scheme 38). This approach commenced with silver(I) complex (98a) formation by the reaction of salt 4g with Ag2O in the mixture of DCM and THF. Subsequent transmetalation of silver(I) complex 98a with (AuCl•tht) allowed to isolate gold(I) complex 99a in high 80% yield, after two steps (Scheme 38). Apart from the catalytic activity, gold(I) complexes described above, including gold(I) complex 99a, have proven antifungal and antibacterial properties [86– 88].

Catalysts 2021, 11, 972 Scheme 38. Synthetic approach to NHC-BIAN-Au complex via transmetalation. 30 of 45

Belpassi’s group [89] shortened the two-step synthetic route, previously proposed by Cowley, to one step by eliminating transmetalation (Scheme 37). The gold(I) complex (99a) was obtainedThe second directly section after covers the reactiongold(I) complexe of the NHCs with precursor confirmed 4g andcatalytic AuCl•tht activity in andthe their applications in catalysis [92,93]. Plenio’s group [92] have obtained a series of gold(I) Catalysts 2021, 11, 972 presence of KHCO3 (Scheme 39). Although the reaction time increased from 12 h to29 72 of 44h, thiscomplexes method bearing afforded a pentiptycene gold(I) complex subunit 99a inand higher proved yield, their compared catalytic toactivity Cowley’s (Scheme method 40). (SchemeIt is worth 38) [20].to mention that gold(I) complex 96a with acenaphthylene-based ligand structure was prepared according to the method described in Plenio’s earlier work [17,47]. In the following years, the authors reported the application of a gold(I) complex as a catalyst in the hydration of 1-phenylacetylene (21a) (Scheme 40). The reaction resulted in 99% conversion of the substrate after 21 h, affording acetophenone 100a as the product. It should be mentioned that the loading of gold complex 99a could be reduced to 0.01 mol%. However, additives such as AgOTf and TfOH were still required to keep the high yield. Zuccacia’s team have also investigated an alkyne hydration catalyzed by gold(I) complexes [94]. In contrast to Plenio’s research, the main goal was to develop an efficient Schemeprocedure 39.39. Synthesisunder silver-, of NHC-BIAN-Au acid-, and even complexes solvent-free directlydirectly conditions. fromfrom NHCNHC precursors. precursors.The authors selected the hydration of hex-3-yne as the model reaction to optimize the reaction conditions. The ligandThe structure second sectionand the covers type gold(I)of counterion complexes appeared with confirmedto have great catalytic influence activity on and the their applications in catalysis [92,93]. Plenio’s group [92] have obtained a series of gold(I) catalytic activity of the gold complex. NBu4OTf was selected as the superior additive for complexesgold(I) complex bearing activation a pentiptycene (Scheme subunit 40). Many and gold proved complexes their catalytic have been activity tested, (Scheme including 40). Ita iscomplex worth to containing mention that an gold(I) acenaphthylene complex 96a fragmentwith acenaphthylene-based in the ligand structure ligand structure 99. The wassynthesis prepared of complex according 99a to was the methodachieved described by the transmetalation in Plenio’s earlier route, work as [ 17described,47]. In the by followingCowley [20] years, (Scheme the authors 38). The reported suitable thecombin applicationation of ofligand a gold(I) and complexcounterion as allowed a catalyst to 21a inobtain the hydration99% substrate of 1-phenylacetylene conversion in 2 h and ( )TOF (Scheme equal 40to). 495. The Among reaction the resulted gold complexes in 99% conversion of the substrate after 21 h, affording acetophenone 100a as the product. It tested, the highest yield was achieved for complex 99c, possessing an acenaphthylene should be mentioned that the loading of gold complex 99a could be reduced to 0.01 mol%. subunit with OTf- as the counterion. It should be mentioned that the addition of silver However, additives such as AgOTf and TfOH were still required to keep the high yield. salts did not influence the reaction outcome.

SchemeScheme 40.40. ApplicationApplication ofof NHC-BIAN-AuNHC-BIAN-Au complexescomplexes forfor hydrationhydration ofof alkynes.alkynes.

Zuccacia’sTu’s group team has presented have also an investigated interesting anapplication alkyne hydration of gold complexes catalyzed for by gold(I)sulfone complexessynthesis [93,95]. [94]. In The contrast gold(I) to chloride Plenio’s research,complexes the (99 main) were goal synthesized was to develop by the an method efficient of procedureNolan [91] under and Gimeno silver-, [90], acid-, and and further even solvent-free transformed conditions. into the respective The authors hydroxides selected 104a the hydrationby the treatment of hex-3-yne of complexes as the 99 model with reactionKOH in a to mixture optimize of toluene the reaction and THF conditions. (Scheme The 41). ligandThe aforementioned structure and the gold(I) type of complexes counterion appeared99a,b were to haveinitially great used influence as catalysts on the catalytic in the activityalkylsulfonylation of the gold reaction complex. of NBu boronic4OTf acid was 40 selected, with K as2S the2O5 superioras the source additive of the for sulfonyl gold(I) complexgroup [93]. activation Equal activity (Scheme wa 40s). observed Many gold with complexes hydroxide have 104a been, whereas tested, the including common a complexIPrAuCl containingprovided the an sulfone acenaphthylene with reduced fragment yield. in the ligand structure 99. The synthesis of complex 99a was achieved by the transmetalation route, as described by Cowley [20] (Scheme 38). The suitable combination of ligand and counterion allowed to obtain 99% substrate conversion in 2 h and TOF equal to 495. Among the gold complexes tested, the highest yield was achieved for complex 99c, possessing an acenaphthylene subunit with - OTf as the counterion. It should be mentioned that the addition of silver salts did not influence the reaction outcome. Catalysts 2021, 11, 972 30 of 44

Catalysts 2021, 11, 972 31 of 45

Tu’s group has presented an interesting application of gold complexes for sulfone synthesisTwo years [93,95 later,]. The the gold(I) same chloride research complexes group developed (99) were the synthesized arylsulfonylation by the reaction method of arylNolan boronic [91] and acid Gimeno (40) with [90 ],diaryliodonium and further transformed salts 102, intoproviding the respective access to hydroxides diaryl sulfones104a 103by the [95]. treatment The gold(I) of complexes chloride complex99 with KOH99a exhibited in a mixture the best of toluene catalytic and activity, THF (Scheme leading 41 to). Thea broad aforementioned range of sulfones gold(I) complexes103, including99a,b heterocyclicwere initially deriva used astives catalysts as well. in theThis alkylsul- easily scalablefonylation protocol reaction offers of boronic a straightforward acid 40, with Kappr2S2Ooach5 as to the diaryl source sulfones of the sulfonyl bearing group sterically [93]. hinderedEqual activity aryl groups, was observed such as with mesityl, hydroxide which104a can ,be whereas found in the drugs common and biologically IPrAuCl provided active compoundsthe sulfone with [96]. reduced yield.

5mol%107a K S O (2.0 equiv) Tu 2017 2 2 5 Na2CO3 (2.0 equiv) dioxane O O O O B(OH)2 100 °C, 24 h S + OR2 1 Br 1 R OR2 42–82% R

40 101 41

Tu 2019 5mol%107a K2S2O5 (1.0 mmol) Na2CO3 (1.0 mmol) MeCN O O OTf B(OH)2 + I 100 °C, 24 h S Mes Mes R R R 50–98%

40 102 103

AuCl(tht) (1.0 equiv)

K2CO3 (14.0 equiv) KOH (2.0 equiv) Cl DCM THF/toluene (v/v) 50 °C, 12 h 60 °C, 24 h R1 R1 R1 R1 R1 R1 N N N N R1 = iPr, R2 = H, 93% ( ) R1 = iPr N N 93a 2 2 2 2 1 2 R R 2 R R 2 2 R =R = Me, 85% (93b) 1 1 R = H, 82% (98a) 1 1 R R R Au R R Au R R1 R1 Cl OH 4 99 104a

Scheme 41. Application of NHC-BIAN-Au complexes for sulfone synthesis.

Plenio’sTwo years group later, have the same reported research good group catalytic developed properties the arylsulfonylation of complex 96b reaction in enyne of cyclizationaryl boronic (Scheme acid (40 42)) with [47]. diaryliodonium The preliminary salts catalytic102, providing study of access96b has to led diaryl to a sulfonesmixture 103of five-[95]. (106 The) and gold(I) six-membered chloride complex (107) rings99a exhibited as products the in best a 72/28 catalytic ratio activity, with excellent leading yield.to a broad In contrast, range of sulfonesa regioselectivity103, including switch heterocyclic in the reaction derivatives catalyzed as well. by This hindered easily IMesAuClscalable protocol was noted, offers affording a straightforward cyclohexene approach derivative to diaryl107 preferentially, sulfones bearing although sterically with diminishedhindered aryl total groups, yield. such as mesityl, which can be found in drugs and biologically active compounds [96]. Plenio’s group have reported good catalytic properties of complex 96b in enyne cyclization (Scheme 42)[47]. The preliminary catalytic study of 96b has led to a mixture of five- (106) and six-membered (107) rings as products in a 72/28 ratio with excellent yield. In contrast, a regioselectivity switch in the reaction catalyzed by hindered IMesAuCl was noted, affording cyclohexene derivative 107 preferentially, although with diminished total yield.

Scheme 42. NHC-BIAN-Au-catalyzed cycloisomerization of enynes.

3.5. NHC-BIAN-Cu and NHC-BIAN-Pt N-Heterocyclic carbene complexes of copper and platinum possessing an acenaphthylene backbone subunit have been marginally reported to date [53,70,97], but have found catalytic applications. In 2018, Shi and co-workers [53] developed an efficient synthesis of chiral NHC copper complex 111 by conducting the reaction of chiral NHC precursor 20a with CuCl

Catalysts 2021, 11, 972 31 of 45

Two years later, the same research group developed the arylsulfonylation reaction of aryl boronic acid (40) with diaryliodonium salts 102, providing access to diaryl sulfones 103 [95]. The gold(I) chloride complex 99a exhibited the best catalytic activity, leading to a broad range of sulfones 103, including heterocyclic derivatives as well. This easily scalable protocol offers a straightforward approach to diaryl sulfones bearing sterically hindered aryl groups, such as mesityl, which can be found in drugs and biologically active compounds [96].

5mol%107a K S O (2.0 equiv) Tu 2017 2 2 5 Na2CO3 (2.0 equiv) dioxane O O O O B(OH)2 100 °C, 24 h S + OR2 1 Br 1 R OR2 42–82% R

40 101 41

Tu 2019 5mol%107a K2S2O5 (1.0 mmol) Na2CO3 (1.0 mmol) MeCN O O OTf B(OH)2 + I 100 °C, 24 h S Mes Mes R R R 50–98%

40 102 103

AuCl(tht) (1.0 equiv)

K2CO3 (14.0 equiv) KOH (2.0 equiv) Cl DCM THF/toluene (v/v) 50 °C, 12 h 60 °C, 24 h R1 R1 R1 R1 R1 R1 N N N N R1 = iPr, R2 = H, 93% ( ) R1 = iPr N N 93a 2 2 2 2 1 2 R R 2 R R 2 2 R =R = Me, 85% (93b) 1 1 R = H, 82% (98a) 1 1 R R R Au R R Au R R1 R1 Cl OH 4 99 104a Scheme 41. Application of NHC-BIAN-Au complexes for sulfone synthesis.

Plenio’s group have reported good catalytic properties of complex 96b in enyne cyclization (Scheme 42) [47]. The preliminary catalytic study of 96b has led to a mixture of five- (106) and six-membered (107) rings as products in a 72/28 ratio with excellent Catalysts 2021, 11, 972 yield. In contrast, a regioselectivity switch in the reaction catalyzed by hindered31 of 44 IMesAuCl was noted, affording cyclohexene derivative 107 preferentially, although with diminished total yield.

SchemeScheme 42.42.NHC-BIAN-Au-catalyzed NHC-BIAN-Au-catalyzed cycloisomerizationcycloisomerization ofof enynes.enynes.

3.5.3.5. NHC-BIAN-CuNHC-BIAN-Cu andand NHC-BIAN-PtNHC-BIAN-Pt NN-Heterocyclic-Heterocyclic carbene carbene complexes complexes of copper of copper and platinum and possessingplatinum anpossessing acenaphthy- an leneacenaphthylene backbone subunit backbone have subunit been marginally have been reportedmarginally to datereported [53,70 to,97 date], but [53,70,97], have found but Catalysts 2021, 11, 972 32 of 45 catalytichave found applications. catalytic applications. InIn 2018, 2018, Shi Shi and and co-workers co-workers [53 ][53] developed develope and efficient an efficient synthesis synthesis of chiral of NHC chiral copper NHC complexcopper complex111 by conducting 111 by conducting the reaction the of reaction chiral NHC of chiral precursor NHC20a precursorwith CuCl 20a (Scheme with CuCl 43). The(Scheme respective 43). copperThe respective complex 111copperwas appliedcomplex in the111 asymmetric was applied hydroboration in the asymmetric reaction, proceedinghydroboration according reaction, to proceeding Markovnikov’s according regioselectivity to Markovnikov’s rule, and regios providingelectivity a plethorarule, and ofproviding secondary a plethora alkylboronic of secondary esters as thealkylb majororonic products esters (as109 the)[ 53major]. It shouldproducts be ( mentioned109) [53]. It thatshould the be application mentioned of that classic the achiralapplication imidazolylidene-based of classic achiral imidazolylidene-based NHC ligand afforded NHC the productligand afforded with much the lowerproduct regioselectivity, with much lower demonstrating regioselectivity, the superior demons propertiestrating the of superior BIAN- typeproperties derivatives. of BIAN-type derivatives.

SchemeScheme 43.43. EnantioselectiveEnantioselective NHC-BIAN-Cu-catalyzedNHC-BIAN-Cu-catalyzed hydroborationhydroboration ofof terminalterminal alkenes. alkenes.

InIn thethe samesame year,year, Tu’sTu’s group group [ 70[70]] proved proved the the high high catalytic catalytic activity activity of ofN N-heterocyclic-heterocyclic carbenecarbene copper copper complexes complexes in thein Sonogashirathe Sonogashira reaction. reaction. Copper complexCopper 36bcomplexand palladium 36b and complexpalladium25a complexwere used 25a as were the catalytic used as system the catalytic in the coupling system in reaction the coupling of 1-phenylacetylene reaction of 1- (phenylacetylene21) with bromoanisole (21) with29b bromoanisoleduring the optimization 29b during the studies. optimization The reaction studies. led The to disubsti- reaction tutedled to alkyne disubstituted34 with varyingalkyne 34 yields, with depending varying yields, on the depending base and solvent on theused base (Schemeand solvent 44). Theused highest (Scheme efficiency 44). The of alkynehighest formation efficiency was of achievedalkyne formation with the application was achieved of the with K2CO the3 baseapplication and DMSO of the as K solvent.2CO3 base It turned and DMSO out that as the solvent. solvent It hadturned a crucial out that role the in thesolvent presented had a reaction,crucial role since in thethe replacement presented reaction, of DMSO sinc withe the THF replacement caused significant of DMSO decrease with THF in the caused yield ofsignificant alkyne 34 decrease(Table2). in the yield of alkyne 34 (Table 2).

Scheme 44. Sonogashira reaction mediated by the simultaneous use of NHC-BIAN-Pd and NHC- BIAN-Cu complexes.

Catalysts 2021, 11, 972 32 of 45

(Scheme 43). The respective copper complex 111 was applied in the asymmetric hydroboration reaction, proceeding according to Markovnikov’s regioselectivity rule, and providing a plethora of secondary alkylboronic esters as the major products (109) [53]. It should be mentioned that the application of classic achiral imidazolylidene-based NHC ligand afforded the product with much lower regioselectivity, demonstrating the superior properties of BIAN-type derivatives.

Scheme 43. Enantioselective NHC-BIAN-Cu-catalyzed hydroboration of terminal alkenes.

In the same year, Tu’s group [70] proved the high catalytic activity of N-heterocyclic carbene copper complexes in the Sonogashira reaction. Copper complex 36b and palladium complex 25a were used as the catalytic system in the coupling reaction of 1- phenylacetylene (21) with bromoanisole 29b during the optimization studies. The reaction led to disubstituted alkyne 34 with varying yields, depending on the base and solvent used (Scheme 44). The highest efficiency of alkyne formation was achieved with the Catalysts 2021, 11, 972 application of the K2CO3 base and DMSO as solvent. It turned out that the solvent32 had of 44 a crucial role in the presented reaction, since the replacement of DMSO with THF caused significant decrease in the yield of alkyne 34 (Table 2).

Catalysts 2021, 11, 972 33 of 45 SchemeScheme 44. 44.Sonogashira Sonogashira reaction reaction mediated mediated by by the the simultaneous simultaneous use use of of NHC-BIAN-Pd NHC-BIAN-Pd and and NHC- NHC- BIAN-CuBIAN-Cu complexes. complexes.

TableTable 2.2.Reaction Reactionconditions conditionsfor forSonogashira Sonogashiracoupling. coupling.

EntryEntry Solvent Solvent Base 34 (%) Base 34 (%) 1 DMSO K3PO4 65 1 DMSO K3PO4 65 2 2DMSO DMSOCsF 26 CsF 26 3 3DMSO DMSONa2CO3 42 Na 2CO3 42 4 DMSO K CO 68 4 DMSO K2CO3 68 2 3 5 DMSO Cs2CO3 20 5 DMSO Cs2CO3 20 6 THF K2CO3 8 6 THF K2CO3 8

LiteratureLiterature reportsreports onon NHC-BIAN-PtNHC-BIAN-Pt complexescomplexes covercover onlyonly aa singlesingle example.example. InIn 2016,2016, TobisuTobisu andand co-workersco-workers [[97]97] publishedpublished aa synthesissynthesis ofof thethe platinumplatinumN N-heterocyclic-heterocyclic carbenecarbene complexcomplex 113113 byby thethe reactionreaction ofof NHCNHC precursorprecursor 4g4g withwith Karstedt’sKarstedt’s complex,complex, yieldingyielding complexcomplex 113113 inin 36%36% yieldyield (Scheme(Scheme 4545).). TheThe authorsauthors reportedreported highhigh catalyticcatalytic activityactivity ofof 113 tert platinumplatinum complexcomplex 113 inin thethe C-HC-H activation/borylation activation/borylation reactionreaction ofof 1,3-dimethyl-5-1,3-dimethyl-5-tert-- butylbenzene (112), affording arylboronic ester 40b in 72% yield. butylbenzene (112), affording arylboronic ester 40b in 72% yield.

SchemeScheme 45.45. SynthesisSynthesis ofof MHC-BIAN-Pt MHC-BIAN-Pt complexes complexes and and their their application application for C-H for activa- C-H tion/borylation.activation/borylation.

3.6. Synthesis of Other Metal Complexes (Rh, Ir, Ag) N-Heterocyclic carbene complexes of other metals have been marginally reported in the literature and have not found practical application in catalysis. In particular, synthetic approaches to rhodium, iridium, and silver complexes will be presented in this subsection. Rhodium complexes could be synthesised directly from the corresponding salts in the presence of a strong base, e.g., a metal alkoxide, and a dimer of rhodium(I) chloride [RhCl(COD)]2 [17]. Plenio and co-workers unequivocally proved that the replacement of alkoxide by K2CO3 and the use of acetone as solvent allow for the preparation of rhodium complexes 114 under mild conditions (Scheme 46) [98]. It should be noted that the combinations of K2CO3/acetone for the synthesis of NHC metal complexes, originally developed by Nolan and co-workers for the synthesis of gold(I) complexes, could be successfully applied for much more sensitive rhodium compounds [91].

Catalysts 2021, 11, 972 33 of 45

Table 2. Reaction conditions for Sonogashira coupling.

Entry Solvent Base 34 (%) 1 DMSO K3PO4 65 2 DMSO CsF 26 3 DMSO Na2CO3 42 4 DMSO K2CO3 68 5 DMSO Cs2CO3 20 6 THF K2CO3 8

Literature reports on NHC-BIAN-Pt complexes cover only a single example. In 2016, Tobisu and co-workers [97] published a synthesis of the platinum N-heterocyclic carbene complex 113 by the reaction of NHC precursor 4g with Karstedt’s complex, yielding complex 113 in 36% yield (Scheme 45). The authors reported high catalytic activity of platinum complex 113 in the C-H activation/borylation reaction of 1,3-dimethyl-5-tert- butylbenzene (112), affording arylboronic ester 40b in 72% yield.

Scheme 45. Synthesis of MHC-BIAN-Pt complexes and their application for C-H activation/borylation. Catalysts 2021, 11, 972 33 of 44 3.6. Synthesis of Other Metal Complexes (Rh, Ir, Ag) N-Heterocyclic carbene complexes of other metals have been marginally reported in the3.6. literature Synthesis and of Other have Metal not found Complexes practical (Rh, Ir, application Ag) in catalysis. In particular, synthetic approachesN-Heterocyclic to rhodium, carbene iridium, complexes and of othersilver metals complexes have been will marginally be presented reported inin this subsection.the literature and have not found practical application in catalysis. In particular, synthetic approachesRhodium to complexes rhodium, iridium, could andbe synthesised silver complexes directly will be from presented the corresponding in this subsection. salts in Rhodium complexes could be synthesised directly from the corresponding salts in the presence of a strong base, e.g., a metal alkoxide, and a dimer of rhodium(I) chloride the presence of a strong base, e.g., a metal alkoxide, and a dimer of rhodium(I) chloride [RhCl(COD)]2 [17]. Plenio and co-workers unequivocally proved that the replacement of [RhCl(COD)]2 [17]. Plenio and co-workers unequivocally proved that the replacement 2 3 alkoxideof alkoxide by K byCO K 2andCO3 theand use the of use acetone of acetone as solvent as solvent allow allow for the for preparation the preparation of rhodium of complexesrhodium complexes114 under114 mildunder conditions mild conditions (Scheme (Scheme 46) [98].46)[98 It]. should It should be be noted thatthat the combinationsthe combinations of K of2CO K23CO/acetone3/acetone forfor the the synthesis synthesis of NHCNHC metal metal complexes, complexes, originally originally developeddeveloped by by Nolan Nolan and and co-workers forfor the the synthesis synthesis of gold(I)of gold(I) complexes, complexes, could could be be successfullysuccessfully applied applied for for much much more sensitivesensitive rhodium rhodium compounds compounds [91]. [91].

Scheme 46. Synthetic approach to NHC-BIAN-Rh complexes.

Analogous conditions could be used for the preparation of iridium complexes. Cow- ley [20] and Plenio [47] described an efficient approach to sterically hindered complexes via in situ generation of carbenes in the presence of a suitable alkoxide, and their fur- ther reaction with iridium dimer [IrCl(COD)]2 to provide complexes 116 in very high yield (Scheme 47). Further ligand exchange with gaseous carbon monoxide furnished NHCIr(CO)3 complexes in virtually quantitative yield. Identical reaction conditions were successfully applied for the synthesis of bifunctional iridium and rhodium complexes 118 by Alcarazo and co-workers (Scheme 48)[51]. In contrast, Liu and co-workers [46] proved that NHC-Ir(CO)3 complexes 117 syntheses could be simplified to one-pot protocol apply- ing Nolan’s method (K2CO3/acetone) under low pressure of carbon monoxide (Scheme 47). Unfortunately, none of the presented NHC-BIAN-Ir or NHC-BIAN-Rh complexes have found a practical application. It should be noted that the partially reduced NHC-BIAN-Ir complex (not shown), developed by Dastgir and Green [99] was investigated in the hy- droformylation of 1-octene. However, a mixture of regioisomeric alcohols and aldehydes was obtained. The last group of complexes, deserving special attention due to the popularity in the synthesis of other metal complexes by transmetalation, are the silver complexes [5]. The most common conditions for the synthesis of silver complexes involve a stoichiometric amount of Ag2O (in DCM with exclusion of light), acting as a base and metal source simultaneously. A series of NHC-BIAN-AgCl complexes was obtained under those clas- sical conditions at rt (Scheme 49, structures 98a [20] and 98c [41]). However, a higher temperature was required to secure the full conversion of the starting NHC precursors in the reaction of sterically hindered derivatives leading to complexes 98d,e [17] and 98b [47] (Scheme 49). Catalysts 2021, 11, 972 34 of 45

Scheme 46. Synthetic approach to NHC-BIAN-Rh complexes.

Analogous conditions could be used for the preparation of iridium complexes. Cowley [20] and Plenio [47] described an efficient approach to sterically hindered complexes via in situ generation of carbenes in the presence of a suitable alkoxide, and their further reaction with iridium dimer [IrCl(COD)]2 to provide complexes 116 in very high yield (Scheme 47). Further ligand exchange with gaseous carbon monoxide furnished NHCIr(CO)3 complexes in virtually quantitative yield. Identical reaction conditions were successfully applied for the synthesis of bifunctional iridium and rhodium complexes 118 by Alcarazo and co-workers (Scheme 48) [51]. In contrast, Liu and co-workers [46] proved that NHC-Ir(CO)3 complexes 117 syntheses could be simplified to one-pot protocol applying Nolan’s method (K2CO3/acetone) under low pressure of carbon monoxide (Scheme 47). Unfortunately, none of the presented NHC-BIAN-Ir or NHC-BIAN-Rh complexes have found a practical application. It should be noted that the partially reduced Catalysts 2021, 11, 972 NHC-BIAN-Ir complex (not shown), developed by Dastgir and Green [99]34of was 44 investigated in the hydroformylation of 1-octene. However, a mixture of regioisomeric alcohols and aldehydes was obtained.

Catalysts 2021, 11, 972 35 of 45

SchemeScheme 47. 47.Synthetic Synthetic approach approach to to NHC-BIAN-Ir NHC-BIAN-Ir complexes. complexes.

SchemeScheme 48. 48.Synthetic Synthetic approach approach to to iridium iridium complexes complexes bearing bearing a a polyaromatic polyaromatic backbone. backbone.

The last group of complexes, deserving special attention due to the popularity in the synthesis of other metal complexes by transmetalation, are the silver complexes [5]. The most common conditions for the synthesis of silver complexes involve a stoichiometric amount of Ag2O (in DCM with exclusion of light), acting as a base and metal source simultaneously. A series of NHC-BIAN-AgCl complexes was obtained under those classical conditions at rt (Scheme 49, structures 98a [20] and 98c [41]). However, a higher temperature was required to secure the full conversion of the starting NHC precursors in the reaction of sterically hindered derivatives leading to complexes 98d,e [17] and 98b [47] (Scheme 49).

Scheme 49. Synthetic approach to NHC-BIAN-Ag complexes.

3.7. Influence of Backbone Modification on Catalytic Activity As mentioned in the introduction, direct comparison of electronic and steric properties of NHC-BIAN type ligands has revealed that the %Vbur parameter (describing the steric properties), as well as electronic properties have similar values as their congener, namely, IPr* ligand (and its derivatives). In addition, comparative analysis of selected X- ray crystallographic data for IPr*-BIAN-AgCl, IPr*-BIAN-AuCl, IPr*-BIAN-AgCl and IPr*-BIAN-AuCl (for details, see Figure 3) has confirmed that the respective bonds distances, such as Ccarbene-metal are also similar. Furthermore, the structural analysis has proved that the angles between N-wingtip substituents are higher in the case of IPr*- BIAN-MetCl complexes (around 150°) than in the case of IPr*MetCl complexes (around 139°). These data contradict some suggestions that the π-expanded rigid acenaphthylene

Catalysts 2021, 11, 972 35 of 45

Scheme 48. Synthetic approach to iridium complexes bearing a polyaromatic backbone.

The last group of complexes, deserving special attention due to the popularity in the synthesis of other metal complexes by transmetalation, are the silver complexes [5]. The most common conditions for the synthesis of silver complexes involve a stoichiometric amount of Ag2O (in DCM with exclusion of light), acting as a base and metal source simultaneously. A series of NHC-BIAN-AgCl complexes was obtained under those classical conditions at rt (Scheme 49, structures 98a [20] and 98c [41]). However, a higher Catalysts 2021, 11, 972 temperature was required to secure the full conversion of the starting NHC precursors35 of in 44 the reaction of sterically hindered derivatives leading to complexes 98d,e [17] and 98b [47] (Scheme 49).

Scheme 49. Synthetic approach to NHC-BIAN-Ag complexes.complexes.

3.7. Influence Influence of Backbone Modification Modification on Catalytic Activity As mentionedmentioned inin the the introduction, introduction, direct direct comparison comparison ofelectronic of electronic and stericand prop-steric properties of NHC-BIAN type ligands has revealed that the %Vbur parameter (describing erties of NHC-BIAN type ligands has revealed that the %Vbur parameter (describing the thesteric steric properties), properties), as wellas well as as electronic electronic properties properties have have similar similar values values asas their congener, namely, IPr*IPr* ligandligand (and (and its its derivatives). derivatives). In In addition, addition, comparative comparative analysis analysis of selectedof selected X-ray X- raycrystallographic crystallographic data data for IPr*-BIAN-AgCl,for IPr*-BIAN-Ag IPr*-BIAN-AuCl,Cl, IPr*-BIAN-AuCl, IPr*-BIAN-AgCl IPr*-BIAN-AgCl and IPr*-and IPr*-BIAN-AuClBIAN-AuCl (for details,(for details, see Figure see 3Figure) has confirmed3) has confirmed that the respectivethat the respective bonds distances, bonds carbene distances,such as C carbenesuch as-metal C are-metal also similar.are also Furthermore,similar. Furthermore, the structural the structural analysis analysis has proved has provedthat the that angles the between angles Nbetween-wingtip N substituents-wingtip substituents are higher are in the higher case ofin IPr*-BIAN-MetClthe case of IPr*- BIAN-MetClcomplexes (around complexes 150◦ )(around than in 150°) the case than of in IPr*MetCl the case of complexes IPr*MetCl (around complexes 139◦ ).(around These 139°).data contradict These data some contradict suggestions some suggestions that the π-expanded that the π-expanded rigid acenaphthylene rigid acenaphthylene backbone pushes N-wingtip aryl substituents closer to the metallic center [19]. In fact, analysis of X-ray crystallographic data has shown that the situation in the solid state is reversed. For these reasons, we could expect that the excellent activity of NHC-BIAN-MetX complexes arises from subtle conformational changes in solution, and in-depth theoretical and ex- perimental studies are highly desirable to shed some light on this unclear aspect. Further studies should also attempt to correlate the parameters that determine the stereoelectronic properties of the ligands with their reactivities. Unfortunately, no systematic investigations on the effect of the backbone modification have appeared. Even worse, direct comparisons of catalytic activity with commonly applied ligands such as IMes, IPr or IPr* are rarely provided. To exemplify the significant role of the backbone modification, some selected examples will be shown in the present chapter. The first examples of differential reactivity come from Tu’s [60] and Organ’s [15] work. The authors have investigated palladium complexes 25a and 120 in the Negishi coupling (Scheme 50). Although a direct comparison is not possible due to different solvents used and the steric hindrance around the palladium center, NHC-BIAN-Pd 25a afforded the product with comparable yield with four-fold lower loading than for the dichloro derivative 120. Irrespective of the ligand structure, the selectivity of the reaction (branched vs. linear product) remained at a very high level. Further studies of Tu’s [60] group have shown comparable yields in the case of Negishi reaction with cyclic organozinc compounds. Catalysts 2021, 11, 972 36 of 45

backbone pushes N-wingtip aryl substituents closer to the metallic center [19]. In fact, analysis of X-ray crystallographic data has shown that the situation in the solid state is reversed. For these reasons, we could expect that the excellent activity of NHC-BIAN- MetX complexes arises from subtle conformational changes in solution, and in-depth theoretical and experimental studies are highly desirable to shed some light on this unclear aspect. Further studies should also attempt to correlate the parameters that determine the stereoelectronic properties of the ligands with their reactivities. Unfortunately, no systematic investigations on the effect of the backbone modification have appeared. Even worse, direct comparisons of catalytic activity with commonly applied ligands such as IMes, IPr or IPr* are rarely provided. To exemplify the significant role of the backbone modification, some selected examples will be shown in the present chapter. The first examples of differential reactivity come from Tu’s [60] and Organ’s [15] work. The authors have investigated palladium complexes 25a and 120 in the Negishi coupling (Scheme 50). Although a direct comparison is not possible due to different solvents used and the steric hindrance around the palladium center, NHC-BIAN-Pd 25a afforded the product with comparable yield with four-fold lower loading than for the dichloro derivative 120. Irrespective of the ligand structure, the selectivity of the reaction Catalysts 2021, 11, 972 (branched vs. linear product) remained at a very high level. Further studies of Tu’s36 of[60] 44 group have shown comparable yields in the case of Negishi reaction with cyclic organozinc compounds.

Scheme 50. InfluenceInfluence of backbone modificationmodification of NHC ligandsligands on catalyticcatalytic activityactivity inin thethe NegishiNegishi coupling.coupling.

A clear trendtrend inin reactivity reactivity with with regard regard to to the the NHC NHC ligand ligand backbone backbone modifications modifications has hasbeen been described described by Organ by Organ and and Feringa Feringa in the in Murahashithe Murahashi cross-coupling cross-coupling (Scheme (Scheme 51)[ 6951)]. The[69]. authorsThe authors observed observed that placingthat placing chloride chloride atoms atoms on the on NHC the NHC core core (structure (structure120), 120 and), andfurther further extension extension of the of skeleton the skeleton to an acenaphthylene to an acenaphthylene subunit (structuresubunit (structure25t) improved 25t) improvedsignificantly significantly the yield of the substitutedyield of the naphthalene substituted30e naphthalene. This trend is30e especially. This trend visible is Catalysts 2021, 11, 972 at −78 ◦C, where complex 121 is unreactive whereas NHC-PEPPSI-Pd 25t provided37 theof 45 especially visible at −78 °C, where complex 121 is unreactive whereas NHC-PEPPSI-Pd product25t provided in 37% the yield. product in 37% yield.

BuLi Br 5 mol% Pd cat. toluene, 1 h, temp.

29c 31 30e

Cl Cl Et Et Et Et Et Et Et Et Et Et Et Et

N N N N N N

Cl Pd Cl Cl Pd Cl Cl Pd Cl Et Et Et Et Et Et Et Et Et Et Et Et N N N

25t 120 121 Cl Cl Cl −62 °C, 99% −62 °C, 91% −62 °C, 88% −78 °C, 37% −78 °C, 22% −78 °C, 0%

SchemeScheme 51. 51.Influence Influence of backboneof backbone modification modification of NHC of NH ligandsC ligands on catalytic on catalytic activity activity in the Mura-in the Murahashi coupling. hashi coupling.

AnAn interesting interesting example example of theof the sensitivity sensitivity towards towards backbone backbone modification, modification, and its and direct its influencedirect influence on catalytic on activitycatalytic has activity been presentedhas been bypresented Liu and co-workersby Liu and [ 68co-workers] (Scheme 52[68]). During(Scheme optimization 52). During studies optimization on the Suzukistudies reaction,on the Suzuki the authors reaction, have the noted authors that have extension noted ofthat the extension NHC core of provided the NHC product core provided30f with product slightly 30f better with 56% slightly yield. better Rather 56% unexpectedly, yield. Rather introductionunexpectedly, of twointroductiontert-butyl groupsof two in tert the-butyl remote groups position in of thethe acenaphthyleneremote position skeleton of the improvedacenaphthylene significantly skeleton the improved yield of the significan biphenyltly derivative the yield of30f the. Bearing biphenyl in mindderivative that the30f. SuzukiBearing cross-coupling in mind that the was Suzuki conducted cross-coupling in aerobic was conditions, conducted the in remarkable aerobic conditions, activity ofthe 27remarkablewas explained activity by of preventing 27 was explained the palladium by preventing catalytic the species palladium to form catalytic the catalytically species to inactiveform the peroxo catalytically NHC-Pd(O-O) inactive peroxo complex. NHC- InPd(O-O) particular, complex. the authors In particular, suggested the that authors the presencesuggested of that bulky thetert presence-butyl groups of bulky in antitert-butyl-orientation groups inhibits in anti-orientation CAr-N bond inhibits rotation C andAr-N preventsbond rotation the oxidation and prevents of the the palladium oxidation center. of the palladium center.

Scheme 52. Influence of backbone modification of NHC ligands on catalytic activity in the Suzuki coupling.

A detailed study focused on the modification of NHC skeleton has been performed by Ye and co-workers in the reductive coupling of imines 62a with alkynes 63a (Scheme 53) [80]. The authors investigated a selected group of phosphines and NHC ligands for this transformation in the optimization studies. They unambiguously proved that phosphines, including electron-rich ones such as Cy3P or (tert-Bu)3P, were ineffective in this reaction, whereas the yield of the allylic amines was strictly dependent on the NHC ligand used. More electron-rich carbene ligands afforded the product with a higher yield (IPr vs. SIPr), while electron-deficient ligands such as naphthoquinone-derived carbene

Catalysts 2021, 11, 972 37 of 45

BuLi Br 5 mol% Pd cat. toluene, 1 h, temp.

29c 31 30e

Cl Cl Et Et Et Et Et Et Et Et Et Et Et Et

N N N N N N

Cl Pd Cl Cl Pd Cl Cl Pd Cl Et Et Et Et Et Et Et Et Et Et Et Et N N N

25t 120 121 Cl Cl Cl −62 °C, 99% −62 °C, 91% −62 °C, 88% −78 °C, 37% −78 °C, 22% −78 °C, 0% Scheme 51. Influence of backbone modification of NHC ligands on catalytic activity in the Murahashi coupling.

An interesting example of the sensitivity towards backbone modification, and its direct influence on catalytic activity has been presented by Liu and co-workers [68] (Scheme 52). During optimization studies on the Suzuki reaction, the authors have noted that extension of the NHC core provided product 30f with slightly better 56% yield. Rather unexpectedly, introduction of two tert-butyl groups in the remote position of the acenaphthylene skeleton improved significantly the yield of the biphenyl derivative 30f. Bearing in mind that the Suzuki cross-coupling was conducted in aerobic conditions, the remarkable activity of 27 was explained by preventing the palladium catalytic species to Catalysts 2021, 11, 972 form the catalytically inactive peroxo NHC-Pd(O-O) complex. In particular, the authors37 of 44 suggested that the presence of bulky tert-butyl groups in anti-orientation inhibits CAr-N bond rotation and prevents the oxidation of the palladium center.

SchemeScheme 52.52. InfluenceInfluence ofof backbonebackbone modificationmodification ofof NHCNHC ligandsligands onon catalyticcatalytic activityactivity inin thethe SuzukiSuzuki coupling.coupling.

AA detaileddetailed study study focused focused on on the the modification modification of of NHC NHC skeleton skeleton has has been been performed performed by Yeby and Ye co-workersand co-workers in the in reductive the reductive coupling coupling of imines of imines62a with 62a alkynes with alkynes63a (Scheme 63a (Scheme 53) [80]. The53) [80]. authors The investigated authors investigated a selected a group selected of phosphinesgroup of phosphines and NHC ligandsand NHC for ligands this trans- for formationthis transformation in the optimization in the optimization studies. They studies. unambiguously They unambiguously proved that phosphines,proved that includingphosphines, electron-rich including electron-rich ones such as ones Cy3 Psuch or (astert Cy-Bu)3P 3orP, ( weretert-Bu) ineffective3P, were ineffective in this reac- in Catalysts 2021, 11, 972 38 of 45 tion,this reaction, whereas whereas the yield the of theyield allylic of the amines allylic wasamines strictly was dependentstrictly dependent on the NHC on the ligand NHC used.ligand More used. electron-rich More electron-rich carbene carbene ligands ligands afforded afforded the product the product with awith higher a higher yield yield (IPr vs.(IPr SIPr), vs. SIPr), while while electron-deficient electron-deficient ligands liga suchnds such as naphthoquinone-derived as naphthoquinone-derived carbene carbene126 gave126 gave amine amine64a 64aa low a low 15% 15% yield. yield. The The best best results results in in terms terms of of yield yield were wereachieved achieved withwith IPr-acenaphthylene ligand 4g.. The authorsauthors alsoalso mentionedmentioned thatthat lessless sterically-hinderedsterically-hindered IMes derivativesderivatives (not(not shown)shown) werewere lessless effectiveeffective [[80].80].

10 mol% Ni(COD)2 10 mol% cat. NHTs NTs 10 mol% KOtBu Ph Ph Ph Ph Ph H i PrOH (65.0 equiv) Ph THF, 100 °C, 18 h 62a 63a 64a

N N N N

Cl Cl

123 (SIPr•HCl), trace 124 (IPr•HCl), 70%

O O

N N N N N N

Cl Cl Cl

125, 54% 126, 15% 4g, 86% 91% (with 5 mol% 4g) Scheme 53.53.Influence Influence of of backbone backbone modification modification of NHC of NHC ligands ligands on the on reductive the reductive coupling coupling of alkynes of withalkynes imines. with imines.

Similar conclusions could bebe drawndrawn forfor Ni-catalyzedNi-catalyzed [3+2][3+2] cross-dimerizationcross-dimerization ofof methylene cyclopropanescyclopropanes with with alkynes, alkynes, developed developed by by Ho Ho and and co-workers co-workers (Scheme (Scheme 54)[ 8154)]. Among[81]. Among NHC ligandsNHC ligands selected selected in the initial in the optimization, initial optimization, the authors the reported authors a higher reported yield a forhigher more yield electron-rich for more ligandselectron-rich (IPrCl 123bligandsvs. IPr(IPr123aCl 123b). Also vs. inIPr this 123a case,). Also acenaphthylene- in this case, acenaphthylene-derived ligand 123d provided methylene cyclopentene 68 with the best yield. It should be mentioned that no clear influence of NHC ligand on selectivity (cross- dimerization vs. homodimerization or oligomerization) could be provided.

5mol% [NHC-Ni(allyl)]Cl Ph Ph Ph NaBArF + Ph CH2OBn toluene 30 °C, 3 h CH2OBn 66 67 68

Cl Cl

N N N N N N N N

123a, 60% 123b, 50% 123c, 75% 123d, 87% Scheme 54. Influence of backbone modification of NHC ligands on cross-dimerization of methylene cyclopropanes with alkynes.

The most interesting and impressive impact of ligand structure arises from the feasibility for the development of efficient enantioselective processes, where subtle modifications can significantly affect the level of enantioselectivity of the reaction. These rare examples could also be found in the group of carbene ligands bearing an acenaphthylene backbone. Cramer and co-workers have performed a detailed analysis of the effect of substituents at the 4,5-positions of the imidazole ring in the NHC ligand on the catalytic performance of nickel complexes catalyzing enantioselective pyridone C–H

Catalysts 2021, 11, 972 38 of 45

126 gave amine 64a a low 15% yield. The best results in terms of yield were achieved with IPr-acenaphthylene ligand 4g. The authors also mentioned that less sterically-hindered IMes derivatives (not shown) were less effective [80].

10 mol% Ni(COD)2 10 mol% cat. NHTs NTs 10 mol% KOtBu Ph Ph Ph Ph Ph H i PrOH (65.0 equiv) Ph THF, 100 °C, 18 h 62a 63a 64a

N N N N

Cl Cl

123 (SIPr•HCl), trace 124 (IPr•HCl), 70%

O O

N N N N N N

Cl Cl Cl

125, 54% 126, 15% 4g, 86% 91% (with 5 mol% 4g) Scheme 53. Influence of backbone modification of NHC ligands on the reductive coupling of alkynes with imines.

Catalysts 2021, 11, 972 Similar conclusions could be drawn for Ni-catalyzed [3+2] cross-dimerization of 38 of 44 methylene cyclopropanes with alkynes, developed by Ho and co-workers (Scheme 54) [81]. Among NHC ligands selected in the initial optimization, the authors reported a higher yield for more electron-rich ligands (IPrCl 123b vs. IPr 123a). Also in this case, acenaphthylene-dderivederived ligand ligand123d 123dprovided provided methylene methylene cyclopentene cyclopentene68 68with with the the best best yield. It should yield. It shouldbe be mentioned mentioned that that no no clear clear influence influence of of NHC NHC ligand ligand on on selectivity selectivity (cross-dimerization (cross- vs. dimerization vs.homodimerization homodimerization or oligomerization)or oligomerization) could could be provided.be provided.

5mol% [NHC-Ni(allyl)]Cl Ph Ph Ph NaBArF + Ph CH2OBn toluene 30 °C, 3 h CH2OBn 66 67 68

Cl Cl

N N N N N N N N

123a, 60% 123b, 50% 123c, 75% 123d, 87% Scheme 54. SchemeInfluence 54. ofInfluence backbone of backbone modification modification of NHC of ligands NHC ligands on cross-dimerization on cross-dimerization of methylene of methylene cyclopropanes with alkynes.cyclopropanes with alkynes.

The most interestingThe most and interesting impressive and impressiveimpact of impactligand ofstructure ligand structure arises from arises the from the feasibil- feasibility fority the for development the development of efficient of efficient enantioselective enantioselective processes, processes, where where subtlesubtle modifications modifications cancan significantlysignificantly affectaffect thethe levellevel of of enantioselectivity enantioselectivity of of the the reaction. reaction. These These rare examples Catalysts 2021, 11, 972rare examplescould could also also be foundbe found in the groupin the ofgroup carbene of ligands carbene bearing ligands an acenaphthylenebearing an backbone. 39 of 45

acenaphthylene backbone.Cramer and co-workers have performed a detailed analysis of the effect of sub- Cramer stituentsand co-workers at the 4,5-positions have performed of the a imidazole detailed ringanalysis in the of NHC the ligandeffect onof the catalytic substituents atperformance the 4,5-position of nickels of the complexes imidazole catalyzing ring in the enantioselective NHC ligand on pyridone the catalytic C–H functionaliza- functionalization (Scheme 55) [52]. The application of the NHC-BIAN type ligand (20a) performance tionof (Schemenickel 55co)mplexes[52]. The applicationcatalyzing ofenanti the NHC-BIANoselective typepyridone ligand (20aC–H) gave promising resultsgave promising (80% ee), but results comparable (80% ee), to other but complexescomparable (124a to– otherc). Further complexes increase (124a in steric–c). Further shieldingincrease aroundin steric the shielding metal center around by theintroduction the metal ofcenter sterically by crowdedthe introduction 3,5-xylyl as of the sterically wingtipcrowdedN-aryl 3,5-xylyl substituent as the (structure wingtip20c N) resulted-aryl substituent in higher enantioselectivity, (structure 20c) namelyresulted 92% in higher ee.enantioselectivity, This unambiguously namely proved 92% the significanceee. This unam of thebiguously acenaphthylene proved motif the in comparisonsignificance of the toacenaphthylene complex 124d. motif in comparison to complex 124d.

SchemeScheme 55. 55.Influence Influence of backboneof backbone modification modification of NHC of NHC ligands ligands on enantioselective on enantioselec C-Htive activation C-H activation ofof 2-pyridones.2-pyridones.

TheThe influence influence of substituentof substituent at positions at positions 4 and 5 of 4 the and NHC 5 coreof the on theNHC enantiose- core on the lectivityenantioselectivity was further was rationalized further byrationalized Cramer and by co-workers Cramer [and52] byco-workers careful analysis [52] ofby careful analysis of steric properties of ligands used (Figure 4). The steric features of a given ligand could be easily quantified by the percent buried volume [23,24] (%Vbur) in a global sense or, more precisely, by topographic steric maps. It should be mentioned that topographic steric maps express steric hindrance around the metal center in quadrants, which can be useful for identification of the catalytic pocket or origin of enantioselectivity [100]. Direct comparison of %Vbur for Ni, Cu or Au complexes did not appear to be decisive for the correlation of enantioselectivity level with steric hindrance for the enantioselective pyridone C–H functionalization [52]. In particular, the value of %Vbur estimated by web application SambVca 2.1 [101] was higher for imidazolium NHC(Cp)NiCl 125a and NHCAuCl 126a complexes in comparison to the acenaphthylene congeners (125b and 126b, respectively), while the situation for copper complexes 127 and 111 was the opposite. More detailed analysis of steric congestion by steric maps revealed that the acenaphthene backbone affects the arrangement of aromatic substituents around the metallic center. In particular, the acenaphthene backbone forces the spatial arrangement of the flanking aryl groups creating C2-symmetric binding pocket, with accessible NW and SE quadrants. In contrast, C2-symmetry is less pronounced for the imidazolium derivatives, as was readily observed for the gold complexes (126a).

Catalysts 2021, 11, 972 39 of 44

steric properties of ligands used (Figure4). The steric features of a given ligand could be easily quantified by the percent buried volume [23,24] (%Vbur) in a global sense or, more precisely, by topographic steric maps. It should be mentioned that topographic steric maps express steric hindrance around the metal center in quadrants, which can be useful for Catalysts 2021, 11, 972 40 of 45 identification of the catalytic pocket or origin of enantioselectivity [100].

%Vbur for Ni and Cu complexes %Vbur and steric maps for Au complexes

Ph Ph Ph Ph Ph Ph Ph Ph

N N N N N N N N

Au Au Ph Ni Ph Ph Ni Ph Ph Cl Ph Ph Cl Ph Cl Cl 125a 125b 126a 126b

%Vbur = 38.2 %Vbur = 35.7 %Vbur = 49.4 %Vbur = 43.5

N N

Ph Ph Ph Ph WECu WECu N N N N

Cu Cu Ph Cl Ph Ph Cl Ph 127 111 S S %Vbur = 52.1 %Vbur = 55.3

Figure 4. Comparison of %Vbur and steric maps for Ni, Co and Au complexes. Adapted with permission from Ref [52] Figure 4. Comparison of %V and steric maps for Ni, Co and Au complexes. Adapted with permission from Ref. [52] Diesel, J.; Finogenova, A. M.;bur Cramer, N. J. Am. Chem. Soc. 2018, 140, 4489-4493. Copyright 2021 American Chemical Diesel, J.; Finogenova, A.M.; Cramer, N. J. Am. Chem. Soc. 2018, 140, 4489–4493. Copyright 2021 American Chemical Society. Society. Direct comparison of %V for Ni, Cu or Au complexes did not appear to be decisive Similar observations havebur been made by Shi for copper-catalyzed borylation of for the correlation of enantioselectivity level with steric hindrance for the enantioselec- terminal alkenes (Scheme 56) [53]. The substituents at the 4- and 5-position in the tive pyridone C–H functionalization [52]. In particular, the value of %Vbur estimated by webimidazole application ring of SambVca copper NHC 2.1 [101 complexes] was higher significantly for imidazolium affected NHC(Cp)NiCl the catalytic properties.125a and NHCAuClThe use of126a acenaphthene-derivedcomplexes in comparison complex to 111 the acenaphthyleneincreased the regios congenerselectivity (125b of andthe 126baddition, respectively), and enantioselectivity while the situation in product for copper 109 complexesformation 127in comparisonand 111 was theto chiral opposite. IPr Morederivative detailed 127. analysis of steric congestion by steric maps revealed that the acenaphthene backbone affects the arrangement of aromatic substituents around the metallic center. In particular, the acenaphthene backbone forces the spatial arrangement of the flanking aryl groups creating C2-symmetric binding pocket, with accessible NW and SE quadrants. In contrast, C2-symmetry is less pronounced for the imidazolium derivatives, as was readily observed for the gold complexes (126a). Similar observations have been made by Shi for copper-catalyzed borylation of ter- minal alkenes (Scheme 56)[53]. The substituents at the 4- and 5-position in the imidazole ring of copper NHC complexes significantly affected the catalytic properties. The use of acenaphthene-derived complex 111 increased the regioselectivity of the addition and enantioselectivity in product 109 formation in comparison to chiral IPr derivative 127.

Scheme 56. Influence of the NHC ligand structure on enantioselective hydroboration of alkynes.

Catalysts 2021, 11, 972 40 of 45

%Vbur for Ni and Cu complexes %Vbur and steric maps for Au complexes

Ph Ph Ph Ph Ph Ph Ph Ph

N N N N N N N N

Au Au Ph Ni Ph Ph Ni Ph Ph Cl Ph Ph Cl Ph Cl Cl 125a 125b 126a 126b

%Vbur = 38.2 %Vbur = 35.7 %Vbur = 49.4 %Vbur = 43.5

N N

Ph Ph Ph Ph WECu WECu N N N N

Cu Cu Ph Cl Ph Ph Cl Ph 127 111 S S %Vbur = 52.1 %Vbur = 55.3

Figure 4. Comparison of %Vbur and steric maps for Ni, Co and Au complexes. Adapted with permission from Ref [52] Diesel, J.; Finogenova, A. M.; Cramer, N. J. Am. Chem. Soc. 2018, 140, 4489-4493. Copyright 2021 American Chemical Society.

Similar observations have been made by Shi for copper-catalyzed borylation of terminal alkenes (Scheme 56) [53]. The substituents at the 4- and 5-position in the imidazole ring of copper NHC complexes significantly affected the catalytic properties. Catalysts 2021, 11, 972 The use of acenaphthene-derived complex 111 increased the regioselectivity 40of of the 44 addition and enantioselectivity in product 109 formation in comparison to chiral IPr derivative 127.

SchemeScheme 56. 56.Influence Influence of of the the NHC NHC ligand ligand structure structure on on enantioselective enantioselective hydroboration hydroboration of of alkynes. alkynes.

4. Conclusions and Outlook Since the first synthesis of an NHC-BIAN-type ligand almost 15 years ago, this family of ligands have enjoyed growing interest in catalysis as the ancillary ligands for transition- metal catalysis. The unique π-extended backbone and ease of modification of N-wingtip substituents have brought many excellent carbene ligands, in particular for palladium, nickel, and gold catalysis. The excellent stability of NHC-BIAN transition metal com- plexes allowed to perform many cross-coupling reactions of challenging low-reactivity compounds under aerobic conditions at very low catalyst loading, not accessible with classical imidazolium or imidazolinium salts. Furthermore, the unique reactivity allowed to develop new exciting transformations, such as gold-catalyzed sulfonylation. The excellent catalytic performance has recently been translated into the area of enan- tioselective catalysis. Although many chiral NHC ligand precursors have been developed so far, there is still lack of privileged structures in this field. The chiral C2 symmetric NHC-BIAN type carbene precursor celebrated an enormous triumph in the last years, enabling the development of cutting-edge transformations, in particular Ni-catalyzed transformations. Despite the significant step forward with NHC-BIAN-type ligands in catalysis, some challenges have remained. First, the remarkable activity of NHC-BIAN-type ligands have been ascribed the so-called “buttressing effect”, resulting in higher steric hindrance than the classical imidazolium ligands. In addition, many authors suggested that NHC-BIAN-type ligands are stronger σ-donors compared to imidazolium carbenes. As exemplified in this review, no clear evidence for higher steric hindrance or modulated electronic properties could be gained from IR spectroscopy, electrochemical studies or X-ray analyses. For these reasons, in-depth investigation of electronic and steric parameters of NHC-BIAN ligands and their metal complexes is required for better understanding and, hence, further development of the field. The second important feature to be resolved is the impractical and user-unfriendly synthetic approach to chiral NHC-BIAN type ligands via enantioselective reduction using a very expensive bisphosphine DuanPhos ligand. Although chiral NHC- BIAN type ligands have shown excellent activity, a user-friendly low-cost protocol must be developed to make NHC-BIAN ligands privileged ones in asymmetric catalysis.

Funding: Financial support for this work was provided by Polish National Science Centre; Grant SONATA BIS 2017/26/E/ST5/00510). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Catalysts 2021, 11, 972 41 of 44

Acknowledgments: We would like to thank Artur Ulikowski for helpful discussion during manuscript preparation. Conflicts of Interest: The authors declare no conflict of interest.

References 1. Arduengo, A.J.; Harlow, R.L.; Kline, M. A stable crystalline carbene. J. Am. Chem. Soc. 1991, 113, 361–363. [CrossRef] 2. Zhao, Q.; Meng, G.; Nolan, S.P.; Szostak, M. N-Heterocyclic Carbene Complexes in C–H Activation Reactions. Chem. Rev. 2020, 120, 1981–2048. [CrossRef][PubMed] 3. Hudnall, T.W.; Ugarte, R.A.; Perera, T.A. N-Heterocyclic Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools (2); The Royal Society of Chemistry: Cambridge, UK, 2017; pp. 178–237. 4. Doddi, A.; Peters, M.; Tamm, M. N-Heterocyclic Carbene Adducts of Main Group Elements and Their Use as Ligands in Transition Metal Chemistry. Chem. Rev. 2019, 119, 6994–7112. [CrossRef] 5. Michalak, M.; Ko´snik,W. Chiral N-heterocyclic Carbene Gold Complexes: Synthesis and Applications in Catalysis. Catalysts 2019, 9, 890. [CrossRef] 6. Bellemin-Laponnaz, S.; Dagorne, S. Group 1 and 2 and Early Transition Metal Complexes Bearing N-Heterocyclic Carbene Ligands: Coordination Chemistry, Reactivity, and Applications. Chem. Rev. 2014, 114, 8747–8774. [CrossRef][PubMed] 7. Danopoulos, A.A.; Simler, T.; Braunstein, P. N-Heterocyclic Carbene Complexes of Copper, Nickel, and Cobalt. Chem. Rev. 2019, 119, 3730–3961. [CrossRef][PubMed] 8. Peris, E. Smart N-Heterocyclic Carbene Ligands in Catalysis. Chem. Rev. 2018, 118, 9988–10031. [CrossRef] 9. Janssen-Muller, D.; Schlepphorst, C.; Glorius, F. Privileged chiral N-heterocyclic carbene ligands for asymmetric transition-metal catalysis. Chem. Soc. Rev. 2017, 46, 4845–4854. [CrossRef] 10. Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-Heterocyclic Carbenes. Chem. Rev. 2007, 107, 5606–5655. [CrossRef] [PubMed] 11. Song, R.; Jin, Z.; Chi, Y.R. NHC-catalyzed covalent activation of heteroatoms for enantioselective reactions. Chem. Sci. 2021, 12, 5037–5043. [CrossRef] 12. Das, T.K.; Biju, A.T. Progress in Heterocyclic Chemistry; Gribble, G.W., Joule, J.A., Eds.; Elsevier: Amsterdam, The Netherlands, 2020; Volume 31, pp. 1–82. 13. Chen, X.-Y.; Gao, Z.-H.; Ye, S. Bifunctional N-Heterocyclic Carbenes Derived from l-Pyroglutamic Acid and Their Applications in Enantioselective Organocatalysis. Acc. Chem. Res. 2020, 53, 690–702. [CrossRef][PubMed] 14. Sau, S.C.; Hota, P.K.; Mandal, S.K.; Soleilhavoup, M.; Bertrand, G. Stable abnormal N-heterocyclic carbenes and their applications. Chem. Soc. Rev. 2020, 49, 1233–1252. [CrossRef][PubMed] 15. Valente, C.; Çalimsiz, S.; Hoi, K.H.; Mallik, D.; Sayah, M.; Organ, M.G. The Development of Bulky Palladium NHC Complexes for the Most-Challenging Cross-Coupling Reactions. Angew. Chem. Int. Ed. 2012, 51, 3314–3332. [CrossRef] 16. Froese, R.D.J.; Lombardi, C.; Pompeo, M.; Rucker, R.P.; Organ, M.G. Designing Pd–N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications. Acc. Chem. Res. 2017, 50, 2244–2253. [CrossRef] 17. Savka, R.; Plenio, H. Metal Complexes of Very Bulky N,N0-Diarylimidazolylidene N-Heterocyclic Carbene (NHC) Ligands with 2,4,6-Cycloalkyl Substituents. Eur. J. Inorg. Chem. 2014, 2014, 6246–6253. [CrossRef] 18. Huynh, H.V. Electronic Properties of N-Heterocyclic Carbenes and Their Experimental Determination. Chem. Rev. 2018, 118, 9457–9492. [CrossRef][PubMed] 19. Chen, C.; Liu, F.-S.; Szostak, M. BIAN-NHC Ligands in Transition-Metal-Catalysis: A Perfect Union of Sterically Encumbered, Electronically Tunable N-Heterocyclic Carbenes? Chem. Eur. J. 2021, 27, 4478–4499. [CrossRef][PubMed] 20. Vasudevan, K.V.; Butorac, R.R.; Abernethy, C.D.; Cowley, A.H. Synthesis and coordination compounds of a bis(imino)acenaphthene (BIAN)-supported N-heterocyclic carbene. Dalton Trans. 2010, 39, 7401–7408. [CrossRef][PubMed] 21. de Frémont, P.; Scott, N.M.; Stevens, E.D.; Ramnial, T.; Lightbody, O.C.; Macdonald, C.L.B.; Clyburne, J.A.C.; Abernethy, C.D.; Nolan, S.P. Synthesis of Well-Defined N-Heterocyclic Carbene Silver(I) Complexes. Organometallics 2005, 24, 6301–6309. [CrossRef] 22. Fructos, M.R.; Belderrain, T.R.; de Frémont, P.; Scott, N.M.; Nolan, S.P.; Díaz-Requejo, M.M.; Pérez, P.J. A Gold Catalyst for Carbene-Transfer Reactions from Ethyl Diazoacetate. Angew. Chem. Int. Ed. 2005, 44, 5284–5288. [CrossRef] 23. Falivene, L.; Credendino, R.; Poater, A.; Petta, A.; Serra, L.; Oliva, R.; Scarano, V.; Cavallo, L. SambVca 2. A Web Tool for Analyzing Catalytic Pockets with Topographic Steric Maps. Organometallics 2016, 35, 2286–2293. [CrossRef] 24. Poater, A.; Cosenza, B.; Correa, A.; Giudice, S.; Ragone, F.; Scarano, V.; Cavallo, L. SambVca: A Web Application for the Calculation of the Buried Volume of N-Heterocyclic Carbene Ligands. Eur. J. Inorg. Chem. 2009, 2009, 1759–1766. [CrossRef] 25. Gottumukkala, A.L.; Teichert, J.F.; Heijnen, D.; Eisink, N.; van Dijk, S.; Ferrer, C.; van den Hoogenband, A.; Minnaard, A.J. Pd-diimine: A highly selective catalyst system for the base-free oxidative Heck reaction. J. Org. Chem. 2011, 76, 3498–3501. [CrossRef] 26. Wang, J.; Ganguly, R.; Yongxin, L.; Díaz, J.; Soo, H.S.; García, F. Synthesis and the Optical and Electrochemical Properties of Indium(III) Bis(arylimino)acenaphthene Complexes. Inorg. Chem. 2017, 56, 7811–7820. [CrossRef][PubMed] 27. Hasan, K.; Zysman-Colman, E. Synthesis, UV–Vis and CV properties of a structurally related series of bis(Arylimino)acenaphthenes (Ar-BIANs). J. Phys. Org. Chem. 2013, 26, 274–279. [CrossRef] Catalysts 2021, 11, 972 42 of 44

28. Evans, D.A.; Lee, L.M.; Vargas-Baca, I.; Cowley, A.H. Aggregation-Induced Emission of Bis(imino)acenaphthene Zinc Complexes: Photophysical Tuning via Methylation of the Flanking Aryl Substituents. Organometallics 2015, 34, 2422–2428. [CrossRef] 29. Gasperini, M.; Ragaini, F.; Cenini, S. Synthesis of Ar-BIAN Ligands (Ar-BIAN = Bis(aryl)acenaphthenequinonediimine) Having Strong Electron-Withdrawing Substituents on the Aryl Rings and Their Relative Coordination Strength toward Palladium(0) and -(II) Complexes. Organometallics 2002, 21, 2950–2957. [CrossRef] 30. Merino, E.; Poli, E.; Díaz, U.; Brunel, D. Synthesis and characterization of new ruthenium N-heterocyclic carbene Hoveyda II-type complexes. Study of reactivity in ring closing metathesis reactions. Dalton Trans. 2012, 41, 10913–10918. [CrossRef] 31. Butorac, R.R.; Al-Deyab, S.S.; Cowley, A.H. Syntheses, structures and antimicrobial activities of bis(imino)acenaphthene (BIAN) imidazolium salts. Molecules 2011, 16, 3168–3178. [CrossRef] 32. El-Ayaan, U.; Murata, F.; El-Derby, S.; Fukuda, Y. Synthesis, structural and solvent influence studies on solvatochromic mixed- ligand copper(II) complexes with the rigid nitrogen ligand: Bis[N-(2,4,6-trimethylphenyl)imino]acenaphthene. J. Mol. Struct. 2004, 692, 209–216. [CrossRef] 33. Mak, C.S.K.; Wong, H.L.; Leung, Q.Y.; Tam, W.Y.; Chan, W.K.; Djuriši´c, A.B. The use of sublimable chlorotricarbonyl bis(phenylimino)acenaphthene rhenium(I) complexes as photosensitizers in bulk-heterojunction photovoltaic devices. J. Organomet. Chem. 2009, 694, 2770–2776. [CrossRef] 34. Coventry, D.N.; Batsanov, A.S.; Goeta, A.E.; Howard, J.A.K.; Marder, T.B. Synthesis and molecular structures of α-diimines and their zinc and palladium dichloride complexes. Polyhedron 2004, 23, 2789–2795. [CrossRef] 35. Tu, T.; Sun, Z.; Fang, W.; Xu, M.; Zhou, Y. Robust Acenaphthoimidazolylidene Palladium Complexes: Highly Efficient Catalysts for Suzuki–Miyaura Couplings with Sterically Hindered Substrates. Org. Lett. 2012, 14, 4250–4253. [CrossRef][PubMed] 36. Tronnier, A.; Pöthig, A.; Metz, S.; Wagenblast, G.; Münster, I.; Strassner, T. Enlarging the π System of Phosphorescent (CˆC*) Cyclometalated Platinum(II) NHC Complexes. Inorg. Chem. 2014, 53, 6346–6356. [CrossRef][PubMed] 37. van Asselt, R.; Elsevier, C.J.; Smeets, W.J.J.; Spek, A.L.; Benedix, R. Synthesis and characterization of rigid bidentate nitrogen ligands and some examples of coordination to divalent palladium. X-ray crystal structures of bis (p-tolylimino) acenaphthene and methylchloro [bis(o,o0-diisopropylphenyl-imino) acenaphthene] palladium (II). Recl. Trav. Chim. Pays-Bas 1994, 113, 88–98. [CrossRef] 38. Balogh, J.; Hlil, A.R.; El-Zoghbi, I.; Rafique, M.G.; Chouikhi, D.; Al-Hashimi, M.; Bazzi, H.S. Phase-Separable Polyisobutylene Palladium-PEPPSI Precatalysts: Synthesis and Application in Buchwald–Hartwig Amination. Macromol. Rapid. Comm. 2017, 38, 1700214. [CrossRef] 39. Wang, J.; Ganguly, R.; Yongxin, L.; Díaz, J.; Soo, H.S.; García, F. A multi-step solvent-free mechanochemical route to indium(iii) complexes. Dalton Trans. 2016, 45, 7941–7946. [CrossRef] 40. Rhinehart, J.L.; Mitchell, N.E.; Long, B.K. Enhancing α-Diimine Catalysts for High-Temperature Ethylene Polymerization. ACS Catal. 2014, 4, 2501–2504. [CrossRef] 41. Guo, L.; Kong, W.; Xu, Y.; Yang, Y.; Ma, R.; Cong, L.; Dai, S.; Liu, Z. Large-scale synthesis of novel sterically hindered acenaphthene-based α-diimine ligands and their application in coordination chemistry. J. Organomet. Chem. 2018, 859, 58–67. [CrossRef] 42. Ma, X.; Hu, X.; Zhang, Y.; Mu, H.; Cui, L.; Jian, Z. Preparation and in situ chain-end-functionalization of branched ethylene oligomers by monosubstituted α-diimine nickel catalysts. Polym. Chem. 2019, 10, 2596–2607. [CrossRef] 43. Lu, D.-D.; He, X.-X.; Liu, F.-S. Bulky Yet Flexible Pd-PEPPSI-IPentAn for the Synthesis of Sterically Hindered Biaryls in Air. J. Org. Chem. 2017, 82, 10898–10911. [CrossRef] 44. Gong, Y.; Li, S.; Gong, Q.; Zhang, S.; Liu, B.; Dai, S. Systematic Investigations of Ligand Steric Effects on α-Diimine Nickel Catalyzed Olefin Polymerization and Copolymerization. Organometallics 2019, 38, 2919–2926. [CrossRef] 45. Lan, X.-B.; Li, Y.; Li, Y.-F.; Shen, D.-S.; Ke, Z.; Liu, F.-S. Flexible Steric Bulky Bis(Imino)acenaphthene (BIAN)-Supported N- Heterocyclic Carbene Palladium Precatalysts: Catalytic Application in Buchwald–Hartwig Amination in Air. J. Org. Chem. 2017, 82, 2914–2925. [CrossRef] 46. Zhang, F.-Y.; Lan, X.-B.; Xu, C.; Yao, H.-G.; Li, T.; Liu, F.-S. Rigid hindered N-heterocyclic carbene palladium precatalysts: Synthesis, characterization and catalytic amination. Org. Chem. Front. 2019, 6, 3292–3299. [CrossRef] 47. Savka, R.; Foro, S.; Plenio, H. Pentiptycene-based concave NHC-metal complexes. Dalton Trans. 2016, 45, 11015–11024. [CrossRef] [PubMed] 48. Poyatos, M.; Mata, J.A.; Peris, E. Complexes with Poly(N-heterocyclic carbene) Ligands: Structural Features and Catalytic Applications. Chem. Rev. 2009, 109, 3677–3707. [CrossRef] 49. Guisado-Barrios, G.; Hiller, J.; Peris, E. Pyracene-Linked Bis-Imidazolylidene Complexes of Palladium and Some Catalytic Benefits Produced by Bimetallic Catalysts. Chem. Eur. J. 2013, 19, 10405–10411. [CrossRef] 50. Vasudevan, K.V.; Findlater, M.; Cowley, A.H. Synthesis and reactivity of tetrakis(imino)pyracene (TIP) ligands; bifunctional analogues of the BIAN ligand class. Chem. Commun. 2008, 1918–1919. [CrossRef][PubMed] 51. Prades, A.; Peris, E.; Alcarazo, M. Pyracenebis(imidazolylidene): A New Janus-Type Biscarbene and Its Coordination to Rhodium and Iridium. Organometallics 2012, 31, 4623–4626. [CrossRef] 52. Diesel, J.; Finogenova, A.M.; Cramer, N. Nickel-Catalyzed Enantioselective Pyridone C–H Functionalizations Enabled by a Bulky N-Heterocyclic Carbene Ligand. J. Am. Chem. Soc. 2018, 140, 4489–4493. [CrossRef] Catalysts 2021, 11, 972 43 of 44

53. Cai, Y.; Yang, X.-T.; Zhang, S.-Q.; Li, F.; Li, Y.-Q.; Ruan, L.-X.; Hong, X.; Shi, S.-L. Copper-Catalyzed Enantioselective Markovnikov Protoboration of α-Olefins Enabled by a Buttressed N-Heterocyclic Carbene Ligand. Angew. Chem. Int. Ed. 2018, 57, 1376–1380. [CrossRef][PubMed] 54. Diesel, J.; Grosheva, D.; Kodama, S.; Cramer, N. A Bulky Chiral N-Heterocyclic Carbene Nickel Catalyst Enables Enantioselective C−H Functionalizations of Indoles and Pyrroles. Angew. Chem. Int. Ed. 2019, 58, 11044–11048. [CrossRef] 55. Albright, A.; Eddings, D.; Black, R.; Welch, C.J.; Gerasimchuk, N.N.; Gawley, R.E. Design and Synthesis of C2-Symmetric N-Heterocyclic Carbene Precursors and Metal Carbenoids. J. Org. Chem. 2011, 76, 7341–7351. [CrossRef][PubMed] 56. Spahn, E.; Albright, A.; Shevlin, M.; Pauli, L.; Pfaltz, A.; Gawley, R.E. Double-Asymmetric Hydrogenation Strategy for the Reduction of 1,1-Diaryl Olefins Applied to an Improved Synthesis of CuIPhEt, a C2-Symmetric N-Heterocyclic Carbenoid. J. Org. Chem. 2013, 78, 2731–2735. [CrossRef] 57. Organ, M.G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E.A.B.; O’Brien, C.J.; Valente, C. A User-Friendly, All-Purpose Pd–NHC (NHC=N-Heterocyclic Carbene) Precatalyst for the Negishi Reaction: A Step Towards a Universal Cross-Coupling Catalyst. Chem. Eur. J. 2006, 12, 4749–4755. [CrossRef] 58. O’Brien, C.J.; Kantchev, E.A.B.; Valente, C.; Hadei, N.; Chass, G.A.; Lough, A.; Hopkinson, A.C.; Organ, M.G. Easily Prepared Air- and Moisture-Stable Pd–NHC (NHC=N-Heterocyclic Carbene) Complexes: A Reliable, User-Friendly, Highly Active Palladium Precatalyst for the Suzuki–Miyaura Reaction. Chem. Eur. J. 2006, 12, 4743–4748. [CrossRef][PubMed] 59. Tu, T.; Fang, W.; Jiang, J. A highly efficient precatalyst for amination of aryl chlorides: Synthesis, structure and application of a robust acenaphthoimidazolylidene palladium complex. Chem. Commun. 2011, 47, 12358–12360. [CrossRef] 60. Liu, Z.; Dong, N.; Xu, M.; Sun, Z.; Tu, T. Mild Negishi Cross-Coupling Reactions Catalyzed by Acenaphthoimidazolylidene Palladium Complexes at Low Catalyst Loadings. J. Org. Chem. 2013, 78, 7436–7444. [CrossRef] 61. Jiang, J.; Zhu, H.; Shen, Y.; Tu, T. Acenaphthoimidazolium chloride-enabled nickel-catalyzed amination of bulky aryl tosylates. Org. Chem. Front. 2014, 1, 1172–1175. [CrossRef] 62. Hu, L.-Q.; Deng, R.-L.; Li, Y.-F.; Zeng, C.-J.; Shen, D.-S.; Liu, F.-S. Developing Bis(imino)acenaphthene-Supported N-Heterocyclic Carbene Palladium Precatalysts for Direct Arylation of Azoles. Organometallics 2018, 37, 214–226. [CrossRef] 63. Huang, F.-D.; Xu, C.; Lu, D.-D.; Shen, D.-S.; Li, T.; Liu, F.-S. Pd-PEPPSI-IPentAn Promoted Deactivated Amination of Aryl Chlorides with Amines under Aerobic Conditions. J. Org. Chem. 2018, 83, 9144–9155. [CrossRef] 64. Ouyang, J.-S.; Li, Y.-F.; Huang, F.-D.; Lu, D.-D.; Liu, F.-S. The Highly Efficient Suzuki–Miyaura Cross-Coupling of (Hetero)aryl Chlorides and (Hetero)arylboronic Acids Catalyzed by “Bulky-yet-Flexible” Palladium–PEPPSI Complexes in Air. ChemCatChem 2018, 10, 371–375. [CrossRef] 65. Leuthäußer, S.; Schmidts, V.; Thiele, C.M.; Plenio, H. π-Face Donor Properties of N-Heterocyclic Carbenes in Grubbs II Complexes. Chem. Eur. J. 2008, 14, 5465–5481. [CrossRef][PubMed] 66. Dunn, M.H.; Konstandaras, N.; Cole, M.L.; Harper, J.B. Targeted and Systematic Approach to the Study of pKa Values of Imidazolium Salts in Dimethyl Sulfoxide. J. Org. Chem. 2017, 82, 7324–7331. [CrossRef] 67. Rayner, P.; Norcott, P.; Appleby, K.; Iali, W.; John, R.; Hart, S.; Whitwood, A.; Duckett, S. Fine-tuning the efficiency of para- hydrogen-induced hyperpolarization by rational N-heterocyclic carbene design. Nat. Commun. 2018, 9, 4251. [CrossRef] [PubMed] 68. Lan, X.-B.; Chen, F.-M.; Ma, B.-B.; Shen, D.-S.; Liu, F.-S. Pd-PEPPSI Complexes Bearing Bulky [(1,2-Di-(tert-butyl)acenaphthyl] (DtBu-An) on N-Heterocarbene Backbones: Highly Efficient for Suzuki–Miyaura Cross-Coupling under Aerobic Conditions. Organometallics 2016, 35, 3852–3860. [CrossRef] 69. Sinha, N.; Heijnen, D.; Feringa, B.L.; Organ, M.G. Murahashi Cross-Coupling at −78 ◦C: A One-Pot Procedure for Sequential C−C/C−C, C−C/C−N, and C−C/C−S Cross-Coupling of Bromo-Chloro-Arenes. Chem. Eur. J. 2019, 25, 9180–9184. [CrossRef] 70. Shen, A.; Wu, Z.; Fang, Y.; Yang, J.; Zhu, H.; Tu, T. A Concerted Catalytic System for Sonogashira Coupling Reactions: Combination of N-Heterocyclic Carbene Palladium and Copper Complexes. Asian J. Org. Chem. 2018, 7, 1113–1117. [CrossRef] 71. Fang, W.; Deng, Q.; Xu, M.; Tu, T. Highly Efficient Aminocarbonylation of Iodoarenes at Atmospheric Pressure Catalyzed by a Robust Acenaphthoimidazolyidene Allylic Palladium Complex. Org. Lett. 2013, 15, 3678–3681. [CrossRef][PubMed] 72. Zhu, H.; Shen, Y.; Deng, Q.; Chen, J.; Tu, T. Pd(NHC)-catalyzed alkylsulfonylation of boronic acids: A general and efficient approach for sulfone synthesis. Chem. Commun. 2017, 53, 12473–12476. [CrossRef][PubMed] 73. Liu, S.; Deng, Q.; Fang, W.; Gong, J.-F.; Song, M.-P.; Xu, M.; Tu, T. Efficient and scalable Pd-catalyzed double aminocarbonylations under atmospheric pressure at low catalyst loadings. Org. Chem. Front. 2014, 1, 1261–1265. [CrossRef] 74. Deng, Q.; Zhang, Y.; Zhu, H.; Tu, T. Robust Acenaphthoimidazolylidene Palladacycles: Highly Efficient Catalysts for the Amination of N-Heteroaryl Chlorides. Chem. Asian. J. 2017, 12, 2364–2368. [CrossRef] 75. Deng, Q.; Shen, Y.; Zhu, H.; Tu, T. A magnetic nanoparticle-supported N-heterocyclic carbene-palladacycle: An efficient and recyclable solid molecular catalyst for Suzuki–Miyaura cross-coupling of 9-chloroacridine. Chem. Commun. 2017, 53, 13063–13066. [CrossRef] 76. Cao, Q.; Howard, J.L.; Wheatley, E.; Browne, D.L. Mechanochemical Activation of Zinc and Application to Negishi Cross-Coupling. Angew. Chem. Int. Ed. 2018, 57, 11339–11343. [CrossRef][PubMed] 77. Cao, Q.; Nicholson, W.; Jones, A.; Browne, D. Robust Buchwald–Hartwig amination enabled by ball-milling. Org. Biomol. Chem. 2018, 17, 1722–1726. [CrossRef] Catalysts 2021, 11, 972 44 of 44

78. Martin, A.R.; Makida, Y.; Meiries, S.; Slawin, A.M.Z.; Nolan, S.P. Enhanced Activity of [Ni(NHC)CpCl] Complexes in Arylamina- tion Catalysis. Organometallics 2013, 32, 6265–6270. [CrossRef] 79. Ben Halima, T.; Masson-Makdissi, J.; Newman, S.G. Nickel-Catalyzed Amide Bond Formation from Methyl Esters. Angew. Chem. Int. Ed. 2018, 57, 12925–12929. [CrossRef][PubMed] 80. Yao, W.-W.; Li, R.; Li, J.-F.; Sun, J.; Ye, M. NHC ligand-enabled Ni-catalyzed reductive coupling of alkynes and imines using isopropanol as a reductant. Green Chem. 2019, 21, 2240–2244. [CrossRef] 81. Huang, J.-Q.; Ho, C.-Y. NHC/Nickel(II)-Catalyzed [3+2] Cross-Dimerization of Unactivated Olefins and Methylenecyclopropanes. Angew. Chem. Int. Ed. 2020, 59, 5288–5292. [CrossRef][PubMed] 82. Zhang, W.-B.; Yang, X.-T.; Ma, J.-B.; Su, Z.-M.; Shi, S.-L. Regio- and Enantioselective C–H Cyclization of Pyridines with Alkenes Enabled by a Nickel/N-Heterocyclic Carbene Catalysis. J. Am. Chem. Soc. 2019, 141, 5628–5634. [CrossRef][PubMed] 83. Wang, Z.-C.; Xie, P.-P.; Xu, Y.; Hong, X.; Shi, S.-L. Low-Temperature Nickel-Catalyzed C−N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand. Angew. Chem. Int. Ed. 2021, 60, 16077–16084. [CrossRef] [PubMed] 84. Grela, K.; Harutyunyan, S.; Michrowska, A. A Highly Efficient Ruthenium Catalyst for Metathesis Reactions. Angew. Chem. Int. Ed. 2002, 41, 4038–4040. [CrossRef] 85. Hlil, A.R.; Moncho, S.; Tuba, R.; Elsaid, K.; Szarka, G.; Brothers, E.N.; Grubbs, R.H.; Al-Hashimi, M.; Bazzi, H.S. Synthesis and catalytic activity of supported acenaphthoimidazolylidene N-heterocyclic carbene ruthenium complex for ring closing metathesis (RCM) and ring opening metathesis polymerization (ROMP). J. Catal. 2016, 344, 100–107. [CrossRef] 86. Butorac, R.; Al-Deyab, S.; Cowley, A. Antimicrobial Properties of Some Bis(Iminoacenaphthene (BIAN)-Supported N-Heterocyclic Carbene Complexes of Silver and Gold. Molecules 2011, 16, 2285–2292. [CrossRef][PubMed] 87. Elzatahry, A.A.; Al-Enizi, A.M.; Elsayed, E.A.; Butorac, R.R.; Al-Deyab, S.S.; Wadaan, M.A.M.; Cowley, A.H. Nanofiber composites containing N-heterocyclic carbene complexes with antimicrobial activity. Int. J. Nanomed. 2012, 7, 2829–2832. [CrossRef] 88. Farooq, M.; Taha, N.; Butorac, R.; Evans, D.; Elzatahry, A.; Elsayed, E.; Wadaan, M.; Al-Deyab, S.; Cowley, A. Biological Screening of Newly Synthesized BIAN N-Heterocyclic Gold Carbene Complexes in Zebrafish Embryos. Int. J. Mol. Sci. 2015, 16, 24718–24731. [CrossRef] 89. Ciancaleoni, G.; Biasiolo, L.; Bistoni, G.; Macchioni, A.; Tarantelli, F.; Zuccaccia, D.; Belpassi, L. NHC-Gold-Alkyne Complexes: Influence of the Carbene Backbone on the Ion Pair Structure. Organometallics 2013, 32, 4444–4447. [CrossRef] 90. Visbal, R.; Laguna, A.; Gimeno, M.C. Simple and efficient synthesis of [MCI(NHC)] (M = Au, Ag) complexes. Chem. Commun. 2013, 49, 5642–5644. [CrossRef] 91. Collado, A.; Gomez-Suarez, A.; Martin, A.R.; Slawin, A.M.Z.; Nolan, S.P. Straightforward synthesis of [Au(NHC)X] (NHC = N- heterocyclic carbene, X = Cl, Br, I) complexes. Chem. Commun. 2013, 49, 5541–5543. [CrossRef][PubMed] 92. Plenio, H.; Heidrich, M.; Bergmann, M.; Müller-Borges, D. Bispentiptycenyl-N-Heterocyclic Carbene (NHC) Gold Complexes: Highly Active Catalysts for the Room Temperature Hydration of Alkynes. Adv. Synth. Catal. 2018, 360, 3572–3578. [CrossRef] 93. Zhu, H.; Shen, Y.; Deng, Q.; Chen, J.; Tu, T. Acenaphthoimidazolylidene Gold Complex-Catalyzed Alkylsulfonylation of Boronic Acids by Potassium Metabisulfite and Alkyl Halides: A Direct and Robust Protocol to Access Sulfones. ACS Catal. 2017, 7, 4655–4659. [CrossRef] 94. Gatto, M.; Del Zotto, A.; Segato, J.; Zuccaccia, D. Hydration of Alkynes Catalyzed by L–Au–X under Solvent- and Acid-Free Conditions: New Insights into an Efficient, General, and Green Methodology. Organometallics 2018, 37, 4685–4691. [CrossRef] 95. Zhu, H.; Shen, Y.; Wen, D.; Le, Z.-G.; Tu, T. Selective Synthesis of ortho-Substituted Diarylsulfones by Using NHC-Au Catalysts under Mild Conditions. Org. Lett. 2019, 21, 974–979. [CrossRef][PubMed] 96. Ma, Y.; Liu, R.; Gong, X.; Li, Z.; Huang, Q.; Wang, H.; Song, G. Synthesis and Herbicidal Activity of N,N-Diethyl-3-(arylselenonyl)- 1H-1,2,4-triazole-1-carboxamide. J. Agric. Food Chem. 2006, 54, 7724–7728. [CrossRef][PubMed] 97. Furukawa, T.; Tobisu, M.; Chatani, N. C–H Borylation by Platinum Catalysis. Bull. Chem. Soc. Jpn. 2017, 90, 332–342. [CrossRef] 98. Savka, R.; Plenio, H. Facile synthesis of [(NHC)MX(cod)] and [(NHC)MCl(CO)2] (M = Rh, Ir; X = Cl, I) complexes. Dalton Trans. 2015, 44, 891–893. [CrossRef][PubMed] 99. Dastgir, S.; Coleman, K.S.; Cowley, A.R.; Green, M.L.H. Stable crystalline annulated diaminocarbenes: Coordination with rhodium(i), iridium(i) and catalytic hydroformylation studies. Dalton Trans. 2009, 35, 7203–7214. [CrossRef] 100. Gómez-Suárez, A.; Nelson, D.J.; Nolan, S.P. Quantifying and understanding the steric properties of N-heterocyclic carbenes. Chem. Commun. 2017, 53, 2650–2660. [CrossRef] 101. Falivene, L.; Cao, Z.; Petta, A.; Serra, L.; Poater, A.; Oliva, R.; Scarano, V.; Cavallo, L. Towards the online computer-aided design of catalytic pockets. Nat. Chem. 2019, 11, 872–879. [CrossRef]