A Decade of Exploration of Transition-Metal-Catalyzed Cross-Coupling Reactions: An Overview

During the previous couple of decades, transition-metal (Fe, Co, Cu, Ni, Ru, Rh, Pd, Ag, Au) catalyzed inter-and intramolecular coupling reactions have attracted huge attention for the construction of C–C and C–heteroatom (like C–N, C–P, C–O, C–S, etc.) bonds to synthesize a diverse range of polymers, fine chemicals


Introduction
Over the past years, the construction of carbon-carbon and carbon-heteroatom bonds via cross-coupling reactions catalyzed by transition metals, such as Suzuki-Miyaura, 1 Heck, 2 Sonogashira, 3 Stille, 4 Negishi, 5 Kumada, 6 and Hiyama 7 reactions, have remained the most widely employed synthesis protocols in the chemical industry.These reactions represent the fundamental criteria for a number of basic technologies in modern synthetic organic chemistry and have been widely applied in a variety of academic and industrial process, 8,9 including the synthesis of natural products, 10,11 biologically active small molecule, materials science, medicinal, supramolecular catalysis, and coordination chemistry.In addition, several of these reactions have been commercially employed in the fields of pharmaceuticals, agrochemical conjugated polymers, 12,13 and crystalline liquids, [14][15][16] in the active components of organic light-emitting diodes (OLEDs), 17,18 and as industrial chemicals 12 etc.
The first breakthrough in the direction of cross-coupling was the copper-catalyzed synthesis of biaryl compounds from aryl halides published by F. Ullmann in 1901. 19his discovery was not limited to a mere presentation of new synthesis methodology, but rather brought the realization that carbon-carbon bonds can be made in a laboratory synthetically.After a long gap of nearly seven decades, the discovery by Ullmann gained the recognition and a variety Deepak Gupta is a guest faculty member at the Department of Applied Chemistry, Delhi Technological University.His research is focused on electrochemical conversions and developing sustainable materials for energy storage.He has published more than 20 research articles with total impact factor of greater than 100.He is a recipient of research funding from various prestigious agencies such as Council of Scientific and Industrial Research (India), DAAD (Germany), European Re-search Council (Belgium) and Science and Engineering Research Board (India).He is a member of Royal Society of Chemistry and reviewer with various high-impact journals.

Gajendra Singh is an Associate
Professor at the Department of Chemistry, Deshbandhu College (University of Delhi).He completed his education at the University of Delhi and CCS University.Dr. Singh has pub-lished several research papers in national and international journals.He has also presented papers at approximately 30 conferences and seminars.In addition to his research and academic achievements, he also serves as a member of the editorial board of the Journal of Heterocyclic Letters and Universe Journal of Education & Humanities.He is a lifetime member of the Indian Society of Analytical Scientists (ISAS).
Anil Kumar is a full professor at the Department of Applied Chemistry, Delhi Technological University (formerly, Delhi College of Engineering), Delhi, India.He received his master's and doctorate degrees in chemistry from University of Roorkee, Roorkee (Now IIT Roorkee) and Indian Institute of Technology, Kanpur, India, respectively.He has worked with Professor Gross at Technion, Israel Institute of Technology, Haifa, Israel, as both a post-doctoral fellow and a visiting associate professor.Kumar gives credit to all his mentors 'Gurujis' (Prof.S. Sarkar, Prof. C. H. Hung and Prof. Zeev Gross) for enlightening him through the path of knowledge.His current research interest is corrole and benziporphodimethene-based coordination chemistry and its applications.Kumar lives in Delhi with his wife (Hemlata) and two children (Sarthak Pal and Tanish Pal).

Review SynOpen
agrochemicals, and biologically active compounds are briefly discussed in the final section.This work includes references published from the year 2011 to date that cover the most important developments in this rapidly progressing field.The content of this review is categorized into various transition-metal-catalyzed reactions such as Pd-mediated reactions.

Pd-Catalyzed Reactions
The discussion in this section is bounded to the use of palladium catalysis in various cross-coupling reactions and is generally presented in chronological order.
At the same time, Raju and co-workers first synthesized aryl imidazolylsulfonates 5 as a cost-effective alternative to triflates, which was shown to participate as a fully competent electrophilic coupling partner in palladium-catalyzed cross-coupling Negishi and Suzuki-Miyaura reactions in excellent yields (Scheme 2, Scheme 3, and Scheme 4). 96heme 2 Synthesis of imidazolylsulfonates 96 The first successful heterogeneous carbonylative Stille cross-coupling reaction of organostannanes 11 with aryl iodides 12 was demonstrated in 2009 by Cai et al. 97 in the presence of a catalytic amount of an MCM-41-supported bidentate phosphine palladium(0) complex [MCM-41-2P-Pd(0)] (13) (Scheme 5).The reaction was carried out at 80 °C under carbon monoxide atmosphere in the presence of DMF, producing a variety of unsymmetrical ketones 14 in high reaction yields.
In 2010, Basu and co-workers 98 deciphered the ligandfree, on-water, Pd-catalyzed Suzuki-Miyaura (SM) coupling of the easily accessible sodium salt of aryl trihydroxyborate (16) with a variety of aryl halides (15) under aerobic conditions.The protocol was also applicable to very challenging substrates like aryl chlorides bearing electron-withdrawing groups, in good to excellent yields.Further, the authors demonstrated that this protocol was effective with heterogeneous palladium-catalysts and also exhibited the synthesis of pharmaceutically important benzotriazole 20 and benzimidazole-based biphenyl scaffolds 19 (Scheme 6 and Scheme 7).S. Kumar et al.

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Lee and co-workers 99 described the synthesis of heterogeneous silica gel-supported -ketoiminatophosphane-Pd complex (Pd@SiO 2 ) (21) and examined its catalytic activity for Sonogashira, Suzuki, and Stille coupling reactions of a broad range of heteroaryl chlorides with different nucleophilic partners such as aryl boronic acids, organostannanes, and alkynes, providing yields up to 96, 94 and 96%, respectively (Scheme 8).The reaction was carried out an aqueous medium with 0.5 mol% catalyst loading, as mild conditions.
Milton and his research group 100 presented a microwave-accelerated synthesis of the [PdCl 2 (L)] pre-catalysts synthesized from Na 2 PdCl 4 and studied the reactivity of the Grignard cross-coupling by screening various ferrocene ligands such as dppf, dippf, dtbpf, and dtbdppf in a new solvent (Scheme 9).The solvent Me-THF has been gaining attention as a greener substitute to THF with no added reaction solvents.The authors performed the cross-coupling of Grignard reagents at 5 molar concentration in Me-THF with the correct matching of catalyst to substrate, and achieved good conversions in short times.This method significantly reduced the amount of solvent in both the Grignard synthesis and Grignard cross-coupling reactions as compared to other typical procedures based on THF.The reaction was found to be strongly dependent on the ligand structure, where 1,1-bis-diphenylphosphino-ferrocene and 1-di-tertbutyl-1-diphenylphosphino-ferrocene seemed to be the suitable ligands.
Peng et al. 101 disclosed stilbazo (stilbene-4,4-bis[(1azo)-3,4-dihydroxybenzene]-2,2-disulfonic acid diammonium salt) (24) promoted, ligand-free Suzuki-Miyaura reaction in the presence of palladium catalyst in water at room temperature, which tolerated functional groups well and proceeded with high efficiency (Figure 1).Marziale and co-workers 102 tested various new palladacyclic catalysts (25-27) in aqueous Suzuki-Miyaura coupling conditions and concluded that catalyst 25 displayed high activities at room temperature for a broad range of products and afforded high yields (Figure 2).The isolated products were of high purity and could be separated by simple filtration.Long and co-workers 103 synthesized monosubstituted ferrocene derivatives 30 by using Suzuki cross-coupling reaction of ferroceneboronic acid (28) with a variety of aryl and vinyl triflates 29.The reaction was carry out in the presence of Pd(PPh 3 ) 4 (0.025 equiv) and K 3 PO 4 (2 equiv) in refluxing dioxane in excellent yields (Scheme 10).The electronic and steric effects were also observed for ortho-, meta-, and para-substituents of aryl triflates.

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For the first time, Chen and co-workers 104 used oxadisilole (31) as a coupling partner in the cross-coupling reaction with aryl halides catalyzed by palladium, affording 2aryl naphthalenes 33 (Scheme 11).The reaction was carried out in the presence of tetrabutylammonium fluoride and this report offered a new path for the synthesis of functionalized acenes and related structures.
Molander and co-workers 105 devised a new avenue to introduce the amidomethyl functional group into substrates (Scheme 12).The amidomethyltrifluoroborates 35 were first synthesized and applied in the cross-coupling as coupling partners with a number of aryl and heteroaryl chlorides in a one-pot fashion.
In 2011, Liu and co-workers 106 achieved the ligand-free SM reaction of arylboronic acids with aryl bromides or nitrogen-based heteroaryl halides in aqueous DMF with K 2 -CO 3 and a catalytic amount of PdCl 2 at room temperature in moderate to excellent yields.This mild and simple method tolerated various functional groups and showed that the water/DMF ratio and presence of base are crucial in the reaction.

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Ali and co-workers 109 used palladium-catalyzed crosscoupling reactions (Buchwald-Hartwig, Sonogashira, and Suzuki-Miyaura) for the synthesis of a chain of peptides that were mono-functionalized with phthalocyanines (Pc) (41) at the N/C-terminal with moderate yields (Figure 4).The authors conjugated Pc with peptide moieties to help establish the selectivity for potential imaging probes for positron emission tomography and fluorescence for applications in the medical field.
A phosphine-free system developed by Modak et al. 110 demonstrated that a new functionalized mesoporous polymer (MPTAT-1) (42) developed by radical polymerization of 2,4,6-triallyloxy-1,3,5-triazine (TAT) in an aqueous medium in the presence of an anionic surfactant (sodium dodecyl sulfate) as template, was an effective catalyst for several cross-coupling reactions such as Suzuki-Miyaura, Mizoroki-Heck, and Sonogashira (Figure 5).The template-free MP-TAT-1 provides assistance in immobilizing Pd(II) and appears to be a very good catalytic scheme for eco-friendly conditions such as the use of water as reaction medium.
Later, an additional report was published by the same group 111 in which they prepared a Pd-grafted periodic mesoporous organosilica material (Pd-LHMS-3) (44) containing a phloroglucinol-diimine moiety within the pores (Scheme 14).This heterogeneous catalyst was investigated for its catalytic activity in Hiyama and Sonogashira couplings, and in cyanation reactions.The Hiyama cross-couplings executed by this protocol were fluoride-free and performed in water at alkaline pH conditions (Scheme 15).Similarly, copperfree Sonogashira cross-coupling reaction proceeded in water with a base such as hexamine.The catalyst promoted the cyanide-free cyanation of aryl halides with K 4 [Fe(CN) 6 ] as the cyanide source rather than using toxic KCN, NaCN or Zn(CN) 2 .Excellent yields were presented for the synthesis of unsymmetrical biphenyls, di-substituted alkynes, and substituted benzonitriles under eco-friendly reaction conditions (Scheme 16).

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nogashira and Stille reactions in aqueous media (Figure 6).According to this report, Pd leaching was extremely low and 50 was reused five times with no significant loss of activity.Mondal et al. 113 produced a catalytic system based on PdCl 2 and sodium sulfate generated in situ for ligand-free cross-coupling reaction in water at room temperature.They also produced a similar catalytic system based on PdCl 2 and sodium chloride or sodium acetate that was found to be equally effective in Suzuki-Miyaura cross-couplings.The Wang group 114 published a report on one-pot tandem Pd(II)-catalyzed Diels-Alder/cross-coupling reactions of 2boron substituted dienes (Scheme 17).They prepared and characterized several new 2-boron substituted dienes and examined their reactivity in Diels-Alder reactions.The boron substituted cycloadducts thus formed were used in Suzuki cross-couplings.
The Liu research group 115 examined Pd(OAc) 2 /(i-Pr) 2 NH/H 2 O as a catalytic system for ligand-free and aerobic Suzuki reaction in water in the absence of any additive.It was demonstrated that the protocol tolerated a broad scope of aryl halides with either hydrophobic or hydrophilic groups.Further, the base was found to play a crucial role in this reaction.Keller et al. 116 synthesized a series of novel dendritic thiazolyl phosphine ligands and deployed them in palladium-catalyzed Suzuki couplings using Pd(OAc) 2 (Figure 7).The efficiency of the catalysts were compared with those of the corresponding triphenylphosphines; for example, in contrast to their triphenylphosphine counterparts, the thiazolyl phosphine-based catalytic arrangements (54).ha and co-workers 117 extended a new protocol for the development of eight-membered benzoxocinoquinoline (55) from quinolines by using a basic alumina-supported microwave-assisted intramolecular Heck reaction (Figure 8).In 2013, the Lu group 118 utilized a nonionic designer amphiphile, (TPGS-750-M) for Pd(P(t-Bu) 3 ) 2 /DABCO catalyzed Stille couplings between a broad range of substrates (aryl and alkenyl halides) and organostannanes in water at room temperature.Oberholzera and Frech 119 designed a series of highly active, cheap, easily accessible, and air-stable dichloro-bis(aminophosphine) complexes of palladium of general formula [(P{(NC 5 H 10 ) 3 -n-(C 6 H 11 ) n }) 2 Pd(Cl) 2 ] (57) (n = 0-3) for Heck cross-coupling reactions with a catalyst loading of 0.05 mol% in DMF at 100 °C using tetrabutylammonium bromide (Scheme 18).The active form of this catalyst was utilized (namely, nanoparticles) in the Heck reaction, which displayed an outstanding functional group tolerance towards aryl bromides containing fluoro, chloro, nitro, nitriles, aldehydes, ketones, esters, ethers, trifluoromethane S. Kumar et al.
Ding and co-workers 121 fabricated the Pd/bentonite catalyst by a simple impregnation method for Suzuki-Miyaura reaction.Clay is abundant, nontoxic, cheap, and a good support for the preparation of green catalysts.This methodology tolerated aryl bromides and iodides using several EDG and EWG such as -COCH 3 , -OCH 3 , -CH 3 , -F, -NO 2 ,-CN, and -Cl in the coupling reaction with loading of catalyst Pd (0.06 mol%) in very low amount under ambient temperature.Yan and co-workers developed an effective palladium-catalyzed synthesis of arylethylene (mono-substituted alkenes) and diarylethylene (disubstituted alkenes) by coupling various aryl halides with olefins in the presence of easily available ligands (Scheme 20). 122ased on functionalized -cyclodextrin, Zhang and coworkers 123 designed and prepared a novel water-soluble complex PdLn@-CD (62) for Suzuki-Miyaura coupling reactions in aqueous medium (Figure 9).This catalyst was based on click-triazole-functionalized -cyclodextrin and gave high turnover frequencies and turnover numbers of up to 4.9 × 108 h -1 and 9.9 × 10 8 , respectively.

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Yuan and co-workers 124 devised a mild and solvent-free procedure for the development of ynones by Pd(PPh 3 ) 4 catalyzed cross-coupling of in-situ-generated alkynylzinc derivatives with acyl chlorides in high yields (Scheme 21).
Ojha et al. 127 achieved the challenging task of regioselective formation of highly branched dienes by a novel palladium-catalyzed selective coupling reaction of hydrazones 72 with t-BuOLi and p-benzoquinone (Scheme 24).They utilized carbene transfer reactions in the Pd(II) catalyzed coupling of hydrazones under oxidative conditions, which led to the formation of a Pd-bis-carbene complex with -hydrogens finally affording branched dienes 73.The reaction was versatile and compatible with a range of functional groups to open new avenues for synthesizing useful heterocyclic molecules 75.
In 2014, the Liu research team 128 envisioned an efficient, recyclable, green and ligand-free method for the Suzuki coupling of aryl or heteroaryl halides in the presence of potassium aryltrifluoroborates with water, in air, using a Pd(OAc) 2 -H 2 O-PEG system to give the desired products in high reaction yields.The catalytic system was recycled eight times without appreciable loss in activity.Similarly, the water and PEG-2000 solvent mixture was utilized by the Zhao research group 129 in which they described the carbonylative Sonogashira coupling reaction of terminal alkynes with aryl iodides in the presence of PdCl 2 (PPh 3 ) 2 and Et 3 N as a base under an atmospheric pressure of CO at 25 °C, giving a scope of alkynyl ketones with satisfactory yields (Scheme 25).This protocol could be effortlessly extended to the synthesis of 2-substituted flavones from o-iodophenol and terminal alkynes.
The Nehra group 130 prepared an efficient ionic-liquidtagged Schiff base palladium complex (76) that was stable in air and was water-soluble (Figure 10).This complex showed catalytic activity and was investigated for Heck and Suzuki cross-coupling reactions in aqueous media.The protocol was found to be very effective for more challenging substrates such as chlorides.
Li et al. 131 reported stereospecific cross-coupling between aryl chlorides and unactivated secondary alkylboron

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nucleophiles under Pd catalysis.Secondary alkyltrifluoroborates and secondary alkylboronic acids were tolerated in this protocol without noteworthy isomerization of the alkyl nucleophile.In this cross-coupling process, optically active secondary alkyltrifluoroborate reagents underwent stereospecific inversion of configuration.This protocol could be utilized in the construction of optically active drugs from optically active alkylboron compounds.Nadaf et al. 132 described the palladium-catalyzed Suzuki-Miyaura crosscoupling reactions between newly synthesized potassium N-methyltrifluoroborate isoindolin-1-one ( 77) and aryl and heteroaryl chlorides to prepare libraries of substituted Nbenzyl isoindolin-1-ones 78 (Scheme 26).
In cross-coupling reactions, one of the limitations is that azobenzenes act as electrophiles, whereby metalation by halogen-metal exchange causes reduction of the azo group yielding hydrazine derivatives in place of the desired metallated azobenzenes.Strueben 133 provided a solution to this problem by developing a mild method to prepare monoand distannylated azobenzenes (79), which were used as nucleophilic partners in Pd-catalyzed Stille cross-coupling reactions with electron-deficient and electron-rich aryl bromides, resulting in the formation of the cross-coupled products 80 in yields as high as 70 to 93% (Scheme 27).
Sun et al. 134 reported a three-step synthesis of 4,8-azaboranaphthalene (ABN) on a gram scale and showed that the reaction tolerated a variety of functional groups and crosscoupling partners in various Sonogashira, palladium-catalyzed Suzuki, and Heck cross-coupling reactions.One of the advantages of the coupled product bearing an ABN motif was that it showed a fluorescence response toward Cd(II) and Zn(II) ions.Thus, this protocol is very significant in designing various fluorescent chemosensors.The Tan group 135 published a Suzuki-Miyaura cross-coupling reaction catalyzed by palladium of unprotected haloimidazoles (81) with various aryl-and heteroarylboronic acids providing a wide array of functionalized imidazoles (83) (Scheme 28).The total synthesis of nortopsentin D was also demonstrated by the group utilizing this method.
Scheme 28 Pd-catalyzed SM cross-coupling reaction of unprotected haloimidazoles 135 In 2015, Shen et al. 136 synthesized D-glucosamine-derived triazole@palladium catalyst (84) via a suitable route in high reaction yields, and its catalytic activity was studied in Heck cross-coupling reactions between olefins (Figure 11).Additionally, the easy synthesis of marketed antitumor drug Axitinib (85) was also demonstrated by the group utilizing this protocol.
Scheme 29 MW-assisted SM cross-coupling reaction of (het)aryl halides and MIDA ester 137 Boruah and co-workers 138 demonstrated a highly efficient, economical alternative and eco-friendly procedure for Suzuki-Miyaura cross-coupling reactions catalyzed by palladium acetate.The reactions were carried out in neat 'water extract of banana' at room temperature in the air within 5-90 min in the absence of any ligand, external base, organic medium, and external promoters like additives.Strappaveccia and co-workers 139 investigated the synthesis of stilbines, cinnamate esters and acids by using of GVL in the Pd-catalyzed Heck reaction.Moreover, poly(phenylenevinylene) (PPV) semiconductors were also prepared using this protocol in high yields with very low amount of Pdcontent.In a later investigation by this group, 140 they presented -valerolactone (GVL) as a non-toxic, biodegradable, biomass-derived dipolar aprotic solvents like DMF or NMP for the Sonogashira cross-coupling reaction using DABCO as a base, affording the desired products in 62-96% yields.Because of the biomass-derived reactants, this method offers an eco-friendly approach leading to higher sustainability as well as high chemical efficiency.
In 2016, Khana et al. 141 prepared an ionic Pd(II) complex stabilized by a water-soluble pyridinium-modified -cyclodextrin, affording the N-octyl-pyridine-2-amine backbone (Pd(II)@Pyr:-CD) (89) and explored the activity of catalyst in Heck cross-coupling and Suzuki-Miyaura coupling reactions in eco-friendly aqueous medium, which provided high yields of the coupled product (Figure 12).Aryl chlorides were also efficiently coupled with phenylboronic acid/styrene using this procedure.The Jadhav research group 142 proposed a ligand-free Suzuki-Miyaura reaction and base-free Heck reactions to synthesize a variety of biaryls, acrylates, and prochiral ketones under mild reaction conditions using Pd supported on activated carbon (Pd/C) in an aqueous hydrotropic solution.A hydrotrope was used as a precious, green reaction medium for the first time.Wang and co-workers 143 developed a novel oxazoline-based palladium microsphere complex (93) by the self-assembly of the bisoxazoline (92) and Pd(OAc) 2 (Scheme 30).This solid microsphere catalyst was explored for phosphine-free Suzuki-Miyaura cross-coupling reactions in aqueous media.
In 2017, Nambo and co-workers 144 described the Pdcatalyzed Suzuki-Miyaura cross-coupling reactions of fluorinated sulfone derivatives as effective electrophiles (Scheme 31).C-SO 2 bonds were activated by introducing an

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EWG on the aryl ring of the sulfones under Pd-catalysis, leading to a diversity of multiple arylated products in satisfactory yields.
Pulipati and co-workers 145 proposed a vigorous approach for the synthesis of 4-aminoquinazoline biaryl compounds from arylboronic acids and quinazoline containing an unprotected NH 2 group (96) via Suzuki-Miyaura coupling reaction using Pd(dcpf)Cl 2 (Scheme 32).The synthesized compounds were also assessed for antimicrobial and antifungal biological activity.
Scheme 33 Pd-catalyzed ligand-free Heck reaction 146 Jadhav et al. 147 utilized a Pd(PPh 3 ) 4 /Et 3 N/H 2 O/98 °C catalyst system for the Mizoroki-Heck coupling reaction carried out in the absence of any additives under aerobic conditions with TOF of 12 to 14 h -1 in a very short reaction time.This procedure was applicable for a broad range of electrondonating and electron-withdrawing aryl chlorides and bromides.The Clavé research group 148 developed a bio-based plant-derived EcoPd from the roots of Eichhornia crassipes for the Suzuki cross-coupling of heteroaryl compounds for the synthesis of a broad range of heterocyclic-heterocyclic biaryl and heterocyclic biaryl compounds with a small amount of catalyst.The reaction promoted the Suzuki cross-coupling without ligands or additives.In 2018, Markovic et al. 149 described a Pd-catalyzed coupling reaction between heterocyclic sulfinates (101) and aryl or heteroaryl halides (102), affording high yields of the corresponding biaryls (103) (Scheme 34).Furthermore, the heterocyclic allylsulfones (104) can function as ideal sulfinate reagents and, when reacted with aryl halide, deallylation could be restricted, leading to efficient desulfinylative cross-coupling under palladium(0) catalysis (106) (Scheme 35).Additionally, the authors also prepared pharmaceutical agents etoricoxib and crizotinib using allyl heteroaryl sulfone coupling partners.

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Miyaura cross-couplings of functionalized reaction partners in either water containing nano micelles or uncommon solvent EtOAc.This catalytic system was very effective even at low amounts of 0.05-0.5 mol%.The high rate of reaction was further improved when the reaction was performed in aqueous micellar media instead EtOAc.

Figure 14
Biaryl phosphine-containing ligand (EvanPhos) 151 In 2019, Gong and co-workers 152 developed an Ullmann biaryl synthesis using Pd(OAc) 2 and N 2 H 4 •H 2 O as the reducing reagent for the coupling of both electron-deficient as well as electron-rich aryl or heteroaryl iodides 109 leading to a variety of biaryls 110 at room temperature in good to excellent yields.The in-situ generated palladium nanoparticles were found to be active catalysts.The advantages of this protocol were cheap reducing agent, cost-effectiveness, and no need for metal reductants (Scheme 36).
Inspired by advantages of heterogeneous catalysts such as high stability, easy separation from reaction mixture, and good recyclability over homogeneous catalysts Liu et al. 155 published the synthesis of three pyridine-functionalized N-heterocyclic carbene-Pd complexes (HCP-Pd) using a simple external cross-linking reaction.In each complex, Pd was immobilized on the hypercrosslinked polymer (HCP) via the formation of a six-membered ring by pyridine, bidentate ligands of NHC, and Pd 2+ .The newly synthesized catalysts were very effective for the coupling reaction in an aqueous medium under mild conditions.The microporous structure of the support ensured the high dispersion of palladium active sites.Of the three complexes, the recovery and reusability were easier for the HCP-Pd-I catalyst compared to the HCP-Pd-II and III catalysts.

C-N Cross-Coupling Reaction
In 2010, Fors and co-workers 158 disclosed an alternative approach to catalyst advancement, in which they prepared a multiligand-based Pd catalyst (Scheme 39).The designed catalyst was then allowed to catalyze C-N cross-coupling reactions.This catalytic system exhibited the same catalyst activity and substrate scope.

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Similar to the Fors report, another group led by Dooleweerdt et al. 159 also described a palladium catalyst based on biaryl phosphine ligands (120-124) (Figure 16) that allowed the coupling of amides and an array of aryl/heteroaryl mesylates (125) (electron-rich, -neutral, and -deficient) to afford the corresponding N-aryl amides 127 in high yields (Scheme 40).Benzamides and aliphatic and heterocyclic amides were also investigated as excellent coupling partners in this protocol.
Tambade et al. 161 disclosed a phosphine-free Pd(OAc) 2 catalyzed procedure for aminocarbonylation or carbonylative cross-coupling that enabled the coupling of a wide range of substituted aryl iodide with ortho-haloaniline to form ortho-haloanilide (131) in water, affording good yields (Scheme 42).Further, ortho-haloanilides 131 underwent cyclization for the synthesis of benzoxazoles 132 using Cu(acac) 2 catalyst.
In 2013, Zhang and co-workers 162 devised a Pd-catalyzed method for the cross-coupling of heteroaryl halides and electron-deficient heteroaromatic amines in the presence of Pd 2 (dba) 3 as a catalyst, 1,10-bis(diphenylphosphi-

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no)ferrocene (DPPF) as ligand, and Cs 2 CO 3 as a base (Scheme 43).This methodology allowed the coupling of several rarely reported electron-deficient heteroaromatic amines in good yields.
In 2014, Wagner et al. 163 described a versatile green catalytic system ([(cinnamyl)PdCl] 2 /t-BuXPhos) (123) for coupling of arylbromides or chlorides with a wide range of amines, carbamates, ureas, and amides under Buchwald-Hartwig cross-coupling reaction conditions in an aqueous micellar medium.The procedure was functional-group tolerant; for example, for esters and halides the reactions were carried out at 30-50 °C providing the target compounds in good to excellent yields (Scheme 44).Compared to the previously reported Takasago's catalyst system (cBRIDP ligand in combination with [(allyl)PdCl] 2 ), this catalytic system was found to be much more efficient for Buchwald-Hartwig reactions with benzamide derivatives or aliphatic primary amines.No racemization was experienced in this method when a substrate with a chiral center was used.In 2020, Fan et al. 164 described the development of a Pd-catalyzed decarbonylative C-N coupling under a nitrogen atmosphere (Scheme 45).

C-P Cross-Coupling Reaction
In 2013, Xu and co-workers 167 developed palladacyclecatalyzed phosphonation of aryl halides with diisopropyl H-phosphonate (144) using cyclopalladated ferrocenylimines 141-142 (Figure 17) with bulky phosphine ligands of X-Phos in water affording the phosphonated products 145 in excellent reaction yields (Scheme 46).The inactive electron-rich and electron-neutral aryl chlorides reacted well in this process.The weak base KF was enough for the activation of C-Cl bond instead of strong bases such as NaO t Bu or KO t Bu.

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The Hayashi group 168 achieved the syntheses of tertiary phosphine derivatives by Pd-catalyzed deformylative C-P cross-couplings of hydroxymethylphosphine derivatives 146 (Scheme 47).Triarylphosphine synthesis was also achieved by sequential triple couplings using this protocol.

Ni-Catalyzed Cross-Coupling Reactions
We will discuss in this section the use of nickel catalysis in various cross-coupling reactions and is generally presented in chronological order.

C-C Cross-Coupling Reaction
In 2011, the Taylor group 169 introduced deuterium-labeled alkylborane reagents 149, which were allowed to undergo nickel-catalyzed Suzuki cross-coupling reactions in the presence of diamine ligands 152 and 153 (Scheme 48), resulting in transmetalation from boron to nickel with retention of configuration.
In 2014, Liu et al. 170 disclosed a method for Ni-catalyzed cross-electrophile coupling of secondary alkyl bromides 154 with halogenated pyridines 155 using zinc as a reductant, yielding different alkyl-substituted pyridines 156 in moderate to excellent yields (Scheme 49).This report pro-vided a solution to the unreported instances in the previous literature on alkylation of halo-pyridines.
Tollefson's research group 171 reported the Ni-catalyzed ring-opening cross-couplings of O-heterocycles such as aryl-substituted tetrahydropyrans, tetrahydrofurans, and lactones to give acyclic alcohols and carboxylic acids (Scheme 50).This method paved the way for the stereochemical synthesis of acyclic polyketide analogs.The authors showed that Ni-catalyzed Kumada-type coupling of aryl-substituted tetrahydropyrans and tetrahydrofurans proceeded with a variety of Grignard reagents to provide acyclic alcohols with excellent diastereoselectivity (Scheme 51).
One year later, in 2015, the Tollefson research group 172 presented further research findings on the Ni-catalyzed Kumada, Negishi, and Suzuki cross-coupling reactions of benzylic ethers such as methyl ethers, tetrahydrofurans, tetrahydropyrans, esters, and lactones as one of the reaction

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partners (Scheme 52).Several Grignard reagents such as aryl, methyl, and n-alkyl Grignard reagents were engaged in Kumada coupling reactions.Specifically, with methylmagnesium iodide as coupling partner, the ligands DPEphos or rac-BINAP afforded the highest reaction yield and stereospecificity (Scheme 53).The functional group tolerance was described in Negishi cross-coupling reactions using dimethylzinc.Similarly, Suzuki reactions using arylboronic esters were also reported, with different stereochemical outcomes employing different achiral ligands giving opposite enantiomers of the product.Using N-heterocyclic carbene ligand (SIMes) in Suzuki reaction caused inversion in the product, and use of the electron-rich phosphine PCy 3 gave retention with stereospecificity (Scheme 54).Various pharmacophores units such as 1,1-diarylalkane and 2-arylalkane have been synthesized by using these cross-coupling reactions.
Dawson and Jarvo 173 published a similar kind of approach as previously described by the Tollefson group (in which they also have been the members), whereby they emphasized the development of stereospecific reactions for use in the field of pharmaceutical chemistry (Scheme 55).They reported a highly stereospecific gram-scale Kumada cross-coupling reaction with inversion at the benzylic position using a sustainable and inexpensive nickel catalyst.

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An unprecedented report was published by the Funicello research group 174 in which they carried out the Ni-catalyzed C-Br/C-H double phenylation of methyl 4-bromocrotonate (176) affording a useful bis-arylated synthon through a cross-coupling reaction (Scheme 56).

Scheme 56 Ni-catalyzed C-Br/C-H double phenylation 174
In 2019, Liao and co-workers 175 developed a catalytic system consisting of 2 mol% NiCl 2 (dppp) in PEG-400 for Suzuki-Miyaura coupling reaction at 100 °C using a base (i.e K 3 PO 4 ), providing a range of biaryls with high reaction yields (Scheme 57).The NiCl 2 (dppp)/PEG-400 catalytic system could be simply recycled and re-applied up to five times without significant loss of activity.The main advantages of this protocol lie in the fact that it avoids the use of toxic and easily volatile toluene or dioxane as solvent, and solves the critical problem of nickel catalyst reuse.

Scheme 57 Ni-catalyzed Suzuki-Miyaura coupling reaction 175 4 Cu-Catalyzed Cross-Coupling Reactions
We will discuss in this section the use of copper catalysis in various cross-coupling reactions and is generally presented in chronological order.

C-C Cross-Coupling Reactions
In 2010, Yalavarty and co-workers 176 found a new copper-catalyzed method of synthesizing podocarpic acid ether derivatives through the one-step cross-coupling reaction of methyl 13-iodo-O-methylpodocarpate (178) with alcohols in excellent yields (Scheme 58).Copper iodide was utilized as an inexpensive catalyst to achieve this transformation.
Scheme 58 Cu-catalyzed synthesis of podocarpic acid ether derivatives 176 In 2011, the Chen research group 177 established an efficient CuI/PPh 3 /PEG-H 2 O catalytic system for Sonogashira coupling of electron-deficient or electron-rich aryl iodides with terminal acetylenes in water-polyethylene glycol under microwave irradiation or reflux to provide good to excellent yields (Scheme 59).

Review SynOpen
Cu 2 O as a catalyst and 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) in the air with high reaction yields (Scheme 60).This methodology offers a possible approach through the generation of all-carbon quaternary centers at the C3 position of oxindoles with outstanding regioselectivity under mild conditions.Scheme 60 Cu-catalyzed tandem oxidative cross-couplings of oxindoles 178 In 2016, Sagadevan and co-workers 179 devised a novel visible-light-initiated Cu-catalyzed process for the crosscoupling reaction of terminal alkynes to furnish bio-active 1,3-unsymmetrical conjugated diynes at room temperature.This method did not require pre-functionalized substrates, ligands, bases, additives, or costly palladium/gold catalysts.
In 2017, Ali and co-workers 180 presented a Cu-catalyzed Sonogashira reaction of alkyl-2-iodobenzoates 183 with alkynes under solvent-, co-catalyst-, and base-free conditions providing coupling product yields up to 97% (Scheme 61).According to the authors, the reported compounds may act as anti-fobic and anti-cizmatic agents and also have the potential to control diseases such as Alzheimer's and schizophrenia.
Scheme 62 Visible-light-initiated Cu-catalyzed denitrogenative oxidative coupling 181 Xu and co-workers 182 prepared an environmentally friendly Cu/C 3 N 4 composite and examined it as a highly effective catalyst for the homo-and cross-coupling reaction of terminal alkynes affording symmetrical and unsymmetrical 1,3-diynes 187 in good yields (Scheme 63).The reaction was performed with oxygen as an oxidant in an isopropanol solution with excellent functional group tolerance under ambient conditions.Scheme 63 Cu/C 3 N 4 composite-catalyzed coupling of terminal alkynes 182 Liao et al. 183 found TEMPO/CuI to be an effective catalyst for the cross-coupling of benzylic amines 189 with indoles 188, generating the corresponding bis(indolyl)phenylmethanes 190 under air at room temperature in high yields (Scheme 64).

Scheme 64 TEMPO/CuI-catalyzed cross-coupling of benzylic amines with indoles 183
A mixed example of a Cu-catalyzed coupling reaction was described by Baig and co-workers, 184 who synthesized a versatile crystalline copper(II)-nicotinamide complex that

C-O Cross-Coupling Reaction
In 2012, Zhang and co-workers 185 developed the first example of a Cu-catalyzed coupling of nitroarenes with arylboronic acid, providing diaryl ethers 201 in moderate to excellent yields (Scheme 68).The reaction did not involve any ligand, and deuterium labeling in mechanistic studies showed that water was essential for this transformation.
Scheme 68 Cu-catalyzed coupling of nitroarenes with arylboronic acid 185 In 2017, Xiong and co-workers 186 described the first report on the Cu-catalyzed oxidative coupling reaction of carbon dioxide, amines, and arylboronic acids to synthesize various O-aryl carbamates 203 using BF 3 •OEt 2 (Scheme 69).A wide functional group tolerance could be seen in this transformation.
In 2019, a new method for the synthesis of bioactive 2substituted benzoxazoles 205 was developed by the Saranya research group 187 via Cu-catalyzed intramolecular C-O cross-coupling of 2-haloanilides 204 in moderate to good yields (Scheme 70).This transformation occurred by employing CuI (5 mol%)/2,2′-bipyridine (10 mol%) as a catalytic system, Cs 2 CO 3 (2 equiv) as base, and DMF solvent with 4 Å molecular sieves at 140 °C.The reaction was observed to be influenced by the amide and aromatic substituents of 2haloanilides.
Scheme 70 Cu-catalyzed intramolecular C-O cross-coupling reaction 187 Chen et al. 188 observed an unprecedented ligand-free Cu-catalyzed O-arylation of arenesulfonamides 206 with phenols generating a range of unsymmetric biaryl ethers 207 in excellent yields (Scheme 71).The reaction involved cleavage of C-S bond with excellent regioselectivity and good functional groups tolerance on phenols.

C-N Cross-Coupling Reaction
In 2010, the Li group 190 developed a simple Cu-catalyzed method for N-arylations of nitrogen-containing heterocycles and aliphatic amines in water as a solvent and (1E,2E)oxalaldehyde dioxime (211) as a ligand at 100 °C (Scheme 73).
In 2011, Liu and co-workers 191 described a microwavepromoted solvent-and ligand-free Cu-catalyzed amination of several halopyridines 210 with various nitrogen nucleophiles 213, giving corresponding N-heteroarylated products 214 in good yields (Scheme 74).
In 2012, Cao and co-workers 192 reported an efficient C-N cross-coupling reaction that allowed the coupling of imidazole (213) with aryl chlorides or bromides by employing an inexpensive catalytic system Cu(I)/HMTA, providing products in moderate to good yields.Moreover, the presence of electron-withdrawing or electron-donating groups in the aryl halides had no adverse effect on the outcome of the reaction (Scheme 75).
In 2015, Sagadevan and co-workers 193 reported a copper(I) chloride catalyzed green process for direct oxidative C sp -N coupling reactions of anilines and alkynes affording biologically important -ketoamides 217 under visiblelight irradiation at room temperature without the need for a base, ligands, or an external oxidant (Scheme 76).
In 2017, Wang et al. 194 established a new Cu-catalyzed ligand-free method for Ullmann-type N-arylation of N-containing heterocycles 213 with aryl 48 or heteroaryl bromides or iodides without the protection of an inert gas, affording the desired products with high reaction yields (Scheme 77).In 2021, Bai et al. 195 reported a simple strategy for the C-N cross-coupling of indazole with a modification of substituted aryl bromides under ligand-free conditions.

C-P Cross-Coupling Reaction
In 2016, the first attractive synthetic tool was provided by the Chen research group 196 for the synthesis of valuable alkynylphosphonates 220, which involved Cu-catalyzed decarboxylative coupling of various arylpropiolic acids 218 with readily available dialkyl hydrazinylphosphonates 219 giving up to 90% yield (Scheme 78).

C-Se Cross-Coupling Reaction
In 2012, Ricordi and co-workers 197 described the Cu-catalyzed cross-coupling reaction of diaryl diselenides 221 including arylboronic acids with CuI and DMSO as additive and glycerol as a recyclable solvent, affording the corresponding diaryl selenides 222 in high reaction yields (Scheme 79).The reaction was performed under an open atmosphere at 110 °C.

C-S Cross-Coupling Reaction
In 2013, Yang et al. 198 demonstrated a Cu-catalyzed aerobic cross-dehydrogenative coupling reaction for the synthesis of alkynyl sulfides 224 from terminal alkynes with thiols using K 2 CO 3 and molecular O 2 as the oxidant under mild reaction conditions (Scheme 80).
Scheme 80 Cu-catalyzed aerobic cross-dehydrogenative coupling 198 In 2014, Shen and co-workers 199 utilized chitosan@copper as a recoverable catalyst for the synthesis of aryl sulfones 226 from aryl halide and sodium sulfinates through cross-coupling reactions with high reaction yields (Scheme 81).Interestingly, the antiulcer drug zolimidine (231) could easily be synthesized by employing this protocol (Scheme 82).
Chen et al. 201 presented a novel Cu(I)-catalyzed method for the cross-coupling of 2-nitro benzenesulfonamides (234) with thiols generating unsymmetrical sulfides (235)  in high to excellent yields by using CuI in DMF as solvent at 100 °C (Scheme 84).This method offered 234 as a new coupling partner for the first time and occurred through cleavage of the Ar-SO 2 NH 2 bond without cleavage of the C-NO 2 bond.
In 2019, Ghodsinia and co-workers 202 synthesized a recyclable heterogeneous SBA-16/GPTMS-TSC-CuI catalytic system in which CuI was anchored onto a mesoporous material (SBA-16) functionalized by aminated 3-glycidyloxypropyltrimethoxysilane (GPTMS) with thiosemicarbazide (TSC).This novel mesostructured catalyst was investigated for the C-S coupling products of aryl halides with S8/thiourea under solvent-free conditions in high reaction yields (Scheme 85).The reaction was performed in notably reduced reaction times in comparison to the earlier reports.

Review SynOpen 5 Fe-Catalyzed Reactions
We will discuss in this section the use of iron catalysis in various cross-coupling reactions and is generally presented in chronological order.

C-C Cross-Coupling Reaction
In 2009, Colacino and co-workers 204 developed Fe-catalyzed cross-coupling reaction of 4-chloropyrrolo [3,2c]quinoline (240) with aryl or alkyl magnesium halides in the presence of Fe(acac) 3 (Scheme 87).The reaction was performed in a mixture of THF and NMP in just 30 min.The coupled products are useful scaffolds for medicinal chemistry and were obtained moderate to excellent yields of 52-94%.
In 2012, Liu et al. 205 discovered a Fe-catalyzed arylation of benzoazoles 243 with aromatic aldehydes with oxygen as an oxidant in good to excellent yields under base-free conditions (Scheme 88).The reaction was achieved by using a mixture of water/diglyme instead of organic solvents and better yields were obtained when benzothiazoles were employed as substrates.
Scheme 92 Fe-catalyzed cross-coupling of aryl sulfamates or tosylates with alkyl Grignard reagents 208 Hajipour and co-workers 209 prepared heterogeneous Febased catalyst supported on acac-functionalized silica, which was employed as a catalyst in Mizoroki-Heck reaction of aryl iodides and olefins in poly(ethylene glycol) as a green solvent (Scheme 93).Interestingly, this protocol allowed selective coupling reaction of aryl iodides in the presence of bromides.The catalyst could be recovered well from the reaction mixture and recycled up to five times.
In 2017, Bisz and co-workers 210 reported that benign cyclic ureas (DMI, DMPU) are efficient and sustainable ligands instead of hazardous NMP in Fe-catalyzed alkylations of aryl chlorides or tosylates with alkyl Grignard reagents (Scheme 94 and Scheme 95).Moreover, this protocol allowed C(sp 2 )-C(sp 3 ) cross-coupling synthesis of a dual NK1/serotonin receptor antagonist.
In 2018, Crockett and co-workers 211 discovered a Fe-catalyzed cross-coupling reaction between alkyl halides and arylboronic esters by employing lithium amide bases coupled with Fe complexes containing deprotonated cyanobis(oxazoline) ligands (A-D) affording up to 89% yields of the coupled products (Scheme 96).Remarkably, the reaction required neither alkyllithium reagents for activation of the boronic ester nor magnesium additives.Moreover, the two-step synthesis of pharmaceutically important Cinacalcet (281) was shown by using this protocol (Scheme 97).

C-S Cross-Coupling Reaction
In their study In 2009, Wu and co-workers 212 developed a catalytic system that is greener and used reusable of Fe-Cl 3 •6H 2 O/cationic 2,2′-bipyridyl for the coupling of aryl iodides with thiols to make C-S bond in refluxed water under aerobic conditions (Scheme 98).

Review SynOpen 6 Co-Catalyzed Reactions
We will discuss in this section the use of cobalt catalysis in various cross-coupling reactions and is generally presented in chronological order.
In 2017, Duong and co-workers 213 described a Co-catalyzed Suzuki-Miyaura cross-coupling reaction of aryl halides and arylboronic esters by employing cobalt(II)/terpyridine catalyst and KOMe, generating the corresponding (hetero)biaryls in moderate to excellent yields (Scheme 99).This procedure tolerated the -electron-rich and -electron-deficient heteroaryl halides and electron-deficient aryl halides.

Transition-Metal Nanoparticle-Promoted Reactions
We will discuss in this section the use of nanoparticle catalysis in various cross-coupling reactions and is generally presented in chronological order.

Pd Nanoparticles
In 2009, Prastaro and co-workers 214 prepared a precatalyst consisting of Pd nanoparticles stabilized within the protein cavity of Dps protein (Pdnp/Te-Dps) (287) and tested its catalytic ability for Suzuki-Miyaura cross-coupling reactions under phosphine-free, aerobic conditions in water (Scheme 100).
Based on the well-known fact that bacteria can recover Pd(0) in the form of nanoparticles, Søbjerg and co-workers 215 decided to investigate the scope of the reactions that could be catalyzed by bio-recovered palladium.They demonstrated that the Mizoroki-Heck and Suzuki-Miyaura reactions were catalyzed by bio-Pd(0) nanoparticles set up

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on the surface of Gram-negative bacteria such as C. necator and P. putida.In 2011, Zhou and co-workers 216 synthesized a water-soluble ammonium-functionalized bidentate nitrogen-containing ligand (294) and its Pd chelating complex (295) and utilized this for Suzuki-Miyaura cross-coupling reaction in neat water under aerobic conditions (Scheme 101).
Khalafi-Nezhad and co-workers 217 published a report on the synthesis of a recyclable heterogeneous catalyst system in which they managed to immobilize Pd NPs on a silicastarch substrate (PNP-SSS) and found an effective catalyst in Heck and copper-free Sonogashira reactions with water as an eco-friendly solvent.The silica-starch substrate effectively stabilized and provided a platform to Pd NPs and prevented their aggregation and separation from the SSS surface.In 2012, Bej and co-workers 218 generated Pd nanoparticles in PEG that catalyzed the reaction of aryl/benzyl halides with bis(pinacolato)diboron to furnish aryl/benzyl boronates in high yield, which, in turn, were used as a reaction partner in the solvent-and ligand-free Suzuki-Miyaura coupling reaction with different aryl/benzyl halides in 53-72% yield (Scheme 102).
Cacchi and co-workers 219 made Pd nanoparticles stabilized by natural beads of an alginate/gellan mixture for the phosphine-and base-free Suzuki-Miyaura cross-coupling reaction of potassium aryltrifluoroborates and arenediazonium tetrafluoroborates in 1:1 molar ratio with catalyst loading of just 0.01-0.002mol% under aerobic conditions in water (Scheme 103, Scheme 104).
In 2014, Huang and co-workers 220 reported a synthetic procedure of Pd nanocomposite by depositing palladium nanoparticles in the micropores of the SBA-15 with hydrophobic triphenylsilyl or trimethylsilyl groups grafted on the mesopores.The authors then allowed ligand-free Hiyama cross-couplings of aryl halides and various aryltriethoxysilanes at 100 °C in air.Puthiaraja and co-workers 221 synthesized a novel nitrogen-rich functional mesoporous covalent organic polymer (MCOP), which offered excellent support for Pd nanoparticles (Pd@MCOP) by nucleophilic substitution reaction of cyanuric chloride (304) and 4,4′-dihydroxybiphenyl (305) (Scheme 105).
In 2015, Mandegani and co-workers 222 developed the synthesis of a novel nano tetraimine Pd(0) complex (310) with the complexation of Pd(OAc) 2 with N,N-bisimine li-

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gand (309) (Scheme 106).The catalytic efficiency of this heterogeneous nano-complex was investigated towards the Heck-Mizoroki reaction in water.The catalyst could be reusable and recycled without loss in catalytic activity.
In 2016, Gautam and co-workers 223 investigated the efficiency of PdNPs supported on fibrous nanosilica (KCC-1) towards carbonylative Suzuki-Miyaura cross-coupling reaction with a low Pd loading of 0.1% (Scheme 107).This KCC-1-PEI/Pd catalytic system displayed a TON 28-times and TOF 51-times bigger than already reported supported Pd catalyst in the literature for this reaction, probably owing to the fibrous nature of the KCC-1 support and because the PEI functionalization enhanced the stability.
Scheme 107 PdNPs/KCC-1 mediated carbonylative SM cross-coupling reaction 223 In 2019, Yamada and co-workers 224 investigated the effect of a co-existing metal in the ligand-free Suzuki-Miyaura coupling reaction of an aryl chloride under continuous irradiation microwave and a PdNPs catalyst (SGlPd), and established that the co-existing metal such as aluminum foil is involved in this reaction due to its microwave absorption ability in the reaction system.Mohazzab and co-workers 225 synthesized reusable mesh-GO/Pd catalyst by immobilization of Pd NPs on stainless-steel mesh.Dhara and co-workers 226 prepared glucose-stabilized palladium nanoparticles with recycling and reusing capability up to four times and explored its catalytic potential for both Suzuki and Heck reactions in aqueous medium supported by microwave irra-diation.This procedure allowed the coupling of various electron-rich and electron-deficient aryl halides in high reaction yields.
Blanco and co-workers 227 impregnated graphene acid (GA) with Pd(OAc) 2 yielding GA-Pd nanohybrids with a size ranging from 1 nm up to 9 nm and applied the material in the Suzuki-Miyaura cross-coupling reaction.

Cu Nanoparticles
In 2009, Jammi and co-workers 228 studied the catalytic behavior of CuO nanoparticles for C-S, C-O, and C-N bond formations through ligand-free cross-coupling reactions of different nucleophiles such as imidazoles, amides, amines, alcohols, thiols, and phenols with aryl halides by using a base (i.e., KOH, K 2 CO 3 , and Cs 2 CO 3 ) at moderate temperature to afford the cross-coupled products in high yield (Scheme 108, Scheme 109, and Scheme 110).

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Scheme 110 CuO nanoparticle-mediated C-S cross-coupling reaction 228 In 2013, Sun and co-workers 229 utilized supported copper NPs for the first time in Pd-, ligand-, and solvent-free coupling reactions of acyl chlorides with terminal alkynes to generate corresponding ynones in 12-98% yield (Scheme 111).
Scheme 111 CuNP-mediated Sonogashira cross-coupling of acyl chlorides 229 In 2017, a similar report for the synthesis of ynones via solvent-free Sonogashira reactions was disclosed by Wang and co-workers 230 by employing mesoporous phenol-formaldehyde resin-supported copper nanoparticles catalyst (Cu NPs@MP) having wide surface areas and narrow pore-size distributions.The catalyst was synthesized by the melt infiltration of copper nitrate hydrates and subsequent in-situ reduction of Cu(II) by template pyrolysis.This catalyst displayed higher catalytic efficiency than copper powder and mesoporous silica SBA-15-supported Cu NPs.

Miscellaneous Reactions
In 2010, Guo and co-workers 231 reported a ligand-free iron/copper co-catalyzed amination of aryl halides affording the corresponding products under microwave irradiation in good yields (Scheme 112).
In 2012, Vaddula and co-workers 232 discovered a magnetically recoverable heterogenized Pd catalyst (317) for the Heck-type arylation of alkenes with diaryliodonium salts in aqueous polyethylene glycol using ultrasonication within 1-5 min (Scheme 113).The protocol was equally well suited for unactivated alkenes such as styrene, allyl aland allyl acetate.
Scheme 113 Pd catalyst for the Heck-type arylation 232 In 2013, Al-Amin and co-workers 233 utilized sulfurmodified gold-supported palladium material (SAPd) and two categories of microwave approaches, single-and multimode in conjunction with Suzuki-Miyaura cross-coupling reactions.The catalyst had very low leaching properties.In 2017, Akiyama and co-workers 234 described novel sulfur modified gold-supported ruthenium nanoparticles (SARu) via a three-step process involving immobilization of ruthenium using Ru(acac) 3 and 4-methoxybenzyl alcohol as a reductant via in-situ metal nanoparticle and nano space organization without requiring any preformed template to immobilize and stabilize metal nanoparticles.The catalyst was evaluated for ligand-free Suzuki-Miyaura coupling of arylboronic acids and aryl halides including aryl chlorides with low Ru leaching.In 2013, Zolfigol and co-workers 235 prepared a stable magnetically divisible Pd nanocatalyst [Fe 3 O 4 @SiO 2 @PPh 2 @Pd(0)] and explored in Sonogashira cross-coupling reactions and O-arylation of phenols using NaOH as a base in water (Scheme 114).

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dides, aromatic halogenated ketones, or imines with various (hetero)arylmagnesium reagents by employing 3% of chromium(II) chloride at 25 °C (Scheme 115).This method produces lower amounts of homo-coupled products in comparison to the corresponding manganese, iron, or cobalt cross-couplings.
Scheme 115 Cr-catalyzed cross-couplings of N-heterocyclic halides 236 In 2014, Karimi and co-workers 237 prepared a novel magnetically recoverable Pd catalyst (Mag-IL-Pd) (328) by anchoring an imidazolium ionic liquid in front of triethylene glycol motifs on the surface of silica-coated iron oxide nanoparticles (Scheme 116).This nanocomposite exhibited notable activity for the Suzuki-Miyaura coupling reaction in water.The protocol allowed the coupling of challenging substrates such as heteroaryl/ortho-substituted aryl halides and aryl chlorides efficiently in excellent yields.
Baig and co-workers 238 synthesized a magnetically recoverable carbon-supported Pd catalyst (332) via in-situ generation of nano ferrites and of carbon from naturally abundant biopolymer cellulose via calcinations (Scheme 117).The catalytic efficiency of this catalyst was investigated for various reactions such as oxidation of alcohols, arylation of aryl halides, and amination reactions.
In 2016, Rathi and co-workers 239 prepared a nanocatalyst made up of ultra-small Pd/PdO nanoparticles supported on maghemite via co-precipitation using inexpensive raw materials and was employed efficiently in various cross-coupling reactions such as Suzuki and Heck-Mizoroki reaction and the allylic oxidation of alkenes.In 2017, Mohammadinezhad and co-workers 240 reported the synthesis of a heterogeneous magnetically separable core-shell-like Fe 3 O 4 @Boehmite-NH 2 -CoII NPs (342) of 13-54 nm size as an eco-friendly catalyst and explored its catalytic efficiency for the Suzuki and Heck cross-coupling reactions in water (Scheme 118).Moreover, the catalyst can be reused at least seven times without a significant and decrease in the catalytic activity.
In 2018, Kaur and co-workers 241 presented a green catalytic approach involving zero-valent Pd-Ni alloy NPs using microwaves as an energy source and ethanol/water as a solvent system.Metallosurfactants were synthesized that capped the Pd-Ni alloy NPs.The synthesized NPs exhibited catalytic efficiency for the Heck coupling reaction.The main attributes of the protocol include short reaction time, wide substrate scope, mild reaction conditions, avoiding the use of toxic organic solvents, and reusability of the catalyst.In 2019, Kazemnejadi and co-workers 242 prepared a magnetically recoverable, heterogeneous Fe 3 O 4 @SiO 2 @Im[Cl]Co(III)-melamine nanocomposite and investigated its efficiency for Sonogashira and Heck crosscoupling reactions.The coupling reaction was phosphine-, base-, and ligand-free, used ethanol as solvent and proceeded with high to excellent yields.

Review SynOpen 9 Perspectives and Future Directions
This review included information and examples of an impressive and appealing range of past and recent developments of the various approaches to transition-metal-catalyzed cross-coupling reactions such as Suzuki, Heck, Sonogashira, Stille, Kumada, Kochi, Murahashi, Corriu, Hiyama, and Negishi reactions, as well as decarboxylative, carbonylative, and -arylative, C-O, C-N, C-S bond-forming reactions for the synthesis of natural products and agrochemicals.The past more than 45 years have seen continuous growth in cross-coupling protocols, and plenty of new tools for cross-coupling have been reported by researchers.In the last twelve years especially, we have observed an explosive development of this chemistry.Modern synthetic organic chemistry has seen a marvelous advancement after the dawn of Pd and later by other transition metals (copper, iron, nickel, cobalt or Zr) catalyzed cross-coupling reactions for C-C and C-heteroatom bond formation.As reflected in this chapter, copper, in some cases, can replace the more traditional palladium systems because of some obvious rea-sons of being cheaper, readily available, and more efficient, using mild reaction conditions, offering high functional group tolerance, and involving less toxic oxygen or nitrogen ligands for selective C-O or C-N bond formation.Similarly, Ni has proved to be an amazingly versatile catalyst for such transformations in large-scale processes compared to the corresponding palladium catalysts, because of its lower cost, greater reactivity toward halocarbon electrophiles such as C-Cl and even inert C-F bonds, C-O-derived electrophiles such as less reactive mesylates and tosylates, phosphates, sulfamates, carbamates, phosphoramides, carbonates, certain esters, activated ethers, and phenols.Apart from the several interesting reports mentioned in this chapter, the field of cobalt and iron-catalyzed cross-coupling reactions is still immature.Since the renaissance of the field of iron-catalyzed cross-coupling in the early 2000s the metal has presented itself as a useful alternative to palladium-catalyzed cross-coupling reactions despite the significant challenges.Finally, it is expected that the recently developed early-transition-metal-catalyzed cross-coupling reactions will serve as an impetus for chemists to address