Palladium-catalyzed oxidative arene C–H alkenylation reactions involving olefins

Palladium-catalyzed oxidative arene C–H alkenylation reactions with alkenes has increased the toolbox of synthetic reactions for C–C bond formation to provide access to biologically relevant molecules and drugs in an efficient, atom-economical, and environmentally friendly way.The use of easily removable or transient directing groups and/or ligands allows control of the site selectivity to achieve selective functionalization of C(sp2)–H bonds at the ortho, meta, para, and even remote positions, also improving the reactivity.The intramolecular variant of these C–H alkenylation reactions can lead to the construction of a variety of heterocyclic systems via exo or endo processes.Ligand design is key to achieving enantioselective C–H alkenylation reactions to generate central, axial, and planar chirality. The palladium-catalyzed selective C–H alkenylation reaction has been established as a central synthetic transformation to enable the construction of carbon–carbon bonds in an efficient, atom-economical, and environmentally friendly way. It provides a powerful alternative to classical cross-coupling reactions for the construction of conjugated organic molecules, including late-stage functionalization. The knowledge of mechanisms, the use of different strategies to control site selectivity, and the development of efficient chiral catalysts for C–H alkenylation reactions have expanded the application of this tool for the synthesis of molecules of increased complexity. The palladium-catalyzed selective C–H alkenylation reaction has been established as a central synthetic transformation to enable the construction of carbon–carbon bonds in an efficient, atom-economical, and environmentally friendly way. It provides a powerful alternative to classical cross-coupling reactions for the construction of conjugated organic molecules, including late-stage functionalization. The knowledge of mechanisms, the use of different strategies to control site selectivity, and the development of efficient chiral catalysts for C–H alkenylation reactions have expanded the application of this tool for the synthesis of molecules of increased complexity. The Mizoroki–Heck reaction (see Glossary) [1.Molander G.A. Science of Synthesis: Cross Coupling and Heck-Type Reactions. Vol. 1–3. Thieme, 2013Google Scholar] is recognized as a fundamental transformation in organic synthesis due to its broad applicability for the formation of C(sp2)–C(sp2) bonds. However, it requires the preinstallation of a carbon–(pseudo)halide (C–X) bond in the substrate. Consequently, the oxidative variant of the Heck reaction, the Fujiwara–Moritani reaction, has recently gained much attention. This reaction, first described by Fujiwara and Moritani in the late 1960s [2.Fujiwara Y. et al.Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate.J. Am. Chem. Soc. 1969; 91: 7166-7169Crossref PubMed Scopus (468) Google Scholar], consists of the palladium-catalyzed alkenylation of C(sp2)–H bonds, and it can be efficiently employed for the synthesis of highly functionalized aromatic molecules (including late-stage functionalization) in an atom-economical way [3.Le Bras J. Muzart J. Intermolecular dehydrogenative Heck reactions.Chem. Rev. 2011; 111: 1170-1214Crossref PubMed Scopus (884) Google Scholar, 4.Kitamura T. Fujiwara Y. Dehydrogenative Heck-type reactions: the Fujiwara–Moritani reaction.in: Li C.-J. C-H to C-C bonds: Cross-Dehydrogenative-Coupling. RSC, 2015: 33-54Google Scholar, 5.Zhou L. Lu W. Towards ideal synthesis: alkenylation of aryl C–H bonds by a Fujiwara–Moritani reaction.Chem. Eur. J. 2014; 20: 634-642Crossref PubMed Scopus (191) Google Scholar, 6.Gensch T. et al.Mild metal-catalyzed C–H activation: examples and concepts.Chem. Soc. Rev. 2016; 45: 2900-2936Crossref PubMed Google Scholar, 7.Carral-Menoyo A. et al.Palladium-catalysed Heck-type alkenylation reactions in the synthesis of quinolines. Mechanistic insights and recent applications.Catal. Sci. Technol. 2020; 10: 5345-5361Crossref Google Scholar, 8.Ali W. et al.Recent development in transition metal-catalysed C–H olefination.Chem. Sci. 2021; 12: 2735-2759Crossref PubMed Google Scholar]. The oxidative coupling of an arene and an alkene takes place via palladium(II) catalysis (i.e., a C–C bond is formed starting from two inert C–H bonds), avoiding the need for prefunctionalization (Figure 1A ). The reaction proceeds through C–H activation of the aryl ring to form a σ-aryl-Pd(II) intermediate, which would coordinate to the olefin partner (Figure 1B). Subsequent 1,2-migratory insertion to the Pd(II)–aryl bond and β-hydride elimination would give the alkenylated arene. The generated Pd(II)–hydride is transformed into a Pd(0) species after reductive elimination, so an oxidant is required to recover the catalytically active Pd(II) species [2.Fujiwara Y. et al.Aromatic substitution of olefins. VI. Arylation of olefins with palladium(II) acetate.J. Am. Chem. Soc. 1969; 91: 7166-7169Crossref PubMed Scopus (468) Google Scholar]. Among the mechanisms proposed for the C–H metalation step, the most common pathways go through the transition states exemplified in Figure 1C for the metalation of benzylamines [9.Engle K.M. et al.Ligand-accelerated C−H activation reactions: evidence for a switch of mechanism.J. Am. Chem. Soc. 2010; 132: 14137-14151Crossref PubMed Scopus (365) Google Scholar]. The first mechanism involves the formation of an aryl–Pd(II) species through the electrophilic palladation of the arene [10.Ryabov A.D. et al.Kinetics and mechanism of ortho-palladation of ring-substituted N,N-dimethylbenzylamines.J. Chem. Soc. Dalton Trans. 1985; : 2629-2638Crossref Google Scholar], so the electronic properties of the arene play a fundamental role. The second mechanism [11.Davies D.L. et al.Computational study of the mechanism of cyclometalation by palladium acetate.J. Am. Chem. Soc. 2005; 127: 13754-13755Crossref PubMed Scopus (604) Google Scholar,12.Lapointe D. Fagnou K. Overview of the mechanistic work on the concerted metallation-deprotonation pathway.Chem. Lett. 2010; 39: 1118-1126Crossref Scopus (792) Google Scholar] consists of a proton abstraction via a concerted and intramolecular transfer of a hydrogen atom to a base: concerted metalation–deprotonation (CMD). Organic molecules possess a wide range of C–H bonds, which is what makes the Fujiwara–Moritani reaction a very attractive method for their functionalization. However, the main challenge is to achieve high site selectivity towards just a given C–H bond. Irrespective of the mechanism operating in the C–H activation process, three main strategies for the control of regioselectivity are utilized [13.Neufeldt S.R. Sanford M.S. Controlling site selectivity in palladium-catalyzed C–H bond functionalization.Acc. Chem. Res. 2012; 45: 936-946Crossref PubMed Scopus (1133) Google Scholar], involving substrate control and/or catalyst system control (Figure 1D). (i) Advantage can be taken of the electronic properties of the arene. Typically, a palladium(II) source is employed without the aid of directing groups and/or ligands. Usually, high loadings of the aryl coupling partner are required. When this strategy is operating, the alkenylation reaction is thought to occur through electrophilic palladation or acetate-mediated CMD (Figure 1Da). (ii) Functional groups (directing groups) that are able to coordinate to the Pd(II) center can be attached to the substrate, approaching it to a specific C–H site. In this strategy, palladation of the C–H bond usually takes place via acetate-mediated CMD (Figure 1Db). (iii) The last approach consists of the use of ligands to tune the properties of the Pd(II) catalyst. Pyridine-based ligands and mono-protected amino acids (MPAAs) are the ones most commonly used. When pyridine ligands are employed, the dehydrogenative coupling is usually proposed to proceed through a scenario similar to that described in Figure 1Da, although with higher catalytic efficiency (Figure 1Dc) [14.Zhang S. et al.Theoretical analysis of the mechanism of palladium(II) acetate-catalyzed oxidative Heck coupling of electron-deficient arenes with alkenes: effects of the pyridine-type ancillary ligand and origins of the meta-regioselectivity.J. Am. Chem. Soc. 2011; 133: 20218-20229Crossref PubMed Scopus (138) Google Scholar]. N-Acetyl amino acids would replace the acetate, the N-acetyl group being responsible for the proton abstraction (Figure 1Dd) [15.Yang Y.-F. et al.Experimental-computational synergy for selective Pd(II)-catalyzed C–H activation of aryl and alkyl groups.Acc. Chem. Res. 2017; 50: 2853-2860Crossref PubMed Scopus (148) Google Scholar]. Selected examples of the application of these strategies will be shown in the following sections. When the Fujiwara–Moritani reaction is carried out over simple arenes, a common proposal is that the C–H activation step takes place via electrophilic metalation. This can be formally considered as an aromatic electrophilic substitution, and thus may lead to mixtures of regioisomers. This issue can be overcome through the adjustment of the electronic properties of the arene by tuning its substituents, although achieving complete site selectivity may become a major challenge, depending on the substrate. Nevertheless, the CMD mechanism cannot be ruled out, since depending on the substitution pattern of the arene, both pathways would lead to similar (if not the same) regioselectivities. For example, when benzene derivatives were alkenylated with allyl amines, the regioselectivity completely depended on their electronic properties: electron-rich arenes led to ortho and para products predominantly, while electron-deficient arenes gave the meta product selectively (Figure 2A ) [16.Lei Y. et al.Palladium-catalyzed direct arylation of allylamines with simple arenes.ChemCatChem. 2015; 7: 1275-1279Crossref Scopus (14) Google Scholar]. By contrast, the para-selective palladium(II)-catalyzed alkenylation of tertiary anilines could be achieved by tuning free aniline concentration using AcOH as cosolvent (Figure 2B) [17.Moghaddam F.M. et al.Oxidative Heck reaction as a tool for para-selective olefination of aniline: a DFT supported mechanism.J. Org. Chem. 2017; 82: 10635-10640Crossref PubMed Scopus (16) Google Scholar]. Thus, the amine moiety did not act as a chelating/directing group to activate the ortho C–H site. Density functional theory (DFT) calculations support an electrophilic metalation process towards the para position of the arene. Positional control ruled by the electronic nature of the arene is a very common approach for heteroaromatic substrates since they possess very active C–H sites, as illustrated by the intermolecular Fujiwara–Moritani reaction of indoles [18.Petrini M. Regioselective direct C-alkenylation of indoles.Chem. Eur. J. 2017; 23: 16115-16151Crossref PubMed Scopus (77) Google Scholar]. C-3 alkenylation occurs due the more nucleophilic character of that site, as shown in an elegant synthesis of indolo[3,4-α]pyrrolo[3,4-c]carbazole-6,8-diones starting from indoles and maleimides [19.An Y.-L. et al.Palladium-catalyzed tandem regioselective oxidative coupling from indoles and maleimides: one-pot synthesis of indolopyrrolocarbazoles and related indolylmaleimides.Org. Lett. 2016; 18: 152-155Crossref PubMed Scopus (50) Google Scholar] (Figure 2Ca). The indole core is firstly palladated at C-3, and this is followed by alkenylation with the maleimide. The cascade reaction follows by palladation at C-2 and C–H arylation with another indole, and thermal cyclization releases the polycyclic compound (Figure 2Ca). A related procedure has been applied to the synthesis of carbazoles via regioselective triple successive oxidative Heck reactions, where the process also starts by regioselective C-3 alkenylation of indole (Figure 2Cb) [20.Verma A.K. et al.Palladium-catalyzed triple successive C–H functionalization: direct synthesis of functionalized carbazoles from indoles.Org. Lett. 2015; 17: 3658-3661Crossref PubMed Scopus (80) Google Scholar]. By contrast, the alkenylation of indole can be switched from C-3 to C-2 in the presence of acetic acid, which favors the migration of the C3–PdX bond to the highly activated 2-position of the iminium ion intermediate [21.Grimster N.P. et al.Palladium-catalyzed regioselective direct C-2 and C-3 functionalization of indoles.Angew. Chem. Int. Ed. 2005; 44: 3125-3129Crossref PubMed Scopus (566) Google Scholar]. Pyrroles have a limited application in the Fujiwara–Moritani reaction due to their instability in acidic and oxidative conditions, although examples involving the alkenylation of this privileged framework have been reported with C-2 versus C-5 regioselectivity control [22.Su Y. et al.Solvent-controlled C2/C5-regiodivergent alkenylation of pyrroles.Chem. Eur. J. 2015; 21: 15820-15825Crossref PubMed Scopus (25) Google Scholar]. C-4-alkenylated pyrroles could be selectively obtained without the use of directing groups or specific N-protecting groups. The reaction proceeded efficiently with a free NH or with electronically diverse N-substituents, using electron-deficient alkenes or styrenes as coupling partners (Figure 2Da) [23.Laha J.K. et al.Site-selective oxidative C4 alkenylation of (NH)-pyrroles bearing an electron-withdrawing C2 group.ChemCatChem. 2017; 9: 1092-1096Crossref Scopus (15) Google Scholar]. C-5-alkenylation of 2-acylpyrroles could also be accomplished (Figure 2Db) [24.Duan J.-H. et al.Regioselective C5 alkenylation of 2-acylpyrroles via Pd(II)-catalyzed C–H bond activation.Org. Chem. Front. 2018; 5: 162-165Crossref Google Scholar] using an N-protecting group. The metalation event takes place via electrophilic palladation, although the coordinating effect of the N-protecting group cannot be ignored. Related heterocycles – such as furans, thiophenes [25.Gao S. et al.Catalyst-controlled regiodivergent dehydrogenative Heck reaction of 4-arylthiophene/furan-3-carboxylates.Adv. Synth. Catal. 2016; 358: 4129-4135Crossref Scopus (19) Google Scholar], or even selenophenes [26.Chen S.-Y. et al.Pd(II)-catalyzed direct dehydrogenative mono- and diolefination of selenophenes.Org. Lett. 2020; 22: 2318-2322Crossref PubMed Scopus (8) Google Scholar] – have been regioselectively alkenylated at the C-2/C-5 position. The most common strategy to achieve site selectivity in the C–H bond activation step is the incorporation of directing groups to the substrate. Those motifs are σ-chelating groups with Lewis basic heteroatoms, which can coordinate to the Pd(II) center and bring it close to a specific C–H bond (usually ortho to the directing group) to form palladacycles [27.Tomberg A. et al.Relative strength of common directing groups in palladium-catalyzed aromatic C−H activation.iScience. 2019; 20: 373-391Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 28.Ma W. et al.Recent advances in positional-selective alkenylations: removable guidance for twofold C–H activation.Org. Chem. Front. 2017; 4: 1435Crossref Google Scholar, 29.Sambiagio C. et al.A comprehensive overview of directing groups applied in metal-catalysed C–H functionalization chemistry.Chem. Soc. Rev. 2018; 47: 6603-6743Crossref PubMed Google Scholar]. The major drawback of this strategy lies in the presence of an additional functionality in the final product. Therefore, the use of directing groups that can easily be removed once the reaction has taken place is utterly desirable [30.Carvalho R.L. et al.Removal and modification of directing groups used in metal-catalyzed C–H functionalization: the magical step of conversion into ‘conventional’ functional groups.Org. Biomol. Chem. 2021; 19: 525-547Crossref PubMed Google Scholar]. Amides are common directing groups in intermolecular Pd(II)-catalyzed alkenylation reactions [31.Jaiswal Y. Palladium-catalyzed regioselective C–H alkenylation of arylacetamides via distal weakly coordinating primary amides as directing groups.J. Org. Chem. 2018; 83: 1223-1231Crossref PubMed Scopus (26) Google Scholar]. It is even possible to use an acetamide as a transient directing group and traceless directing group. As shown in Figure 3A , an acetamide-directing group is generated in situ from the corresponding aniline, which undergoes ortho-olefination with acrylates. In the course of the reaction, the amide is hydrolyzed and subsequent cyclization affords quinolones in a one-pot procedure (Figure 3A) [32.Wu J. et al.Practical route to 2-quinolinones via a Pd-catalyzed C–H bond activation/C–C bond formation/cyclization cascade reaction.Org. Lett. 2015; 17: 222-225Crossref PubMed Scopus (72) Google Scholar]. Alternatively, the directing group may be further transformed and embedded in a more complex structure. Thus, a careful design of the reaction conditions may allow directing groups to undergo cascade reactions once the coupling with the olefin partner has occurred. This is illustrated in the synthesis of phenanthridines and carbazoles via Pd(II)-catalyzed C–H bond activation of biaryls with an iminoquinone as directing group and internal oxidant or co-oxidant [33.Raju S. et al.Palladium-catalyzed C–H bond activation by using iminoquinone as a directing group and an internal oxidant or a co-oxidant: production of dihydrophenanthridines, phenanthridines, and carbazoles.Org. Lett. 2017; 19: 4134-4137Crossref PubMed Scopus (26) Google Scholar]. The benzamide-directed olefination of 2-amidophenols with acrylates leads to 4-alkenyl benzoxazoles through acid-catalyzed condensation of the phenol and the amide director, once the alkenylative coupling has taken place (Figure 3B) [34.Panda N. Sahoo K. Synthesis of 4-alkenyl benzoxazoles via Pd-catalyzed ortho C−H functionalization of 2-amidophenols.Adv. Synth. Catal. 2019; 361: 617-627Crossref Scopus (11) Google Scholar]. Related reactivity can be accomplished using a carboxylate directing group [35.Nandi D. et al.One-step synthesis of isocoumarins and 3-benzylidenephthalides via ligandless Pd-catalyzed oxidative coupling of benzoic acids and vinylarenes.J. Org. Chem. 2013; 78: 3445-3451Crossref PubMed Scopus (89) Google Scholar], which may also be used as a traceless directing group. For instance, carboxylate-directed olefination of dearomatized benzoic acids with acrylates and styrenes provides the corresponding vinylarenes, followed by rearomatization upon decarboxylation (Figure 3C) [36.Tsai H.-C. et al.Rapid access to ortho-alkylated vinylarenes from aromatic acids by dearomatization and tandem decarboxylative C–H olefination/rearomatization.Org. Lett. 2018; 20: 1328-1332Crossref PubMed Scopus (19) Google Scholar]. A Pd/Ag bimetallic system is proposed to play a key role in the tandem decarboxylative C–H olefination process followed by rearomatization. Sulfonamide-based auxiliary groups have also been effectively used as directors for intermolecular Fujiwara–Moritani/cyclization cascade reactions. A representative example is the reaction between N-tosyl-2-aminobiphenyls and 1,3-dienes for the diastereoselective synthesis of dibenzo[b,d]azepines with two different stereogenic elements. In contrast to the reactions of alkenes, the transformation is proposed to proceed through migratory insertion of the aryl-Pd(II) species (formed after C–H palladation of the arene) to the diene, followed by reductive elimination of the intermediate palladacycle (Figure 3D) [37.Bai L. et al.Diastereoselective synthesis of dibenzo[b,d]azepines by Pd(II)-catalyzed [5 + 2] annulation of o-arylanilines with dienes.Org. Lett. 2017; 19: 1734-1737Crossref PubMed Scopus (36) Google Scholar]. A related cascade reaction between N-sulfonamidoarylcarboxamides and 1,3-dienes afforded 3,4-dihydroisoquinolones [38.Sun M. et al.Palladium-catalyzed [4+2] annulation of aryl and alkenyl carboxamides with 1,3-dienes via C–H functionalization: synthesis of 3,4-dihydroisoquinolones and 5,6-dihydropyridinones.Synthesis. 2020; 52: 1253-1265Crossref Scopus (14) Google Scholar]. Furthermore, the (2-pyridyl)sulfonyl framework stands out as a widely employed directing group. The versatility and usefulness of this moiety lies not only in its capability of efficiently coordinating the palladium center, but also in the fact that it can be easily removed and derivatized [39.García-Rubia A. et al.Palladium(II)-catalyzed regioselective direct C2 alkenylation of indoles and pyrroles assisted by the N-(2-pyridyl)sulfonyl protecting group.Angew. Chem. Int. Ed. 2009; 48: 6511-6515Crossref PubMed Scopus (308) Google Scholar,40.García-Rubia A. et al.PdII-catalysed C–H functionalisation of indoles and pyrroles assisted by the removable N-(2-pyridyl)sulfonyl group: C2-alkenylation and dehydrogenative homocoupling.Chem. Eur. J. 2010; 16: 9676-9685Crossref PubMed Scopus (166) Google Scholar]. This group was initially used in the intermolecular Fujiwara–Moritani reaction for the directed C-2 alkenylation of indoles with different olefin coupling partners. The methodology was also found to be effective for the mono- and di-alkenylation of the pyrrole nucleus (Figure 3Ea). This framework has also been utilized as the N-protecting/directing group for the alkenylation of simple arenes (Figure 3Eb,c) [41.García-Rubia A. et al.Pd(II)-catalyzed C–H olefination of N-(2-pyridyl)sulfonyl anilines and arylalkylamines.Angew. Chem. Int. Ed. 2011; 50: 10927-10931Crossref PubMed Scopus (124) Google Scholar, 42.García-Rubia A. et al.Pd-catalyzed directed ortho-C–H alkenylation of phenylalanine derivatives.J. Org. Chem. 2015; 80: 3321-3331Crossref PubMed Scopus (34) Google Scholar, 43.Legarda P.D. et al.Palladium-catalyzed remote ortho-C–H alkenylation of alkyl aryl sulfones: access to densely functionalized indane derivatives.Adv. Synth. Catal. 2016; 358: 1065-1072Crossref Scopus (18) Google Scholar]. Besides the examples shown in the previous sections, there are still problems associated with the control of regioselectivity. The control provided by the substrate leads in many cases to low regioselectivities (as not only electronic factors take part) and offers a narrow scope for the aromatic coupling partners. In the case of directing-group control, the problem is that not all the directors can be efficiently removed. Therefore, the development of ligands for the oxidative Heck reaction has been an important breakthrough, since they are able to improve the site selectivity and reactivity, sometimes in combination with directing groups [44.Engle K.M. Yu J.-Q. Developing ligands for palladium(II)-catalyzed C–H functionalization: intimate dialogue between ligand and substrate.J. Org. Chem. 2013; 78: 8927-8955Crossref PubMed Scopus (411) Google Scholar]. Among the ligands used nowadays, two classes stand out: pyridine-based ligands [45.Kubota A. et al.Pyridine ligands as promoters in PdII/0-catalyzed C–H olefination reactions.Org. Lett. 2012; 14: 1760-1763Crossref PubMed Scopus (137) Google Scholar] and mono-protected amino acids (MPAAs) [46.Shao Q. et al.From Pd(OAc)2 to chiral catalysts: the discovery and development of bifunctional mono-N-protected amino acid ligands for diverse C–H functionalization reactions.Acc. Chem. Res. 2020; 53: 833-851Crossref PubMed Scopus (155) Google Scholar], which can be used in both the nondirected (without directing groups) or directed (with directing groups) Fujiwara–Moritani reactions. Selected examples to illustrate both strategies will be disclosed. In the past decade, pyridine derivatives have been developed as ligands for the Pd(II) center to modulate reactivity and site selectivity in the olefination of different arenes without the aid of directing groups [45.Kubota A. et al.Pyridine ligands as promoters in PdII/0-catalyzed C–H olefination reactions.Org. Lett. 2012; 14: 1760-1763Crossref PubMed Scopus (137) Google Scholar]. Recently, the use of pyridone-based ligands for the nondirected site-selective Pd(II)-catalyzed C–H alkenylation of simple arenes and heteroarenes with electron-deficient alkenes [47.Chen X.-Y. et al.Synthesis of β-arylethenesulfonyl fluoride via Pd-catalyzed nondirected C−H alkenylation.Org. Lett. 2019; 21: 1426-1429Crossref PubMed Scopus (54) Google Scholar] – utilizing the aromatic substrate as the limiting reagent – led to the olefinated products in good yields. Less reactive electron-deficient arenes can also be olefinated, affording the meta-substituted products with moderate to good regioselectivities (Figure 4A ) [48.Wang P. et al.Ligand-accelerated non-directed C–H functionalization of arenes.Nature. 2017; 551: 489-493Crossref PubMed Scopus (198) Google Scholar]. In addition, the dual activation enabled by the combination of pyridine ligands and protected amino acid (N-acetyl-glycine) has allowed the efficient alkenylation of a wide variety of arenes [49.Chen H. et al.Dual ligand-enabled nondirected C–H olefination of arenes.Angew. Chem. Int. Ed. 2018; 57: 2497-2501Crossref PubMed Scopus (53) Google Scholar]. This is the most common scenario when ligand-aided Pd(II)-catalyzed alkenylations are carried out, and thus several ligands have been utilized combined with different directing groups. The ligand has to be carefully designed since it has to generate a pretransition state where the Pd(II) is coordinated to both the ligand and the substrate (Figure 4B). Therefore, a matched coordinative affinity of both the directing group and the ligand should be achieved, avoiding over-coordination of any of those components to the metal center [9.Engle K.M. et al.Ligand-accelerated C−H activation reactions: evidence for a switch of mechanism.J. Am. Chem. Soc. 2010; 132: 14137-14151Crossref PubMed Scopus (365) Google Scholar]. With these precepts in mind, a wide variety of MPAAs, which enhance the efficiency and the C–H activation step rate, have been developed [46.Shao Q. et al.From Pd(OAc)2 to chiral catalysts: the discovery and development of bifunctional mono-N-protected amino acid ligands for diverse C–H functionalization reactions.Acc. Chem. Res. 2020; 53: 833-851Crossref PubMed Scopus (155) Google Scholar,50.Engle K.M. The mechanism of palladium(II)-mediated C–H cleavage with mono-N-protected amino acid (MPAA) ligands: origins of rate acceleration.Pure Appl. Chem. 2016; 88: 119-138Crossref Scopus (53) Google Scholar]. Furthermore, those ligands could also affect the regioselectivity of the transformation. Thus, when the phenylacetic acid shown in Figure 4C was alkenylated using N-formyl-isoleucine (For-Ile-OH) as ligand, the olefination at the C–H bond ortho to the methoxyl group was highly favored, the reaction being unselective in the absence of the ligand [51.Wang D.-H. et al.Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C–H olefination.Science. 2010; 327: 315-319Crossref PubMed Scopus (628) Google Scholar]. The combination of a bidentate directing group in a benzyl phosphonamide with an MPAA has also allowed the use of unbiased unactivated alkenes in these olefination reactions, with a broad scope regarding both the arene and the aliphatic alkene [52.Seth K. et al.Incorporating unbiased, unactivated aliphatic alkenes in Pd(II)-catalyzed olefination of benzyl phosphamide.ACS Catal. 2017; 7: 7732-7736Crossref Scopus (30) Google Scholar]. Beyond the development of several ortho-selective functionalization reactions [29.Sambiagio C. et al.A comprehensive overview of directing groups applied in metal-catalysed C–H functionalization chemistry.Chem. Soc. Rev. 2018; 47: 6603-6743Crossref PubMed Google Scholar,50.Engle K.M. The mechanism of palladium(II)-mediated C–H cleavage with mono-N-protected amino acid (MPAA) ligands: origins of rate acceleration.Pure Appl. Chem. 2016; 88: 119-138Crossref Scopus (53) Google Scholar], directing groups have also been designed to allow selective meta- [53.Dutta U. Maiti D. Emergence of pyrimidine-based meta-directing group: journey from weak to strong coordination in diversifying meta-C−H functionalization.Acc. Chem. Res. 2022; 55: 354-372Crossref PubMed Scopus (7) Google Scholar] and para-alkenylations with the aid of MPAAs [54.Dey A. et al.Accessing remote meta- and para-C(sp2)–H bonds with covalently attached directing groups.Angew. Chem. Int. Ed. 2019; 58: 10820-10843Crossref PubMed Scopus (201) Google Scholar]. Selected examples are shown in Figure 4D (Figure 4Da [55.Xu J. et al.Sequential functionalization of meta-C−H and ipso-C−O bonds of phenols.J. Am. Chem. Soc. 2019; 141: 1903-1907Crossref PubMed Scopus (51) Google Scholar], b [56.Bag S. et al.Template-assisted meta-C−H alkylation and alkenylation of arenes.Angew. Chem. Int. Ed. 2017; 56: 3182-3186Crossref PubMed Scopus (76) Google Scholar], and c [57.Dutta U. et al.Catalytic arene meta-C–H functionalization exploiting a quinoline-based template.ACS Catal. 2017; 7: 3162-3168Crossref Scopus (62) Google Scholar]) and Figure 4E [58.Bag S. et al.Remote para-C–H functionalization of arenes by a D-shaped biphenyl template-based assembly.J. Am. Chem. Soc. 2015; 137: 11888-11891Crossref PubMed Scopus (229) Google Scholar,59.Patra T. et al.Palladium-catalyzed directed para C–H functionalization of phenols.Angew. Chem. Int. Ed. 2016; 55: 7751-7755Crossref PubMed Scopus (141) Google Scholar]. Remote functionalization on various heterocyclic systems has also been achieved using related templates [60.Yang G. et al.Remote C–H activation of various N-heterocycles using a single template.Chem. Eur. J. 2018; 24: 3434-3438Crossref PubMed Scopus (27) Google Scholar]. Although these templates provide an effective method for the functionalization of distal C–H bonds, the main drawback is that they are covalently bonded to the substrate, meaning that a specific functional group is required to anchor those directing groups to the starting molecule. With the aim of overriding this disadvantage, the design of a bifunctional template capable of directing the meta-C–H functionalization through a reversible coor