Modern strategies for C–H functionalization of heteroarenes with alternative coupling partners

The abundance of the heteroaryl structural motif in drugs, in natural products, and in material science has made the strategy of C–H functionalization of heteroarenes a priority of synthetic chemists. Compared with the widely used organic halides (I, Br, and Cl) as coupling partners, the cleavage of less reactive C–Het (F, O, S, N, and P) and C–C bonds in C–H functionalization of heteroarenes allows to construct complex molecules from simple, readily available feedstocks. This review article broadly describes strategies for C–H functionalization of heteroarenes with these alternative coupling partners emerging over the last decade. Selected examples of this approach include (1) heteroarylation of C–F bonds, (2) heteroarylation of C–O bonds, (3) heteroarylation of C–S bonds, (4) heteroarylation of C–N bonds, (5) heteroarylation of C–P bonds, and (6) heteroarylation of C–C bonds. Heteroarenes containing oxygen, nitrogen, and/or sulfur are important in numerous aspects of chemistry and everyday life. C–H functionalization of heteroarenes represents the fastest and most atom-economical approach for the synthesis of complex molecules. This strategy avoids the requirement of de novo synthesis and is beneficial for the late-stage modification of structurally complex molecules. Although early protocols for C–H functionalization using organic halides (I, Br, and Cl) as coupling partners remain in active use today, a range of modern strategies allows the cleavage of less reactive C–Het (F, O, S, N, and P) and C–C bonds to form essential links to the feedstock chemicals, highlighting their renewable and sustainable features. This review focuses on modern strategies for the C–H functionalization of heteroarenes with these alternative coupling partners. Most of the transformations can be achieved through catalytic processes. Some non-catalytic strategies involving new reagents and techniques are also introduced. Heteroarenes containing oxygen, nitrogen, and/or sulfur are important in numerous aspects of chemistry and everyday life. C–H functionalization of heteroarenes represents the fastest and most atom-economical approach for the synthesis of complex molecules. This strategy avoids the requirement of de novo synthesis and is beneficial for the late-stage modification of structurally complex molecules. Although early protocols for C–H functionalization using organic halides (I, Br, and Cl) as coupling partners remain in active use today, a range of modern strategies allows the cleavage of less reactive C–Het (F, O, S, N, and P) and C–C bonds to form essential links to the feedstock chemicals, highlighting their renewable and sustainable features. This review focuses on modern strategies for the C–H functionalization of heteroarenes with these alternative coupling partners. Most of the transformations can be achieved through catalytic processes. Some non-catalytic strategies involving new reagents and techniques are also introduced. Heteroaromatics are important components of pharmaceuticals and play vital roles in pharmacological function.1Trent J.O. Clark G.R. Kumar A. Wilson W.D. Boykin D.W. Hall J.E. Tidwell R.R. Blagburn B.L. Neidle S. Targeting the minor groove of DNA: crystal structures of two complexes between furan derivatives of berenil and the DNA dodecamer d(CGCGAATTCGCG)2.J. Med. Chem. 1996; 39: 4554-4562Crossref PubMed Scopus (0) Google Scholar, 2Wong H.N.C. Regiospecific synthesis of polysubstituted furans and their application in organic synthesis.Pure Appl. Chem. 2009; 68: 335-344Crossref Scopus (29) Google Scholar, 3Hiroya K. Suzuki N. Yasuhara A. Egawa Y. Kasano A. Sakamoto T. Total syntheses of three natural products, vignafuran, 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzofuran-3-carboxylic acid methyl ester, and coumestrol from a common starting material.J. Chem. Soc. Perkin Trans. 2000; 1: 4339-4346Crossref Scopus (90) Google Scholar, 4Joule J.A. Mills K. Heterocyclic Chemistry. Wiley, 2000Google Scholar The virtual exploratory heterocyclic library (VEHICLe) is a complete set of heteroaromatic ring systems. Of the 2,461 drug molecules extracted from the MDL drug data report (MDDR) (Symyx Technologies), there were over 1,000 occurrences of VEHICLe rings. The FDA orange book has arranged the top 10 heteroaromatic rings shown in Figure 1 from small molecule drugs in descending frequency. Therefore, the development of efficient strategies for the atom-economical, streamlined synthesis of these molecules is of commercial value. Many well-known classical methods are now available by de novo construction, but changing the substituent groups used in these methods typically needs considerable synthetic effort. Over the past decade, atom- and step-economical C–H functionalization strategies have attracted the attention of many research groups in both academic and industrial sectors. 5Dalton T. Faber T. Glorius F. C–H activation: toward sustainability and applications.ACS Cent. Sci. 2021; 7: 245-261Crossref PubMed Scopus (0) Google Scholar Reflecting the ubiquity of heteroarenes, strategies that enable late-stage modification of these molecules by directed functionalization of their C–H bonds have become highly desirable. Significant progress has been made in the C–H functionalization of heteroarenes, typically involving four types of coupling partners (Figure 2). The most common method involves the reaction of organic halides (I, Br, and Cl) with an extensive choice of heteroarenes in the presence of a transition metal (TM) (path I).6Alberico D. Scott M.E. Lautens M. Aryl−aryl bond formation by transition-metal-catalyzed direct arylation.Chem. Rev. 2007; 107: 174-238Crossref PubMed Scopus (3201) Google Scholar,7McGlacken G.P. Bateman L.M. Recent advances in aryl–aryl bond formation by direct arylation.Chem. Soc. Rev. 2009; 38: 2447-2464Crossref PubMed Scopus (786) Google Scholar Heteroaromatic C–H bonds can be transformed into C (heteroaryl)-C (aryl) bonds with a range of organometallic reagents (Mg, Zn, B, Si, Sn, etc.) (path II). Although high conversions and selectivities can be obtained by these methods, the substrates should be preprepared from sustainable chemical feedstocks. The direct method for C–H functionalization of heteroarenes through cleavage of the less reactive chemical bonds has also reached impressive levels of sophistication and efficiency during the past decade. Among them, oxidative C–H/C–H coupling reactions to build C-heteroaryl bonds have been widely studied and summarized (path III).8Yang Y. Lan J. You J. Oxidative C−H/C−H coupling reactions between two (hetero)arenes.Chem. Rev. 2017; 117: 8787-8863Crossref PubMed Scopus (0) Google Scholar Due to the ubiquitous C–Het (F, O, S, N, and P) and C–C bonds in organic compounds, modern strategies based on the activation of these chemical bonds for the C–H functionalization of heteroarenes have become highly desirable (path IV). Such coupling partners are classified as alternatives in this review. Although substantial evolution has been achieved in this area, a systematic review on the C–H functionalization of heteroarenes with these alternative coupling partners has not yet been conducted. The goal of this review is to support researchers regarding key areas of modern strategies that have been developed for the direct C–H functionalization of heteroarenes over cleavage of unreactive chemical bonds. Such transformations pose challenges ostensibly due to the high energetic cost of breaking these chemical bonds and the deactivation of metal catalysts in the presence of strong coordination heteroatoms. Two general strategies have been employed to overcome these difficulties: catalyst activation and substrate activation (Figure 3). Catalyst activation involves the development of more reactive catalytic systems. For example, the unique properties of nickel catalysts facilitate the activation of these inert C–Het and C–C bonds to couple with heteroarenes. The substrate activation approach introduces directing groups or reagents to overcome the inherent stability of unreactive chemical bonds. Typically, these two strategies can be used together, enabling high selectivity and functional group tolerance in the direct C–H functionalization of heteroarenes with milder reaction conditions. The well-known approach for substrate activation via the preformation of aryl sulfonates (e.g., OTf and OTs) using phenols shows comparable reactivities with the corresponding aryl halides, which will not be defined in detail with the exception of noting that they are closely associated. Based on understanding from the seminal works, the reaction pathways for cleavage of these chemical bonds mainly include oxidative addition with TM catalysts, TM-catalyzed β-X elimination, and radical-induced processes. The C–H bond cleavage events in heteroarenes mainly involves C–H metalation and functionalization and Minisci-type reactions.9Proctor R.S.J. Phipps R.J. Recent advances in Minisci-type reactions.Angew. Chem. Int. Ed. Engl. 2019; 58: 13666-13699Crossref PubMed Scopus (189) Google Scholar These reactions can be achieved using a variety of transition-metal catalysts and some organocatalysts in the photoredox process. Some non-catalytic modern strategies using new reagents and techniques are also introduced in this article. This topic is categorized as follows: (1) heteroarylation of C–F bonds, (2) heteroarylation of C–O bonds, (3) heteroarylation of C–S bonds, (4) heteroarylation of C–N bonds, (5) heteroarylation of C–P bonds, and (6) heteroarylation of C–C bonds. Moreover, the discovery and development of the reactions, the limitations and scopes of these approaches, and the mechanistic pathways are highlighted. Due to the exceptional chemical and biological properties of fluorinated organic compounds, they are considered as important motifs in pharmaceuticals and agrochemistry.10Kirsch P. Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applications. Wiley-VCH Press, 2004Crossref Scopus (138) Google Scholar Organofluorine chemistry has rapidly developed in modern years, since the demand for these compounds has promptly increased. Conventional approaches for the synthesis of fluorinated compounds predominantly focus on the formation of new C–F bonds. Recently, increased attention toward facile access to complex fluorinated compounds has turned to selective C–F bond cleavage of poly- or perfluorinated molecules. Functionalization of C–F bonds typically involves coupling polyfluorinated arenes with aryl nucleophiles such as Grignard reagents, zinc, boronic acids, or tin reagents. Some elegant catalytic manifolds have been developed for the C–H functionalization of heteroarenes via the selective cleavage of C–F bonds in fluoroarenes and fluoroalkenes. In these reactions, C–F bond cleavage primarily occurs through oxidative addition of C–F bonds in the presence of TM catalysts, radical-induced defluorination, and β-F elimination. Seminal work by Lu and Shen in 2013 described the palladium-catalyzed cross-coupling of polyfluoroarenes and benzoxazoles via sequential C–F/C–H activation for the first time (Scheme 1A).11Yu D. Lu L. Shen Q. Palladium-catalyzed coupling of polyfluorinated arenes with heteroarenes via C–F/C–H activation.Org. Lett. 2013; 15: 940-943Crossref PubMed Scopus (48) Google Scholar The installation of a 2-pyridinyl substituent in substrates as a directing group to assist palladium-catalyzed selective C–F bond activation is the key to this accomplishment. The reaction proceeds at first, and Pd(0) species undergo oxidative addition to the C–F bond of fluoroarene 1 to afford cyclometalated intermediate 4. Further C–H activation of heteroarene 2 with the assistance of LiOtBu, and transmetalation to provide intermediate 5, affords the final product 3 through reductive elimination with regeneration of Pd(0) species for the next catalytic cycle. Later work by Bai, Lan, and Zhang extended the scope of C–F bond functionalization of inactivated aryl fluorides with oxazoles as coupling partners under nickel catalysis (Scheme 1B).12Yin Y. Yue X. Zhong Q. Jiang H. Bai R. Lan Y. Zhang H. Ni-catalyzed C–F bond functionalization of unactivated aryl fluorides and corresponding coupling with oxazoles.Adv. Synth. Catal. 2018; 360: 1639-1643Crossref Scopus (0) Google Scholar In the absence of a directing group, the nickel (0) species can undergo oxidative addition to fluoroarene, accordingly promoting the subsequent heteroarylation. The emerging field of photochemistry has offered new possibilities for the functionalization of C–F bonds under mild conditions. In 2016, Weaver and coworkers reported an efficient approach for defluorinative heteroarylation of polyfluoroarenes 6 with heteroarenes 7 using an Ir-photocatalyst, blue light, and an amine (Scheme 2).13Senaweera S. Weaver J.D. Dual C−F, C−H functionalization via photocatalysis: access to multifluorinated biaryls.J. Am. Chem. Soc. 2016; 138: 2520-2523Crossref PubMed Scopus (80) Google Scholar Both N-containing heterocycles and electron-rich arenes could be functionalized in this reaction, showing unconventional Minisci selectivity. From a mechanistic perspective, an electron adds to the low-lying LUMO of the perfluoroarene, resulting in an unstable radical anion 9, which undergoes fluoride extrusion to generate perfluoroaryl radical 10. Subsequent addition of radical 10 to the π systems of 7 results in radical species 11. Final oxidation and rearomatization through either SET (12) or deprotonation (12′) provides coupling products 8. In this transformation, only polyfluorinated arenes could be employed in C–F functionalization because the LUMO (π∗ orbital) decreases in energy as the degree of fluorination increases; yet, the rate of C–F bonds fragmentation increases.14Arora A. Weaver J.D. Visible light photocatalysis for the generation and use of reactive azolyl and polyfluoroaryl intermediates.Acc. Chem. Res. 2016; 49: 2273-2283Crossref PubMed Scopus (65) Google Scholar Fluoroalkenes are considered as advantaged structural motifs and have been extensively found in pharmaceutical chemistry.15Landelle G. Bergeron M. Turcotte-Savard M.O. Paquin J.F. Synthetic approaches to monofluoroalkenes.Chem. Soc. Rev. 2011; 40: 2867-2908Crossref PubMed Scopus (188) Google Scholar,16Jakobsche C.E. Peris G. Miller S.J. Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues.Angew. Chem. Int. Ed. Engl. 2008; 47: 6707-6711Crossref PubMed Scopus (107) Google Scholar In 2015, Loh and Feng first described an Rh-catalyzed vinylic C–F bond heteroarylation of gem-difluoroalkenes 13 in which substrates 14, including indoles and pyrroles with N-directing groups, were used as coupling partners (Scheme 3A).17Tian P. Feng C. Loh T.P. Rhodium-catalysed C(sp2)-C(sp2) bond formation via C-H/C-F activation.Nat. Commun. 2015; 6: 7472Crossref PubMed Scopus (0) Google Scholar Treatment of easily prepared aryl- and alkyl-substituted gem-difluoroalkenes as electrophiles with heteroarenes, delivers a highly efficient and operationally simple introduction of α-fluoroalkenyl motifs onto the heteroarenes to access product 15 under oxidant-free conditions. Mechanistic studies revealed that rhodium-catalyzed β-F elimination was a key step during the transformation. Due to the requirement of rhodium catalysts, the improvement of earth-abundant metal catalysts for the earlier mentioned transformations is highly desirable. The following year, a related cobalt-catalyzed defluorinative functionalization was uncovered by the Li group in which a series of Z-alkenyl fluorides were produced under mild and redox-neutral conditions (Scheme 3B).18Kong L. Zhou X. Li X. Cobalt(III)-catalyzed regio- and stereoselective α-fluoroalkenylation of arenes with gem-difluorostyrenes.Org. Lett. 2016; 18: 6320-6323Crossref PubMed Scopus (87) Google Scholar In 2017, Loh and Feng also found that manganese catalysts could also be used in this C–F/C–H coupling reaction (Scheme 3C).19Cai S.H. Ye L. Wang D.X. Wang Y.Q. Lai L.J. Zhu C. Feng C. Loh T.P. Manganese-catalyzed synthesis of monofluoroalkenes via C–H activation and C–F cleavage.Chem. Commun. (Camb). 2017; 53: 8731-8734Crossref PubMed Google Scholar Interestingly, this strategy has emerged for the synthesis of monofluoroalkenes with predominant unusual E-selectivity, which serves as complement to the existing protocols to access these molecular architectures. In addition to vinylic C–F bond heteroarylation, the functionalization of allylic C–F bonds was also realized. In 2017, the Ackermann group showed manganese(I)-catalyzed allylic C–F heteroarylation between a variety of perfluoroalkenes and (hetero)arenes bearing pyridyl groups (Scheme 4).20Zell D. Dhawa U. Müller V. Bursch M. Grimme S. Ackermann L. C−F/C−H functionalization by manganese(I) catalysis: expedient (per) fluoro-allylations and alkenylations.ACS Catal. 2017; 7: 4209-4213Crossref Scopus (0) Google Scholar The scope of the reaction is very high with respect to both coupling partners, and a variety of indoles and pyrroles can undergo C–H perfluoroalkenylation. Notably, high positional-, diastereo-, and chemoselectivities were observed in (per)fluoro alkenylation and allylation reactions. Complete computational and experimental studies were conducted to investigate the mechanism in which β-F elimination was a key step. Meanwhile, the same group further explored the use of cobalt salts as catalysts for similar transformations under mild reaction conditions.21Zell D. Müller V. Dhawa U. Bursch M. Presa R.R. Grimme S. Ackermann L. Mild cobalt(III)-catalyzed allylative C-F/C-H functionalizations at room temperature.Chemistry. 2017; 23: 12145-12148Crossref PubMed Scopus (0) Google Scholar Phenol and alcohol derivatives are important starting materials used to construct numerous value-added chemicals, such as pharmaceuticals and resins. To explore new reactivities and efficient transformations, many synthetic chemists have been engaged and have devoted enormous effort for the functionalization of C–O bonds in recent decades.22Su B. Cao Z.C. Shi Z.J. Exploration of earth-abundant transition metals (Fe, Co, and Ni) as catalysts in unreactive chemical bond activations.Acc. Chem. Res. 2015; 48: 886-896Crossref PubMed Scopus (452) Google Scholar Although the replacement of aryl halides with phenols may lead to more cost-effective and environmental-friendly methods, initial studies are limited to using activated phenols such as triflates and tosylates for cross-coupling reactions under transition-metal catalysis. Recently, aryl ethers and carboxylates were employed for cross-coupling reactions by C–O bond activation, which has attracted significant attention in organic synthesis. In the field of aliphatic C–O bonds, some elegant approaches have been established for the direct heteroarylation of alcohols by the SET process instead of the traditional Friedel-Crafts-type alkylation of alcohols with aromatic rings with the requirement of some Lewis acids. From this perspective, C–O/C–H coupling reactions have delivered new synthetic routes toward heteroarylation products. Based on the diverse class of substrates, this topic can be classified into heteroarylation of aromatic C–O bonds (phenol esters and ethers), vinylic C–O bonds (enol derivatives), allylic C–O bonds (allylic alcohols and derivatives), and aliphatic C–O bonds (alcohols and oxalate salts). The cleavage of C–O in this transformation proceeds through the oxidative addition of C–O bonds in the presence of TM catalysts, nucleophilic aromatic substitution, β-O elimination, and radical-induced deoxygenation. Wenkert and coworkers first reported a nickel-catalyzed cross-coupling of aryl ethers with the Grignard reagent via C–O bond cleavage in 1979.23Wenkert E. Michelotti E.L. Swindell C.S. Nickel-induced conversion of carbon-oxygen into carbon−carbon bonds. One-step transformations of enol ethers into olefins and aryl ethers into biaryls.J. Am. Chem. Soc. 1979; 101: 2246-2247Crossref Scopus (315) Google Scholar The nickel catalyst was found to be a superior catalyst for activating inert C(aryl)-O bonds. In 2012, Itami and coworkers reported pioneering work on C–O/C–H coupling between phenol derivatives 16 and azoles 17 under Ni-catalysis (Scheme 5A).24Muto K. Yamaguchi J. Itami K. Nickel-catalyzed C−H/C−O coupling of azoles with phenol derivatives.J. Am. Chem. Soc. 2012; 134: 169-172Crossref PubMed Scopus (0) Google Scholar The use of catalytic Ni(cod)2 together with 1,2-bis-(dicyclohexylphosphino)ethane (dcype) as a ligand and Cs2CO3 as a base is important for the accomplishment of this coupling process. A wide range of protected phenol-derived pivalates and triflates were suitable substrates under the developed system. Based on this discovery, the swift identification of novel biologically active compounds by late-stage functionalization of naturally occurring structures can be accessed. Importantly, the isolation of arylnickel(II) pivalate 19 confirmed by X-ray analysis supports a catalytic cycle involving C–O bond oxidative addition, C–H nickelation, and final reductive elimination. In addition, it also provides insights into the strong ligand effect in this coupling reaction (Scheme 5B).25Muto K. Yamaguchi J. Lei A. Itami K. Isolation, structure, and reactivity of an arylnickel(II) pivalate complex in catalytic C-H/C-O biaryl coupling.J. Am. Chem. Soc. 2013; 135: 16384-16387Crossref PubMed Scopus (0) Google Scholar The effect of the base was further studied with the help of computational experiments.26Xu H. Muto K. Yamaguchi J. Zhao C. Itami K. Musaev D.G. Key mechanistic features of Ni-catalyzed C−H/C−O biaryl coupling of azoles and naphthalen-2-yl pivalates.J. Am. Chem. Soc. 2014; 136: 14834-14844Crossref PubMed Scopus (122) Google Scholar Azole C–H activation was accomplished by the catalysis of 20 generated through C–O bond oxidative addition in the absence of Cs2CO3, which requires overcoming the ΔG = 34.7 kcal/mol barrier. Alternatively, when Cs2CO3 was present, cluster complex 21 was formed with the release of ΔG = 36.1 kcal/mol. During the C–H activation of azole 17, the formed weak Cs−heteroatom(azole) bond increases the acidity of the C–H bond, which is responsible for the dramatically reduced barrier of C–H activation. Compared with aryl pivalates and carbamates, aryl ethers with C–OMe bonds have higher dissociation energy. An early example by Tsuchimoto and coworkers disclosed an indium-catalyzed SNAr reaction for the construction of heteroaryl−heteroaryl bonds using thiophene ethers as electrophiles with indole derivatives as nucleophiles (Scheme 6).27Tsuchimoto T. Iwabuchi M. Nagase Y. Oki K. Takahashi H. Indium-catalyzed heteroaryl–heteroaryl bond formation through nucleophilic aromatic substitution.Angew. Chem. Int. Ed. Engl. 2011; 50: 1375-1379Crossref PubMed Scopus (34) Google Scholar Soft metal salts with non-coordinating counterions were selected as good candidates to facilitate this transformation. In addition to In(OTf)3, other hard Lewis acids involving In(ONf)3, AgOTf, and Bi(OTf)3 were also investigated as alternative catalysts to attain the anticipated products. Meanwhile, the authors provided two plausible pathways to explain the mechanistic details of this reaction. The deuterium experiments indicated that the two different allylindium complexes that were generated during this catalytic route were attacked by heteroaromatic rings with high π-electron density in which the indium metal served as an electron-withdrawing moiety to improve the electrophilicity of the thiophene rings. In 2018, Zhao and Ong further disclosed that aryl methyl ethers can also be employed as coupling partners via C–O activation using a catalytic amount of Ni(cod)2 and IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) ligand employed for heteroarene C–H activation (Scheme 7).28Wang T.S. Ambre R. Wang Q. Lee W.-C. Wang P.-C. Liu Y. Zhao L. Ong T.-G. Nickel-catalyzed heteroarenes cross coupling via tandem C−H/C−O activation.ACS Catal. 2018; 8: 11368-11376Crossref Scopus (0) Google Scholar The use of sterically demanding o-tolylMgBr is a key success in both C–O and C–H activation. This procedure is highly effective in a wide range of substrate scopes with anisoles, naphthyl methyl ethers, and a variety of other heteroarenes. However, aryl methyl ethers containing withdrawing groups are not appropriate for this catalysis due to their possible interaction with Grignard reagents. The synergistic effect of nickel and Grignard reagent is driving for C–O bond cleavage acquired by detailed mechanistic studies, and the sterically demanding Grignard reagent is crucial to avoid the byproducts in this transformation. TM-catalyzed Mizoroki-Heck reaction is an expedient synthetic method for the construction of alkenyl-substituted arenes from simple arylboronic acids. Different from this traditional process, Itami and Yamaguchi disclosed the cross-coupling between enol derivatives and heteroarenes through C–O/C–H activation using the developed Ni/dcype catalytic system to build alkenyl-substituted products (Scheme 8A).29Meng L. Kamada Y. Muto K. Yamaguchi J. Itami K. C−H alkenylation of azoles with enols and esters by nickel catalysis.Angew. Chem. Int. Ed. Engl. 2013; 52: 10048-10051Crossref PubMed Scopus (0) Google Scholar Enol derivatives, including styryl pivalate and carbamate, could be utilized to couple with benzoxazoles and oxazoles, and in most cases, the styryl carbamates exhibited greater reactivity than the related pivalates. However, benzothiazole was not compatible with the developed conditions. Later, the same research group explored nickel-catalyzed vinylic C–O heteroarylation using imidazole derivatives as one of the partners (Scheme 8B).30Muto K. Hatakeyama T. Yamaguchi J. Itami K. C–H arylation and alkenylation of imidazoles by nickel catalysis: solvent-accelerated imidazole C–H activation.Chem. Sci. 2015; 6: 6792-6798Crossref PubMed Google Scholar Instead of using dcype, a new dcypt (3,4-bis(dicyclohexylphosphino)thiophene) ligand was employed in this reaction. Positively, the phenol derivatives were also compatible with imidazoles in this developed catalytic approach. TM-catalyzed C–H allylation has been intensively studied over the last decade, emerging as a powerful tool to build C–C bonds.31Dutta S. Bhattacharya T. Werz D.B. Maiti D. Transition-metal-catalyzed C–H allylation reactions.Chem. 2021; 7: 555-605Abstract Full Text Full Text PDF Scopus (0) Google Scholar In 2014, Glorius and coworkers reported an efficient cocatalyzed C–H allylation of indoles with allyl carbonate by N-pyrimidin-2-yl directing group (Scheme 9A).32Yu D.G. Gensch T. de Azambuja F. Vásquez-Céspedes S. Glorius F. Co(III)-catalyzed C−H activation/formal SN-type reactions: selective and efficient cyanation, halogenation, and allylation.J. Am. Chem. Soc. 2014; 136: 17722-17725Crossref PubMed Scopus (0) Google Scholar It is noted that the use of Co(III) catalyst in this reaction showed excellent turnover number (up to 2,200) at room temperature. Instead of using the preactivated allyl carbonate, Matsunaga and Kanai later found that many nonactivated allyl alcohols could be employed in the C2-allylation of indoles and pyrrole directly in the presence of a cationic Co catalyst (Scheme 9B).33Suzuki Y. Sun B. Sakata K. Yoshino T. Matsunaga S. Kanai M. Dehydrative direct C-H allylation with allylic alcohols under [Cp∗CoIII] catalysis.Angew. Chem. Int. Ed. Engl. 2015; 54: 9944-9947Crossref PubMed Scopus (0) Google Scholar Mechanistic investigations have revealed that the δ-selective substitution reaction proceeded by C–H metalation and the addition of a C=C bond, with subsequent β-OH elimination. Using dioxolanones as coupling partners, the Ackermann group further developed the Mn(I)-catalyzed C–H allylation with indoles (Scheme 9C).34Wang H. Lorion M.M. Ackermann L. Air-stable manganese(I)-catalyzed C-H activation for decarboxylative C-H/C-O cleavages in water.Angew. Chem. Int. Ed. Engl. 2017; 56: 6339-6342Crossref PubMed Scopus (0) Google Scholar Remarkably, the C–H activation manifold was tolerant of air and water. In addition, indole C–H allylation has also been successfully applied in bioorthogonal late-stage diversification of structurally complex peptides. In 2018, Ackermann and coworkers uncovered cobalt-catalyzed C–H allylation of tryptophan-containing peptides, compatibility with various functional groups, and excellent regioselectivity (Scheme 9D).35Lorion M.M. Kaplaneris N. Son J. Kuniyil R. Ackermann L. Late-stage peptide diversification through cobalt-catalyzed C−H activation: sequential multicatalysis for stapled peptides.Angew. Chem. Int. Ed. Engl. 2019; 58: 1684-1688Crossref PubMed Scopus (61) Google Scholar Combined with olefin metathesis and hydrogenation, a library of structurally complex cyclic peptides was obtained. Furthermore, free stapled peptides were generated via traceless removal of the pyridyl directing group. Direct functionalization of alcohol C–O bonds can be considered the most challenging but sustainable route for the synthesis of high-value products and for late-stage functionalization of pharmaceuticals and biomolecules. In 2015, the MacMillan group developed a general method by using alcohols 22 as simple alkylating agents, allowing prompt late-stage derivatization of heteroarenes 23 through the successful merger of photoredox and hydrogen atom transfer (HAT) catalysis 24 (Scheme 10A).36Jin J. MacMillan D.W.C. Alcohols as alkylating agents in heteroarene C–H functionalization.Nature. 2015; 525: 87-90Crossref PubMed Scopus (386) Google Scholar These authors achieved the alkylation of a wide range of heterocycles, such as isoquinolines, quinolines, phthalazines, phenanthridines, and pyridines, with methanol and higher alcohols. The importance