Ruthenium-Catalyzed C–H Activations for the Synthesis of Indole Derivatives

: The synthesis of substituted indoles has received great attention in the ﬁeld of organic synthesis methodology. C–H activation makes it possible to obtain a variety of designed indole derivatives in mild conditions. Ruthenium catalyst, as one of the most signiﬁcant transition-metal catalysts, has been contributing in the synthesis of indole sca ﬀ olds through C–H activation and C–H activation on indoles. Herein, we attempt to present an overview about the construction strategies of indole sca ﬀ old and site-speciﬁc modiﬁcations for indole sca ﬀ old via ruthenium-catalyzed C–H activations in recent years. C–O pivaloyl directing group Sulfonamidation with azide as well as vinylization with unsaturated esters were reported in this work. Notable features of this strategy include unprecedented carboxylate-assisted ruthenium-catalyzed C7–H activation of indoles and expedient C7–H activations enabling amidations and alkenylations under exceedingly mild conditions.


Introduction
Substituted indoles are omnipresent in pharmaceutical industry. Some of them are the most sold drugs worldwide, presenting extraordinary efficacy in anti-cancer [1][2][3][4][5], sexual health [6], or anti-genetic disorders [7]. The indole containing compounds also exhibit wide range of pharmacological activity in bench work, such as antihistaminic, antimicrobial, anti-HIV, anti-inflammatory, and analgesic, as well as, anti-SARS-CoV-2 [8]. In natural products and marine compounds, indole moieties are also widely prevalent [9]. The interesting biological activities and structural features of substituted indoles have attracted intensive attention. Thus, the synthesis of substituted indoles has received great interest.
Since the beginning of 19th century, researchers, some of whom were written about in textbooks, have made great contributions for the synthesis of indole scaffolds. However, most of these reactions require well designed, uneasily synthesized, and relatively unstable substrates or harsh conditions, such as Fischer indole synthesis, Bartoli indole synthesis, and Hinsberg indole synthesis, suffering from poor functional group tolerance and limited substrate scopes [10].
Transition-metal-catalyzed direct C-H activation would eliminate the need for prefunctionalization of substrates. Obviously, the direct C-H activation would provide convenient methods for the synthesis of functionalized organic molecules. Recently, transition-metal-catalyzed C-H activation has been well studied and established for the synthesis of indole scaffold compounds [11]; especially, the use of more stable and easy-to-handle ruthenium catalysts has tremendously contributed to the discovery of novel and efficient catalytic systems. The success of ruthenium catalysts is likely ascribed to their easy transformation into cyclometalated species via CMD (concerted metalation/deprotonation) process, their compatibility with frequently-used oxidants, and the stability to air or water. Within the last few years, the use of ruthenium catalysts has promoted the discovery of C−H activation processes. It is the objective of this review to show the progressive discoveries of ruthenium-catalyzed C-H activations Inspired by the high reactivity of diazo compounds, our group [13] developed a highly efficient synthetic strategy to construct 3-phosphorylindole scaffolds via selective reversible C-H bond activations of N-phenylbenzimidamide, and the subsequent divergent couplings with diazophosphonate compounds were achieved successfully with Ru(II) catalyst systems (Scheme 3). The yields of the examples are 60-90%. Alkynes are now a developing sorts of coupling partners to construct divergent scaffolds. Recently, Rh-catalyzed and Pd-catalyzed C-H activation leading to the construction of indoles with alkynes have emerged as a powerful strategy. In addition, Ru-catalyzed C-H activation for the synthesis of indole scaffolds using alkynes as substrates has attracted much attention due to the high efficiency (Scheme 4). In 2012, Ackermann's group [14], based on their previous work and experience on heterocycle construction, achieved [3+2] annulation of anilines bearing removable pyrimidyl group as directing group, which led to the formation of 2, 3-disubstituted indoles, with the use of the most applied cationic ruthenium complex [RuCl2(p-cymene)]2 as catalyst. The reaction conducting C-H/N-H bonds cleavage efficiently occurs in water as a sustainable solvent. The initiation of the proposed catalytic cycle is the reversible cyclometallation with cationic ruthenium complex to form the key intermediate, a six-membered ruthenacycle. Then, the complex undergoes coordination and migratory insertion with the alkyne followed to furnish ruthacycle. At last, the desired product is given by reductive elimination. The scope of the substrates has a wide range. Examples, including electron-donating groups, such as the methyl group, and electron-withdrawing groups, such as the trifluoromethyl group, on the benzene are well tolerated in this method, as well as aromatic or alkyl Alkynes are now a developing sorts of coupling partners to construct divergent scaffolds. Recently, Rh-catalyzed and Pd-catalyzed C-H activation leading to the construction of indoles with alkynes have emerged as a powerful strategy. In addition, Ru-catalyzed C-H activation for the synthesis of indole scaffolds using alkynes as substrates has attracted much attention due to the high efficiency (Scheme 4). In 2012, Ackermann's group [14], based on their previous work and experience on heterocycle construction, achieved [3+2] annulation of anilines bearing removable pyrimidyl group as directing group, which led to the formation of 2, 3-disubstituted indoles, with the use of the most applied cationic ruthenium complex [RuCl 2 (p-cymene)] 2 as catalyst. The reaction conducting C-H/N-H bonds cleavage efficiently occurs in water as a sustainable solvent. The initiation of the proposed catalytic cycle is the reversible cyclometallation with cationic ruthenium complex to form the key intermediate, a six-membered ruthenacycle. Then, the complex undergoes coordination and migratory insertion with the alkyne followed to furnish ruthacycle. At last, the desired product is given by reductive elimination. The scope of the substrates has a wide range. Examples, including electron-donating groups, such as the methyl group, and electron-withdrawing groups, such as the trifluoromethyl group, on the benzene are well tolerated in this method, as well as aromatic or alkyl alkynes. The catalytically active cationic complex is regenerated with reoxidation. In 2017, Cai [15] reported a similar method using PEG400/water as solvent to provide a sustainable way to achieve indole derivatives. Notably, the catalyst can be recycled in this catalytic system. In addition, Kumara [16] and his coworkers described a similar Ru-catalyzed [3+2] annulation of 6-anilinopurines with internal alkynes, giving indole-substituted purine nucleobases. In this work, a ruthenacycle intermediate was characterized indicating that the N-1 nitrogen atom of the purine acts as a directing group for this transformation. Catalysts 2020, 10   In 2019, the first ruthenium-catalyzed double aryl C(sp 2 )-H bond activation of antipyrine and alkyne annulation reaction was reported by Sanjib Gogoi [17] and his co-workers. Two equivalents of anilines participated in the reaction to afford indolo [2,1-a]isoquinolines (Scheme 5). The possible mechanism was proposed (Scheme 6). First of all, ruthenium catalyst conducted irreversible C(sp 2 )-H activation with the directing group assisted. Subsequently, ruthenium-alkyne coordination occurs, followed by migratory alkyne insertion into Ru-C bond. Then, the weak N-N bond cleavages with the oxidation of Ru(II) to Ru(IV) to provide a six-membered Ru(IV) complex. Next, before further C(sp 2 )-H activation of the substituted phenyl ring, the Ru metal is reductive eliminated, and a nine-membered Ru complex is formed. After that, the nine-membered ring is contracted by elimination of a ketene type of fragment to generate Ru(IV) complex. Again, 3aa is afforded with the insertion of another molecular of 2a into the Ru-C bond and reductive elimination of Ru. Emma Gallo [19] and his coworkers screened out ruthenium bis-imido Ru(TPP)(NAr)2 complex(TPP=dianion of tetraphenyl porphyrin, Ar=3,5-(CF3)2C6H3), also named ruthenium porphorin, to catalyze indole synthesis from alkynes with aryl azide (Scheme 8). The alkyne interacts with one NAr imido ligand of Ru(TPP)(NAr)2 to form a residually dangling C(Ph) group, forming a 5+6 bicyclic molecule by coupling with a C(H) unit of the N-aryl substituent, a two-step outer sphere H-migration occurs to make the bicycle isomerize to indole. Eventually, a Ru(TPP)(NAr) mono-imido active catalyst is reformed after each azide/alkyne reaction. The steric hindrance of alkynes influenced the reaction productivity to a greater extent than the electronic effect, as the monosubstituted alkynes were efficiently converted into corresponding indole independently for the position where the substituent was placed, while the substitution on the phenyl azide shows lower selectivity. Scheme 8. Ruthenium porphyrin-catalyzed C-H activation with alkynes and aryl azides to afford indoles.
In the methods above, most of the catalytic cycle needs additional oxidant to reform the catalyst such as Cu salt. Xu's group [20] developed a ruthenium-catalyzed electrochemical dehydrogenative Emma Gallo [19] and his coworkers screened out ruthenium bis-imido Ru(TPP)(NAr) 2 complex(TPP=dianion of tetraphenyl porphyrin, Ar=3,5-(CF 3 ) 2 C 6 H 3 ), also named ruthenium porphorin, to catalyze indole synthesis from alkynes with aryl azide (Scheme 8). The alkyne interacts with one NAr imido ligand of Ru(TPP)(NAr)2 to form a residually dangling C(Ph) group, forming a 5+6 bicyclic molecule by coupling with a C(H) unit of the N-aryl substituent, a two-step outer sphere H-migration occurs to make the bicycle isomerize to indole. Eventually, a Ru(TPP)(NAr) mono-imido active catalyst is reformed after each azide/alkyne reaction. The steric hindrance of alkynes influenced the reaction productivity to a greater extent than the electronic effect, as the mono-substituted alkynes were efficiently converted into corresponding indole independently for the position where the substituent was placed, while the substitution on the phenyl azide shows lower selectivity. Emma Gallo [19] and his coworkers screened out ruthenium bis-imido Ru(TPP)(NAr)2 complex(TPP=dianion of tetraphenyl porphyrin, Ar=3,5-(CF3)2C6H3), also named ruthenium porphorin, to catalyze indole synthesis from alkynes with aryl azide (Scheme 8). The alkyne interacts with one NAr imido ligand of Ru(TPP)(NAr)2 to form a residually dangling C(Ph) group, forming a 5+6 bicyclic molecule by coupling with a C(H) unit of the N-aryl substituent, a two-step outer sphere H-migration occurs to make the bicycle isomerize to indole. Eventually, a Ru(TPP)(NAr) mono-imido active catalyst is reformed after each azide/alkyne reaction. The steric hindrance of alkynes influenced the reaction productivity to a greater extent than the electronic effect, as the monosubstituted alkynes were efficiently converted into corresponding indole independently for the position where the substituent was placed, while the substitution on the phenyl azide shows lower selectivity. Scheme 8. Ruthenium porphyrin-catalyzed C-H activation with alkynes and aryl azides to afford indoles.
In the methods above, most of the catalytic cycle needs additional oxidant to reform the catalyst such as Cu salt. Xu's group [20] developed a ruthenium-catalyzed electrochemical dehydrogenative annulation reaction of aniline derivatives and alkynes (Scheme 9). Electric current is used to recycle the active ruthenium-based catalyst, and the reaction, notably, is operationally convenient due to a simple undivided cell employed. The process is insensitive to air, proceeding in an aqueous solution.
In the methods above, most of the catalytic cycle needs additional oxidant to reform the catalyst such as Cu salt. Xu's group [20] developed a ruthenium-catalyzed electrochemical dehydrogenative annulation reaction of aniline derivatives and alkynes (Scheme 9). Electric current is used to recycle the active ruthenium-based catalyst, and the reaction, notably, is operationally convenient due to a simple undivided cell employed. The process is insensitive to air, proceeding in an aqueous solution. Similarly, alkenyl groups can also be applied to form indole derivatives with C-H activation reactions. Xiao [21] and his coworkers developed a visible light-induced intramolecular cyclization of styryl azide in the presence of Ru(bpy)3Cl2, to construct 2-substituted N-free indoles in good to excellent yields with high functional group tolerance. Through this method, 2 aromatic indoles including electron-donating phenyl and electron-withdrawing phenyl indoles are efficiently obtained. (Scheme 10). A molecular of N2 is removed under irradiation of visible light, and then a concerted nitrene insertion occurs through the transition state to deliver the designed indoles. Yang's group [22] developed a new approach to the synthesis of 2-phosphinoylindoles from 1isocyano-2-styrylbenzenes through photoredox catalysis (Scheme 11). Unlike Xiao's work, the benzyl group on the alkenylphenylisocyanide is ultimately substituted on the C3 of the synthesized indole. The proposed mechanism of the phosphorylation/ cyclization reaction was outlined by the author (Scheme 12). The photoredox catalyst A Ru(bpy)3Cl2·6H2O irradiated by visible light, leading to the formation of excited state B *Ru II . After that, oxidation of the conjugate base of B should be thermodynamically feasible, to generate phosphorus radical D. Then, a proton from diphenylphosphine oxide 2 is captured by DBU. After that, phosphorus radical D is rapidly trapped by 1-isocyano-2-styrylbenzene (1a) to generate alkene radical E, followed by 5-exo-trig cyclizationforming benzyl radical F. Finally, the reduction in the resulting benzyl radical F by SET from available Ru species C should generate benzyl anion G and regenerate the ground-state photoredox catalyst A. A range of 1-isocyano-2-styrylbenzenes can be applied efficiently in this transformation, making it appealing for late-stage synthesis strategies. Similarly, alkenyl groups can also be applied to form indole derivatives with C-H activation reactions. Xiao [21] and his coworkers developed a visible light-induced intramolecular cyclization of styryl azide in the presence of Ru(bpy) 3 Cl 2 , to construct 2-substituted N-free indoles in good to excellent yields with high functional group tolerance. Through this method, 2 aromatic indoles including electron-donating phenyl and electron-withdrawing phenyl indoles are efficiently obtained. (Scheme 10). A molecular of N 2 is removed under irradiation of visible light, and then a concerted nitrene insertion occurs through the transition state to deliver the designed indoles. Similarly, alkenyl groups can also be applied to form indole derivatives with C-H activation reactions. Xiao [21] and his coworkers developed a visible light-induced intramolecular cyclization of styryl azide in the presence of Ru(bpy)3Cl2, to construct 2-substituted N-free indoles in good to excellent yields with high functional group tolerance. Through this method, 2 aromatic indoles including electron-donating phenyl and electron-withdrawing phenyl indoles are efficiently obtained. (Scheme 10). A molecular of N2 is removed under irradiation of visible light, and then a concerted nitrene insertion occurs through the transition state to deliver the designed indoles. Yang's group [22] developed a new approach to the synthesis of 2-phosphinoylindoles from 1isocyano-2-styrylbenzenes through photoredox catalysis (Scheme 11). Unlike Xiao's work, the benzyl group on the alkenylphenylisocyanide is ultimately substituted on the C3 of the synthesized indole. The proposed mechanism of the phosphorylation/ cyclization reaction was outlined by the author (Scheme 12). The photoredox catalyst A Ru(bpy)3Cl2·6H2O irradiated by visible light, leading to the formation of excited state B *Ru II . After that, oxidation of the conjugate base of B should be thermodynamically feasible, to generate phosphorus radical D. Then, a proton from diphenylphosphine oxide 2 is captured by DBU. After that, phosphorus radical D is rapidly trapped by 1-isocyano-2-styrylbenzene (1a) to generate alkene radical E, followed by 5-exo-trig cyclizationforming benzyl radical F. Finally, the reduction in the resulting benzyl radical F by SET from available Ru species C should generate benzyl anion G and regenerate the ground-state photoredox catalyst A. A range of 1-isocyano-2-styrylbenzenes can be applied efficiently in this transformation, making it appealing for late-stage synthesis strategies. Yang's group [22] developed a new approach to the synthesis of 2-phosphinoylindoles from 1-isocyano-2-styrylbenzenes through photoredox catalysis (Scheme 11). Unlike Xiao's work, the benzyl group on the alkenylphenylisocyanide is ultimately substituted on the C3 of the synthesized indole. The proposed mechanism of the phosphorylation/ cyclization reaction was outlined by the author (Scheme 12). The photoredox catalyst A Ru(bpy) 3 Cl 2 ·6H 2 O irradiated by visible light, leading to the formation of excited state B *Ru II . After that, oxidation of the conjugate base of B should be thermodynamically feasible, to generate phosphorus radical D. Then, a proton from diphenylphosphine oxide 2 is captured by DBU. After that, phosphorus radical D is rapidly trapped by 1-isocyano-2-styrylbenzene (1a) to generate alkene radical E, followed by 5-exo-trig cyclization-forming benzyl radical F. Finally, the reduction in the resulting benzyl radical F by SET from available Ru species C should generate benzyl anion G and regenerate the ground-state photoredox catalyst A. A range of 1-isocyano-2-styrylbenzenes can be applied efficiently in this transformation, making it appealing for late-stage synthesis strategies.
Catalysts 2020, 10, 1253 8 of 27 diphenylphosphine oxide 2 is captured by DBU. After that, phosphorus radical D is rapidly trapped by 1-isocyano-2-styrylbenzene (1a) to generate alkene radical E, followed by 5-exo-trig cyclizationforming benzyl radical F. Finally, the reduction in the resulting benzyl radical F by SET from available Ru species C should generate benzyl anion G and regenerate the ground-state photoredox catalyst A. A range of 1-isocyano-2-styrylbenzenes can be applied efficiently in this transformation, making it appealing for late-stage synthesis strategies. Scheme 11. Ruthenium-catalyzed photoredox reactions to afford 2-phosphinoylindoles. Scheme 11. Ruthenium-catalyzed photoredox reactions to afford 2-phosphinoylindoles. Sulfur ylides also serve as significant substrates forming indole derivatives in rutheniumcatalyzed reactions. Our lab [23] developed the first sulfoxonium ylides derived from a Ru(II)carbene complex insertion arene C-H bond cascade reactions to constitute 3-ketoindole skeleton via C-H activation. The catalytic system generated 3-acetyl indole scaffolds by C-N and C-S bond cleavage with imidamides and sulfoxonium ylides through a [4+1] cyclization process. In addition, Huang and his coworkers developed a method for the synthesis of 2-arylindoles with N-aryl-2aminopyridines and α-carbonyl sulfoxonium ylides (Scheme 13). Some 2-aromatic-substituted indoles including halogenatedphenyl, trifluoromethylphenyl, and methoxylphenyl indoles are obtained in good yields. Scheme 13. Ruthenium-catalyzed indole scaffold construction with sulfur ylides.
In 2017, Dilman's group [24] developed a method for the synthesis of 3-fluoroindoles starting Sulfur ylides also serve as significant substrates forming indole derivatives in ruthenium-catalyzed reactions. Our lab [23] developed the first sulfoxonium ylides derived from a Ru(II)-carbene complex insertion arene C-H bond cascade reactions to constitute 3-ketoindole skeleton via C-H activation. The catalytic system generated 3-acetyl indole scaffolds by C-N and C-S bond cleavage with imidamides and sulfoxonium ylides through a [4+1] cyclization process. In addition, Huang and his coworkers developed a method for the synthesis of 2-arylindoles with N-aryl-2-aminopyridines and α-carbonyl sulfoxonium ylides (Scheme 13). Some 2-aromatic-substituted indoles including halogenatedphenyl, trifluoromethylphenyl, and methoxylphenyl indoles are obtained in good yields.
C-H activation. The catalytic system generated 3-acetyl indole scaffolds by C-N and C-S bond cleavage with imidamides and sulfoxonium ylides through a [4+1] cyclization process. In addition, Huang and his coworkers developed a method for the synthesis of 2-arylindoles with N-aryl-2aminopyridines and α-carbonyl sulfoxonium ylides (Scheme 13). Some 2-aromatic-substituted indoles including halogenatedphenyl, trifluoromethylphenyl, and methoxylphenyl indoles are obtained in good yields. In 2017, Dilman's group [24] developed a method for the synthesis of 3-fluoroindoles starting from -CF2I-substituted N-arylamines, which was mediated by a ruthenium photocatalyst upon irradiation with blue light in the presence of a substoichiometric amount of triphenylphosphine (Scheme 14). The combination of ruthenium photocatalyst and triphenylphosphine to generate fluoroalkyl radicals is the key factor affecting the reaction efficiency. In 2017, Dilman's group [24] developed a method for the synthesis of 3-fluoroindoles starting from -CF 2 I-substituted N-arylamines, which was mediated by a ruthenium photocatalyst upon irradiation with blue light in the presence of a substoichiometric amount of triphenylphosphine (Scheme 14). The combination of ruthenium photocatalyst and triphenylphosphine to generate fluoroalkyl radicals is the key factor affecting the reaction efficiency. There are also additional methods using variety of substrates. According to Shim's report [25], substituted indoles can be synthesized from anilines and alkanolammonium chlorides in the presence of a ruthenium catalyst together with SnCl2 2H2O in moderate to good yields. In this transformation, SnCl2 2H2O is important for the formation of indoles. Karvembu [26] utilizes [RuCl2(p-cymene)]2 complexes containing picolyl-based pseudo-acylthiourea ligands to form 3-isopropoxy-1H-indole from nitro 2-nitrocinnamaldehyde and 2-propanol. Jana [27] and his coworkers developed a ruthenium-catalyzed divergent synthesis of 2-methylindoles and indolines via a C-H allylation/oxidative cyclization cascade. The 2-methylindoles are obtained through a C−H allylation/carboamination/β-hydride elimination/double bond isomerization cascade, whereas for ortho-substituted anilines, the indolines are obtained via a C−H allylation/carboamination/protodemetalation cascade in trifluoroethanol. Yi [28] and his coworkers reported a dehydrative C-H coupling reaction of arylamines with 1,2-diols catalyzed by the cationic ruthenium-hydride complex to afford 2-phenyl indoles (Scheme 15). There are also additional methods using variety of substrates.

Site-Specific Modification for Indole Scaffold via Ruthenium-Catalyzed C-H Activation
Site-specific direct C-H functionization is a simple and significant way to obtain desired indole derivatives [29]. In order to discuss conveniently, these C-H activation strategies will be sorted according to the site of C-H bond on indoles.

C-H Activation on C2 and C3
Cross coupling is gradually becoming the most significant and one of the most applied reactions in the pharmaceutical industry. A significant number of methods exist for Ru-catalyzed

Site-Specific Modification for Indole Scaffold via Ruthenium-Catalyzed C-H Activation
Site-specific direct C-H functionization is a simple and significant way to obtain desired indole derivatives [29]. In order to discuss conveniently, these C-H activation strategies will be sorted according to the site of C-H bond on indoles.

C-H Activation on C2 and C3
Cross coupling is gradually becoming the most significant and one of the most applied reactions in the pharmaceutical industry. A significant number of methods exist for Ru-catalyzed functionalization at the C2 position of indole scaffolds, such as alkylation, arylation, and so on. In 2011, Ackermann [30] and his coworkers reported C-H bond arylations in a high chemo-and site-selective manner using the removable directing group with aryl halides as coupling partners. The catalytic system is reported broadly applicable and tolerated a variety of valuable functional groups, such as halogen, cyano, and carbonyl group, as well as additional heteroaromatic moieties in medium-to-good yields. Based on Ackermann's work, in 2015 and 2018, Pilarski [31] and Szostak [32] reported the similar C-H arylation reactions for the synthesis of 2-arylated indoles with aryl borate and aryl silicone compounds, respectively (Scheme 16).
Catalysts 2020, 10, x 12 of 28 functionalization at the C2 position of indole scaffolds, such as alkylation, arylation, and so on. In 2011, Ackermann [30] and his coworkers reported C-H bond arylations in a high chemo-and siteselective manner using the removable directing group with aryl halides as coupling partners. The catalytic system is reported broadly applicable and tolerated a variety of valuable functional groups, such as halogen, cyano, and carbonyl group, as well as additional heteroaromatic moieties in medium-to-good yields. Based on Ackermann's work, in 2015 and 2018, Pilarski [31] and Szostak [32] reported the similar C-H arylation reactions for the synthesis of 2-arylated indoles with aryl borate and aryl silicone compounds, respectively (Scheme 16).
In 2016, Ackermann [33] reported a methylation reaction using MeBF3K as methylating agent, with the catalysis of [RuCl2(p-cymene)]2 (Scheme 17). Notably, the reaction can be applied in the methylation of tryptophan, which may be used in the chemical biology field or pharmaceutical industry. In 2016, Ackermann [33] reported a methylation reaction using MeBF 3 K as methylating agent, with the catalysis of [RuCl 2 (p-cymene)] 2 (Scheme 17). Notably, the reaction can be applied in the methylation of tryptophan, which may be used in the chemical biology field or pharmaceutical industry. Diazo compounds are critical and reactive substrates to participate all sorts of insertion reactions by forming metal carbenes. In 2010, Yu reported a directing group-free approach for C2-selective carbenoid functionalization of NH indoles [34]. With [RuCl2(p-cymene)]2 as catalyst and 2aryldiazoesters as carbenoid source, 2-alkylated indoles were obtained in up to 96% isolated yield. In 2019, Gryco [35] described the photoalkylation of indoles and pyrroles with diazo esters. C2alkylated indoles are obtained with good yields even though the photocatalyst loading is as low as 0.075 mol % (Scheme 18). Both EWG (electron donating groups)-EWG-and EWG-EDG (electron withdrawing groups)-substituted diazo esters are suitable as alkylating agents in this transformation. For EWG-substituted substrates, the addition of a catalytic amount of N, N-dimethyl-4methoxyaniline is required to promote the transfer from the Ru(bpy)3* 2+ to Ru(bpy)3 + , which has much more potential to catalyze the reaction. The same situation appears in Stephenson's work [36]. Substituted indoles were obtained by photoredox intermolecular direct C-H functionization with indoles and diethyl bromomalonate. The replacement of Et3N with N, N-dimethyl-4-methoxyaniline increased the yield of desired product from 25% to 85%. Meanwhile, furans and pyrroles were also investigated and found to work well under the conditions. In 2017, Hansen reported a similar method and developed a novel visible-light photocatalytic double C-H functionalization of indoles to afford 2,3-difunctionalized indoles (Scheme 19). Mechanistic studies indicated that electrophilic C-3 bromination occurs through an Diazo compounds are critical and reactive substrates to participate all sorts of insertion reactions by forming metal carbenes. In 2010, Yu reported a directing group-free approach for C2-selective carbenoid functionalization of NH indoles [34]. With [RuCl 2 (p-cymene)] 2 as catalyst and 2-aryldiazoesters as carbenoid source, 2-alkylated indoles were obtained in up to 96% isolated yield. In 2019, Gryco [35] described the photoalkylation of indoles and pyrroles with diazo esters. C2-alkylated indoles are obtained with good yields even though the photocatalyst loading is as low as 0.075 mol % (Scheme 18). Both EWG (electron donating groups)-EWG-and EWG-EDG (electron withdrawing groups)-substituted diazo esters are suitable as alkylating agents in this transformation. For EWG-substituted substrates, the addition of a catalytic amount of N, N-dimethyl-4-methoxyaniline is required to promote the transfer from the Ru(bpy) 3 * 2+ to Ru(bpy) 3 + , which has much more potential to catalyze the reaction. Diazo compounds are critical and reactive substrates to participate all sorts of insertion reactions by forming metal carbenes. In 2010, Yu reported a directing group-free approach for C2-selective carbenoid functionalization of NH indoles [34]. With [RuCl2(p-cymene)]2 as catalyst and 2aryldiazoesters as carbenoid source, 2-alkylated indoles were obtained in up to 96% isolated yield. In 2019, Gryco [35] described the photoalkylation of indoles and pyrroles with diazo esters. C2alkylated indoles are obtained with good yields even though the photocatalyst loading is as low as 0.075 mol % (Scheme 18). Both EWG (electron donating groups)-EWG-and EWG-EDG (electron withdrawing groups)-substituted diazo esters are suitable as alkylating agents in this transformation. For EWG-substituted substrates, the addition of a catalytic amount of N, N-dimethyl-4methoxyaniline is required to promote the transfer from the Ru(bpy)3* 2+ to Ru(bpy)3 + , which has much more potential to catalyze the reaction. The same situation appears in Stephenson's work [36]. Substituted indoles were obtained by photoredox intermolecular direct C-H functionization with indoles and diethyl bromomalonate. The replacement of Et3N with N, N-dimethyl-4-methoxyaniline increased the yield of desired product from 25% to 85%. Meanwhile, furans and pyrroles were also investigated and found to work well under the conditions. In 2017, Hansen reported a similar method and developed a novel visible-light photocatalytic double C-H functionalization of indoles to afford 2,3-difunctionalized indoles (Scheme 19). Mechanistic studies indicated that electrophilic C-3 bromination occurs through an The same situation appears in Stephenson's work [36]. Substituted indoles were obtained by photoredox intermolecular direct C-H functionization with indoles and diethyl bromomalonate. The replacement of Et 3 N with N, N-dimethyl-4-methoxyaniline increased the yield of desired product Catalysts 2020, 10, 1253 13 of 27 from 25% to 85%. Meanwhile, furans and pyrroles were also investigated and found to work well under the conditions. In 2017, Hansen reported a similar method and developed a novel visible-light photocatalytic double C-H functionalization of indoles to afford 2,3-difunctionalized indoles (Scheme 19). Mechanistic studies indicated that electrophilic C-3 bromination occurs through an independent photocatalytic oxidation of bromide ions formed during the reaction to generate molecular bromine [37].
Catalysts 2020, 10, x 14 of 28 independent photocatalytic oxidation of bromide ions formed during the reaction to generate molecular bromine [37].
In the field of drug research and development, metabolism of drugs leading to low bioavailability or toxicity is a huge challenge to be solved [38]. Trifluoromethylation on the active metabolic site gives medicinal chemists new hope to guarantee the efficacy of drugs [39]. It is clearly important to develop easy methods to realize trifluoromethylation reaction under mild conditions with simple starting materials. In 2011, MacMillan [40] introduced a photoredox-based method allowing for facile trifluoromethylation of heteroaromatic systems including indoles without the need for an aryl ring pre-activation (Scheme 20). With the Ru(phen)3 2+ as photoredox catalyst, as well as trifluorosulfonyl chloride as CF3 source, 2-CF3-indole and 3-CF3-N-Ac-indole were afforded in this catalytic system, respectively. In addition, on all kinds of hetero-or benzene cycles, the substitutions majorly rely on the electro property. In 2012, Cho [41] reported the similar trifluoromethylation of indole substrates utilizing CF3I as CF3 source. The trifluoromethylation reaction can occur on substituted indoles. Then, in 2014, continuous flow was used to accelerate the trifluoromethylation and multifluoroalkylation process, shortening the time from tens of hours to dozens of minutes [42]. In the field of drug research and development, metabolism of drugs leading to low bioavailability or toxicity is a huge challenge to be solved [38]. Trifluoromethylation on the active metabolic site gives medicinal chemists new hope to guarantee the efficacy of drugs [39]. It is clearly important to develop easy methods to realize trifluoromethylation reaction under mild conditions with simple starting materials. In 2011, MacMillan [40] introduced a photoredox-based method allowing for facile trifluoromethylation of heteroaromatic systems including indoles without the need for an aryl ring pre-activation (Scheme 20). With the Ru(phen) 3 2+ as photoredox catalyst, as well as trifluorosulfonyl chloride as CF 3 source, 2-CF 3 -indole and 3-CF 3 -N-Ac-indole were afforded in this catalytic system, respectively. In addition, on all kinds of hetero-or benzene cycles, the substitutions majorly rely on the electro property. In 2012, Cho [41] reported the similar trifluoromethylation of indole substrates utilizing CF 3 I as CF 3 source. The trifluoromethylation reaction can occur on substituted indoles. Then, in 2014, continuous flow was used to accelerate the trifluoromethylation and multifluoroalkylation process, shortening the time from tens of hours to dozens of minutes [42]. Growing interest in the utility of arylsilanes or heteroarylsilanes in synthesis [43] and medicinal chemistry has fueled the development of powerful C-H silylation methods. Tatsumi [44] and his group developed selective Ru-catalyzed C3-H silylation of N-methyl indoles (Scheme 21). Either with or without the assistance of the directing group, the transformation proceeds well. The C-H activation occurs as a manner of merging cooperative Si-H bond activation and electrophilic aromatic substitution, which make the C3 selective functionalization controlled by electronic factors (Scheme 22). Ru cooperates with S to form an unsaturated cationic complex before splitting the Si-H bond, which gives a sulfur-stabilized silicon electrophile. The sulfur atom then participates the deprotonation of the Wheland intermediate of the Friedel-Crafts-type process. Solvent does not participate the overall catalysis, with only dihydrogen liberated.
need for an aryl ring pre-activation (Scheme 20). With the Ru(phen)3 2+ as photoredox catalyst, as well as trifluorosulfonyl chloride as CF3 source, 2-CF3-indole and 3-CF3-N-Ac-indole were afforded in this catalytic system, respectively. In addition, on all kinds of hetero-or benzene cycles, the substitutions majorly rely on the electro property. In 2012, Cho [41] reported the similar trifluoromethylation of indole substrates utilizing CF3I as CF3 source. The trifluoromethylation reaction can occur on substituted indoles. Then, in 2014, continuous flow was used to accelerate the trifluoromethylation and multifluoroalkylation process, shortening the time from tens of hours to dozens of minutes [42]. Growing interest in the utility of arylsilanes or heteroarylsilanes in synthesis [43] and medicinal chemistry has fueled the development of powerful C-H silylation methods. Tatsumi [44] and his group developed selective Ru-catalyzed C3-H silylation of N-methyl indoles (Scheme 21). Either with or without the assistance of the directing group, the transformation proceeds well. The C-H activation occurs as a manner of merging cooperative Si-H bond activation and electrophilic aromatic substitution, which make the C3 selective functionalization controlled by electronic factors (Scheme 22). Ru cooperates with S to form an unsaturated cationic complex before splitting the Si-H bond, which gives a sulfur-stabilized silicon electrophile. The sulfur atom then participates the deprotonation of the Wheland intermediate of the Friedel-Crafts-type process. Solvent does not participate the overall catalysis, with only dihydrogen liberated. Growing interest in the utility of arylsilanes or heteroarylsilanes in synthesis [43] and medicinal chemistry has fueled the development of powerful C-H silylation methods. Tatsumi [44] and his group developed selective Ru-catalyzed C3-H silylation of N-methyl indoles (Scheme 21). Either with or without the assistance of the directing group, the transformation proceeds well. The C-H activation occurs as a manner of merging cooperative Si-H bond activation and electrophilic aromatic substitution, which make the C3 selective functionalization controlled by electronic factors (Scheme 22). Ru cooperates with S to form an unsaturated cationic complex before splitting the Si-H bond, which gives a sulfur-stabilized silicon electrophile. The sulfur atom then participates the deprotonation of the Wheland intermediate of the Friedel-Crafts-type process. Solvent does not participate the overall catalysis, with only dihydrogen liberated. Pilarski [45] and his coworkers utilize [RuH 2 (CO)(PPh 3 ) 3 ] as catalyst to conduct direct C-H sililation at C2 position of NH indoles (Scheme 23). Gramines and tryptamines can be converted efficiently, although the C-H activation on C-4 site was detected when conducting mechanism research with little side reactions. Good-to-excellent yields of designed products were effectively obtained from a different silane source such as triaryl, trialkyl, and mixed alkyl/aryl silanes.
Catalysts 2020, 10, x 16 of 28 efficiently, although the C-H activation on C-4 site was detected when conducting mechanism research with little side reactions. Good-to-excellent yields of designed products were effectively obtained from a different silane source such as triaryl, trialkyl, and mixed alkyl/aryl silanes.

Scheme 23. Ruthenium-catalyzed C2-H siliconization on indoles.
Alkynes also serve as a vital sort of substrates for C-H activation. In 2010, Gimeno [46] and his coworkers reported a ruthenium/trifluoroacetate-catalyzed regioselective C-3-alkylation reaction of indoles with terminal alkynes, affording a branch alkyl chain on the scaffold (Scheme 24).
Catalysts 2020, 10, x 16 of 28 efficiently, although the C-H activation on C-4 site was detected when conducting mechanism research with little side reactions. Good-to-excellent yields of designed products were effectively obtained from a different silane source such as triaryl, trialkyl, and mixed alkyl/aryl silanes.

Scheme 23. Ruthenium-catalyzed C2-H siliconization on indoles.
Alkynes also serve as a vital sort of substrates for C-H activation. In 2010, Gimeno [46] and his coworkers reported a ruthenium/trifluoroacetate-catalyzed regioselective C-3-alkylation reaction of indoles with terminal alkynes, affording a branch alkyl chain on the scaffold (Scheme 24).
Catalysts 2020, 10, x 16 of 28 efficiently, although the C-H activation on C-4 site was detected when conducting mechanism research with little side reactions. Good-to-excellent yields of designed products were effectively obtained from a different silane source such as triaryl, trialkyl, and mixed alkyl/aryl silanes.

Scheme 23. Ruthenium-catalyzed C2-H siliconization on indoles.
Alkynes also serve as a vital sort of substrates for C-H activation. In 2010, Gimeno [46] and his coworkers reported a ruthenium/trifluoroacetate-catalyzed regioselective C-3-alkylation reaction of indoles with terminal alkynes, affording a branch alkyl chain on the scaffold (Scheme 24).
In 2012, Haak [49] and his coworkers introduced a ruthenium-catalyzed functionalization of indoles and pyrroles with propargyl alcohols utilizing ruthenium complex 1Ba (Scheme 27). Notably, this protocol can be used for the construction of multi-substituted indole scaffolds with the cascade cyclization on pyrroles. In 2018, they also developed a cascade annulation reaction with propargyl alcohols catalyzed by ruthenium to give benzene-fused indoles [50]. In 2012, Haak [49] and his coworkers introduced a ruthenium-catalyzed functionalization of indoles and pyrroles with propargyl alcohols utilizing ruthenium complex 1Ba (Scheme 27). Notably, this protocol can be used for the construction of multi-substituted indole scaffolds with the cascade cyclization on pyrroles. In 2018, they also developed a cascade annulation reaction with propargyl alcohols catalyzed by ruthenium to give benzene-fused indoles [50]. Similarly, olefins are widely used in indole substitution to perform vinylation or alkylation reactions. In 2013, Wang's lab [51] and Song's lab [52], respectively, developed a similar efficient protocol for vinylation selectively on C2 of indoles assisted by the employment of N,Ndimethylcarbamoyl moiety as a directing group (Scheme 28). A wide scope of olefins, including electron-donating groups, such as the phenyl group, and electron-withdrawing groups, such as sulfonyl, phosphate, and cyano groups, are applicable in this reaction. Similarly, olefins are widely used in indole substitution to perform vinylation or alkylation reactions. In 2013, Wang's lab [51] and Song's lab [52], respectively, developed a similar efficient protocol for vinylation selectively on C2 of indoles assisted by the employment of N,N-dimethylcarbamoyl moiety as a directing group (Scheme 28). A wide scope of olefins, including electron-donating groups, such as the phenyl group, and electron-withdrawing groups, such as sulfonyl, phosphate, and cyano groups, are applicable in this reaction.
Among the substituted alkenes, α, β-unsaturated esters are well studied. Prabhu [53] and his coworkers developed a novel versatile regioselective C-2 alkenylation strategy catalyzed by ruthenium for the synthesis of indole derivatives with benzoyl group as a directing group (Scheme 29). A variety of esters such as methyl, ethyl, cyclohexyl, and phenyl esters perform in good yield. Notably, hydrolysis happens on tert-butyl ester after the designed reaction. Similar conclusions can be found in Wu's work [54].
In 2018, Liu [55] reported a traceless directing group assisted by C2-H vinylation reaction on indoles with broad substrate scope in an aqueous solution (Scheme 30). Decarboxylation occurs after intramolecular alkenylation affording tetrahydropyridoindoles. This method provides efficient access to synthesize various indole-fused derivatives under mild conditions. Similarly, olefins are widely used in indole substitution to perform vinylation or alkylation reactions. In 2013, Wang's lab [51] and Song's lab [52], respectively, developed a similar efficient protocol for vinylation selectively on C2 of indoles assisted by the employment of N,Ndimethylcarbamoyl moiety as a directing group (Scheme 28). A wide scope of olefins, including electron-donating groups, such as the phenyl group, and electron-withdrawing groups, such as sulfonyl, phosphate, and cyano groups, are applicable in this reaction. Among the substituted alkenes, α, β-unsaturated esters are well studied. Prabhu [53] and his coworkers developed a novel versatile regioselective C-2 alkenylation strategy catalyzed by ruthenium for the synthesis of indole derivatives with benzoyl group as a directing group (Scheme Scheme 28. Ruthenium-catalyzed C2-H activation with active olefins. Catalysts 2020, 10, x 18 of 28 29). A variety of esters such as methyl, ethyl, cyclohexyl, and phenyl esters perform in good yield.
Notably, hydrolysis happens on tert-butyl ester after the designed reaction. Similar conclusions can be found in Wu's work [54].
In 2018, Liu [55] reported a traceless directing group assisted by C2-H vinylation reaction on indoles with broad substrate scope in an aqueous solution (Scheme 30). Decarboxylation occurs after intramolecular alkenylation affording tetrahydropyridoindoles. This method provides efficient access to synthesize various indole-fused derivatives under mild conditions. Scheme 30. Ruthenium-catalyzed C2-H activation to afford tetrahydropyridoindoles.
In 2014, Dong [56] developed a simple and highly efficient Ru-catalyzed C3 alkylation of indoles with α, β-unsaturated ketones without the chelation assistance (Scheme 31). Besides indoles, a broad scope of substances, such as pyrroles and other azoles, are exhibited with further applications leading to 3,4-fused tricyclic indoles. Scheme 31. Ruthenium-catalyzed C3-H activation with unsaturated esters.
Notably, hydrolysis happens on tert-butyl ester after the designed reaction. Similar conclusions can be found in Wu's work [54].
In 2018, Liu [55] reported a traceless directing group assisted by C2-H vinylation reaction on indoles with broad substrate scope in an aqueous solution (Scheme 30). Decarboxylation occurs after intramolecular alkenylation affording tetrahydropyridoindoles. This method provides efficient access to synthesize various indole-fused derivatives under mild conditions. Scheme 30. Ruthenium-catalyzed C2-H activation to afford tetrahydropyridoindoles.
In 2014, Dong [56] developed a simple and highly efficient Ru-catalyzed C3 alkylation of indoles with α, β-unsaturated ketones without the chelation assistance (Scheme 31). Besides indoles, a broad scope of substances, such as pyrroles and other azoles, are exhibited with further applications leading to 3,4-fused tricyclic indoles. In 2014, Dong [56] developed a simple and highly efficient Ru-catalyzed C3 alkylation of indoles with α, β-unsaturated ketones without the chelation assistance (Scheme 31). Besides indoles, a broad scope of substances, such as pyrroles and other azoles, are exhibited with further applications leading to 3,4-fused tricyclic indoles.
Allylation reactions are universally researched in organic chemistry. Bruneau [58] in 2009 constructed a tertiary carbon center on C3 of indole utilizing dimethyl allyl alcohol with the synthesized catalyst complex C, resulting in the formation of the branched product as a major compound. In 2007, Pregosin [59] developed a regioselective allylation of a variety of indole compounds using allyl alcohol as substrate with a novel Ru(IV) salt under mild conditions (Scheme 33). Scheme 30. Ruthenium-catalyzed C2-H activation to afford tetrahydropyridoindoles.
In 2014, Dong [56] developed a simple and highly efficient Ru-catalyzed C3 alkylation of indoles with α, β-unsaturated ketones without the chelation assistance (Scheme 31). Besides indoles, a broad scope of substances, such as pyrroles and other azoles, are exhibited with further applications leading to 3,4-fused tricyclic indoles. Dong [57] also reported direct alkylation or cascade cyclization reactions on C3 of indoles (Scheme 32). With the Ru(PPh3)3Cl2 catalyst, the reaction provides C3-substituted β-ketone indoles and [Ru(p-cymene)Cl2]2 affords 5,12-dihydrobenzo [6,7] cyclohepta [1,2-b] indoles. The selective pathway may be attributed to the difference in binding affinity of a metal center with but-3-en-2-ol. In 2010, the reaction of indoles with amines was studied by Beller and his coworkers (Scheme 34). Shvo 1 was reported as a catalyst to promote the alkylation on C3 of indoles with alkylamine [60]. Such an alkylation process, based on the so-called "borrowing hydrogen methodology", which is initially dehydrogenated before undergoing a functionalization reaction, followed by a rehydrogenation reaction, led to ammonia as the only side product. In 2010, the reaction of indoles with amines was studied by Beller and his coworkers (Scheme 34). Shvo 1 was reported as a catalyst to promote the alkylation on C3 of indoles with alkylamine [60]. Such an alkylation process, based on the so-called "borrowing hydrogen methodology", which is initially dehydrogenated before undergoing a functionalization reaction, followed by a re-hydrogenation reaction, led to ammonia as the only side product. In the same year, Che's group [61] reported work involving ruthenium-catalyzed alkylation of indoles with tertiary amines by C(sp 3 )-H Bond activation and dehydrogenation coupling (Scheme 35). Interestingly, products with one carbon insertion between the para-site of the phenyl ring and C3 of the indoles were detected at good yields. A mechanism proposed in the article shows that Ru catalyst is oxidized by peroxide before participating the oxidation from the N-methyl compound to imine intermediate. Then, a molecular of formaldehyde is removed to form the one carbon insertion product with the presence of Lewis acid. There are also additional C-H functionalization reactions on C2 or C3 of indoles. Prabhu [62] selectively functionalize C-2 in the presence of highly reactive C-3 in indole derivatives using [Ru(pcymene)Cl2]2 catalyst, with a conjugate addition product instead of Heck-type product or C3 substitution achieved (Scheme 36). Wu [63] developed a Ru-catalyzed carbonylative coupling of indoles and aryl iodides for the synthesis of 3-acylindoles. However, no desired products were detected when indole or 3-methyl-1H-indole was used as the substrate, indicating that the C2 methyl group of indoles played a crucial role in this C−H activation reaction. In the same year, Che's group [61] reported work involving ruthenium-catalyzed alkylation of indoles with tertiary amines by C(sp 3 )-H Bond activation and dehydrogenation coupling (Scheme 35). Interestingly, products with one carbon insertion between the para-site of the phenyl ring and C3 of the indoles were detected at good yields. A mechanism proposed in the article shows that Ru catalyst is oxidized by peroxide before participating the oxidation from the N-methyl compound to imine intermediate. Then, a molecular of formaldehyde is removed to form the one carbon insertion product with the presence of Lewis acid. In the same year, Che's group [61] reported work involving ruthenium-catalyzed alkylation of indoles with tertiary amines by C(sp 3 )-H Bond activation and dehydrogenation coupling (Scheme 35). Interestingly, products with one carbon insertion between the para-site of the phenyl ring and C3 of the indoles were detected at good yields. A mechanism proposed in the article shows that Ru catalyst is oxidized by peroxide before participating the oxidation from the N-methyl compound to imine intermediate. Then, a molecular of formaldehyde is removed to form the one carbon insertion product with the presence of Lewis acid. There are also additional C-H functionalization reactions on C2 or C3 of indoles. Prabhu [62] selectively functionalize C-2 in the presence of highly reactive C-3 in indole derivatives using [Ru(pcymene)Cl2]2 catalyst, with a conjugate addition product instead of Heck-type product or C3 substitution achieved (Scheme 36). Wu [63] developed a Ru-catalyzed carbonylative coupling of indoles and aryl iodides for the synthesis of 3-acylindoles. However, no desired products were detected when indole or 3-methyl-1H-indole was used as the substrate, indicating that the C2 methyl group of indoles played a crucial role in this C−H activation reaction. There are also additional C-H functionalization reactions on C2 or C3 of indoles. Prabhu [62] selectively functionalize C-2 in the presence of highly reactive C-3 in indole derivatives using [Ru(p-cymene)Cl 2 ] 2 catalyst, with a conjugate addition product instead of Heck-type product or C3 substitution achieved (Scheme 36). Wu [63] developed a Ru-catalyzed carbonylative coupling of indoles and aryl iodides for the synthesis of 3-acylindoles. However, no desired products were detected when indole or 3-methyl-1H-indole was used as the substrate, indicating that the C2 methyl group of indoles played a crucial role in this C−H activation reaction. Catalysts 2020, 10,

C-H activation on C4-C7
There are fewer reports on ruthenium-catalyzed C-H functionalization of indoles on the C4 to C7. However, the use of ortho-directing groups has become the preeminent strategy. With the assistance of an aldehyde group on C3, Prabhu [64] achieved vinylation on C4 of indoles under mild conditions (Scheme 37). In this study, it was found that the reaction may involve a six membered transition state that leads to the expected 4-substituted indoles. Many sorts of olefins including α, βunsaturated esters, cyano olifins, or vinyl phosphorate can proceed in good yields. Frost [65] achieved remote C-6 selective ruthenium-catalyzed C-H alkylation of pyrimidinylindole derivatives via a C2 cyclometallation σ-activation pathway with the assistance of an ancillary directing group at the C3 position (Scheme 38). Fukui index was calculated in this work indicating that the coordination and C-H activation of the Ru at C2 gives the most active C-H at C6. A mechanism study shows that the reaction is involved in a free radical process (Scheme 39). First of all, The proposed catalytically active monomer [RuCl2(p-cymene)] is formed by breaking apart the Scheme 36. Ruthenium-catalyzed C3-H activation with other substrates.

C-H Activation on C4-C7
There are fewer reports on ruthenium-catalyzed C-H functionalization of indoles on the C4 to C7. However, the use of ortho-directing groups has become the preeminent strategy. With the assistance of an aldehyde group on C3, Prabhu [64] achieved vinylation on C4 of indoles under mild conditions (Scheme 37). In this study, it was found that the reaction may involve a six membered transition state that leads to the expected 4-substituted indoles. Many sorts of olefins including α, β-unsaturated esters, cyano olifins, or vinyl phosphorate can proceed in good yields.

C-H activation on C4-C7
There are fewer reports on ruthenium-catalyzed C-H functionalization of indoles on the C4 to C7. However, the use of ortho-directing groups has become the preeminent strategy. With the assistance of an aldehyde group on C3, Prabhu [64] achieved vinylation on C4 of indoles under mild conditions (Scheme 37). In this study, it was found that the reaction may involve a six membered transition state that leads to the expected 4-substituted indoles. Many sorts of olefins including α, βunsaturated esters, cyano olifins, or vinyl phosphorate can proceed in good yields. Frost [65] achieved remote C-6 selective ruthenium-catalyzed C-H alkylation of pyrimidinylindole derivatives via a C2 cyclometallation σ-activation pathway with the assistance of an ancillary directing group at the C3 position (Scheme 38). Fukui index was calculated in this work indicating that the coordination and C-H activation of the Ru at C2 gives the most active C-H at C6. A mechanism study shows that the reaction is involved in a free radical process (Scheme 39). First of all, The proposed catalytically active monomer [RuCl2(p-cymene)] is formed by breaking apart the Scheme 37. Ruthenium-catalyzed C4-H activation with assistance of carboxylic acid.
Frost [65] achieved remote C-6 selective ruthenium-catalyzed C-H alkylation of pyrimidinyl-indole derivatives via a C2 cyclometallation σ-activation pathway with the assistance of an ancillary directing group at the C3 position (Scheme 38). Fukui index was calculated in this work indicating that the coordination and C-H activation of the Ru at C2 gives the most active C-H at C6. A mechanism study shows that the reaction is involved in a free radical process (Scheme 39). First of all, The proposed catalytically active monomer [RuCl 2 (p-cymene)] is formed by breaking apart the dimer using KOAc.
Then, carboxylate-assisted cyclometallation at C2 occurs, including a proposed ring slip of the para-cymene to accommodate the primary and ancillary directing groups. Tertiary alkyl radical is created by the Ru(II) via single electron transfer before the cyclometalated species being attacked by the alkyl radical at the most activated vacant position, C6. After that, redox rearomatization takes place using the Ru(III) generated previously and an equivalent of potassium acetate. Protodemetalation then occurs using AcOH to give the C6 C-H alkylated product (4a).
Catalysts 2020, 10, x 22 of 28 dimer using KOAc. Then, carboxylate-assisted cyclometallation at C2 occurs, including a proposed ring slip of the para-cymene to accommodate the primary and ancillary directing groups. Tertiary alkyl radical is created by the Ru(II) via single electron transfer before the cyclometalated species being attacked by the alkyl radical at the most activated vacant position, C6. After that, redox rearomatization takes place using the Ru(III) generated previously and an equivalent of potassium acetate. Protodemetalation then occurs using AcOH to give the C6 C-H alkylated product (4a) Scheme 38. Ruthenium-catalyzed C6-H activation with assistance of carboxylic acid. Scheme 38. Ruthenium-catalyzed C6-H activation with assistance of carboxylic acid.
Catalysts 2020, 10, x 22 of 28 dimer using KOAc. Then, carboxylate-assisted cyclometallation at C2 occurs, including a proposed ring slip of the para-cymene to accommodate the primary and ancillary directing groups. Tertiary alkyl radical is created by the Ru(II) via single electron transfer before the cyclometalated species being attacked by the alkyl radical at the most activated vacant position, C6. After that, redox rearomatization takes place using the Ru(III) generated previously and an equivalent of potassium acetate. Protodemetalation then occurs using AcOH to give the C6 C-H alkylated product (4a) Scheme 38. Ruthenium-catalyzed C6-H activation with assistance of carboxylic acid.

Scheme 39. Proposed reaction mechanism.
With the assistance of the carboxyl group on the C5 position of indoles, C-H functionalization on C4 and C6 of indole scaffolds can be achieved. Larrosa's group developed a Ru-catalyzed C-H arylation reaction on indole carboxylic acids allowing access to C7-, C6-, C5-, C4-arylated indole compounds [66]. In addition, Echavarren [67] discovered ruthenium-catalyzed ortho-alkynylation of benzoic acids with bromoalkynes under mild conditions (Scheme 40). In one example of this work, 1H-indole-5-carboxylic acid was alkynylated to give the double alkynylation products in moderate yield. With the assistance of the carboxyl group on the C5 position of indoles, C-H functionalization on C4 and C6 of indole scaffolds can be achieved. Larrosa's group developed a Ru-catalyzed C-H arylation reaction on indole carboxylic acids allowing access to C7-, C6-, C5-, C4-arylated indole compounds [66]. In addition, Echavarren [67] discovered ruthenium-catalyzed ortho-alkynylation of benzoic acids with bromoalkynes under mild conditions (Scheme 40). In one example of this work, 1H-indole-5-carboxylic acid was alkynylated to give the double alkynylation products in moderate yield. With the assistance of the carboxyl group on the C5 position of indoles, C-H functionalization on C4 and C6 of indole scaffolds can be achieved. Larrosa's group developed a Ru-catalyzed C-H arylation reaction on indole carboxylic acids allowing access to C7-, C6-, C5-, C4-arylated indole compounds [66]. In addition, Echavarren [67] discovered ruthenium-catalyzed ortho-alkynylation of benzoic acids with bromoalkynes under mild conditions (Scheme 40). In one example of this work, 1H-indole-5-carboxylic acid was alkynylated to give the double alkynylation products in moderate yield.

Scheme 40.
Ruthenium-catalyzed C-H activation with the assistance of C5 carboxylic acid. C7 functionalization usually needs directing group. In 2016, Miura reported a C7 C-H activation reaction on indoles with the assistance of pyrimidine [68] (Scheme 41). This work demonstrated that N-pyridylindoles underwent regioselective acetoxylation, which is expected to be applicable to a variety of dehydrogenative C-O coupling reactions. In this year, Ackermann [69] disclosed the first ruthenium bicarboxylate-catalyzed C7-H activation of indoles via a weak coordinated unfavorable six membered ruthenacycle intermediate with pivaloyl directing group (Scheme 42). Sulfonamidation with azide as well as vinylization with unsaturated esters were reported in this work. Notable features of this strategy include unprecedented carboxylate-assisted ruthenium-catalyzed C7-H activation of indoles and expedient C7-H activations enabling amidations and alkenylations under exceedingly mild conditions. Scheme 41. Ruthenium-catalyzed C7-H activation to construct C-O bond.
In this year, Ackermann [69] disclosed the first ruthenium bicarboxylate-catalyzed C7-H activation of indoles via a weak coordinated unfavorable six membered ruthenacycle intermediate with pivaloyl directing group (Scheme 42). Sulfonamidation with azide as well as vinylization with unsaturated esters were reported in this work. Notable features of this strategy include unprecedented carboxylate-assisted ruthenium-catalyzed C7-H activation of indoles and expedient C7-H activations enabling amidations and alkenylations under exceedingly mild conditions.