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

catalysts

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

Haoran Zhu 1,2, Sen Zhao 1, Yu Zhou 1,2, Chunpu Li 1,2,* and Hong Liu 1,2,*

1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; [email protected] (H.Z.); [email protected] (S.Z.); [email protected] (Y.Z.) 2 School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China * Correspondence: [email protected] (C.L.); [email protected] (H.L.)

Received: 15 September 2020; Accepted: 23 October 2020; Published: 29 October 2020

Abstract: 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 scaffolds through C–H activation and C–H activation on indoles. Herein, we attempt to present an overview about the construction strategies of indole scaffold and site-specific modifications for indole scaffold via ruthenium-catalyzed C–H activations in recent years.

Keywords: ruthenium; C–H activation; indole

1. Introduction Substituted indoles are omnipresent in pharmaceutical industry. Some of them are the most sold drugs worldwide, presenting extraordinary efficacy in anti-cancer [1–5], 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

Catalysts 2020, 10, 1253; doi:10.3390/catal10111253 www.mdpi.com/journal/catalysts Catalysts 2020, 10, x 2 of 28

Catalysts 2020, 10, 1253 2 of 27 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 for the synthesis of indole derivatives. The currentfor the synthesisreview will of indole focus derivatives. on indole Thescaffold current construction review will focusand site-specific on indole sca modificationsffold construction via ruthenium-catalyzedand site-specific modifications C–H activations. via ruthenium-catalyzed C–H activations.

Indole Scaffold Scaffold Construction via Ruthenium-Catalyzed C–H Activation Recently, transition-metal-catalyzed carbenoid carbenoid in insertionsertion has has been developed as a widely used tool to to form form C-C C-C bond. bond. Li’s Li’sgroup group [12] reported [12] reported the facile the facileconstruction construction of 3-substituted of 3-substituted NH indoles NH andindoles 2,3-disubstituted and 2,3-disubstituted 3H-indoles 3H -indolesby Ru(II)-catalyzed by Ru(II)-catalyzed C–H activation C–H activation of imidamides of imidamides with diazo with compounds,diazo compounds, which enabled which enabledthe synthesis the synthesis of two ki ofnds two of substituted kinds of substituted indoles by indoles[4+1] annulation by [4+1] (Schemeannulation 1). (Scheme On condition1). On condition A, [RuCl A, [RuCl2(p-cymene)]2(p-cymene)]2 was 2 usedwas usedto catalyze to catalyze with with AgSbF AgSbF66 added additionally, thethe transformation transformation of ααof-diazoketoesters αα-diazoketoesters to form to C-3-substitutedform C-3-substituted indoles. Whenindoles. changing When changingthe diazo the substrate diazo substrate into αα-diazomalonate, into αα-diazomalonate, 3H-indoles 3H-indoles were given were asgiven the as designed the designed product product with with[Ru(p -cymene)(MeCN)[Ru(p-cymene)(MeCN)3](SbF36](SbF)2 participated6)2 participated as catalyst. as catalyst. They also They proposed also proposed the possible the mechanism possible mechanismof the process of (Schemethe process2). A(Scheme CMD process2). A CMD is conducted process is to conducted a fford the to metalacyclic afford the intermediatemetalacyclic intermediateA with the cyclometallation A with the cyclometallation of the imidamides. of the Then, imidamides.αα-diazoketoesters Then, αα-diazoketoesters or αα-diazomalonate or αα is- diazomalonatecoordinate to the is intermediatecoordinate to Athe before intermediate denitrogenation A before to denitrogenation generate ruthenium to generate carbene ruthenium species B. carbeneThen the species seven-membered B. Then the ruthenacyclic seven-membered intermediate ruthenacyclic C is furnished intermediate with the C migratoryis furnished insertion with the of migratorythe ruthenium-aryl insertion bond. of the After ruthenium-aryl that, intermediate bond. DAf ister then that, formed intermediate by Ru-C(alkyl) D is then migratory formed insertion by Ru- C(alkyl)into the Cmigratory=N bond. insertion For diazoketoester into the C=N substrates, bond. For protonolysis diazoketoester and substr intramolecularates, protonolysis nucleophilic and intramolecularaddition and subsequent nucleophilic elimination addition and of one subsequent molecule elimination of NH amide of one is conducted molecule withof NHNH amide-indole is conductedproduct 3 eventually with NH released-indole fromproduct D. For 3 diazomalonates,eventually released the intermediate from D. DFor undergoes diazomalonates, elimination the of intermediateammonia with D assistance undergoes of elimination Ru(II) or acetic of ammonia acid, forming with 3H assistance-indole 5 asof theRu(II) final or product. acetic acid, This forming reaction 3constitutesH-indole 5 the as the first final intermolecular product. This coupling reaction of constitu arenes withtes the diazo first substrates intermolecular by ruthenium-catalyzed coupling of arenes withC–H diazo activation, substrates which by may ruthenium-catalyzed lead to applications C–H in the ac discoverytivation, which of bioactive may lead compounds to applications with medium in the discoveryto good yields. of bioactive compounds with medium to good yields.

Scheme 1. 1. Ru-catalyzedRu-catalyzed C–H activation C–H activation for the synthesis for the of synthesis3-substituted of indole 3-substituteds or 3,3-disubstituted indoles or indoles.3,3-disubstituted indoles.

Catalysts 2020, 10, 1253 3 of 27 Catalysts 2020,, 10,, xx 3 of 28

Scheme 2. ProposedProposed reaction reaction mechanism. mechanism.

InspiredInspired by by the the high high reactivity reactivity of diazo of diazo compou compounds,nds, our group our group[13] deve [13loped] developed a highly aefficient highly syntheticeﬃcient syntheticstrategy strategyto construct to construct 3-phosphorylindole 3-phosphorylindole scaffolds sca viaﬀolds selective via selective reversible reversible C–H bond C–H N activationsbond activations of N of-phenylbenzimidamide,-phenylbenzimidamide, and andthe thesubs subsequentequent divergent divergent couplings couplings with diazophosphonate compounds compounds were were achieved achieved success successfullyfully with with Ru(II) Ru(II) catalyst catalyst systems systems (Scheme (Scheme 33).). The yields of the examples are 60–90%.

Scheme 3. Carbene insertion reaction to afford phosphorous indoles. Scheme 3. Carbene insertion reaction to afford phosphorous indoles. Alkynes are now a developing sorts of coupling partners to construct divergent scaffolds. Recently, Alkynes are now a developing sorts of coupling partners to construct divergent scaffolds. Rh-catalyzed and Pd-catalyzed C–H activation leading to the construction of indoles with alkynes Recently, Rh-catalyzed and Pd-catalyzed C–H activation leading to the construction of indoles with have emerged as a powerful strategy. In addition, Ru-catalyzed C–H activation for the synthesis of alkynes have emerged as a powerful strategy. In addition, Ru-catalyzed C–H activation for the indole scaffolds using alkynes as substrates has attracted much attention due to the high efficiency synthesis of indole scaffolds using alkynes as substrates has attracted much attention due to the high (Scheme4). In 2012, Ackermann’s group [ 14], based on their previous work and experience on efficiency (Scheme 4). In 2012, Ackermann’s group [14], based on their previous work and experience heterocycle construction, achieved [3+2] annulation of anilines bearing removable pyrimidyl group as on heterocycle construction, achieved [3+2] annulation of anilines bearing removable pyrimidyl directing group, which led to the formation of 2, 3-disubstituted indoles, with the use of the most applied group as directing group, which led to the formation of 2, 3-disubstituted indoles, with the use of the cationic ruthenium complex [RuCl (p-cymene)] as catalyst. The reaction conducting C–H/N–H bonds most applied cationic ruthenium complex2 [RuCl2 2(p-cymene)]2 as catalyst. The reaction conducting C– most applied cationic ruthenium complex [RuCl2(p-cymene)]2 as catalyst. The reaction conducting C– cleavage efficiently occurs in water as a sustainable solvent. The initiation of the proposed catalytic H/N–H bonds cleavage efficiently occurs in water as a sustainable solvent. The initiation of the cycle is the reversible cyclometallation with cationic ruthenium complex to form the key intermediate, proposed catalytic cycle is the reversible cyclometallation with cationic ruthenium complex to form a six-membered ruthenacycle. Then, the complex undergoes coordination and migratory insertion the key intermediate, a six-membered ruthenacycle. Then, the complex undergoes coordination and with the alkyne followed to furnish ruthacycle. At last, the desired product is given by reductive migratory insertion with the alkyne followed to furnish ruthacycle. At last, the desired product is elimination. The scope of the substrates has a wide range. Examples, including electron-donating given by reductive elimination. The scope of the substrates has a wide range. Examples, including groups, such as the methyl group, and electron-withdrawing groups, such as the trifluoromethyl 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

Catalysts 2020, 10, 1253 4 of 27 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, x 5 of 28

Scheme 4.SchemeRu-catalyzed 4. Ru-catalyzed C–H C–H activation activation with with alkynes and and anilines anilines to afford to a indolesﬀord indoles derivatives. derivatives.

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In 2019, the first ruthenium-catalyzed double aryl C(sp2)–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 (Scheme5). The possible mechanism was proposed (Scheme6). 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(sp2)–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 Catalysts 2020, 10, x 6 of 28 molecularCatalysts of 2a into2020, 10 the, x Ru-C bond and reductive elimination of Ru. 6 of 28

SchemeScheme 5.SchemeRuthenium(II)-catalyzed 5. Ruthenium(II)-catalyzed 5. Ruthenium(II)-catalyzed oxidative oxidative oxidative doubledouble double CC −−HHH activation activation andand annulation andannulation annulation to to a ffaordfford toindolo indolo afford indolo − [2,1-a]isoquinolines.[2,1-[2,1-a]isoquinolines.a]isoquinolines.

Scheme 6. Proposed reaction mechanism.

Inspired by the C–H activations directed by the groups on benzenes, Chen [18] and his Scheme 6. Proposed reaction mechanism. coworkers developed Ruthenium(II)-catalyzedScheme 6. Proposed [3+2] reaction annulation mechanism. of N-nitrosoanilines with alkynes for the synthesis of indole derivatives (Scheme 7). This ruthenium(II)-catalyzed C–H bond redox-neutral Inspired by the C–H activations directed by the groups on benzenes, Chen [18] and his [3+2] cycloaddition features a broad range of functional group tolerance and excellent sterically coworkers developed Ruthenium(II)-catalyzed [3+2] annulation of N-nitrosoanilines with alkynes for controlled regioselectivity. the synthesis of indole derivatives (Scheme 7). This ruthenium(II)-catalyzed C–H bond redox-neutral [3+2] cycloaddition features a broad range of functional group tolerance and excellent sterically controlled regioselectivity.

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Inspired by the C–H activations directed by the groups on benzenes, Chen [18] and his coworkers developed Ruthenium(II)-catalyzed [3+2] annulation of N-nitrosoanilines with alkynes for the synthesis of indole derivatives (Scheme7). This ruthenium(II)-catalyzed C–H bond redox-neutral [3+2] cycloaddition features a broad range of functional group tolerance and excellent sterically controlledCatalysts 2020 regioselectivity., 10, x 7 of 28

Catalysts 2020, 10, x 7 of 28

Scheme 7. Ruthenium(II)-catalyzedRuthenium(II)-catalyzed C–H C–H bond bond [3+2] [3+2] annulation annulation of ofN-nitrosoanilinesN-nitrosoanilines with with alkynes alkynes in inwater. water. Scheme 7. Ruthenium(II)-catalyzed C–H bond [3+2] annulation of N-nitrosoanilines with alkynes in water. Emma Gallo [[19]19] andand hishis coworkerscoworkers screenedscreened outout rutheniumruthenium bis-imidobis-imido Ru(TPP)(NAr)Ru(TPP)(NAr)22 complex(TPPcomplex(TPP=dianionEmma=dianion Gallo [19]of and tetraphenyltetrap hishenyl coworkers porphyrin,porphyrin, screen ed ArAr=3,5-(CF =out3,5-(CF ruthenium33)2C66HH 3bis-imido3),), also also named Ru(TPP)(NAr) rutheniumruthenium2 porphorin,porphorin,complex(TPP=dianion toto catalyzecatalyze indole of synthesissytetrapnthesishenyl from porphyrin, alkynesalkynes withwithAr=3,5-(CF aryl azideaz3)2ideC6H (Scheme3), also 8 8).named). The The alkyne alkyneruthenium interacts interacts withwith porphorin, oneone NArNAr imidoimido to catalyze ligandligand indole ofof Ru(TPP)(NAr)2Ru(TPP)(NAr)2 synthesis from alkynes to form with a residuallyaryl azide (Scheme dangling 8). C(Ph)The alkyne group, interacts forming a 55+6+6 bicyclic bicyclicwith one molecule moleculeNAr imido by byligand coupling coupling of Ru(TPP)(NAr)2 with with a C(H) a C(H) unit to form unit of the a ofresidually N-aryl the N-aryl substituent, dangling substituent, C(Ph) a two-step group, a two-step forming outer sphere a outer sphereH-migration5+6 H-migration bicyclic occurs molecule to occurs make by coupling the to make bicycle with the isomerize a bicycleC(H) unit isomerizeto of indole. the N-aryl Eventually, to substituent, indole. a Eventually, Ru(TPP)(NAr) a two-step aouter Ru(TPP)(NAr) mono-imido sphere H-migration occurs to make the bicycle isomerize to indole. Eventually, a Ru(TPP)(NAr) mono-imido mono-imidoactive catalyst active is reformed catalyst isafter reformed each afterazide/ eachalkyne azide reaction./alkyne The reaction. steric The hindrance steric hindrance of alkynes of active catalyst is reformed after each azide/alkyne reaction. The steric hindrance of alkynes alkynes influenced the reaction productivity to a greater extent than the electronic effect, as the influencedinfluenced the thereaction reaction productivity productivity to to aa greatergreater extentextent than than the the electronic electronic effect, effect, as the as mono-the mono- mono-substituted alkynes were efficiently converted into corresponding indole independently for substitutedsubstituted alkynes alkynes were were efficiently efficiently converted converted intoto correspondingcorresponding indole indole independently independently for thefor the theposition positionposition where where the thesubstituent the substituent substituent was was wasplaced, placed, placed, whilewhile while thee substitutionsubstitution the substitution on on the the phenyl on phenyl the azide phenyl azide shows azideshows lower showslower lowerselectivity.selectivity. selectivity.

SchemeScheme 8. 8.Ruthenium Ruthenium porphyrin-catalyzed C–H C–H activation activation with alkynes with alkynesand aryl andazides aryl to afford azides to aﬀordindoles. indoles.

SchemeIn the 8. methodsRuthenium above, porphyrin-catalyzed most of the catalytic C–H cycle activation needs additional with alkynes oxidant and toaryl reform azides the to catalyst afford suchindoles. 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 theIn the active methods ruthenium-based above, most catalyst, of the and catalytic the reaction, cycle needs notably, additional is operationally oxidant convenient to reform due the to catalyst a such simpleas Cu undividedsalt. Xu’s groupcell employed. [20] developed The process a ru is thenium-catalyzedinsensitive to air, proceeding electrochemical in an aqueous dehydrogenative solution. 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.

Catalysts 2020, 10, 1253 7 of 27

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 (Scheme9). Electric current is used to recycle the active ruthenium-based catalyst, and the reaction, notably, is operationally convenient due to a Catalystssimple 2020 undivided,, 10,, xx cell employed. The process is insensitive to air, proceeding in an aqueous solution.8 of 28

Scheme 9. Ruthenium-catalyzedRuthenium-catalyzed electrochemical dehydrogenative alkyne annulation.

Similarly, alkenyl groups can alsoalso bebe appliedapplied toto formform indoleindole derivativesderivatives with C–H activation reactions. Xiao Xiao [21] [21] and his coworkerscoworkers developeddeveloped aa visiblevisible light-inducedlight-induced intramolecularintramolecular cyclizationcyclization of styryl azide azide in in the the presence presence of of Ru(bpy) Ru(bpy)3Cl3Cl2, 2to, to construct construct 2-substituted 2-substituted N-freeN-free indoles indoles in ingood good to excellentto excellent yields yields with with high high func functionaltional group group tolerance. tolerance. Through Through this this method, method, 2 2 aromatic aromatic indolesindoles including electron-donatingelectron-donating phenyl phenyl and and electron-withdrawing electron-withdrawing phenyl phenyl indoles indoles are eﬃ cientlyare efficiently obtained. (Schemeobtained. 10 (Scheme). A molecular 10). A molecular of N2 is removed of N2 is underremoved irradiation under irradiation of visible light,of visible and light, then aand concerted then a concertednitrene insertion nitrene occurs insertion through occurs the through transition the statetransition to deliver state theto deliver designed the indoles. designed indoles.

Scheme 10. Ruthenium-catalyzedRuthenium-catalyzed cyclizations of styryl azides induced by visible light.

Yang’s group [22] [22] developed developed a a new new approach approach to to the the synthesis synthesis ofof 2-phosphinoylindoles 2-phosphinoylindoles from from 1- 1-isocyano-2-styrylbenzenesisocyano-2-styrylbenzenes through through photoredox photoredox cataly catalysissis (Scheme (Scheme 11).11). Unlike Unlike Xiao’s Xiao’s work, work, the the benzyl benzyl group on on the the alkenylphenylisocyanide alkenylphenylisocyanide is ultimately is ultimately substituted substituted on the on C3 the of C3the ofsynthesized the synthesized indole. Theindole. proposed The proposed mechanism mechanism of the phosphorylation/ of the phosphorylation cyclization/ cyclization reaction was reaction outlined was by outlined the author by the author (Scheme 12). The photoredox catalyst A Ru(bpy) Cl 6H O irradiated by visible light, (Scheme 12). The photoredox catalyst A Ru(bpy)3Cl2·6H2O irradiated3 2 by2 visible light, leading to the II · formationleading to of the excited formation state of B excited *RuIIII. After state Bthat,*Ru oxidation. After that,of the oxidation conjugate of thebase conjugate of B should base be of thermodynamicallyB should be thermodynamically feasible, to feasible, generate to generatephosphorus phosphorus radical radicalD. Then,D. Then, a aproton proton from diphenylphosphine oxideoxide2 2is is captured captured by by DBU. DBU. After After that, that, phosphorus phosphorus radical radicalD Dis rapidlyis rapidly trapped trapped by 1-isocyano-2-styrylbenzeneby 1-isocyano-2-styrylbenzene (1a) to(1a generate) to generate alkene alkene radical radicalE, followed E, followed by 5-exo-trig by 5-exo-trig cyclization-forming cyclization- formingbenzyl radical benzylF radical. Finally, F. Finally, the reduction the reduction in the resultingin the resulting benzyl benzyl radical radicalF by F SET by SET from from available available Ru Ruspecies speciesC should C should generate generate benzyl benzyl anion anionG andG and regenerate regenerate the the ground-state ground-state photoredox photoredox catalyst catalystA. A. rangeA range of 1-isocyano-2-styrylbenzenesof 1-isocyano-2-styrylbenzenes can can be be applied applied eﬃ efficientlyciently in in this this transformation, transformation, making making it itappealing appealing for for late-stage late-stage synthesis synthesis strategies. strategies.

Scheme 11. Ruthenium-catalyzed photoredox reactions to afford 2-phosphinoylindoles.

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Scheme 9. Ruthenium-catalyzed electrochemical dehydrogenative alkyne annulation.

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.

Scheme 10. Ruthenium-catalyzed cyclizations of styryl azides induced by visible light.

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)3Cl2·6H2O irradiated by visible light, leading to the formation of excited state B *RuII. 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 CatalystsA. A range2020, of10, 1-isocyano-2-styrylbenzenes 1253 can be applied efficiently in this transformation, making8 of 27 it appealing for late-stage synthesis strategies.

Catalysts 2020Scheme, 10, x 11. Ruthenium-catalyzedRuthenium-catalyzed photoredox photoredox reacti reactionsons to afford aﬀord 2-phosphinoylindoles. 9 of 28

Scheme 12. Proposed reaction mechanism.

Sulfur ylidesylides also also serve serve as significantas significant substrates substr formingates forming indole indole derivatives derivatives in ruthenium-catalyzed in ruthenium- catalyzedreactions. Ourreactions. lab [23 Our] developed lab [23] the developed first sulfoxonium the first ylidessulfoxonium derived ylides from a derived Ru(II)-carbene from a complex Ru(II)- carbeneinsertion complex arene C–H insertion bond arene cascade C–H reactions bond cascade to constitute reactions 3-ketoindole to constitute skeleton 3-ketoindole via C–H skeleton activation. via TheC–H catalytic activation. system The generated catalytic 3-acetyl system indole generated scaffolds 3-acetyl by C-N indole and C-S scaffolds bond cleavage by C-N with and imidamides C-S bond cleavageand sulfoxonium with imidamides ylides through and sulfoxonium a [4+1] cyclization ylides through process. a In [4+1] addition, cyclization Huang process. and his In coworkers addition, Huangdeveloped and a his method coworkers for the developed synthesis of a 2-arylindolesmethod for the with synthesisN-aryl-2-aminopyridines of 2-arylindoles andwithα -carbonylN-aryl-2- aminopyridinessulfoxonium ylides and (Scheme α-carbonyl 13). Somesulfoxonium 2-aromatic-substituted ylides (Scheme indoles 13). includingSome 2-aromatic-substituted halogenatedphenyl, indolestrifluoromethylphenyl, including halogenatedphenyl, and methoxylphenyl trifluorom indolesethylphenyl, are obtained and in good methoxylphenyl yields. 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 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.

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Scheme 12. Proposed reaction mechanism.

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

Catalystsindoles2020 including, 10, 1253 halogenatedphenyl, trifluoromethylphenyl, and methoxylphenyl indoles9 ofare 27 obtained in good yields.

Scheme 13. Ruthenium-catalyzed indole scaffold scaﬀold construction with sulfur ylides.

In 2017,2017, Dilman’sDilman’s group group [24 [24]] developed developed a methoda method for for the the synthesis synthesis of 3-fluoroindoles of 3-fluoroindoles starting starting from -CFfrom2I-substituted -CF2I-substitutedN-arylamines, N-arylamines, which waswhich mediated was mediated by a ruthenium by a ruthenium photocatalyst photocatalyst upon irradiation upon withirradiation blue light with in blue the presencelight in the of apresence substoichiometric of a substoichiometric amount of triphenylphosphine amount of triphenylphosphine (Scheme 14). The(Scheme combination 14). The of combination ruthenium photocatalyst of ruthenium and photoc triphenylphosphineatalyst and triphenylphosphine to generate fluoroalkyl to generate radicals isfluoroalkylCatalysts the key 2020 factor , radicals10, x affecting is the thekey reaction factor affecting efficiency. the reaction efficiency. 10 of 28

Scheme 14.14. Ruthenium-catalyzed ﬂuorine-containingfluorine-containing indoles inducedinduced byby visiblevisible light.light.

ThereThere are are also also additional additional methods methods using using variety variety of substrates. of substrates. According According to Shim’s report to Shim’s [25], reportsubstituted [25], indoles substituted can be indoles synthesized can be from synthesized anilines fromand alkanolammonium anilines and alkanolammonium chlorides in the chlorides presence in the presence of a ruthenium catalyst together with SnCl 2H O in moderate to good yields. of a ruthenium catalyst together with SnCl2 2H́ 2O in moderate to2· good2 yields. In this transformation, In this transformation, SnCl 2H O is important for the formation of indoles. Karvembu [26] SnCl2 2H́ 2O is important for 2the· formation2 of indoles. Karvembu [26] utilizes [RuCl2(p-cymene)]2 utilizescomplexes [RuCl containing2(p-cymene)] picolyl-based2 complexes pseudo-acylthiourea containing picolyl-based ligands to pseudo-acylthiourea form 3-isopropoxy-1 ligandsH-indole to formfrom 3-isopropoxy-1nitro 2-nitrocinnamaldehydeH-indole from and nitro 2-propan 2-nitrocinnamaldehydeol. Jana [27] and andhis 2-propanol.coworkers developed Jana [27 a] andruthenium-catalyzed his coworkers developeddivergent asynthesis ruthenium-catalyzed of 2-methylindoles divergent and synthesis indolines of 2-methylindoles via a C–H andallylation/oxidative indolines via acyclization C–H allylation cascade./oxidative The 2-methylindoles cyclization cascade. are obtained The 2-methylindoles through a C are−H obtained through a C H allylation/carboamination/β-hydride elimination/double bond isomerization allylation/carboamination/− β-hydride elimination/double bond isomerization cascade, whereas for cascade, whereas for ortho-substituted anilines, the indolines are obtained via a C H ortho-substituted anilines, the indolines are obtained via a C−−H allylationallylation/carboamination/protodemetalation/carboamination/protodemetalation cascade in triﬂuoroethanol.trifluoroethanol. Yi [[28]28] and hishis coworkerscoworkers reportedreported aa dehydrativedehydrative C–HC–H couplingcoupling reactionreaction ofof arylaminesarylamines withwith 1,2-diols1,2-diols catalyzedcatalyzed byby thethe cationiccationic ruthenium–hydrideruthenium–hydride complexcomplex toto aaffordﬀord 2-phenyl2-phenyl indolesindoles (Scheme(Scheme 15 15).).

Catalysts 2020, 10, 1253 10 of 27 Catalysts 2020, 10, x 11 of 28

Scheme 15. Ruthenium-catalyzed indole scaffold scaffold constructionconstruction with other substrates. 2. Site-Specific Modification for Indole Scaffold via Ruthenium-Catalyzed C–H Activation 2. 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 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 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. according to the site of C–H bond on indoles.

2.1. 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

Catalysts 2020, 10, 1253 11 of 27

2.1. C–H Activation on C2 and C3

CatalystsCross 2020, coupling 10, x is gradually becoming the most significant and one of the most applied reactions12 of 28 in the pharmaceutical industry. A significant number of methods exist for Ru-catalyzed functionalization functionalizationat the C2 position at of the indole C2 scapositionffolds, of such indole as alkylation, scaffolds, arylation, such as alkylation, and so on. arylation, In 2011, Ackermann and so on. [30 In] 2011,and his Ackermann coworkers [30] reported and his C–H coworkers bond arylations reported in C–H a high bond chemo- arylations and site-selectivein a high chemo- manner and using site- selectivethe removable manner directing using the group removable with aryldirecting halides group as couplingwith aryl partners.halides as Thecoupling catalytic partners. system The is catalyticreported system broadly is applicablereported broadly and tolerated applicable a variety and tolerated of valuable a variety functional of valuable groups, functional such as halogen,groups, suchcyano, as and halogen, carbonyl cyano, group, and as wellcarbonyl as additional group, as heteroaromatic well as additional moieties heteroaromatic in medium-to-good moieties yields. in medium-to-goodBased on Ackermann’s yields. work, Based in on 2015 Ackermann’s and 2018, Pilarski work, in [31 2015] and and Szostak 2018, [Pilarski32] reported [31] and the Szostak similar C–H[32] reportedarylation the reactions similar for C–H the synthesisarylation ofreactions 2-arylated for indolesthe synthesis with aryl of borate2-arylated and indoles aryl silicone with compounds,aryl borate andrespectively aryl silicone (Scheme compounds, 16). respectively (Scheme 16).

Scheme 16. Ruthenium-catalyzedRuthenium-catalyzed C–H C–H arylation on C2 of indoles.

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.

Catalysts 2020, 10, 1253 12 of 27

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 Catalystsmethylation 20202020,, 1010 of,, xx tryptophan, which may be used in the chemical biology ﬁeld or pharmaceutical industry.1313 ofof 2828

Scheme 17. Ruthenium-catalyzed C–H methylation on C2 of indoles.

Diazo compounds compounds are are critical critical and and reactive reactive substrates substrates to participate to participate all sorts all of insertion sorts of reactions insertion byreactions forming by metal forming carbenes. metal In carbenes. 2010, Yu Inreported 2010, Yu a directing reported group-free a directing approach group-free for approach C2-selective for carbenoidC2-selectivecarbenoid functionalizationfunctionalization carbenoid functionalization ofof NH indoles of NH [34]. indoles With [ 34[RuCl]. With22((p-cymene)]-cymene)] [RuCl2(p-cymene)]22 asas catalystcatalyst2 as catalystandand 2-2- aryldiazoestersand 2-aryldiazoesters as carbenoid as carbenoid source, source,2-alkylated 2-alkylated indoles indoleswere obtained were obtained in up to in96% up isolated to 96% yield. isolated In yield.2019, Gryco In 2019, [35] Gryco described [35] described the photoalkylation the photoalkylation of indoles of indoles and pyrroles and pyrroles with diazo with diazo esters. esters. C2- alkylatedC2- alkylated indoles indoles are obtained are obtained with with good good yields yields even even though though the thephotocatalyst photocatalyst loading loading is as is low as low as 0.075as 0.075 mol mol % %(Scheme (Scheme 18). 18 ).Both Both EWG EWG (electron (electron donating donating groups)–EWG- groups)–EWG- and and EWG–EDG (electron withdrawingwithdrawing groups)-substituted diazodiazo esters are suitable as alkylating alkylating agentsagents inin thisthis this transformation.transformation. transformation. For EWG-substitutedEWG-substituted substrates, substrates, the additionthe addition of a catalytic of a amountcatalytic of N,amount N-dimethyl-4-methoxyaniline of N, N-dimethyl-4--dimethyl-4- 2+ + 2+ + methoxyanilineis required to promote is required the transfer to promote from the the transfer Ru(bpy) from3* tothe Ru(bpy) Ru(bpy)3 33*,*2+ which toto Ru(bpy)Ru(bpy) has much33+,, whichwhich more hashas potential muchmuch moreto catalyze potential the reaction.to catalyze the reaction.

Scheme 18. Visible-light-inducedVisible-light-induced C–H activation cataly catalyzedzedzed by by ruthenium ruthenium with diazo compounds.compounds.

The samesame situationsituation appearsappears inin Stephenson’sStephenson’s workwork [[36].[36].36]. Substituted Substituted indolesindoles were were obtained obtained by by photoredoxphotoredox intermolecular intermolecular direct direct C–HC–H C–H functionizationfunctionization functionization withwith with indoleindole indolesss andand and diethyldiethyl diethyl bromomalonate.bromomalonate. bromomalonate. TheThe The replacement of Et3N with N, N-dimethyl-4-methoxyaniline increased the yield of desired product replacementreplacement ofof EtEt33N with N, N-dimethyl-4-methoxyaniline-dimethyl-4-methoxyaniline increasedincreased thethe yieldyield ofof desireddesired productproduct fromfrom 25%25% toto 85%.85%. Meanwhile,Meanwhile, furansfurans andand pyrrolespyrroles werewere alsoalso investigatedinvestigated andand foundfound toto workwork wellwell under the conditions. In 2017, Hansen reported a similarsimilar methodmethod andand developeddeveloped aa novelnovel visible-lightvisible-light photocatalytic double C–H functionalization of indoles to afford 2,3-difunctionalized indoles (Scheme(Scheme 19).19). MechanisticMechanistic studiesstudies indicatedindicated thatthat electrophilic C-3 bromination occurs through an

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-lightCatalysts 2020, 10 photocatalytic, x double C–H functionalization of indoles to aﬀord 2,3-difunctionalized14 of 28 indoles (Scheme 19). Mechanistic studies indicated that electrophilic C-3 bromination occurs through anindependent independent photocatalytic photocatalytic oxidation oxidation of ofbromide bromide ions ions formed formed during during the the reaction reaction to generate molecular bromine [[37].37].

Scheme 19.19.Visible-light-induced Visible-light-induced C–H activationC–H activation catalyzed catalyzed by ruthenium by withruthenium diethyl bromomalonate.with diethyl bromomalonate. In the field of drug research and development, metabolism of drugs leading to low bioavailability or toxicityIn the is field a huge of challengedrug research to be solved and developm [38]. Trifluoromethylationent, metabolism onof thedrugs active leading metabolic to low site givesbioavailability medicinal or chemists toxicity newis a huge hope challenge to guarantee to be the solved efficacy [38]. of Trifluorom drugs [39].ethylation It is clearly on importantthe active tometabolic develop site easy gives methods medicinal to realize chemists trifluoromethylation new hope to guarantee reaction the under efficacy mild of conditions drugs [39]. with It is simpleclearly startingimportant materials. to develop In 2011, easy MacMillanmethods to [40 realize] introduced trifluoromethylation a photoredox-based reaction method under allowing mild conditions for facile trifluoromethylationwith simple starting ofmaterials. heteroaromatic In 2011, systems MacMil includinglan [40] indolesintroduced without a photoredox-based the need for an arylmethod ring 2+ pre-activationallowing for facile (Scheme trifluoromethylation 20). With the Ru(phen) of heteroaromatic3 as photoredox systems catalyst, including as well indoles as trifluorosulfonyl without the chlorideneed for an as CFaryl3 source,ring pre-activation 2-CF3-indole (Scheme and 3-CF 20).3- WithN-Ac-indole the Ru(phen) were3 a2+ff asorded photoredox in this catalytic catalyst, system,as well respectively.as trifluorosulfonyl In addition, chloride on as all CF kinds3 source, of hetero- 2-CF3-indole or benzene and cycles,3-CF3-N the-Ac-indole substitutions were majorlyafforded rely in this on thecatalytic electro system, property. respectively. In 2012, Cho In addition, [41] reported on all the kinds similar of hetero- trifluoromethylation or benzene cycles, of indolethe substitutions substrates utilizingmajorly rely CF3 Ion as the CF3 electrosource. property. The trifluoromethylation In 2012, Cho [41] reaction reported can the occur similar on substituted trifluoromethylation indoles. Then, of inindole 2014, substrates continuous utilizing flow was CF used3I as to CF accelerate3 source. the The trifluoromethylation trifluoromethylation and reaction multifluoroalkylation can occur on process,substituted shortening indoles. theThen, time in from 2014 tens, continuous of hours flow to dozens was used of minutes to accelerate [42]. the trifluoromethylation and multifluoroalkylationGrowing interest in the process, utility ofshortening arylsilanes the or time heteroarylsilanes from tens of hours in synthesis to dozens [43 ]of and minutes medicinal [42]. 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.

Scheme 20. Visible-light-induced trifluoromethylation on indoles catalyzed by ruthenium.

Catalysts 2020, 10, x 14 of 28

independent photocatalytic oxidation of bromide ions formed during the reaction to generate molecular bromine [37].

Scheme 19. Visible-light-induced C–H activation catalyzed by ruthenium with diethyl bromomalonate.

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)32+ 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 Catalystssubstituted2020, 10, 1253 indoles. Then, in 2014, continuous flow was used to accelerate the trifluoromethylation14 of 27 and multifluoroalkylation process, shortening the time from tens of hours to dozens of minutes [42].

Catalysts 2020,, 10,, xx 15 of 28

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 deprotonationSchemeScheme 20. of 20.Visible-light-induced the Visible-light-induced Wheland intermediate triﬂuoromethylation trifluoromethylation of the Friedel–Crafts-type on on indoles indoles catalyzed catalyzed process. by ruthenium. by Solvent ruthenium. does not participate the overall catalysis, with only dihydrogen liberated.

SchemeScheme 21. 21.Ruthenium-catalyzed Ruthenium-catalyzed C2–H C2–H siliconization siliconization on onindoles. indoles.

SchemeScheme 22. 22.Proposed Proposed reaction mechanism. mechanism.

Pilarski [45] and his coworkers utilize [RuH2(CO)(PPh3)3] as catalyst to conduct direct C–H sililation at C2 position of NH indoles (Scheme 23). Gramines and tryptamines can be converted

Catalysts 2020, 10, 1253 15 of 27

Catalysts 2020, 10, x 16 of 28 CatalystsPilarski 2020,, 10 [,, 45 xx ] and his coworkers utilize [RuH2(CO)(PPh3)3] as catalyst to conduct direct16 C–H of 28 sililation at C2 position of NH indoles (Scheme 23). Gramines and tryptamines can be converted efficiently,efficiently, althoughalthough the the C–H C–H activation activation on C-4on siteC-4 wassite detected was detected when conductingwhen conducting mechanism mechanism research withresearch little with side reactions.little side Good-to-excellentreactions. Good-to-excelle yields ofnt designed yields productsof designed were products effectively were obtained effectively from obtaineda different from silane a different source such silane as triaryl,source such trialkyl, as triaryl,triaryl, and mixed trialkyl,trialkyl, alkyl andand/aryl mixedmixed silanes. alkyl/arylalkyl/aryl silanes.silanes.

Scheme 23. Ruthenium-catalyzed C2–H siliconization on indoles. Scheme 23. Ruthenium-catalyzed C2–H siliconization on indoles.

Alkynes also serve as a vital sortsort ofof substratessubstrates forfor C–HC–H activation.activation. In 2010, Gimeno [46] [46] and his coworkers reported a rutheniumruthenium/trifluoroacetate-cat/trifluoroacetate-catalyzedalyzed regioselective C-3-alkylation reaction of indolesindoles withwith terminalterminal alkynes,alkynes, aaffordingaffordingffording aaa branchbranbranch alkylalkyl chainchain onon thethe scascaffoldffold (Scheme(Scheme 24 24).).

Scheme 24. Ruthenium-catalyzed alkylation on C3 of indoles. Scheme 24. Ruthenium-catalyzed alkylation on C3 of indoles.

In 2016, Dixneuf’s group [47] developed an indole-fused isocoumarins synthetic method from In 2016, Dixneuf’s group [47] developed an indole-fused isocoumarins synthetic method from 1-methylindole-3-carboxylic acid by annulationannulation withwith alkynesalkynes underunder [RuCl[RuCl2(2(pp-cymene)]-cymene)]22 catalyst 1-methylindole-3-carboxylic acid by annulation with alkynes under [RuCl22(p-cymene)]22 catalyst (Scheme 2525)).. It It shows shows that that this this catalytic annulation pe performsrforms well in water, withwith medium-to-goodmedium-to-good (Scheme 25).. ItIt showsshows thatthat thisthis catalyticcatalytic annulationannulation peperforms well in water, with medium-to-good yields and regio-selectivity, with dialkylalkynes, diarylalkynes, or mixed alkynes as substrates. yields and regio-selectivity, with dialkylalkynes,, diarylalkynes,diarylalkynes, oror mixedmixed alkynesalkynes asas substrates.substrates.

Scheme 25. Ruthenium-catalyzed C2–H activa activationtion of indoles with alkynes. Scheme 25. Ruthenium-catalyzed C2–H activationtion ofof indolesindoles withwith alkynes.alkynes. Our lab [48] reported Ru(II)-catalyzed redox-neutral [3+2] annulation reactions on Our lab [48] reported Ru(II)-catalyzed redox-neutral [3+2] annulation reactions on N- N-ethoxycarbamoylOur lab [48] indolesreported with Ru(II)-catalyzed substituted alkynes redox-neutral (Scheme 26 ).[3+2] Many annulation sorts of internal reactions alkyne on show N- ethoxycarbamoyl indoles with substituted alkynes (Scheme 26). Many sorts of internal alkyne show ethoxycarbamoylgood-to-excellent regio-selectivitiesindoles with substi andtuted mild alkynes reaction (Scheme conditions, 26). Many and various sorts of aryl internal/alkyl-, alkyne alkyl /showalkyl, good-to-excellent regio-selectivities and mild reaction conditions, and various aryl/alkyl-, alkyl/alkyl, good-to-excellentand diaryl-substituted regio-selectivities alkynes are included. and mild reaction conditions, and various aryl/alkyl-, alkyl/alkyl, and diaryl-substituted alkynes are included.

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).

Scheme 24. Ruthenium-catalyzed alkylation on C3 of indoles.

In 2016, Dixneuf’s group [47] developed an indole-fused isocoumarins synthetic method from 1-methylindole-3-carboxylic acid by annulation with alkynes under [RuCl2(p-cymene)]2 catalyst (Scheme 25). It shows that this catalytic annulation performs well in water, with medium-to-good yields and regio-selectivity, with dialkylalkynes, diarylalkynes, or mixed alkynes as substrates.

Scheme 25. Ruthenium-catalyzed C2–H activation of indoles with alkynes.

Our lab [48] reported Ru(II)-catalyzed redox-neutral [3+2] annulation reactions on N- ethoxycarbamoyl indoles with substituted alkynes (Scheme 26). Many sorts of internal alkyne show

Catalystsgood-to-excellent2020, 10, 1253 regio-selectivities and mild reaction conditions, and various aryl/alkyl-, alkyl/alkyl,16 of 27 and diaryl-substituted alkynes are included.

Catalysts 2020, 10, x 17 of 28

Scheme 26. 26. Ruthenium-catalyzedRuthenium-catalyzed C2–H activa C2–Htion activation of indoles ofwith indoles alkynes withto afford alkynes Pyrroloindolone to aﬀord PyrroloindoloneScaffold. Scaﬀold.

In 2012, Haak [[49]49] andand hishis coworkerscoworkers introducedintroduced aa ruthenium-catalyzedruthenium-catalyzed functionalization of indoles and pyrroles with propargyl alcohols utilizing ruthenium complex 1Ba (Scheme(Scheme 27).27). Notably, Notably, this protocol can be used forfor thethe constructionconstruction of multi-substituted indole scascaffoldsﬀolds 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 indolesindoles [[50].50].

Scheme 27. Ruthenium-catalyzedRuthenium-catalyzed C–H activation to af aﬀfordord substituted indoles with alkynol.

Similarly,olefinsSimilarly, olefins are are widely widely used used in indole in indole substitution substitution to perform to perform vinylation vinylation or alkylation or alkylation reactions. Inreactions. 2013, Wang’s In 2013, lab Wang’s [51] and lab Song’s [51] and lab [Song’s52], respectively, lab [52], respectively, developed adeve similarloped effi acient similar protocol efficient for vinylationprotocol for selectively vinylation on C2select of indolesively assistedon C2 byof theindoles employment assisted of N,Nby -dimethylcarbamoylthe employment of moiety N,N- asdimethylcarbamoyl a directing group (Schememoiety as28 ).a Adirecting wide scope group of olefins,(Scheme including 28). A wide electron-donating scope of olefins, groups, including such as theelectron-donating phenyl group, andgroups, electron-withdrawing such as the phenyl groups, group, such and as electron-withdra sulfonyl, phosphate,wing and groups, cyano such groups, as aresulfonyl, applicable phosphate, in this and reaction. 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.

Scheme 28. Ruthenium-catalyzed C2–H activation with active olefins.

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

Catalysts 2020, 10, x 17 of 28

Scheme 26. Ruthenium-catalyzed C2–H activation of indoles with alkynes to afford Pyrroloindolone Scaffold.

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].

Scheme 27. Ruthenium-catalyzed C–H activation to afford substituted indoles with alkynol.

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 Catalysts 2020, 10, 1253 17 of 27 sulfonyl, phosphate, and cyano groups, are applicable in this reaction.

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 Scheme 28. Ruthenium-catalyzed C2–H activationactivation with active oleﬁns.olefins. be found in Wu’s work [54]. 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 29. Ruthenium-catalyzed C2–H activation with unsaturated esters.

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 SchemeScheme 29. 29.Ruthenium-catalyzed Ruthenium-catalyzed C2–HC2–H activa activationtion with with unsaturated unsaturated esters. esters. access to synthesize various indole-fused derivatives under mild conditions. 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-catalyzedRuthenium-catalyzed C2–H C2–H activation to afford aﬀord tetrahydropyridoindoles.

In 2014, Dong [56] [56] developed developed a simple simple and and highly highly efficient efficient Ru-catalyzed C3 alkylation of indoles α β with α, β-unsaturated-unsaturatedScheme ketones 30. Ruthenium-catalyzed without the chelationC2–H activation assistanceassistance to afford (Scheme tetrahydropyridoindoles. 3131).). Besides indoles, a broad scope of substances, such as pyrroles and other azol azoles,es, are are exhibited exhibited with further further applications applications leading In 2014, Dong [56] developed a simple and highly efficient Ru-catalyzed C3 alkylation of indoles to 3,4-fused tricyclic indoles. Dongwith α,[ β57-unsaturated] also reported ketones direct without alkylation the chelation or cascadeassistance cyclization (Scheme 31). reactions Besides indoles, on C3 a ofbroad indoles scope of substances, such as pyrroles and other azoles, are exhibited with further applications leading (Scheme 32). With the Ru(PPh3)3Cl2 catalyst, the reaction provides C3-substituted β-ketone indoles to 3,4-fused tricyclic 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. 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 31. Ruthenium-catalyzed C3–H activation with unsaturated esters. Scheme 31. Ruthenium-catalyzed C3–H activation with unsaturated esters. Dong [57] also reported direct alkylation or cascade cyclization reactions on C3 of indoles (Scheme 32).Dong With [57] thealso Ru(PPh reported3) 3Cldirect2 catalyst, alkylation the orreaction cascade provides cyclization C3-substituted reactions on C3β-ketone of indoles indoles and [Ru(p-cymene)Cl(Scheme 32). With 2the]2 affordsRu(PPh 35,12-dihydrobenzo)3Cl2 catalyst, the reaction [6,7] provides cyclohepta C3-substituted [1,2-b] indoles. β-ketone The indoles selective pathwayand may[Ru(p-cymene)Cl be attributed2]2 toaffords the difference 5,12-dihydrobenzo in bindin [6,7]g affinity cyclohepta of a metal [1,2-b ]center indoles. with The but-3-en-2-ol. selective pathway may be attributed to the difference in binding affinity of a metal center with but-3-en-2-ol.

Catalysts 2020, 10, x 18 of 28

Scheme 29. Ruthenium-catalyzed C2–H activation with unsaturated esters.

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 Catalystsscope2020 of, 10 substances,, 1253 such as pyrroles and other azoles, are exhibited with further applications leading18 of 27 to 3,4-fused tricyclic indoles.

Catalysts 2020, 10, x 19 of 28

SchemeScheme 31. 31.Ruthenium-catalyzed Ruthenium-catalyzed C3–H activa activationtion with with unsaturated unsaturated esters. esters. Catalysts 2020, 10, x 19 of 28 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.

Scheme 32. Ruthenium-catalyzed C3–H activation with allylic alcohol.

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 usingScheme Schemeallyl 32.alcohol 32.Ruthenium-catalyzed Ruthenium-catalyzed as substrate with C3–H a novel activa activation Ru(IV)tion withsalt with underallylic allylic alcohol.mild alcohol. conditions (Scheme 33). 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).

SchemeScheme 33. 33.Ruthenium-catalyzed Ruthenium-catalyzed C3–H activa activationtion with with allylic allylic alcohol. alcohol.

In 2010,In 2010, the reactionthe reaction of indoles of indoles with with amines amines was was studied studied by by Beller Beller andand hishis coworkerscoworkers (Scheme (Scheme 34). Shvo34). 1 was Shvo reported 1 was asreported a catalyst as a to catalyst promote to thepromote alkylation the alkylation on C3 of indoleson C3 of with indoles alkylamine with alkylamine [60]. Such an [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,Scheme led 33. to Ruthenium-catalyzed ammonia as the only C3–H side activa product.tion with allylic alcohol.

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.

Catalysts 2020, 10, 1253 19 of 27 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,Catalysts 2020 led, 10 to, x ammonia as the only side product. 20 of 28

Scheme 34. Ruthenium-catalyzed C3–H alkylationalkylation with alkylated amines.

InIn thethe samesame year,year, Che’sChe’s groupgroup [[61]61] reportedreported workwork involvinginvolving ruthenium-catalyzedruthenium-catalyzed alkylationalkylation ofof 3 indolesindoles withwith tertiarytertiary amines amines by by C(sp C(sp)–H3)–H Bond Bond activation activation and and dehydrogenation dehydrogenation coupling coupling (Scheme (Scheme 35). Interestingly,35). Interestingly, products products with with one carbonone carbon insertion insertion between between the para-site the para-site of the of phenyl the phenyl ring and ring C3 and of theC3 of indoles the indoles were detected were detected at good at yields. good yields. A mechanism A mechanism proposed proposed in the article in the shows article that shows Ru catalystthat Ru iscatalyst oxidized is oxidized by peroxide by peroxide before participating before participating the oxidation the oxidation from the fromN-methyl the N-methyl compound compound to imine to intermediate.imine intermediate. Then, aThen, molecular a molecular of formaldehyde of formaldehy is removedde is removed to form to the form one carbonthe one insertion carbon insertion product withproduct the with presence the presence of Lewis of acid. Lewis acid.

Scheme 35. Ruthenium-catalyzed C3–H activationactivation with methylated amines.

There areare alsoalso additionaladditional C–HC–H functionalizationfunctionalization reactionsreactions onon C2C2 oror C3C3 ofof indoles.indoles. PrabhuPrabhu [[62]62] selectively functionalize functionalize C-2 C-2 in in the the presence presence of highly of highly reactive reactive C-3 in C-3 indole in indole derivatives derivatives using [Ru( usingp- [Ru(p-cymene)Cl2]2 catalyst, with a conjugate addition product instead of Heck-type product or C3 cymene)Cl2]2 catalyst, with a conjugate addition product instead of Heck-type product or C3 substitution achieved (Scheme(Scheme 3636).). Wu Wu [63] [63] developed a Ru-catalyzedRu-catalyzed carbonylativecarbonylative couplingcoupling ofof indolesindoles andand aryl aryl iodides iodides for for the the synthesis synthesis of 3-acylindoles. of 3-acylindoles. However, However, no desired no desired products products were detected were H whendetected indole when or indole 3-methyl-1 or 3-methyl-1-indoleH was-indole used was as the used substrate, as the substrate, indicating indicating that the C2 that methyl the C2 group methyl of indoles played a crucial role in this C H activation reaction. group of indoles played a crucial role− in this C−H activation reaction.

Catalysts 2020, 10, 1253 20 of 27 Catalysts 2020, 10, x 21 of 28

Catalysts 2020, 10, x 21 of 28

Scheme 36. Ruthenium-catalyzed C3–H activationactivation with other substrates. Scheme 36. Ruthenium-catalyzed C3–H activation with other substrates. 2.2. C–H Activation on C4–C7 2.2. C–H2.2. C–Hactivation activation on C4–C7on C4–C7 There are fewer reports on ruthenium-catalyzed C–H functionalization of indoles on the C4 to C7. ThereThere are arefewer fewer reports reports on on ruthenium-catalyzed ruthenium-catalyzed C–C–HH functionalization functionalization of indolesof indoles on the on C4 the to C4 to However, the use of ortho-directing groups has become the preeminent strategy. With the assistance of C7. However,C7. However, the theuse use of ofortho-directing ortho-directing groupsgroups hashas becomebecome the the preeminent preeminent strategy. strategy. With With the the an aldehyde group on C3, Prabhu [64] achieved vinylation on C4 of indoles under mild conditions assistanceassistance of an of aldehyde an aldehyde group group on on C3, C3, Prabhu Prabhu [64] achievedachieved vinylation vinylation on onC4 C4of indoles of indoles under under mild mild (Scheme 37). In this study, it was found that the reaction may involve a six membered transition state conditionsconditions (Scheme (Scheme 37). 37). In Inthis this study, study, it it was was fofound thatthat the the reaction reaction may may involve involve a six a memberedsix membered that leads to the expected 4-substituted indoles. Many sorts of oleﬁns including α, β-unsaturated transitiontransition state state that that leads leads to tothe the expected expected 4-subs 4-substituted indoles. indoles. Many Many sorts sorts of olefinsof olefins including including α, β- α, β- esters, cyano oliﬁns, or vinyl phosphorate can proceed in good yields. unsaturatedunsaturated esters, esters, cyano cyano olif olifins,ins, or or vinyl vinyl phosphorate phosphorate ca cann proceed proceed in ingood good yields. yields.

SchemeScheme 37. 37.Ruthenium-catalyzed Ruthenium-catalyzed C4–HC4–H activation wi withth assistance assistance of carboxylic of carboxylic acid. acid.

FrostFrost [65] achieved[65] achieved remote remote C-6 selectiveC-6 selective ruthenium-catalyzed ruthenium-catalyzed C–H C–H alkylation alkylation of of pyrimidinyl-indole pyrimidinyl- Scheme 37. Ruthenium-catalyzed C4–H activation with assistance of carboxylic acid. derivativesindole derivatives via a C2 cyclometallation via a C2 cyclometallationσ-activation σ-activation pathway pathway with the with assistance the assistance of an of ancillary an ancillary directing directing group at the C3 position (Scheme 38). Fukui index was calculated in this work indicating groupFrost at the [65] C3 achieved position remote (Scheme C-6 38 ).selective Fukui indexruthenium-catalyzed was calculated inC–H this alkylation work indicating of pyrimidinyl- that the that the coordination and C–H activation of the Ru at C2 gives the most active C–H at C6. A coordination and C–H activation of the Ru at C2 gives the most active C–H at C6. A mechanism study indolemechanism derivatives study via shows a C2 cyclometallation that the reaction is σ involved-activation in apathway free radical with process the assistance (Scheme 39). of anFirst ancillary of shows that the reaction is involved in a free radical process (Scheme 39). First of all, The proposed directingall, The group proposed at the catalytically C3 position active (Scheme monomer 38). [RuClFukui2( pindex-cymene)] was iscalculated formed by in breaking this work apart indicating the catalytically active monomer [RuCl2(p-cymene)] is formed by breaking apart the dimer using KOAc. 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

Catalysts 2020, 10, 1253 21 of 27 Catalysts 2020, 10, x 22 of 28

Catalysts 2020, 10, x 22 of 28 Then,dimer using carboxylate-assisted KOAc. Then, carboxylat cyclometallatione-assisted at cyclometallation C2 occurs, including at C2 occurs, a proposed including ring a slip proposed of the para-cymenering slipdimer of using the to para-cymene accommodateKOAc. Then, carboxylatto the accommodate primarye-assisted and the cyclometallation ancillary primary directing and at ancillary C2 groups.occurs, directing including Tertiary groups. a alkyl proposed radical Tertiary is alkylcreated ringradical by slip the ofis Ru(II) thecreated para-cymene via by single the Ru(II) electronto accommodate via transfer single the beforeel ectronprimary the transfer and cyclometalated ancillary before directing the species cyclometalated groups. being Tertiary attacked species by beingthe alkylalkyl attacked radical radical by atis thecreatedthe most alkyl by activated theradical Ru(II) vacantat via the single position,most el ectronactivated C6. transfer After vacant that, before redoxposition, the rearomatizationcyclometalated C6. After speciesthat, takes redox place rearomatizationusingbeing the Ru(III)attacked takes generated by placethe alkyl previouslyusing radical the Ru(III)at and the anmost genera equivalent activatedted previously ofvacant potassium position, and an acetate. C6.equivalent After Protodemetalation that, of potassiumredox acetate.thenrearomatization occurs Protodemetalation using AcOH takes toplace then give using occurs the C6the using C–HRu(III) alkylatedAcOH genera tedto productgive previously the (C64a ).and C–H an alkylated equivalent product of potassium (4a) acetate. Protodemetalation then occurs using AcOH to give the C6 C–H alkylated product (4a)

SchemeScheme 38. 38.Ruthenium-catalyzedRuthenium-catalyzed Ruthenium-catalyzed C6–H C6–H activation wi wi withthth assistance assistance of carboxylicof carboxylic acid. acid.

Scheme 39. Proposed reaction mechanism.

Catalysts 2020, 10, x 23 of 28

Scheme 39. Proposed reaction mechanism. Catalysts 2020, 10, x 23 of 28 CatalystsWith2020 the, 10, assistance 1253 of the carboxyl group on the C5 position of indoles, C–H functionalization22 of 27 on C4 and C6 of indole scaffoldsScheme can be 39. achieved. Proposed reaction Larrosa’s mechanism. group developed a Ru-catalyzed C–H arylation reaction on indole carboxylic acids allowing access to C7-, C6-, C5-, C4-arylated indole With the assistance of the carboxyl group on the C5 position of indoles, C–H functionalization compoundsWith the [66]. assistance In addition, of the Echavarren carboxyl group [67] ondisc theovered C5 position ruthenium-catalyzed of indoles, C–H ortho-alkynylation functionalization onof C4 andon C6C4 ofand indole C6 of sca indoleﬀolds scaffolds can be achieved.can be achieved. Larrosa’s Larrosa’s group group developed developed a Ru-catalyzed a Ru-catalyzed C–H C–H arylation benzoicarylation acids reactionwith bromoalkynes on indole carboxylic under mildacids conditallowingions access (Scheme to C7-, 40). C6-, In C5-,one C4-arylatedexample of indole this work, reaction on indole carboxylic acids allowing access to C7-, C6-, C5-, C4-arylated indole compounds [66]. 1H-indole-5-carboxyliccompounds [66]. In addition, acid was Echavarren alkynylated [67] todisc giveovered the ruthenium-catalyzed double alkynylation ortho-alkynylation products in moderate of Inyield. addition,benzoic Echavarrenacids with bromoalkynes [67] discovered under ruthenium-catalyzed mild conditions (Scheme ortho-alkynylation 40). In one example of benzoic of this work, acids with bromoalkynes1H-indole-5-carboxylic under mild conditionsacid was alkynylated (Scheme 40 to). give In one the exampledouble alkynylation of this work, products 1H-indole-5-carboxylic in moderate acid wasyield. alkynylated to give the double alkynylation products in moderate yield.

SchemeScheme 40. Ruthenium-catalyzed40. Ruthenium-catalyzed C–H C–H activationactiactivation with with the the assistance assistance of C5 of C5carboxylic carboxylic acid. acid.

C7 functionalizationC7 functionalization usuallyusually usually needsneeds needs directingdirecting directing group.group. In In 2016, 2016, Miura Miura reported reported a C7 a C–H C7 C–H activation activation reactionreaction onon indolesindoles on indoles withwith with thethe the assistanceassistance assistance ofof of pyrimidinepyrimidine pyrimidine [68] [[68]68] (Scheme (Scheme(Scheme 41). 4141). This). This work work demonstrated demonstrated that that N-pyridylindoles underwent regioselective acetoxylation, which is expected to be applicable to a N-pyridylindoles underwent regioselective acetoxylat acetoxylation,ion, which which is is expected to be applicable to aa variety of dehydrogenative C–O coupling reactions. variety ofof dehydrogenativedehydrogenative C–O C–O coupling coupling reactions. reactions.

Scheme 41. Ruthenium-catalyzed C7–H activation to construct C–O bond. Scheme 41. Ruthenium-catalyzed C7–H activation to construct C–O bond. In this year,Scheme Ackermann 41. Ruthenium-catalyzed [69] disclosed C7–Hthe first activa rutheniumtion to construct bicarboxylate-catalyzed C–O bond. C7–H activation of indoles via a weak coordinated unfavorable six membered ruthenacycle intermediate In this year, Ackermann [69] disclosed the ﬁrst ruthenium bicarboxylate-catalyzed C7–H activation withIn this pivaloyl year, directing Ackermann group [69](Scheme disclosed 42). Sulfonamidation the first ruthenium with azide bicarboxylate-catalyzed as well as vinylization with C7–H ofactivation indolesunsaturated viaof indoles a weak esters coordinatedvia were a weak reported coordinated unfavorable in this unfa sixwork memberedvorable. Notable six ruthenacycle memberedfeatures of intermediateruthenacyclethis strategy withintermediateinclude pivaloyl directingwith unprecedentedpivaloyl group directing (Scheme carboxylate-assisted group42). Sulfonamidation (Scheme ruthenium-cata 42). Sulfonamidation with azidelyzed as C7–H well with asactivation vinylization azide asof indoleswell with as and unsaturatedvinylization expedient esters with wereunsaturatedC7–H reported activations inesters this work.enablingwere Notablereported amidations features in and this of alke thisworknylations strategy. Notable under include exceedingly features unprecedented mildof this conditions. carboxylate-assisted strategy include ruthenium-catalyzedunprecedented carboxylate-assisted C7–H activation ruthenium-cata of indoles andlyzed expedient C7–H C7–H activation activations of indoles enabling and amidations expedient andC7–H alkenylations activations enabling under exceedingly amidations mild and conditions.alkenylations under exceedingly mild conditions.

Catalysts 2020, 10, 1253 23 of 27 Catalysts 2020, 10, x 24 of 28

Scheme 42. C7–H activation with the chelation of N-Piv and ruthenium.

3. Summary The importance of indoles as valuable structural subunits in pharmaceuticals, natural products, and biologicallybiologically active active compounds compounds means means that newthat syntheticnew synthetic methods methods are being are perpetually being perpetually developed. Thedeveloped. last two The decades last two have decades seen a remarkable have seen a development remarkable ofdevelopment ruthenium-catalyzed of ruthenium-catalyzed C–H activations C–H for theactivations synthesis for of the indole synthesis derivatives. of indole There derivatives. are still many There challenges are still many to overcome, challenges such to asovercome, the control such of regioselectivity at other C H sites than at the ortho-position of directing groups or the development of as the control of regioselectivity− at other C−H sites than at the ortho-position of directing groups or newthe development directing groups. of new Moreover, directing installation groups. Moreover, and removal installation of directing and removal auxiliaries of directing decrease theauxiliaries overall edecreaseﬃciency the of theoverall C–H efficiency activation of process. the C–H More activati importantly,on process. enantioselective More importantly, C–H enantioselective functionalization C– areH functionalization highly desired to are produce highly indole desired derivatives, to produce and indole the derivatives, relevant methodologies and the relevant should methodologies also be paid considerableshould also be attention paid considerable in this area. attention Therefore, in furtherthis area. developments Therefore, further are expected developments to be able are to expected address theseto be able questions. to address these questions.

Author Contributions: Design, C.L. and Y.Z.; writing—original draft preparation, H.Z. and S.Z.; writing—review andAuthor editing, Contributions: H.Z., S.Z. and Design, H.L.; editing,C.L. and C.L. Y.Z.; and writing—original Y.Z. All authors have draft read preparation, and agreed H.Z. to the and published S.Z.; writing— version ofreview the manuscript. and editing, H.Z., S.Z., and H.L.; editing, C.L. and Y.Z. All authors have read and agreed to the published Funding:version of Wethe aremanuscript. grateful to the National Natural Science Foundation of China (No. 81620108027, 21632008 and 91229204), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050411 and Funding: We are grateful to the National Natural Science Foundation of China (No. 81620108027, 21632008 and XDA12020375) and the Youth Innovation Promotion Association CAS for financial support. 91229204), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050411 and Conflicts of Interest: The author declares no conflict of interest. XDA12020375) and the Youth Innovation Promotion Association CAS for financial support.

ReferencesConflicts of Interest: The author declares no conflict of interest.

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