Recent Progress Concerning the N-Arylation of Indoles

molecules

Review Review RecentRecent ProgressProgress Concerningconcerning the the NN-Arylation-Arylation of of Indoles Indoles Petr Oeser, Jakub Koudelka, Artem Petrenko and Tomáš Tobrman * Petr Oeser, Jakub Koudelka , Artem Petrenko and Tomáš Tobrman *

Department of Organic Chemistry, University of Chemistry and Technology, 16628 Prague, Czech Republic; [email protected] of Organic (P.O.); Chemistry, [email protected] University of Chemistry (J.K.); [email protected] and Technology, 16628 (A.P.) Prague, Czech Republic; [email protected]* Correspondence: (P.O.); [email protected] [email protected] (J.K.); [email protected] (A.P.) * Correspondence: [email protected] Abstract: This review summarizes the current state-of-the-art procedures in terms of the prepara- Abstract:tion of N-arylindoles.This review summarizesAfter a short the intr currentoduction, state-of-the-art the transition-metal procedures-free in procedures terms of the available preparation for oftheN N-arylindoles.-arylation of After indoles a short are briefly introduction, discussed. the Th transition-metal-freeen, the nickel-catalyzed procedures and palladium-catalyzed available for the NN-arylation-arylation ofof indoles are brieflyboth discussed. discussed. In Then,the next the section, nickel-catalyzed copper-catalyzed and palladium-catalyzed procedures for the NN-arylation-arylation ofof indolesindoles areare bothdescribed. discussed. The final In the sectio nextn section,focuses copper-catalyzedon recent findings procedures in the field forof bio- the Nlogically-arylation active of indolesN-arylindoles. are described. The final section focuses on recent findings in the field of biologically active N-arylindoles. Keywords: N-arylation; indole; Buchwald–Hartwig amination; Ullmann condensation; Chan–Lam Keywords:coupling N-arylation; indole; Buchwald–Hartwig amination; Ullmann condensation; Chan– Lam coupling

1. Introduction 1. Introduction Heterocyclic compounds are cyclic compounds that each contain either a heteroatom Heterocyclic compounds are cyclic compounds that each contain either a heteroatom or a number of heteroatoms. Among the most important groups of heterocyclic com- orpounds a number are ofthe heteroatoms. aromatic heterocyclic Among the comp mostounds. important Well-known groups of heterocyclicexamples of compounds such com- Citation: Oeser, P.; Koudelka, J.; arepounds the aromaticinclude pyridine, heterocyclic pyrrole, compounds. thiophene, Well-known and furan. Indoles examples occupy of such a unique compounds position Petrenko,Citation: A.;Oeser, Tobrman, P.; Koudelka, T. Recent J.; includewithin the pyridine, field of pyrrole, heterocyclic thiophene, compounds. and furan. An Indolesindole is occupy a condensed a unique compound position within that is Petrenko, A.; Tobrman, T. Recent Progress Concerning the N-Arylation thecomposed field of heterocyclicof a benzene compounds. and pyrrole Ancore. indole The isimportance a condensed of indoles compound and thattheir is derivatives composed Progress ConcerningMolecules 2021 the 26 of a benzene and pyrrole core. The importance of indoles and their derivatives is illustrated of Indoles. , , 5079. is illustrated by the examples shown in Figure 1. Tryptophan is an aromatic essential https://doi.org/10.3390/N-Arylation of Indoles. Molecules by the examples shown in Figure1. Tryptophan is an aromatic essential amino acid, amino acid, and sattazolin [1] and umifenovir [2] are indole derivatives with antiviral ef- molecules261650792021, 26, 5079. https://doi.org/ and sattazolin [1] and umifenovir [2] are indole derivatives with antiviral effects. N- fects. N-arylated indoles also belong to the group of important indole derivatives. An ex- 10.3390/molecules26165079 arylated indoles also belong to the group of important indole derivatives. An example ample of such a compound is sertindole, which is used as an antipsychotic drug [3]. Due Academic Editors: David StC Black of such a compound is sertindole, which is used as an antipsychotic drug [3]. Due to the to the significant biological activity of the indole derivatives, much attention has been andAcademic Naresh Editors: Kumar David StC Black significant biological activity of the indole derivatives, much attention has been paid to the paid to the modification of the indole unit [4–8]. and Naresh Kumar modification of the indole unit [4–8]. Received: 31 July 2021 H Accepted:Received: 1831 AugustJuly 2021 2021 N Published:Accepted: 2218 August 2021 O N Published: 22 August 2021

Publisher’s Note: MDPI stays neutral O N Publisher’s Note: MDPI stays neu- with regard to jurisdictional claims in CO2H Me2N tral with regard to jurisdictional published maps and institutional afﬁl- CO2Et NH2 OH HO Cl iations.claims in published maps and institutional affiliations. N N Br N SPh N H H Me tryptofan (+)-sattazolin umifenovir (arbidol)

Copyright: © 2021 by the authors. F Copyright: © 2021 by the authors. Li- Licensee MDPI, Basel, Switzerland. sertindole censee MDPI, Basel, Switzerland. This article is an open access article This article is an open access article FigureFigure 1.1. SelectedSelected examplesexamples ofof importantimportant indoleindole derivatives.derivatives. distributed under the terms and distributed under the terms and con- conditions of the Creative Commons ditions of the Creative Commons At- TheThe signiﬁcantsignificant biologicalbiological activityactivity exhibitedexhibited byby sertindolesertindole hashas inspiredinspired thethe searchsearch forfor Attribution (CC BY) license (https:// tribution (CC BY) license (http://crea- newnew procedures for for the the preparation preparation of of N-arylindoles.N-arylindoles. Every Every indole indole contains contains a pyrrole a pyrrole core, creativecommons.org/licenses/by/ tivecommons.org/licenses/by/4.0/). core, so it can be expected that the N-arylation of indoles will proceed in a similar manner 4.0/).

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so it can be expected that the N-arylation of indoles will proceed in a similar manner to the N-arylation of pyrroles. Among the group of aromatic heterocyclic compounds with one heteroatom, pyrrole is unique in terms of its reactivity. Unlike pyrrole, modifications of heteroatoms in furan and thiophene to form stable derivatives of the starting compound are not feasible. In some cases, phospholes can be P-arylated to form pentasubstituted phospholes [9], although the reactivity of the phosphole is affected by its low aromaticity Molecules 2021, 26, 5079 2 of 44 [10–13]. By contrast, pyrroles can be very easily arylated at position 1 [14,15] or 2 [16,17]. In addition, the dearomatizations of pyrroles are important [18–22]. Similar reactivity can to the N-arylation of pyrroles. Among the group of aromatic heterocyclic compounds withbe expected one heteroatom, even pyrrole in isthe unique case in termsof indole of its reactivity. arylations. Unlike pyrrole,The typical modifi- approach for the N-arylation cationsof amines, of heteroatoms including in furan nitrogen-containing and thiophene to form stable derivativesheteroaromatic of the starting compounds, involves the use of compound are not feasible. In some cases, phospholes can be P-arylated to form penta- substitutedtransition-metal-catalyzed phospholes [9], although the reactions reactivity of the (Scheme phosphole is1). affected In these by its lowcases, Ullman condensation [23– aromaticity25], Buchwald–Hartwig [10–13]. By contrast, pyrroles amination can be very easily[26–28], arylated and at position Chan–Lam 1 [14,15] coupling [29–31] are all fre- or 2 [16,17]. In addition, the dearomatizations of pyrroles are important [18–22]. Similar reactivityquently can used. be expected A common even in the case feature of indole arylations.of these The procedures typical approach is for the the reaction of amines with orga- Nnohalides-arylation of amines, or boronic including nitrogen-containingacids in the presence heteroaromatic of compounds,a transition involves metal catalyst and a base. A rel- the use of transition-metal-catalyzed reactions (Scheme1). In these cases, Ullman conden- sationatively [23–25 large], Buchwald–Hartwig number of amination N-arylation [26–28], and reactions Chan–Lam couplingof indoles [29–31] have are been reported over the last alldecade. frequently However, used. A common to featurethe best of these of proceduresour knowledge, is the reaction only of amines a few with review articles have addressed organohalides or boronic acids in the presence of a transition metal catalyst and a base. A relativelythe preparation large number of ofN-arylation N-arylindoles reactions of indoles[32–34]. have beenThus, reported we overdeci theded last to summarize the procedures decade.that have However, been to the used best of ourfor knowledge, the preparation only a few review of N articles-arylindoles have addressed over the past decade. The scope the preparation of N-arylindoles [32–34]. Thus, we decided to summarize the procedures thatof havethe beenpresent used for review the preparation is limite of N-arylindolesd to works over the that past decade. focused The scope on the N-arylation of indoles or ofotherwise the present review significantly is limited to workscontributed that focused to on this the N field.-arylation of indoles or otherwise significantly contributed to this field.

SchemeScheme 1. Transition-metal-catalyzed 1. Transition-metal-catalyzed approaches to N-arylamines. approaches to N-arylamines. 2. Transition-Metal-Free N-Arylation of Indoles 2. Transition-Metal-FreeThe preparation of N-arylindoles N without-Arylation transition of metal Indoles catalysts can be easily carried out using benzynes. This approach was ﬁrst reported in 2018 (Scheme2)[ 35]. In this study,The thepreparation starting indole ofS2-1 Nwas-arylindoles treated with 2-bromoacetophenone without transition (S2-2 )me in tal catalysts can be easily car- the presence of tBuOK to produce N-phenylindole S2-3 in a 66% yield. The proposed mechanismried out accounts using for benzynes. the formation This of a benzyne approach intermediate was (S2-6 firs) andt reported ketene (S2-5 )in 2018 (Scheme 2) [35]. In this fromstudy, the enolate the startingS2-4. The scope indole of the S2-1 reaction was is limited treated to the with indole 2-bromoacetophenoneS2-3. However, (S2-2) in the pres- Chen and Wu published another benzyne-involving route to functionalized indoles, which t inence contrast, of furnishesBuOK mainly to produce C3-arylated N indole-phenylindole derivatives, along S2-3 with N -arylatedin a 66% indoles yield. The proposed mechanism asaccounts side-products for [36 ].the formation of a benzyne intermediate (S2-6) and ketene (S2-5) from the enolate S2-4. The scope of the reaction is limited to the indole S2-3. However, Chen and Wu published another benzyne-involving route to functionalized indoles, which in contrast, furnishes mainly C3-arylated indole derivatives, along with N-arylated indoles as side-products [36].

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Scheme 2. N-arylation of an indole using a benzyne intermediate.

The second and seemingly most frequently used approach is based on nucleophilic aromatic substitution.SchemeScheme The 2. 2.N N-arylation -arylationintramolecular of anof indolean indole usingN-arylation using a benzyne a benzyne intermediate.of indoles intermediate. S3-1 was used for the preparation of dibenzo[b,f][1,4]oxazepines S3-3 (Scheme 3) [37]. Based on the general re- TheThe second second and and seemingly seemingly most most frequently frequently used approachused approach is based is on based nucleophilic on nucleophilic action, it appearsaromatic aromaticthat the substitution. substitution.methodology The The intramolecularrelies intramolecular on SmilesN-arylation N rearrangement.-arylation of indoles of indolesS3-1 Thiswas S3-1 assumption used was for used the for the preparation of dibenzo[b,f][1,4]oxazepines S3-3 (Scheme3)[ 37]. Based on the general has been experimentallypreparation confirmed, of dibenzo[b,f][1,4]oxazepines and the proposed mechanism S3-3 (Scheme assumes 3) [37]. Based the formation on the general re- reaction, it appears that the methodology relies on Smiles rearrangement. This assumption of diaryl ether S3-4hasaction,, beenwhich it experimentally appears is converted that conﬁrmed,the methodologyinto the and N the-arylated proposedrelies on mechanismindoleSmiles rearrangement.S3-3 assumes by means the formation This of assumptionthe Smiles rearrangement.ofhas diaryl been Selected ether experimentallyS3-4 examples, which isconfirmed, converted (S3-3a–S3-3c and into th thee) N proposedshow-arylated that mechanism indole theS3-3 describedby assumes means proce- ofthe the formation dure works in relationSmilesof diaryl rearrangement.to theether preparation S3-4, Selectedwhich ofis examples convertedpyridine (S3-3a–S3-3c intoderivatives the) N show-arylated of that S3-3b the indole described and S3-3 in procedure theby meanscase of the of the regioisomerworksSmiles S3-3c in rearrangement. relationof the tostarting the preparation Selected materials ofexamples pyridine S3-2. derivatives(S3-3a–S3-3c of S3-3b) showand that in thethe case described of the proce- regioisomerdure worksS3-3c in relationof the starting to the preparation materials S3-2 of. pyridine derivatives of S3-3b and in the case of the regioisomer S3-3c of the starting materials S3-2.

Scheme 3. Preparation of dibenzo[b,f][1,4]oxazepines S3-3 by means of Smiles rearrangement. SchemeScheme 3. Preparation 3. Preparation of dibenzo[b,f][1,4]oxazepines of dibenzo[b,f][1,4]oxazepines S3-3 S3-3by means by means of Smiles of rearrangement. Smiles rearrangement. A similar concept for the N-arylation of indoles, which is based on intramolecular A similar concept for the N-arylation of indoles, which is based on intramolecular nu- A similar conceptcleophilicnucleophilic for aromatic the aromatic N substitution,-arylation substitution, hasof beenindoles, has described been which described by both is based Annareddygari by both on intramolecularAnnareddygari [38] and Chen [38] and nucleophilic aromaticMaChen [39 substitution,]Ma (Scheme [39] (Scheme4). The has ﬁrst 4). been procedureThe first described procedur for the preparation bye for both the Annareddygaripreparation of indolo[1,2-a]quinoxalines of indolo[1,2-a]quinox- [38] and Chen Ma [39] (SchemeS4-3alinesmakes 4).S4-3 The usemakes first of the use procedur condensation of the condensatione for reaction the preparation of reaction 2-formylindole of of 2-formylindole indolo[1,2-a]quinox-S4-1 with substituted S4-1 with substi- anilinestuted anilinesS4-2 in S4-2N,N-dimethylformamide in N,N-dimethylformamide (DMF) at 120(DMF)◦C. Similarly,at 120 °C. the Similarly, condensation– the condensa- alines S4-3 makes use of the condensation reaction of 2-formylindole S4-1 with substi- intramolecular-basedtion–intramolecular-based transition-metal-free transition-metal-free arylation approach arylation was usedapproach by Ngernmeesri was used by tuted anilines S4-2forNgernmeesri in the N synthesis,N-dimethylformamide for of the indolo[1,2-a]quinolines synthesis of indolo[1,2-a]q (DMF) [40 ].at Ma’s 120uinolines procedure°C. Similarly, [40]. starts Ma’s with the procedure amidescondensa-S4-4 starts, with tion–intramolecular-basedamides S4-4 ,transition-metal-free and the N-arylation of thearylation indole is achievedapproach via doublewas intramolecularused by nu- Ngernmeesri for thecleophilic synthesis aromatic of indolo[1,2-a]q substitution. Inuinolines both cases, [40]. the Ma’sscope procedureof the studied starts reaction with was lim- amides S4-4, and itedthe toN -arylationthe preparation of the of indole five indole is achieved derivatives, via S4-6double. Intramolecular intramolecular nucleophilic nu- aro- cleophilic aromaticmatic substitution. substitution In has both also cases,been used the forscope the preparationof the studied of 9H reaction-pyrrolo[1,2-a]indol-9-ones was limited to the preparation of five indole derivatives, S4-6. Intramolecular nucleophilic aromatic substitution has also been used for the preparation of 9H-pyrrolo[1,2-a]indol-9-ones

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Molecules 2021, 26, x FOR PEER REVIEW 4 of 43 and the N-arylation of the indole is achieved via double intramolecular nucleophilic aromatic substitution. In both cases, the scope of the studied reaction was limited to the preparation of ﬁve indole derivatives, S4-6. Intramolecular nucleophilic aromatic sub- and 10stitutionH-indolo[1,2-a]indol-10-ones has also been used for the by preparation means of 9theH-pyrrolo[1,2-a]indol-9-ones base-mediated N-arylation and of pyr- 10H-indolo[1,2-a]indol-10-ones by means of the base-mediated N-arylation of pyrroles and roles indolesand indoles [41]. [41].

SchemeScheme 4. 4.Transition-metal-freeTransition-metal-free syntheses syntheses of indolo[1,2-a]quinoxalines. of indolo[1,2-a]quinoxalines.

Intermolecular nucleophilic aromatic substitution can also be used to prepare N- Intermolecular nucleophilic aromatic substitution can also be used to prepare N-ar- arylindoles (Scheme5). This concept for the preparation of N-arylindoles is usually based ylindoleson the (Scheme reaction of 5). aryl This fluorides concept with indoles for the under preparation basic conditions. of N-arylindoles Diness et al. developed is usually based on thetwo reaction procedures of aryl for the fluorides preparation with of Nindoles-arylindoles. under In basic the first conditions. procedure, theDiness reaction et al. devel- opedof two pentafluorobenzene procedures for with the anpreparation indole in the of presence N-arylindoles. of tBuONa In afforded the firstN-arylindole procedure, the re- actionS5-2 of ,pentafluorobenzene which was then used for with the an preparation indole in of the pentasubstituted presence of t benzeneBuONa (Schemeafforded5, N-arylin- Diness’s N-arylation of indoles) [42]. The analogous reaction with a halogenated aromate dole S5-2containing, which only was one fluorinethen used atom for proceeded the preparatio under harshn of reaction pentasubstituted conditions, as illustrated benzene (Scheme 5, Diness’sby the selected N-arylation synthesis of of indoles) indole S5-3 [42].. However, The analogous the overall reactionreaction scope with was a limitedhalogenated to aromate threecontaining examples only of N -arylatedone fluo indolesrine atom [43]. Similarproceeded reaction under conditions harsh were reaction used for conditions, the as illustratedpreparation by the ofbis selectedN-arylindoles synthesis with structuresof indole represented S5-3. However, by the indole the S5-5overall(Scheme reaction5, scope Chang’s N-arylation of indoles). The prepared N-arylindoles were polymerized, and their was limitedoptical and to three electrochemical examples properties of N-arylated and thermal indoles stability [43]. wereSimilar determined reaction [44 conditions]. The were used resultsfor the summarized preparation in Scheme of bis5 indicateN-arylindoles that the use with of nucleophilic structures aromatic represented substitution by the indole S5-5 for(Scheme the preparation 5, Chang´s of N N-arylindoles-arylation proceeds of indoles). best in The the caseprepared of pentafluorobenzenes. N-arylindoles were polymerized,This conclusion and their was optical confirmed and electrochemica by the work of Zhangl properties [45], who and prepared thermal a stability series of were de- terminedtetrafluorophenylbenzenes [44]. The results summarized through the reaction in Scheme of indoles 5 indicate with pentafluorobenzenes that the use of nucleophilic in the presence of sodium hydroxide under mild reaction conditions (Scheme5, Zhang’s aromaticN-arylation substitution of indoles). for Similarthe preparation reaction conditions of N-arylindoles (KOH, DMSO, proceeds 100 ◦C, 24best h) werein the case of pentafluorobenzenes.used by Hua to prepare This a conclusion series of N-arylated was confirmed indoles (23 by compounds, the work 24–87%of Zhang isolated [45], who pre- paredyields) a series [46]. of tetrafluorophenylbenzenes through the reaction of indoles with pentafluorobenzenes in the presence of sodium hydroxide under mild reaction conditions (Scheme 5, Zhang´s N-arylation of indoles). Similar reaction conditions (KOH, DMSO, 100 °C, 24 h) were used by Hua to prepare a series of N-arylated indoles (23 compounds, 24– 87% isolated yields) [46]. In addition to the above-mentioned procedures for the transition-metal-free arylation of indoles by means of intermolecular nucleophilic aromatic substitution, other procedures have also been used to achieve limited N-arylation of indoles as parts of general procedures for the preparation of N-arylated amines. Such works include the preparation of benzimidazole-pyrrolo[1,2-a]quinoxaline [47], arene-metal π-complexation mediated C–H arylation [48], base-promoted nucleophilic fluoroarene substitution of C–F bonds [49], and the preparation N-arylation of amines via triarylsulfonium triflates [50].

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Scheme 5.Scheme Intermolecular 5. Intermolecular nucleophilic nucleophilic aromatic aromatic substitution substitution forfor the the synthesis synthesis of N of-arylindoles. N-arylindoles.

The organocatalyticIn preparation addition to the of above-mentioned N-aryl carbazoles procedures and for indoles the transition-metal-free was reported arylationin of indoles by means of intermolecular nucleophilic aromatic substitution, other procedures 2020 (Scheme 6) [51].have The also reacti beenon used between to achieve the limited azonaphthaleneN-arylation ofS6-2 indoles and as N parts-nucleophiles of general proce- was catalyzed by chiraldures phosphoric for the preparation acid deri of N-arylatedvatives. amines.Although Such the works majority include of the reported preparation of N-arylations have beenbenzimidazole-pyrrolo[1,2-a]quinoxaline performed on carbazole (26 examples), [47], arene-metal the reactionπ-complexation has also mediated been C–H used for the preparationarylation of [ten48], base-promotedN-arylindoles. nucleophilic It was proposed fluoroarene that substitution the formation of C–F bonds of the [49 ], and the preparation N-arylation of amines via triarylsulfonium triflates [50]. reaction products S6-3 involvesThe organocatalytic the asymmetric preparation nucleophilic of N-aryl carbazoles addition and of indolesindoles was S6-1 reported to in the reaction center, and2020 that (Scheme the6 final)[ 51]. product The reaction of the between reaction the azonaphthalene S6-3 is obtainedS6-2 viaand rearoma-N-nucleophiles tization. Unfortunately,was catalyzedthe scope by of chiral the phosphoricreaction was acid limited derivatives. to azonaphthalene Although the majority S6-2 of, reported and N- the scope of the indolesarylations was havealso beenlimited. performed on carbazole (26 examples), the reaction has also been used for the preparation of ten N-arylindoles. It was proposed that the formation of the reaction products S6-3 involves the asymmetric nucleophilic addition of indoles S6-1 to the reaction center, and that the final product of the reaction S6-3 is obtained via rearomatization. Unfortunately, the scope of the reaction was limited to azonaphthalene S6-2, and the scope of the indoles was also limited.

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Scheme 6. Atroposelective N-arylation of indoles by arene C–H amination.

Scheme 6. AtroposelectiveScheme 6. AtroposelectiveA N -arylationdifferent ofapproachN -arylationindoles by ofto arene indolesthe N C–H-arylation by arene amination. C–H of amination. indoles, which involves aza-Michael addition and aromatization, was reported in 2018 (Scheme 7) [52]. The developed methodol- A different approachogyA is different basedto the N approachon-arylation the reaction to the of Nindoles,-arylation of azoles which of with indoles, involves cyclohexa-2,4-dienones which aza-Michael involves aza-Michael addi- in addi-the presence of a tioncatalytic and aromatization, amount of wasscandium reported triflate in 2018 (Scheme in acetonitrile.7)[ 52]. The The developed procedure methodology can be used for the tion and aromatization,is based was on thereported reaction in of 2018 azoles (Scheme with cyclohexa-2,4-dienones 7) [52]. The developed in the presence methodol- of a catalytic ogy is based on theamountregioselective reaction of scandium of azoles preparation triﬂate with in acetonitrile.cyclohexa-2,4-dienones of N-aryl The pyrazoles, procedure 1,2,4-triazoles, canin bethe used presence for the benzimidazoles, regioselectiveof a and 1,2,3- catalytic amount ofpreparationbenzotriazoles scandium of triflateN-aryl in high pyrazoles,in acetonitrile. yields. 1,2,4-triazoles, In the The case procedure benzimidazoles, of substituted can be and indoles,used 1,2,3-benzotriazoles for the the low selectivity of the regioselective preparationinarylation high yields. of reactionN-aryl In the pyrazoles, casewas ofobserved. substituted 1,2,4-triazoles, Thus, indoles, 3-methylindole benzimidazoles, the low selectivity S7-1a and of the 1,2,3-reacted arylation with re- the starting benzotriazoles in highactiondienone yields. was to observed. Inform the acase mixture Thus, of substituted 3-methylindole of C2- and indoles, NS7-1a-arylatedreacted the low indoles with selectivity the S7-2a starting ofand the dienone S7-3a . to By contrast, 3- arylation reaction formwasethylindole aobserved. mixture S7-1b of C2-Thus, exclusively and 3-methylindoleN-arylated gave indoles N -arylindoleS7-1aS7-2a reactedand S7-3a S7-2b with. By in contrast, thea 75% starting yield. 3-ethylindole The observed reac- S7-1b exclusively gave N-arylindole S7-2b in a 75% yield. The observed reactivity was dienone to form a mixturenottivity explained. was of C2-not explained.and N-arylated indoles S7-2a and S7-3a. By contrast, 3- ethylindole S7-1b exclusively gave N-arylindole S7-2b in a 75% yield. The observed reactivity was not explained.

SchemeScheme 7. 7.Synthesis Synthesis of N of-arylindoles N-arylindoles via an aza-Michaelvia an aza-Michael addition and addition aromatization and aromatization sequence. sequence.

N S8-3 S8-2 Scheme 7. Synthesis of NThe-arylindolesThe transition-metal-free transition-metal-free via an aza-Michael synthesis synthesis ad ofdition-arylindoles andof N aromatization-arylindolesfrom 1,2-allenic sequence.S8-3 from ketones 1,2-allenic ketones S8- and variously substituted indoles S8-1 via a Cs2CO3-promoted tandem benzannulation reaction2 and variously has recently substituted been demonstrated indoles by S8-1 Li et via al. (Schemea Cs2CO8)[3-promoted53]. The substrate tandem scope benzannulation The transition-metal-freewithreaction respect has synthesis to recently both indoles of been N-arylindolesS8-1a demonstratedand S8-1b S8-3and byfrom allenicLi 1,2-allenicet al. ketones (Scheme ketonesS8-2 8)is [53]. quiteS8- The broad. substrate scope 2 and variously substitutedInterestingly,with respect indoles the to C2-substituted both S8-1 indoles via a Cs indoles S8-1a2CO3-promoted wereand eitherS8-1b unreactivetandem and allenic benzannulation or reactedketones poorly S8-2 under is quite broad. In- reaction has recentlytheterestingly, been reaction demonstrated conditions, the C2-substituted likely by dueLi et to al. indoles steric (Scheme hindrance. were 8) ei[53]. Ather mechanism The unreactive substrate that involvesor scope reacted a series poorly under the with respect to bothofreaction indoles Michael conditions, additionsS8-1a and followed S8-1blikely and bydue cyclization allenicto steric ketones andhindrance. benzannulation S8-2 Ais quitemechanism may broad. be operative, thatIn- involves as a series of proposed by the authors. terestingly, the C2-substitutedMichael additions indoles followedwere either by unreactivecyclization or and reacted benzannulation poorly under may the be operative, as pro- reaction conditions,posed likely by due the to authors. steric hindrance. A mechanism that involves a series of Michael additions followed by cyclization and benzannulation may be operative, as proposed by the authors.

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Scheme 8. CascadeScheme benzannulation 8. Cascade benzannulation for the synthesis for the synthesis N-arylatedN-arylated indoles. indoles.

3. Transition-Metal-Catalyzed N-Arylation of Indoles 3. Transition-Metal-Catalyzed3.1. Nickel-Catalyzed N-Arylation N-Arylation of of Indoles Indoles 3.1. Nickel-Catalyzed N-ArylationNickel(0) complexes of Indoles are highly reactive toward oxidative addition, and therefore, nickel catalysts are used for the cross-coupling reactions of aryl chlorides. Rull [54] Nickel(0) complexeswas the first are to highly report the reactive Ni(0)-catalyzed toward arylation oxidative of indole addition,S9-1 using and aryl therefore, chlorides nickel catalysts areS9-2 used(Scheme for the9). The cross-couplingN-arylations were reactions carried out of using aryl the chlorides. [(IPr)Ni(styrene) Rull2] complex[54] was t the first to report the[IPr=1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene] Ni(0)-catalyzed arylation of indole S9-1 in using the presence aryl ofchloridesBuOLi in 1,4-S9-2 dioxane at 100 ◦C. As illustrated by selected examples S9-3a–S9-3h, the yields of the (Scheme 9). The NN-arylations-arylindoles were were high. carried No reaction out was using observed the with [(IPr)Ni(styrene) aryl chlorides bearing2] complex trifluo- [IPr=1,3-Bis(2,6-diisopropylphenyl)imidromethyl and benzoyl groupsazol-2-ylidene] or ortho-substituted in chlorobenzenes. the presence Yet, of the tBuOLi preparation in of1,4- dioxane at 100 °C. indolesAs illustrated with heteroaryl by selected substituents examples required 10 S9-3a mol%– ofS9-3h the catalyst, the loadingyields to of achieve the N- high yields of the corresponding indoles S9-3g and S9-3h. The need to use 10 mol% of the arylindoles were high.catalyst No was reaction explained was by theobserv competitiveed with coordination aryl chlorides of heteroaryl bearing halide trifluorome- during the thyl and benzoyl groupsN-arylation or reaction.ortho-substituted chlorobenzenes. Yet, the preparation of indoles with heteroaryl Differentsubstitu catalyticalents required systems 10 for mol% the N-arylation of the ofcatalyst indoles wereloading studied to byachieve Stra- diotto [55], who investigated the reactivity of DPPF-based ligands (Scheme 10) dur- high yields of the correspondinging the Ni(0)-catalyzed indolesN-arylation S9-3g and of indoles S9-3h (Scheme. The need10). Heteroaryl to use 10 chlorides mol% wereof the catalyst was explainedcoupled by withthe competitive alkylamines and coor indoledination in the presenceof heteroaryl of ten structurally halide during diverse the 1,1 0N- - X arylation reaction. bis(bis(alkyl/aryl)phosphino)ferrocene ligands (L ) and Ni(COD)2. The electron-poor ligand LCF3 proved to be extremely potent. It was the only ligand that gave the N-arylated indole S10-3a bearing a naphthyl substituent in a 80% yield. By contrast, the N-arylation of an indole with 4-chlorobenzonitrile proceeded efficiently with several LX variants, including LiPr,LCy,LPh,LCF3,LOMe, and LMe. The amination of 4-chloroquinaldine with the ligand LPh represents the first room-temperature N-arylation of an indole. In addition, ligands with ortho-substituted phenyl (Lo-tol and L1-nap), a sterically demanding dialkylphosphino group (LtBu), and difuranylphosphino variants (Lfur) proved ineffective under the studied conditions. The comparable catalytic performance of LPh,LCF3, and LOMe in the studied nickel-catalyzed N-arylations suggests that the electronic perturbations arising from arylphosphine substitution do not significantly affect the behavior of nickel in this branch of chemistry.

Scheme 9. Scope of the N-arylation of indoles with aryl chlorides catalyzed by [(IPr)Ni(styrene)2].

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Scheme 8. Cascade benzannulation for the synthesis N-arylated indoles.

3. Transition-Metal-Catalyzed N-Arylation of Indoles 3.1. Nickel-Catalyzed N-Arylation of Indoles Nickel(0) complexes are highly reactive toward oxidative addition, and therefore, nickel catalysts are used for the cross-coupling reactions of aryl chlorides. Rull [54] was the first to report the Ni(0)-catalyzed arylation of indole S9-1 using aryl chlorides S9-2 (Scheme 9). The N-arylations were carried out using the [(IPr)Ni(styrene)2] complex [IPr=1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene] in the presence of tBuOLi in 1,4- dioxane at 100 °C. As illustrated by selected examples S9-3a–S9-3h, the yields of the N- arylindoles were high. No reaction was observed with aryl chlorides bearing trifluoromethyl and benzoyl groups or ortho-substituted chlorobenzenes. Yet, the preparation of indoles with heteroaryl substituents required 10 mol% of the catalyst loading to achieve high yields of the corresponding indoles S9-3g and S9-3h. The need to use 10 mol% of the Molecules 2021catalyst, 26, 5079 was explained by the competitive coordination of heteroaryl halide during the8 of 44 N- arylation reaction.

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Different catalytical systems for the N-arylation of indoles were studied by Stradiotto [55], who investigated the reactivity of DPPF-based ligands (Scheme 10) during the Ni(0)- catalyzed N-arylation of indoles (Scheme 10). Heteroaryl chlorides were coupled with alkylamines and indole in the presence of ten structurally diverse 1,1′-bis(bis(alkyl/aryl)phosphino)ferrocene ligands (LX) and Ni(COD)2. The electron-poor ligand LCF3 proved to be extremely potent. It was the only ligand that gave the N-arylated indole S10- 3a bearing a naphthyl substituent in a 80% yield. By contrast, the N-arylation of an indole with 4-chlorobenzonitrile proceeded efficiently with several LX variants, including LiPr, LCy, LPh, LCF3, LOMe, and LMe. The amination of 4-chloroquinaldine with the ligand LPh represents the first room-temperature N-arylation of an indole. In addition, ligands with ortho-substituted phenyl (Lo-tol and L1-nap), a sterically demanding dialkylphosphino group (LtBu), and difuranylphosphino variants (Lfur) proved ineffective under the studied conditions. The comparable catalytic performance of LPh, LCF3, and LOMe in the studied nickel- catalyzed N-arylations suggests that the electronic perturbations arising from ar-

ylphosphine substitution do not significantly affect the behavior of nickel in this branch SchemeScheme 9. Scope 9. Scope of ofthe of thechemistry. NN-arylation-arylation of of indoles indoles with with aryl chlorides aryl ch catalyzedlorides catalyzed by [(IPr)Ni(styrene) by [(IPr)Ni(styrene)2]. 2].

SchemeScheme 10. 10.Comparative Comparative catalytic catalytic screening screening during during the nickel-catalyzed the nickel-catalyzedN-arylation N-arylation of indoles. of indoles.

AA different different procedure procedure for N for-arylation N-arylation is based is onbased the reaction on the ofreac aminestion of or amines heterocyclic or heterocy- compoundsclic compounds with phenolswith phenols (Scheme (Scheme 11)[56 ].11) Phenols [56]. Phenols are reluctant are reluctant to react duringto react cross- during cross- couplingcoupling reactions, reactions, so so the the starting starting phenol phenol is converted is converted into into a cyanuric a cyanuric acid acid ester esterS11-4 S11-4 via the reaction with cyanuric chloride (TCT) in 1,4-dioxane in the presence of a base. The conditions for the formation of the cyanuric acid ester S11-4 were obtained through extensive optimization. For example, the N-arylation of indole S11-1 with activated phenol S11-4 was performed using the NiCl2(dppf) catalytic system to give the N-arylated indole S11-3 in a 78% yield. Morpholine, carbazole, indoline, and pyrazole are examples of the other tested amines.

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Molecules 2021, 26, x FOR PEER REVIEW via the reaction with cyanuric chloride (TCT) in 1,4-dioxane in the presence of a base. 9 of 43

The conditions for the formation of the cyanuric acid ester S11-4 were obtained through extensive optimization. For example, the N-arylation of indole S11-1 with activated phenol Molecules 2021, 26, x FOR PEER REVIEWS11-4 was performed using the NiCl2(dppf) catalytic system to give the N-arylated indole 9 of 43 S11-3 in a 78% yield. Morpholine, carbazole, indoline, and pyrazole are examples of the other tested amines.

Scheme 11. Ni-catalyzed N-arylation of phenols via C–O bond activation by means of a TCT reagent.

SchemeSchemeThe nickel-catalyzed 11. 11.Ni-catalyzed Ni-catalyzedN-arylation decarbN-arylationonylation of phenols of phenols via of C–O substituted via bond C–O activation bond N activation-acyl by means indoles by of ameans TCT S12-1 reagent. of representsa TCT rea- anothergent. approach for the preparation of N-arylated indoles (Scheme 12) [57]. Two condi- The nickel-catalyzed decarbonylation of substituted N-acyl indoles S12-1 represents tions were optimized for the Ni(0)-catalyzed decarbonylation of the starting indoles. First, anotherThe approach nickel-catalyzed for the preparation decarbonylation of N-arylated of substituted indoles (Scheme N-acyl 12 )[indoles57]. Two S12-1 condi- represents stoichiometric amounts of Ni(cod)2 and PCy3 preferred quantitative decarbonylation at 80 tionsanother were approach optimized for for the the Ni(0)-catalyzedpreparation of decarbonylationN-arylated indoles of the (Scheme starting indoles.12) [57]. First, Two condi- °C (Conditionstoichiometric A). amounts Second, of catalytic Ni(cod) decarbonylationand PCy preferred was quantitative achieved decarbonylation through the use at of the tions were optimized for the Ni(0)-catalyzed2 3 decarbonylation of the starting indoles. First, 1,2-ethanediylbis[dicyclohexyl]p80 ◦C (Condition A). Second, catalytichosphine decarbonylation (dcype) ligand was achieved at 180 °C through (Condition the use B). of Condi- stoichiometric amounts of Ni(cod)2 and PCy3 preferred quantitative◦ decarbonylation at 80 tion theB proved 1,2-ethanediylbis[dicyclohexyl]phosphine to be suitable for N-acylindoles (dcype) bearing ligand an at 180electronC (Condition withdrawing B). Con- group, dition°C (Condition B proved toA). be Second, suitable catalytic for N-acylindoles decarbonylation bearing an was electron achieved withdrawing through group, the use of the whereas Condition A was suitable for N-acylindoles bearing an acyl group with electron- whereas1,2-ethanediylbis[dicyclohexyl]p Condition A was suitable forhosphineN-acylindoles (dcype) bearing ligand an acylat 180 group °C (Condition with electron- B). Condi- neutralneutraltion and B andproved electron-rich electron-rich to be suitable subs substituents.tituents. for N Selected-acylindoles Selected examples examples bearingS12-2a–S12-2f S12-2a–S12-2f an electronindicate withdrawing indicate that this that group, this methodmethodwhereas tolerates tolerates Condition esters, esters, A nitriles, nitriles,was suitable andthe the for ketone ketoneN-acylindoles functional functional bearing group. group.In an addition acyl In additiongroup to benzoic with to electron-benzoic acidacid neutralderivatives, derivatives, and electron-rich this this method method subs has tituents. provenproven suitable Selected suitable for examples for the formationthe formation S12-2a–S12-2f of N-alkenylindoles of N -alkenylindolesindicate that this S12-2eS12-2emethod andand N tolerates-heteroarylindolesN-heteroarylindoles esters, nitriles, S12-2f and. . the ketone functional group. In addition to benzoic acid derivatives, this method has proven suitable for the formation of N-alkenylindoles S12-2e and N-heteroarylindoles S12-2f.

SchemeScheme 12. 12. Ni-catalyzedNi-catalyzed decarbonylationdecarbonylation of Nof-acylated N-acylated heteroarenes. heteroarenes. Scheme 12. Ni-catalyzed decarbonylation of N-acylated heteroarenes. Recently, the use of NiO nanoparticles for the N-arylation of indoles by means of the reaction ofRecently, boronic the acids use withof NiO indoles nanoparticles in the presence for the N -arylationof NiO nanoparticles of indoles by as means a catalyst of the has beenreaction reported of boronic [58]. acidsPure NiOwith nanoparticindoles in theles werepresence prepared of NiO using nanoparticles the quercetin-medi- as a catalyst ated has(F2-1 been, Figure reported 2) hydrothermal [58]. Pure NiO method. nanopartic les were prepared using the quercetin-mediated (F2-1, Figure 2) hydrothermal method.

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Molecules 2021, 26, x FOR PEER REVIEWRecently, the use of NiO nanoparticles for the N-arylation of indoles by means of the 10 of 43 Molecules 2021 , 26, x FOR PEER REVIEW reaction of boronic acids with indoles in the presence of NiO nanoparticles as a catalyst10 of 43 has been reported [58]. Pure NiO nanoparticles were prepared using the quercetin-mediated (F2-1, Figure2) hydrothermal method.

Figure 2. The structure of quercetin.

In addition to the above-mentioned nickel-based catalytic systems for the N-arylation Figure 2. The structure of quercetin. of indoles, the use of Figurenickel catalysts 2. The F3-1 structure [59], F3-2 of [60], quercetin. F3-3 [61], F3-4 [62], and Ni(COD)2 with a polymeric triazine-phosphiteIn addition to the ligand above-mentioned [63] for the nickel-based reaction catalytic of amines systems or for heterocycles the N-arylation with electrophiles hasof indoles, also been the use reported of nickel catalysts(FigureF3-1 3). [A59 ],uniqueF3-2 [60 ],procedureF3-3 [61], F3-4 for[62 the], and prepara- Ni(COD)2 tion of N-aryl amineswith and a polymeric indolesIn addition triazine-phosphitemakes use to of the th ligande nickel-catalyzedabove-mentioned [63] for the reaction decarbonylative of amines nickel-based or heterocycles ami- catalytic systems for the N-arylation with electrophiles has also been reported (Figure3). A unique procedure for the preparation nation of carboxylicof acidofN-aryl indoles, esters amines [64]. and the indolesHowever, use makes of such use nickel of procedures the nickel-catalyzed catalysts have decarbonylative mainlyF3-1 [59],been amination devel-F3-2 [60], F3-3 [61], F3-4 [62], and Ni(COD)2 oped for the N-arylationofwith carboxylic of amines,a acidpolymeric esters whereas [64]. However, thetriazine-phosphite N-arylation such procedures of indoles have mainly ligandhas been been developed achieved[63] for for the reaction of amines or heterocycles for only a limited numberthe N-arylation of indole of amines, derivatives. whereas the N-arylation of indoles has been achieved for only a limitedwith number electrophiles of indole derivatives. has also been reported (Figure 3). A unique procedure for the preparation of N-aryl amines and indoles makes use of the nickel-catalyzed decarbonylative amination of carboxylic acid esters [64]. However, such procedures have mainly been developed for the N-arylation of amines, whereas the N-arylation of indoles has been achieved for only a limited number of indole derivatives.

Figure 3. ExamplesFigure of nickel 3. Examples catalysts of nickel used catalysts for the used N-arylation for the N-arylation of amines. of amines.

3.2. Palladium-Catalyzed3.2. Palladium-Catalyzed N-Arylation of Indoles N-Arylation of Indoles Similarly to the palladium-catalyzed arylation of pyrroles, the formation of 1, 2, and Similarly to the3-arylated palladium-catalyzed indoles can also bearylation observed of in thepyrroles, palladium-catalyzed the formation arylation of 1, of2, indolesand 3-arylated indoles can(Scheme also 13 be)[65 observed–67]. The regioselectivity in the palladium-catalyzed of palladium-catalyzed arylation indole arylation of indoles can be (Scheme 13) [65–67].influenced The regiosel by the detailedectivity optimization of palladium-catalyzed of the reaction conditions. indole Thisarylation was demonstrated can be in 2019 by Zhang et al., who reported the palladium-catalyzed cascade decarboxylative influenced by the detailedarylation optimization of indoles [68]. of The the authors reaction optimized conditions. the course This of was the demonstrated reaction of indolyl in 2019 by Zhang etcarboxylic al., who acids reportedS13-1 with the diaryliodoniumpalladium-catalyzed salts S13-2 cascadeand determined decarboxylative that N1/C2 or arylation of indolesC2/C3 [68]. The arylations authors of indoles optimized can be the performed course with of the high reaction regioselectivity. of indolyl The reaction carboxylic acids S13-1 allowswith diaryliodonium the introduction of variously salts S13-2 substituted and determined biphenyls. The that proposed N1/C2 key intermediatesor C2/C3 forFigure both C2/C3 3. andExamples N1/C2 arylation, of nickelS13-5 and catalystsS13-6, show thatused the Nfor-arylation the N of indoles-arylation of amines. arylations of indolesis can the firstbe performed step in N1/C2 with arylation. high However,regioselectivity. the C3 arylation The reaction of the starting allows material the introduction of variouslyoccurs firstsubs intituted the case biphenyls. of C2/C3 arylation The proposed of the starting key indolyl intermediates carboxylic acid forS13-1 both. C2/C3 and N1/C2 arylation,3.2. Palladium-Catalyzed S13-5 and S13-6, show that N-Arylation the N-arylation of Indolesof indoles is the first step in N1/C2 arylation. However, the C3 arylation of the starting material occurs first in the case of C2/C3 arylationSimilarly of the starting to theindolyl palladium-catalyzed carboxylic acid S13-1. arylation of pyrroles, the formation of 1, 2, and 3-arylated indoles can also be observed in the palladium-catalyzed arylation of indoles (Scheme 13) [65–67]. The regioselectivity of palladium-catalyzed indole arylation can be influenced by the detailed optimization of the reaction conditions. This was demonstrated in 2019 by Zhang et al., who reported the palladium-catalyzed cascade decarboxylative arylation of indoles [68]. The authors optimized the course of the reaction of indolyl carboxylic acids S13-1 with diaryliodonium salts S13-2 and determined that N1/C2 or C2/C3 arylations of indoles can be performed with high regioselectivity. The reaction allows the introduction of variously substituted biphenyls. The proposed key intermediates for both C2/C3 and N1/C2 arylation, S13-5 and S13-6 , show that the N-arylation of indoles is the Scheme 13. Palladium-catalyzedfirst step site-selective in N1/C2 N1/C2 arylation. and C3/C2 arylation However, of indoles. the C3 arylation of the starting material occurs first in the case of C2/C3 arylation of the starting indolyl carboxylic acid S13-1.

Scheme 13. Palladium-catalyzed site-selective N1/C2 and C3/C2 arylation of indoles.

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Figure 2. The structure of quercetin.

In addition to the above-mentioned nickel-based catalytic systems for the N-arylation of indoles, the use of nickel catalysts F3-1 [59], F3-2 [60], F3-3 [61], F3-4 [62], and Ni(COD)2 with a polymeric triazine-phosphite ligand [63] for the reaction of amines or heterocycles with electrophiles has also been reported (Figure 3). A unique procedure for the preparation of N-aryl amines and indoles makes use of the nickel-catalyzed decarbonylative amination of carboxylic acid esters [64]. However, such procedures have mainly been developed for the N-arylation of amines, whereas the N-arylation of indoles has been achieved for only a limited number of indole derivatives.

Figure 3. Examples of nickel catalysts used for the N-arylation of amines.

3.2. Palladium-Catalyzed N-Arylation of Indoles Similarly to the palladium-catalyzed arylation of pyrroles, the formation of 1, 2, and 3-arylated indoles can also be observed in the palladium-catalyzed arylation of indoles (Scheme 13) [65–67]. The regioselectivity of palladium-catalyzed indole arylation can be influenced by the detailed optimization of the reaction conditions. This was demonstrated in 2019 by Zhang et al., who reported the palladium-catalyzed cascade decarboxylative arylation of indoles [68]. The authors optimized the course of the reaction of indolyl carboxylic acids S13-1 with diaryliodonium salts S13-2 and determined that N1/C2 or C2/C3 arylations of indoles can be performed with high regioselectivity. The reaction allows the introduction of variously substituted biphenyls. The proposed key intermediates for both C2/C3 and N1/C2 arylation, S13-5 and S13-6, show that the N-arylation of indoles is the Molecules 2021, 26, 5079 11 of 44 first step in N1/C2 arylation. However, the C3 arylation of the starting material occurs first in the case of C2/C3 arylation of the starting indolyl carboxylic acid S13-1.

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SchemeScheme 13. 13.Palladium-catalyzed Palladium-catalyzed site-selective site-selective N1/C2 N1/C2 and C3/C2 and C3/C2 arylation arylation of indoles. of indoles.

AA differentdifferent approachapproach forfor thethe preparationpreparation ofof diarylateddiarylated indolesindoles waswas reportedreported inin 20202020 (Scheme(Scheme 1414))[ [69].69]. Muller Muller et et al al.. used used 5-bromoindole 5-bromoindole to toprepare prepare diarylated diarylated indoles indoles via via se- sequentialquential Suzuki Suzuki reaction reaction and and Buchwald–Hartwig Buchwald–Hartwig amination. amination. The The Suzuki Suzuki reaction reaction was wasper- performedformed first ﬁrst to avoid to avoid any side any reactions. side reactions. The subsequent The subsequent amination amination reaction reactionuses the same uses thecatalytic same system catalytic as system the Suzuki as the reaction, Suzuki although reaction, althoughpotassium potassium carbonate carbonateis used instead is used of insteadCsF. Selected of CsF. examples Selected examplesS14-2a andS14-2a S14-2band illustrateS14-2b howillustrate the Suzuki how the reaction Suzuki of reaction bromoin- of bromoindoledole S14-1 withS14-1 1-naphthylboronicwith 1-naphthylboronic acid gives acid worse gives yields worse of yields the indole of the S14-2b indole thanS14-2b the thanBuchwald–Hartwig the Buchwald–Hartwig amination amination with naphthyl with naphthylbromide. This bromide. approach This is approach also suitable is also for suitablethe preparation for the preparation of diarylated of carbazoles diarylated and carbazoles 10H-phenothiazines. and 10H-phenothiazines.

1 Ar B(OH)2 (1 equiv) Pd(dba) (5 mol%), [t-Bu PH]BF (5 mol%) Br 2 3 4 Ar1 CsF (3 equiv), 1,4-dioxane, 120 °C, 1 4h N then N H 2 2 S14-1 Ar Br (1.1 equiv), K2CO3 (1.5 equiv) S14-2 Ar 120 °C, 16 h 14 examples 29 88% Selected examples:

MeO F3C

N N N

S14-2b 29% OMe S14-2c 70% CF S14-2a 58% 3 SchemeScheme 14.14. SequentialSequential Suzuki Suzuki arylation arylation and and Buchwald Buchwald–Hartwig–Hartwig amination amination for for the the synthesis synthesis of N of- Narylated-arylated indoles. indoles.

AnAn alternativealternative approach approach to toN -arylatedN-arylated indoles indoles utilizes utilizes reactions reactions the the substituted substituted indole in- S15-1dole S15-1withsubstrates with substrates with activated with activated C–O and C–O C–N and bonds. C–N Selected bonds. examples Selected areexamples presented are inpresented Scheme 15in. Scheme In some 15. cases, In some the palladium-catalyzed cases, the palladium-catalyzed reaction of quaternary reaction of ammonium quaternary saltsammonium with indoles salts with in the indoles presence in the of potassiumpresence oftert potassium-butoxide tert can-butoxide be used can to prepare be usedN to- arylatedprepare indoles,N-arylated although indoles, the although reported the scope reported of the scope reaction of isthe limited reaction to theis limited preparation to the ofpreparation four simple of Nfour-arylindoles, simple N-arylindoles,S15-4. However, S15-4 the. However, synthesis the of synthesisN-alkylated of N indoles-alkylated by meansindoles of by this means approach of this is convenientapproach is [70 convenient]. Additionally, [70]. tosylatesAdditionally, are sufficiently tosylates are reactive suffi- forciently the preparationreactive for oftheN -arylindoles.preparation of In N this-arylindoles. way, a large In groupthis way, of quinazolines a large groupS15-2 of werequinazolines prepared S15-2 in high were isolated prepared yields, in high although isolated similar yields, nonaflates although do similar not react nonaflates under the do developednot react under reaction the conditionsdeveloped [reaction71]. A similar conditio approachns [71]. A for similar the synthesis approach of Nfor-arylindoles the synthe- S15-3sis of wasN-arylindoles reported inS15-3 2018 was by Kwong,reported albeit in 2018 with by a Kwong, significantly albeit narrower with a significantly scope [72]. narrower scope [72].

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Scheme 15. Palladium-catalyzed N-arylation of indoles via the reactions with substrates with acti- SchemeScheme 15. 15. Palladium-catalyzed NN-arylation-arylation of of indoles indoles via via the the reac reactionstions with with substr substratesates with with activated C–O and C–N bonds. activatedvated C–O C–O and and C–N C–N bonds. bonds. A hydrogen-transfer-mediated cross-coupling reaction can also be used for the prep- AA hydrogen-transfer-mediated hydrogen-transfer-mediated cross-coupling cross-coupling reaction reaction can can also also be be used used for for the the prepa- prep- rationaration of ofN -arylindolesN-arylindoles (Scheme (Scheme 16 16))[73 [73].]. The The starting starting material, material, as as represented represented by by the the structurestructure ofof substitutedsubstituted indolinesindolines S16-1, reacts reacts with with 2-naphthols 2-naphthols and and their their derivatives derivatives in inthe the presence presence of of Pd/C Pd/C and and sodium sodium methoxide. methoxide. Optimized Optimized conditions conditions were were applied applied to pre- to preparepare 27 27 indole indole derivatives derivatives S16-2S16-2 withwith a a naphthyl naphthyl group at positionposition 1.1. TheThe reactionreaction can can tolerate,tolerate, for for example,example, anan ester and a a hydroxy hydroxy functional functional group. group. However, However, 1-naphthols 1-naphthols do donot not react react under under the the optimized optimized reaction reaction conditions, conditions, as illustrated as illustrated in Scheme in Scheme 16. 16The. Thepro- proposedposed mechanism mechanism assumes assumes the fo thermation formation of active of active catalyst catalyst S16-5 S16-5by meansby meansof the reaction of the reactionof Pd(0) ofwith Pd(0) indoline. with indoline. The resultant The resultant palladium palladium catalyst S16-5 catalyst subsequentlyS16-5 subsequently hydrogenates hy- drogenates2-naphthol 2-naphtholS16-6 to formS16-6 theto intermediate form the intermediate S16-7. The finalS16-7 reaction. The ﬁnal product reaction is formed product by isthe formed condensation by the condensation of intermediate of intermediateS16-7 with indolineS16-7 withS16-1a indoline, followedS16-1a by palladium-me-, followed by palladium-mediateddiated dehydrogenation. dehydrogenation.

SchemeScheme 16. 16.Hydrogen-transfer-mediated Hydrogen-transfer-mediatedN N-arylation-arylation of of indolines indolines en en route route to toN N-arylated-arylated indoles. indoles.

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The two-step one-pot procedure for the preparation of N-arylindoles relies on the MoleculesMolecules2021 2021, 26, 26, 5079, x FOR PEER REVIEW 1313 of of 43 44 palladium-catalyzed cyclization of 2-bromophenethylamines S17-1, which is followed by the palladium-catalyzed N-arylation of the resulting indoles S17-2a (Scheme 17) [74]. The optimization of the reaction conditions revealed that the cyclization of amines S17-1 into TheThe two-steptwo-step one-potone-pot procedureprocedure forfor thethe preparationpreparation of N-arylindoles relies relies on on the the indoles S17-3 must be carried out at 200 °C. Running the same cyclisation reaction at 140 palladium-catalyzedpalladium-catalyzed cyclizationcyclization ofof 2-bromophenethylamines2-bromophenethylamines S17-1,, which which is is followed followed by by °C theexclusivelythe palladium-catalyzed palladium-catalyzed produces indolineN N-arylation-arylation derivatives ofof thethe resultingresulting S17-2b indolesindoles and S17-2aintermediates. (Scheme 17)17In)[ [74].the74]. nextThe The step, theoptimization arylationoptimization of of ofthe thethe resulting reactionreaction conditionsconditionsindole S17-2a revealedrevealed is performed that the cyclization using the of of aminessame amines catalytic S17-1S17-1 intointo system at 180indolesindoles °C. S17-3S17-3 mustmust be carried carried out out at at 200 200 °C.◦C. Running Running the the same same cyclisation cyclisation reaction reaction at 140 at 140°C ◦exclusivelyC exclusively produces produces indoline indoline derivatives derivatives S17-2bS17-2b and intermediates.and intermediates. In the In next the step, next step,the arylation the arylation 10%of the Pd/C of resulting the (2 mol%) resulting indole indole S17-2aS17-2a is performedis performed using the using same the catalytic same catalytic system ◦ DPPF (3 mol%) systemat 180 °C. atNH 180 2 C. t-BuONa (3 equiv) ArBr (1.5 equiv) mesitylene 180 °C, 24 h R N N R Br 10%200 Pd/C °C, 24 (2 mol%)h H R DPPF (3 mol%) S17-2a S17-1 NH2 Ar t-BuONa (3 equiv) or ArBr (1.5 equiv) S17-3 44 99% mesitylene 180 °C, 24 h R N N R Br 200 °C, 24 h H R 16 examples S17-1 S17-2a Selected examples: Ar or N R H S17-3 44 99% 16 examples S17-2b Selected examples: N N N exclusivelyR N fromed at 140H °C S17-2b N N exclusively fromed N N N at 140 °C N N S17-3a 83% S17-2b 91% S17-2c 82% S17-3a 83% S17-2b 91% Scheme 17. Palladium-catalyzed one-pot synthesis of N-arylated indoles. S17-2c 82% SchemeScheme 17. 17.Palladium-catalyzed Palladium-catalyzed one-potone-pot synthesissynthesis of N-arylated indoles. A similar approach for the preparation of N-arylated indoles was reported by Stra- diotto (SchemeAA similar similar 18) approachapproach [75]. In forfor this thethe case, preparationpreparation the starting of N-arylated alkynes indoles indoles S18-1 was wasreacts reported reported with by byammonia Stra- Stra- to formdiottodiotto indole-based (Scheme (Scheme 18 18) )[intermediates75 [75].]. In In this this case, case, S18-3 the the starting. Instarting the alkynes next alkynes step,S18-1 S18-1 thereacts Nreacts-arylation with with ammonia ammonia of the to formresulting to indoleindole-basedform is indole-basedperformed intermediates intermediatesusing theS18-3 same. S18-3 In thecatalytic. In next the step, next system the step,N -arylation inthe the N-arylation presence of the resultingof of the potassium resulting indole tert- butoxide.isindole performed Thisis performed procedure using the using same led the to catalytic thesame preparation catalytic system insystem theof 13 presence inindole the presence ofderivatives. potassium of potassium Fromtert-butoxide. the tert selected- Thisbutoxide. procedure This ledprocedure to the preparation led to the preparation of 13 indole of derivatives.13 indole derivatives. From the selectedFrom the examples selected examples S18-2a–S18-2e, it is evident that the N-arylation of indoles also tolerates ortho- S18-2a–S18-2eexamples S18-2a–S18-2e, it is evident, it that is evident the N-arylation that the N of-arylation indoles also of indoles tolerates alsoortho tolerates-disubstituted ortho- disubstitutedaryldisubstituted halides. aryl The aryl halides. reaction halides. conditionsTh Thee reactionreaction for theconditionsconditionsN-arylation for for the of the indolesN-arylation N-arylation developed of indoles of inindoles relation devel- devel- opedtooped thein relation two-stepin relation to one-pot tothe the two-step two-step procedure one-one- canpot also procedure procedure be used can for can also the also Nbe-arylation usedbe used for thefor of independentlyN the-arylation N-arylation of of independentlypreparedindependently indoles. prepared prepared indoles. indoles.

Scheme 18. Double N-arylation for the preparation of N-arylated indoles.

SchemeScheme 18. 18.Recently,Double DoubleN a -arylation Nseries-arylation of forpapers for the preparationthe have preparation been ofpublishedN-arylated of N-arylated on indoles. the N indoles.-arylation of indoles using palladium catalysts immobilized on mesoporous silica SBA-15 [76,77], carbon nanotubes [78],Recently, or magnetic a series Fe3O of4 nanoparticlespapers have [79]. been Scheme published 19 illustrates on the theN-arylation immobilization of indoles of the using palladium catalysts immobilized on mesoporous silica SBA-15 [76,77], carbon nanotubes [78], or magnetic Fe3O4 nanoparticles [79]. Scheme 19 illustrates the immobilization of the

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Molecules 2021, 26, x FOR PEER REVIEW 14 of 43

Molecules 2021, 26, x FOR PEER REVIEW 14 of 43 Recently, a series of papers have been published on the N-arylation of indoles using palladium catalysts immobilized on mesoporous silica SBA-15 [76,77], carbon nanotubes [78], palladium catalyst on the surface of SBA-15 through the coordination of palladium to the or magnetic Fe O nanoparticles [79]. Scheme 19 illustrates the immobilization of the amidoxime group3 4[76]. The major advantages offered by immobilized catalysts are their palladium catalystpalladium on the catalyst surface on of theSBA-15 surface through of SBA-15 the coordination through the of coordination palladium ofto palladiumthe to the recyclability and reusability. This was demonstrated by reusing the immobilized catalyst amidoxime groupamidoxime [76]. The group major [76 advantages]. The major offered advantages by immobilized offered by immobilizedcatalysts are their catalysts are their in five catalytic cycles [76]. recyclability andrecyclability reusability. and This reusability. was demonstrated This was demonstrated by reusing the by immobilized reusing the immobilizedcatalyst catalyst in five catalytic cycles [76]. in ﬁve catalytic cycles [76]. (0) R1 R1 Structure of SBA-15/AO/Pd : (0) SBA-15/AO/Pd(0) 1 1(0) Structure of SBA-15/AO/Pd : R 2 SBA-15/AO/PdR 2 R + Ar I R Pd OH HO Pd Et N, DMF, 110 °C SBA-15/AO/Pd(0) N (0) 3 N N N 2 SBA-15/AO/Pd 2 R + Ar I H R Pd OH HO Pd NH Et N, DMF, 110 °C Ar H2N 2 N S19-1 3 N S19-2 N N H Selected examples: Ar 11 examplesH2N NH2 S19-1 S19-2 72 98% Si MeO Si Selected examples: 11 examples O O O O OH O OH 72 98% Si MeO Si N N N O O O O OH O OH SBA-15 N N N SBA-15

Me OMe NO2 O S19-2b 96% S19-2c 72% Me S19-2a 96% OMe NO2 O S19-2b 96% S19-2c 72% S19-2a 96% Scheme 19. Amidoxime-functionalized mesoporous SBA-15 as a heterogeneous and recyclable nanocatalyst for indole N-arylation. Scheme 19. Amidoxime-functionalizedScheme 19. Amidoxime-functionalized mesoporous SBA-15 mesoporous as a heterogeneous SBA-15 as and a heterogeneous recyclable nanocatalyst and recyclable for indole N-arylation. nanocatalyst for indole N-arylation. Palladium-catalyzed NN-arylation-arylation of of indoles indoles has has been been used used for for the the total total synthesis synthesis of of(– Palladium-catalyzed)-aspergilazine(–)-aspergilazine N-arylation A A(Scheme (Scheme of indoles20) 20 [80].)[80 has In]. Inthisbeen this re usedport, report, for the the preparation total preparation synthesis of of(–)-aspergilazine of (–)-aspergilazine (– A )-aspergilazine(A(S20-3 AS20-3 (Scheme) was) was achieved 20) achieved [80]. by In means by this means re ofport, a ofcross-coupling athe cross-coupling preparation reaction of reaction (–)-aspergilazine between between non-brominated non-brominated A S20- (S20-3) was achieved1S20-1 and brominatedand by means brominated of indole a cross-coupling indole S20-2S20-2 to form reactionto (–)-aspergilazine form between (–)-aspergilazine non-brominated A (S20-3 A) ( S20-3at aS20- 9%) at yield. a 9% When yield. 1 and brominatedevaluatingWhen indole evaluating this S20-2 approach this to form approach to (–)-aspergilazine (–)-aspergilazine to (–)-aspergilazine A A, (S20-3 it should A,) itat should a be 9% noted yield. be noted that When the that starting the starting sub- evaluating thisstancessubstances approach contained containedto (–)-aspergilazine four fourN–H N–H bonds A, bonds itthat should thatcould be could be noted arylated. be that arylated. theIn addition,starting In addition, sub- 80% of 80% the ofunre- the stances containedactedunreacted four starting N–H starting material bonds material thatS20-1 couldS20-1 was beisolatedwas arylated. isolated together In together addition, with withthe 80% reaction the of reaction the product unre- product S20-3S20-3. . acted starting material S20-1 was isolated together with the reaction product S20-3.

Scheme 20.SchemeUse of 20.N Use-arylation of N-arylation of indoles of for indoles the preparation for the preparation of (–) Aspergilazine of (–) Aspergilazine A. A. Scheme 20. Use of N-arylation of indoles for the preparation of (–) Aspergilazine A. Other examples examples of of Buchwald–Hartwig Buchwald–Hartwig indole indole N-arylationN-arylation include include the the use use of the of lig- the Other examplesandsligands F4-1 F4-1of [81],Buchwald–Hartwig[81 F4-2], F4-2 [82],[82 and], and tBuXphos indoletBuXphos N -arylation(F4-3 (F4-3) [83])[83 include (Figure] (Figure the4).4). Inuse In addition, addition, of the lig- the the palladium- ands F4-1 [81],catalyzed F4-2 [82], amination and tBuXphos of triflates triﬂates (F4-3 )[84,85]; [ 84[83],85 (Figure]; cross-coupling 4). In addition, reactions the palladium- of silylated indoles with catalyzed aminationaryl halides of triflates [86,87]; [86,87 ];[84,85]; and reactions cross-coupling that are reactions catalyzed of by silylated Pd/ZnO indoles nanoparticles nanoparticles with [88], [88], palla- palla- aryl halides [86,87];dium immobilized and reactions on that graphene are catalyzed [89], [89], or by silica-starch Pd/ZnO nanoparticles substrates [90] [90 [88],] were palla- used to prepare dium immobilizedN-arylindoles.-arylindoles. on graphene However, [89], or thesethese silica-starch procedures procedures substrates have have mainly mainly [90] were been been developedused developed to prepare for for the theN-arylation N-aryla- N-arylindoles.tionof However, amines, of amines, whereasthese whereas procedures the theN-arylation N -arylationhave mainly of of indoles indoles been wasdeveloped was given given forfor for onlythe only N a -aryla-a limited limited numbernumber of tion of amines,indoleindole whereas derivatives. the N-arylation of indoles was given for only a limited number of indole derivatives.

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FigureFigure 4. 4.Selected Selected examples examples of general of general palladium-catalyzed palladium-catalyzed N-arylations Nused-arylations for the preparation used for the preparation Figureof N-arylindoles. 4. Selected examples of general palladium-catalyzed N-arylations used for the preparation ofofN N-arylindoles.-arylindoles.

3.3.3.3. Copper-CatalyzedCopper-Catalyzed N-ArylationN-Arylation ofof IndolesIndoles 3.3. Copper-Catalyzed N-Arylation of Indoles Ligand-freeLigand-free cross-coupling cross-coupling reactions reactions can can be consideredbe considered economical economical and advantageousand advanta- duegeous to Ligand-freedue the costto the reductions cost cross-couplingreductions associated associated with reactions thewith designed the can designed be chemical considered chemical transformations. transformations. economical In and advanta- addition,Ingeous addition, due indole indole to Nthe-arylations N -arylationscost reductions have have been been associated the the subjects subjects with of of ligandless ligandless the designed experimental experimental chemical setups.setups. transformations. This approach for the preparation of N-aryl azoles, including N-arylindoles, was reported ThisIn addition, approach for indole the preparation N-arylations of N-aryl have azoles, been including the subjectsN-arylindoles, of ligandless was reported experimental setups. byby TeoTeo inin 2011 2011 (Scheme (Scheme 21 21))[ 91[91].]. TheThe reactionreaction of of unsubstituted unsubstituted indoles indoleswith with aryl aryl iodides iodides This approach for the preparation of N-aryl azoles, including N-arylindoles, was reported inin thethe presencepresence ofof catalytic catalytic amounts amounts of of copper copper oxide oxide and and tetrabutylammonium tetrabutylammonium bromidebromide (TBAB)(TBAB)by Teo asas in phase-transferphase-transfer 2011 (Scheme catalystscatalysts 21) [91]. inin waterwater The gavereactiongave NN-arylindoles-arylindoles of unsubstituted S21-2S21-2 inin highhigh indoles isolatedisolated with aryl iodides yields.yields.in the OnlyOnly presence arylaryl iodidesiodides of catalytic cancan bebe usedused amounts forfor thethe reaction,reaction, of copper becausebecause oxide thethe useuseand ofof thetetrabutylammoniumthe correspondingcorresponding bromide bromidesbromides(TBAB) leadsleadsas phase-transfer toto signiﬁcantlysignificantly lowerlower catalysts isolatedisolated in yieldsyields water ofof the thegave targettarget N-arylindoles compounds, compounds,S20-2 S20-2 S21-2.. The The in high isolated developed reaction conditions can also be used for the N-arylation of imidazole, pyrrole, developedyields. Only reaction aryl conditions iodides can can alsobe used be used for for the the reaction,N-arylation because of imidazole, the use pyrrole, of the corresponding 7-azaindole,7-azaindole, andand indazole.indazole. Alternatively,Alternatively, 55 mol%mol% ofof copper(II)copper(II) sulphatesulphate hashas beenbeen usedused toto catalyzecatalyzebromides indoleindole leads andand to azoleazole significantly NN-arylation-arylation lower inin thethe presence presenceisolated ofof yields sodiumsodium of hydroxidehydroxide the target atat 110compounds,110◦ °CC inin S20-2. The dimethyldimethyldeveloped sulfoxidesulfoxide reaction [[92].92]. conditions can also be used for the N-arylation of imidazole, pyrrole, 7-azaindole, and indazole. Alternatively, 5 mol% of copper(II) sulphate has been used to catalyze indole and azole N-arylation in the presence of sodium hydroxide at 110 °C in dimethyl sulfoxide [92].

SchemeScheme 21.21. Ligand-freeLigand-free copper-catalyzedcopper-catalyzedN N-arylation-arylation ofof indole.indole.

CopperCopper nanocatalystsnanocatalysts have have become become a populara popular tool tool for thefor preparationthe preparation of N -arylindoles.of N-arylin- Recentdoles. Recent examples examples of the useof the of use such of nanocatalystssuch nanocatalysts for the for synthesis the synthesis of N -arylindolesof N-arylindoles are listedare listed in Table in Table1. In 1. most In most cases, cases, nanocatalysts nanocatalysts catalyze catalyze the theN N-arylation-arylation of of indoles indoles under under ligandlessligandless conditions.conditions. An An exception exception to to this this concerns concerns the the preparation preparation of of NN-arylindoles-arylindoles in Scheme 21. Ligand-free copper-catalyzed N-arylation of indole. inthe the presence presence of 1,10-phenanthroline of 1,10-phenanthroline as a asligan a ligand,d, which which is catalyzed is catalyzed by electrospun by electrospun copper copperoxide nanoparticles oxide nanoparticles [93] and [93 ceria-supported] and ceria-supported copper copper [94] (Table [94] (Table1, entries1, entries 1 and 12). and Other 2). Othercopper-based copper-basedCopper nanocatalysts nanocatalysts nanocatalysts include have include CuO become nano CuOflakes nanoflakesa popular(CuO NFs@MP) (CuO tool NFs@MP)for prepared the preparation preparedby reduc- of N-arylin- byingdoles. reducing copper(II) Recent copper(II) chloride examples with chloride fruit of withthe waste use fruit [95] of waste and such CuO [95 nanocatalysts] nanoparticles, and CuO nanoparticles, whichfor the are synthesis easily which avail- are of N-arylindoles easilyableare bylisted available reducing in Table by copper(II) reducing 1. In mostacetate copper(II) cases, by means acetate nanocatalysts of by water means extraction of catalyze water from extraction the fresh N-arylation fromRosa canina fresh of indoles under Rosa canina fruits [96] (Table1, entries 3 and 4). The structures of both nanocatalysts fruitsligandless [96] (Table conditions. 1, entries 3 Anand exception4). The structures to this of bothconcerns nanocatalysts the preparation were determined of N -arylindoles in wereusing determined physicochemical using methods, physicochemical including methods, X-ray diffraction, including Fourier X-ray diffraction, transform Fourierinfrared transformspectroscopy,the presence infrared field of spectroscopy,1,10-phenanthrolineemission scanning field emissionelectron as microscopy, scanninga ligand, electron which and others. microscopy, is catalyzed However, and bythe others. electrospuntest- copper However,ingoxide of their nanoparticles the ability testing to ofcatalyze their[93] abilityand the Nceria-supported-arylation to catalyze of the indolesN-arylation copper is limited [94] of indoles to (Table only isa 1, limitedfew entries cases. to 1 and 2). Other onlySubstantiallycopper-based a few cases. better Substantiallynanocatalysts scopes were better reported include scopes for CuO werecarbon reportednano nanotube-copperflakes forcarbon (CuO oxide nanotube-copperNFs@MP) (CNT–CuO) prepared by reduc- oxide (CNT–CuO) [97], copper oxide nanoparticles [98,99], and copper nanoparticles [97],ing coppercopper(II) oxide chloride nanoparticles with [98,99], fruit waste and copper [95] andnanoparticles CuO nanoparticles, decorated with which organ- are easily avail- decoratedically modified with organicallymontmorillonite modified (copper-decorated montmorillonite OMMT) (copper-decorated [100] (Table 1,OMMT) entries 5–7). [100 ] (Tableable1 by, entries reducing 5–7). copper(II) acetate by means of water extraction from fresh Rosa canina

fruits [96] (Table 1, entries 3 and 4). The structures of both nanocatalysts were determined using physicochemical methods, including X-ray diffraction, Fourier transform infrared spectroscopy, field emission scanning electron microscopy, and others. However, the testing of their ability to catalyze the N-arylation of indoles is limited to only a few cases. Substantially better scopes were reported for carbon nanotube-copper oxide (CNT–CuO) [97], copper oxide nanoparticles [98,99], and copper nanoparticles decorated with organically modified montmorillonite (copper-decorated OMMT) [100] (Table 1, entries 5–7).

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Table 1. Nanocatalyzed N-arylations of indoles.

Molecules 2021, 26, 5079 16 of 44 No. of Molecules 2021, 26, x FOR PEER REVIEWEntry Conditions indoleFG Ar/hetAr16 FGof 43 Examples No. of Entry CuOConditions nano (5 indoleFG Ar/hetArFG Table 1. N Examples TableNanocatalyzed 1. Nanocatalyzedmol%),-arylations N 1,10-phen-arylations of of indoles. indoles. CuO(50 mol%)nano (5 4 1 – Cl mol%),KOH (2 1,10-phen equiv), 56–80% (50 mol%) 4 1 DMSO, reflux, 24 – Cl KOH (2 equiv), 56–80% h DMSO, reflux, 24 Cu@CeO2 (5 No.No. of of EntryEntry ConditionsConditions indoleindoleFGFG Ar/hetArAr/hetArFG FG mol%), 1,10-phenh ExamplesExamples Cu@CeO2 (5 CuO nano(50 (5CuO mol%),mol%) nano (5 6 2 – Cl 1,10-phenmol%),KOHmol%), (50 (2 mol%)1,10-phen equiv), 1,10-phen 82–89%4 1 (50 mol%) 4 – Cl KOH1 (2DMSO, equiv),(50 mol%) DMSO,reflux, 24 56–80%6 – Cl 2 reflux,KOH 24 h (2 equiv), 56–80% – Cl KOH (2h equiv), 82–89% Cu@CeODMSO,2DMSO,(5 mol%), reflux, reflux, 24 24 1,10-phen (50PhI, mol%) CuOh 6 2 h – Cl KOH (2 equiv),NFs@MPCu@CeO DMSO, (152 (5 82–89% PhI, CuO reflux,mol%),mg/mmol) 24 h 1,10-phen 3 NFs@MP (15 N PhI, CuOK NFs@MP2CO(503 mol%) (1.5 6 2 – Cl (15equiv), mg/mmol)mg/mmol)KOH DMF, (2 equiv), 100 82–89% 97% Ph 3 3 N K2CO3 (1.5 equiv),K2CO3 DMF,(1.5 ◦DMSO,°C, 6 reflux,h 24 100 C, 6 h 97% Ph equiv),CuO NPsDMF,h (10 100 PhI, CuO mg/1 °C,mmol 6 h of in- CuO NPs (10 mg/1NFs@MP mmol (15 4 dole),CuO NPs TEA (10 (2 4 of indole), TEAmg/mmol) (2 equiv), 3 DMF,mg/1 reflux, equiv),mmol 2 h of in- N K2CO3 (1.5 4 DMF,dole), reflux, TEA (22 h 97% Ph equiv), DMF, 100 Cl, F, COMe, CNT–CuOCNT–CuO (5equiv), mol%), (5 Cl, F, COMe, t °C, 6 h 21 CO2Me, CN, CF3, 5 BuONa (3DMF, equiv), reflux,t DMSO, 2 h Cl, F mol%),◦ CuO BuONa NPs (10 42–95%21 CO3,4-(CH2Me, 2CN,OCH CF2),3, 5 120 CNT–CuOC, 12 h (5 Cl, F Cl, F, COMe, (3 equiv),mg/1 mmol DMSO, of in- 42–95% 3,4-(CHNO2,2 SMeOCH2), 4CuO nanomol%), (5dole), mol%), tBuONa TEA (2 21 CO2Me, CN, CF3, 120 °C, 12 h 15 Br, CN, NO , NO2, SMe 6 5 K CO (1 equiv), DMF, Cl, F 2 NO 2 3 (3 equiv),equiv), DMSO, 62–98%42–95% OMe 3,4-(CH2OCH2 2), reflux,CuO 8 hnano (5 120DMF, °C, reflux, 12 h 2 h NO2, SMe Copper-decoratedmol%), K OMMT2CO3 (1 15 Br, CN, NO2, 6 CuOCNT–CuO nano (5 (5 Cl, F, COMe,NO2 (5 mol%),equiv), K2 CODMF,3 re- 62–98%8 OMe 7 mol%), tBuONa 21 CNCO2Me, OH, CN, NH CF23,, 5 (2mol%), equiv),flux, K 82CO h 3 (1 73–97%15 Br, Cl,CN, F NO2, 6 (3 equiv),◦ DMSO, 42–95% 3,4-(CH2OCHNO2 2), DMSO,equiv), 130 C, DMF, 6 h re- 62–98% OMe Copper-deco-120 °C, 12 h NO2, SMe flux, 8 h ratedCuO OMMT nano (5(5 Copper-deco- An alternativemol%), routemol%), K to2 COKN2CO-arylindoles3 (23 (1 is815 based on theBr, CN, two-step NO2, N-arylation of indoles 7 6 CN NOOH,2 NH2, starting from eitherrated indolines,equiv),equiv), OMMT DMF,S22-1a (5 re- , or indoline73–97%62–98% carboxylicOMe acids, S22-1b (Scheme 22) [101]. The reaction of themol%), startingflux, K2CO compounds 8 h3 (2 S22-1a8 and S22-1b with predominantly aryl io- 7 DMSO, 130 °C, 6 CN OH, NH2, dides is catalyzed by a recyclable nano-copper oxide catalyst. Based on the available Copper-deco-equiv),h 73–97% literature, the authorsDMSO,rated assume 130 OMMT °C, that 6(5 the preparation of the target compounds S22-2 starts with the aromatizationmol%), ofh indolines K2CO3 (2 into indoles,8 followed by N-arylation. During this An alternative7 route to N-arylindoles is based on the two-stepCN N-arylationOH, NH of2, indoles study, 27 N-arylated indolesequiv), were prepared.73–97% Selected examples S22-2a–S22-2d show that starting from either indolines, S22-1a, or indoline carboxylic acids, S22-1b (Scheme 22) the scope of the reactionDMSO, is mainly 130 °C, limited6 to unsubstituted indoles and aryl iodides with [101].An The alternative reaction of route the starting to N-arylindoles compounds is based S22-1a on and the S22-1b two-step with N-arylation predominantly of indoles aryl simple substituents. The authorsh also confirmed that the nano-copper oxide catalyst can be iodidesstarting isfrom catalyzed either indolines,by a recyclable S22-1a nano-copper, or indoline oxide carboxylic catalyst. acids, Based S22-1b on the(Scheme available 22) [101].reused The in reaction up to four of cyclesthe starting without compounds a significant S22-1a loss and in activity. S22-1b with predominantly aryl literature,CopperAn the alternative catalystsauthors assumeroute and to nitrogen Nthat-arylindoles the ligands preparation is based represent on of the the a two-step populartarget compounds N-arylation combination of S22-2 indoles for starts cross- iodides is catalyzed by a recyclable nano-copper oxide catalyst. Based on the available withcoupling startingthe aromatization reactions. from either This indolines,of is indolines also trueS22-1a forinto, or the indoles, indolineN-arylation followedcarboxylic of indoles. byacids, N-arylation. S22-1b A first (Scheme example During 22) of this the literature, the authors assume that the preparation of the target compounds S22-2 starts use of[101].N-ligands The reaction concerns of the thestarting preparation compounds of NS22-1a-arylindoles, and S22-1b which with ispredominantly catalyzed by aryl copper with iodidesthe aromatization is catalyzed byof aindolines recyclable into nano-copper indoles, oxidefollowed catalyst. by NBased-arylation. on the availableDuring this iodide and ligand L1 (Table2, entry 1) [ 102]. The authors succeeded in the preparation of literature, the authors assume that the preparation of the target compounds S22-2 starts 25 N-arylindoles, although a limited number of functional groups were introduced by this with the aromatization of indolines into indoles, followed by N-arylation. During this procedure. Significantly greater tolerance on the part of the functional groups was achieved by using the hydroxyquinalidine ligand L2 (Table1, entry 2) [ 103]. In contrast to previous work [102], the N-arylation can be performed at 90 ◦C, and the reaction can also be used to

prepare N-aryl imidazoles, pyrazoles, pyrroles, benzoimidazoles, and carbazoles. Ligands in the form of natural amino acids allow the N-arylation of indoles under similarly mild Molecules 2021, 26, x FOR PEER REVIEW 17 of 43

study, 27 N-arylated indoles were prepared. Selected examples S22-2a–S22-2d show that the scope of the reaction is mainly limited to unsubstituted indoles and aryl iodides with simple substituents. The authors also confirmed that the nano-copper oxide catalyst can be reused in up to four cycles without a significant loss in activity.

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reaction conditions [103]. Unfortunately, the scope of the reaction is almost exclusively limitedstudy, 27 to N-arylated the preparation indoles were of Nprepared.-arylindoles Selected (Table examples2, entries S22-2a– 3S22-2d [ 104 show] and that 4 [ 105]). The use of N N metforminthe scope of the as reaction the ligand is mainly for limited-arylation to unsubstituted led to the indoles formation and aryl ofiodides-arylindoles, with although thesimple reactions substituents. were The carried authors out also in confir DMFmed at that 130 the◦C nano-copper (Table2, entry oxide catalyst 5) [ 106 can]. The scope of this Scheme 22. Synthesis of N-arylindoles from indolines or indoline carboxylic acids. Nbe-arylation reused in up is to limited four cycles to thewithout preparation a significant of lossN -arylindoles.in activity. Copper catalysts and nitrogen ligands represent a popular combination for cross- coupling reactions. This is also true for the N-arylation of indoles. A first example of the use of N-ligands concerns the preparation of N-arylindoles, which is catalyzed by copper iodide and ligand L1 (Table 2, entry 1) [102]. The authors succeeded in the preparation of 25 N-arylindoles, although a limited number of functional groups were introduced by this procedure. Significantly greater tolerance on the part of the functional groups was achieved by using the hydroxyquinalidine ligand L2 (Table 1, entry 2) [103]. In contrast to previous work [102], the N-arylation can be performed at 90 °C, and the reaction can also be used to prepare N-aryl imidazoles, pyrazoles, pyrroles, benzoimidazoles, and carbazoles. Ligands in the form of natural amino acids allow the N-arylation of indoles under similarly mild reaction conditions [103]. Unfortunately, the scope of the reaction is almost exclusively limited to the preparation of N-arylindoles (Table 2, entries 3 [104] and 4 [105]). The use of metformin as the ligand for N-arylation led to the formation of N-arylindoles, SchemeSchemealthough 22. 22. SynthesisSynthesis the ofreactions N-arylindoles of N-arylindoles were from carried indolines from out or indolines inindoline DMF carboxylic orat indoline130 °Cacids. (Table carboxylic 2, entry acids. 5) [106]. The scope of this N-arylation is limited to the preparation of N-arylindoles. Copper catalysts and nitrogen ligands represent a popular combination for cross- coupling reactions. This is also true for the N-arylation of indoles. A first example of the TableTable 2. Nitrogen-based 2. Nitrogen-based ligands ligands for for the the N-arylation-arylation of indoles. indoles. use of N-ligands concerns the preparation of N-arylindoles, which is catalyzed by copper iodide and ligand L1 (Table 2, entry 1) [102]. The authors succeeded in the preparation of 25 N-arylindoles, although a limited number of functional groups were introduced by this procedure. Significantly greater tolerance on the part of the functional groups was achieved by using the hydroxyquinalidine ligand L2 (Table 1, entry 2) [103]. In contrast to previous work [102], the N-arylation can be performed at 90 °C, and the reaction can also be usedEn- to prepare N-aryl imidazoles, pyrazoles,No. pyrroles, of No. benzoimidazoles, of and carba- Entry ConditionsConditions indoleindoleFGFG Ar/hetArAr/hetArFG FG zoles. Ligandstry in the form of natural amino acidsExamples allow Examplesthe N-arylation of indoles under similarly mild reactionCuI (15 conditions mol%)/ L1[103]. (15 Unfort mol%)unately, the scope of the reaction is almost exclusively limitedCuI to (15 the mol%)/preparationL1 of N-arylindoles (Table25 2, entries 3 [104]CH=O, and 4 [105]). 1 tBuOK (2 equiv), DMSO, 120 NO2, OMe, The use of metformin(15 as mol%)the ligand for N-arylation 25led to 50–93%the formation of NOMe-arylindoles, 1 CH=O, OMe NO2, OMe, although the reactionstBuOK were (2°C, equiv), carried 36–48 outh in DMF50–93% at 130 °C (Table 2, entry 5) [106]. The ◦ scope of this NDMSO,-arylation 120 is limitedC, 36–48 to the h preparation of N-arylindoles. Cl, CF3, CN, CuICuI (2 (2 mol%)/ mol%)/L2L2 (4 mol%) 19 COCH3, Table 2. Nitrogen-based2 ligands for the N-arylation of indoles. – Cl, CF3, CN, K2CO(43 (2.5 mol%) equiv), DMSO, 90 °C 19 31–98% CO2H, F, 2 – COCH3, CO2H, K2CO3 (2.5 equiv), 31–98% NH2, NO2 Molecules 2021, 26, x FOR PEER REVIEW ◦ F, NH182, of NO 43 2 DMSO, 90 C CuI (5 mol%)/L-proline (10 mol%), K CO 18 Br, Cl, F, OMe, 3 2 3 Br, Cl, F, MeO, En- (5 equiv) No.51–97% of OH CuI (5 mol%)/L-proline (10 indole Ar/hetAr DMSO,Conditions 80–90 ◦C, 24 h 18 FG Br, Cl, F,FG Br, Cl, F, try 3 mol%), K2CO3 (5 equiv)Examples CuI (15 CuImol%)/ (5 mol%),L1 (15 mol%) 51–97% MeO, OMe, OH DMSO, 80–90 °C, 24 h 25 CH=O, 1 tBuOKL-methionine (2 equiv), (10DMSO, mol%), 120 16 Br, F, NONO2, OBn,2, OMe, 4 CuI (5 mol%), L-methionine 50–93%(10 OMe F, CF3, NO2, K2CO°C,3 (2 36–48 equiv), h DMF, 72–92% 16 OMe,Br, F, NO2, 4 mol%),◦ K2CO3 (2 equiv), DMF, F, CF3, NO2, 100 C, 24 h 72–92% OBn,Cl, CFOMe,3, CN, 100 °C, 24 h CuICuI (2 mol%)/ (10 mol%),L2 (4 mol%)L3 19 COCH3, 2 – K2CO3(20 (2.5CuI mol%), equiv), (10 mol%), CsDMSO,2CO L3 390 (20 °C mol%),31–98% 29 CO2H, F, Br, Cl, NO2, 5 ◦ 29 CHO,CHO, NO2, OMeNO2, Br, Cl, NO2, 5 (2Cs equiv),2CO3 (2 DMF, equiv), 130 DMF,C, 130 °C,62–91% NH2, NO2 OMe 62–91% OMe OMe 3–24 h3–24 h

The copper-catalyzed N-arylation of indoles in the presence of an L-proline ligand was used to prepare indolo[1,2-a]quinoxalines (Scheme 23) [107]. The authors used the Ugi multicomponent reaction to prepare 2-substituted indoles S23-2, and the subsequent intramolecular cyclization gave the target compounds S23-3. The Ugi reaction is limited to unsubstituted 2-iodaniline and 2-indolyl carboxylic acid. From the examples of S23-3a and S23-3b, it is clear that the scope of the two-step one-pot protocol for the synthesis of indolo[1,2-a]quinoxalines S23-3 is limited to aldehydes and isonitriles without functional groups. It is worth noting that the copper-catalyzed N-arylation gave better yields of N- arylated indoles S23-3 than the palladium-catalyzed cyclization (Pd(OAc)2, BINAP, K2CO3, toluene, reflux, 24 h).

Scheme 23. Ugi four-component reaction and subsequent post-modification for the synthesis of indolo[1,2-a]quinoxalines S23-3.

A similar approach for the intramolecular cyclization of Ugi adducts was reported by Liu in 2013 (Scheme 24) [108]. In this approach, the Ugi reaction is carried out among 2-indolylcarbaldehyde S24-1a, 2-iodobenzoic acid S24-1c, amine S24-1b, and isonitriles S24-1d. The Ugi adduct S24-2 is subsequently cyclized under different conditions. The N- arylation products S24-4 are obtained via a copper-catalyzed reaction in the presence of an L-proline ligand. The products of 2,3-cyclization S24-5 are formed during the palla-

Molecules 2021, 26, x FOR PEER REVIEW 18 of 43

CuI (5 mol%)/L-proline (10 18 Br, Cl, F, Br, Cl, F, 3 mol%), K2CO3 (5 equiv) 51–97% MeO, OMe, OH DMSO, 80–90 °C, 24 h CuI (5 mol%), L-methionine (10 16 Br, F, NO2, 4 mol%), K2CO3 (2 equiv), DMF, F, CF3, NO2, 72–92% OBn, OMe, 100 °C, 24 h CuI (10 mol%), L3 (20 mol%), 29 CHO, NO2, Br, Cl, NO2, 5 Cs2CO3 (2 equiv), DMF, 130 °C, 62–91% OMe OMe 3–24 h

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The copper-catalyzed N-arylation of indoles in the presence of an L-proline ligand The copper-catalyzed N-arylation of indoles in the presence of an L-proline ligand was used to prepare indolo[1,2-a]quinoxalines (Scheme 23) [107]. The authors used the was used to prepare indolo[1,2-a]quinoxalines (Scheme 23)[107]. The authors used the Ugi multicomponent reaction to prepare 2-substituted indoles S23-2, and the subsequent Ugi multicomponent reaction to prepare 2-substituted indoles S23-2, and the subsequent intramolecular cyclization gave the target compounds S23-3. The Ugi reaction is limited intramolecular cyclization gave the target compounds S23-3. The Ugi reaction is limited toto unsubstitutedunsubstituted 2-iodaniline2-iodaniline andand 2-indolyl2-indolyl carboxyliccarboxylic acid.acid. FromFrom thethe examplesexamples ofofS23-3a S23-3a andand S23-3bS23-3b,, itit isis clearclear thatthat thethe scopescope ofof thethe two-step two-step one-potone-pot protocolprotocol forfor thethe synthesissynthesis ofof indolo[1,2-a]quinoxalinesindolo[1,2-a]quinoxalines S23-3S23-3is is limitedlimited toto aldehydesaldehydes andand isonitrilesisonitriles withoutwithout functionalfunctional groups.groups. ItIt isis worthworth notingnoting thatthat thethe copper-catalyzedcopper-catalyzed NN-arylation-arylation gavegave betterbetter yieldsyields ofof NN-- arylated indoles S23-3 than the palladium-catalyzed cyclization (Pd(OAc)2, BINAP, arylated indoles S23-3 than the palladium-catalyzed cyclization (Pd(OAc)2, BINAP, K2CO3, toluene,K2CO3, toluene, reﬂux, 24 reflux, h). 24 h).

SchemeScheme 23.23.Ugi Ugi four-component four-component reaction reaction and and subsequent subsequent post-modification post-modification for the for synthesis the synthesis of indolo[1,2- of a]quinoxalinesindolo[1,2-a]quinoxalinesS23-3. S23-3.

AA similarsimilar approachapproach forfor thethe intramolecularintramolecular cyclizationcyclization ofof UgiUgi adductsadducts waswas reportedreported byby LiuLiu inin 20132013 (Scheme(Scheme 2424))[ [108].108]. InIn thisthis approach,approach, thethe UgiUgi reactionreaction isis carriedcarried outout amongamong 2-indolylcarbaldehyde2-indolylcarbaldehyde S24-1aS24-1a,, 2-iodobenzoic2-iodobenzoic acidacid S24-1cS24-1c,, amineamine S24-1bS24-1b,, andand isonitrilesisonitriles S24-1dS24-1d.. The Ugi adduct adduct S24-2S24-2 isis subsequently subsequently cyclized cyclized under under different different conditions. conditions. The The N- Narylation-arylation products products S24-4S24-4 areare obtained obtained via via a a copper-catalyzed copper-catalyzed reaction in the presencepresence ofof anan L-prolineL-proline ligand. ligand. The The products products of 2,3-cyclizationof 2,3-cyclizationS24-5 S24-5are formedare formed during during the palladium- the palla- catalyzed reaction. Cyclization performed without a transition metal produced isoindolin- 1-ones S24-3. The scope of the discovered transformations is limited to a few examples, although a more extensive scope was reported by the same author in 2014 [109].

Molecules 2021, 26, x FOR PEER REVIEW 19 of 43

Molecules 2021, 26, 5079 dium-catalyzed reaction. Cyclization performed without a transition metal produced19 of iso- 44 indolin-1-ones S24-3. The scope of the discovered transformations is limited to a few examples, although a more extensive scope was reported by the same author in 2014 [109].

SchemeScheme 24. 24.Diverse Diverse synthesis synthesis of of heterocyclic heterocyclic compounds compounds from from the the Ugi Ugi adducts adductsS24-2 S24-2. .

NN,N,N0-Dimethylethylenediamine′-Dimethylethylenediamine (DMEDA)(DMEDA) isis aa popularpopular ligandligand forfor useuse inin thethe copper-copper- catalyzedcatalyzedN N-arylation-arylation of of indoles. indoles. Lim Lim used used stoichiometric stoichiometric amounts amounts of of copper copper oxide oxide for for the the arylationarylation ofof indolesindoles inin pyridinepyridine (Table(Table3 ,3, entry entry 1) 1) [ 110[110].]. Unfortunately, Unfortunately, the the reaction reaction scope scope isis limited limited to to the the preparation preparation of of indoles indoles with with an an ethoxycarbonyl ethoxycarbonyl group group at at position position 2 2 of of the the indoleindole moiety.moiety. AnAn interesting interesting route route for for the the preparation preparation of of functionalized functionalizedN N-arylindoles-arylindoles waswas reportedreported inin 2013 (Table 3 3,, entryentry 2) [[111].111]. In In their their study, study, Ham Ham and and Kim Kim developed developed the thechemoselective chemoselective arylation arylation of halogen of halogen aryltriflu aryltrifluoroboratesoroborates to form to form functionalized functionalized organotri- organ- otrifluoroborates.fluoroborates. Only Only two two indole indole derivatives derivatives were were prepared prepared by this bythis procedure procedure (in 72% (in 72% and and73% 73% yields, yields, respectively). respectively). The presence The presence of a trifluoroborate of a trifluoroborate group group in the in structure the structure of N- ofarylindolesN-arylindoles can be can used be used in the in Suzuki the Suzuki reaction reaction to prepare to prepare N-arylindolesN-arylindoles with withmore more com- complexplex substituents substituents at atposition position 1 1[111]. [111 ].The The complementary complementary method method for the NN-arylation-arylation of of indolesindoles was was performed performed under under similar similar reaction reaction conditions conditions (Table 3(Table, entries 3, 3 andentries 4) [ 1123 and,113 ].4) [112,113].

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Table 3. Copper-catalyzed N-arylation of indoles in the presence of a DMEDA ligand. TableTable 3. Copper-catalyzed 3.3. Copper-catalyzed N-arylation NN-arylation-arylation of indoles ofof indolesindoles in the inin thethe presence presencepresence of ofaof DMEDA aa DMEDADMEDA ligand. ligand.ligand.

No. of No. of indole Ar/hetAr Entry Conditions No. ofNo. of indoleFG Ar/hetArFG EntryEntry Conditions Conditions Examples indoleindoleFGFGFG Ar/hetArAr/hetArFGFGFG ExamplesExamplesExamples 2 3 CuO (2 equiv), K2CO3 (2 CuO (2 equiv), K CO (2 11 Cl, F, CO2Et, CF3, F, CuOCuO (2 equiv),(2 equiv), K2CO K32CO(2 3 (2 11 Cl, F, CO2Et, CF3, F, 1 equiv), pyridine, reflux, 2–3 11 11 Cl, F,Cl, CO F,2 Et,CO2Et, CF3, F, 11 equiv), pyridine,pyridine, reﬂux, reflux, 2–3 15–96% OBn CFOMe,3, F, OMe, d 15–96%15–96%15–96% OBnOBnOBn OMe,OMe, 2–3d dd CuI (10 mol%), DMEDA (20 CuICuICuI (10 (10 (10 mol%), mol%), DMEDADMEDA DMEDA (20 (20 (20 2 mol%), Cs2CO3 (1 equiv) 2 2 mol%),mol%), CsCs2COCO3 (1(1 equiv) equiv) 2 mol%),2 Cs2CO3 3 (1 equiv) DMSO,DMSO, 120120◦ °C,C, 4 4 h h DMSO,DMSO, 120 120 °C, °C, 4 h 4 h

CuI (10 mol%), DMEDA (20 CuICuI (10 (10 mol%), DMEDADMEDA (20 (20 2 CuI (10 mol%), DMEDA (20 1313 Cl,Cl, CO 2Et, F, 3 mol%), K3PO4 (2 equiv), tolu- 13 Ph Cl, CO2Et, 3 3 mol%),mol%), K3PO K3PO4 (24 (2equiv), equiv), tolu- 13 PhPh Cl, CO2Et, 3 mol%), K3PO4◦ (2 equiv), tolu- 74–91%74–91% Ph F, OMe toluene,ene, 110 110 °C,C, 24 24 h h 74–91%74–91% F, OMeF, OMe ene,ene, 110 110 °C, °C, 24 24h h CuI (10 mol%), K3PO4 (3 CuICuI (10 mol%),mol%), K K3PO3PO4 (34 (3 CuI (10 mol%), K3PO4 (3 4 4 equiv),equiv), DMEDA DMEDA (20(20 mol%), mol%), 4 equiv),toluene, DMEDA 110 ◦C, 12 (20 h mol%), toluene, 110 °C, 12 h toluene, 110 °C, 12 h

Dichotomies during the arylations of 3-substituted indoles S25-1a and S25-1b were DichotomiesDichotomies during during the the arylatio arylationsns of of 3-substituted 3-substituted indoles indoles S25-1aS25-1a andand S25-1b were re- reportedDichotomies by Schnürch during (Scheme the 25)arylatio [114].ns The of 3-substituted starting indole, indoles which S25-1a featured and a S25-1b Boc-pro- were reportedported by by Schnürch (Scheme(Scheme 25 25))[ 114[114].]. The The starting starting indole, indole, which which featured featured a Boc-protecting a Boc-pro- tectingreported group, by reactedSchnürch with (Scheme arylboronic 25) [114]. acids The in thestarting presence indole, of a which palladium featured catalyst a Boc-pro- and tectinggroup, group, reacted reacted with with arylboronic arylboronic acids acids in thein the presence presence of aofpalladium a palladium catalyst catalyst and and one onetecting equivalent group, of reacted copper withacetate arylboronic to give 2-arylindoles acids in the S25-3apresence–S25-3c of a palladium in moderate catalyst yields. and oneequivalent equivalent of of copper copper acetate acetate to to give give 2-arylindoles 2-arylindolesS25-3a S25-3a–S25-3c–S25-3cin in moderate moderate yields. yields. The Theone formation equivalent of Nof-arylindoles copper acetate was to not give observed 2-arylindoles in this S25-3acase. The–S25-3c low yieldsin moderate of indoles yields. TheTheformation formation formation of ofN -arylindolesofN-arylindoles N-arylindoles was was not was not observed not observed observed in this in thisin case. this case. The case. The low The low yields low yields ofyields indoles of ofindoles indolesS25-3a , S25-3aS25-3b, S25-3b, and,S25-3c and S25-3cwere were explained explained by the by inferior the inferior steric steric requirements requirements for substitution for substi- at tutionS25-3a at position, S25-3b 2., and Changing S25-3c thewere catalytic explained system by theto ferric inferior chloride steric with requirements a DMEDA for ligand substi- tutionpositiontution at positionat 2.position Changing 2. Changing 2. Changing the catalytic the the catalytic catalytic system system tosystem ferric to ferricto chloride ferric chloride chloride with with a DMEDAwith a DMEDA a DMEDA ligand ligand ligand led to ledthe to the formation formation of N of-arylated N-arylated indoles indolesS25-4a S25-4a–S25-4e–S25-4ein highin high yields. yields.N -arylationN-arylation can can also alsoled be to performed the formation in the of ca Nse-arylated of unprotected indoles S25-4aindole –S25-1bS25-4e, inalthough high yields. in this N case-arylation a cata- can alsoalsobe be performed beperformed performed in in the thein casethe ca seca of seof unprotected unprotectedof unprotected indole indole indoleS25-1b S25-1b S25-1b, although, although, although in in this thisin this case case case a a catalytic cata- a cata- lyticamount amount of of copper copper iodide iodide with with aa DMEDADMEDA li ligandgand and and cesium cesium fluoride ﬂuoride as as a base a base had had to to be lyticused. amount of copper iodide with a DMEDA ligand and cesium fluoride as a base had to be beused. used.

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SchemeScheme 25. 25.DichotomiesDichotomies in inthe the transiti transition-metal-catalyzedon-metal-catalyzed arylation arylatio ofn of substituted substituted indoles. indoles.

A Aseries series of of NN-arylation-arylation reactions usingusing ligands ligands or or reagents reagents obtained obtained from from natural natural sources included the N-arylation of indoles, which was carried out in glycerol (Table4, sources included the N-arylation of indoles, which was carried out in glycerol (Table 4, entry 1) [115]. Glycerol is considered a cheap and environmentally-friendly alternative to entrythe 1) commonly [115]. Glycerol used solvents is considered DMF and a DMSO. cheap Aand common environmentally-friendly feature of N-arylation reactionsalternative to theperformed commonly in used glycerol, solvents DMF, DMF and DMSOand DMSO. is the A high common reaction feature temperature. of N-arylation The authors reactions performedhypothesize in thatglycerol, one equivalent DMF, and of DMSODMSO acts is asthe a ligandhigh reaction to help the temperature. oxidative addition The authors of hypothesizethe copper that catalyst one to equivalent the C-halogen of DMSO bond. Theacts goodas a ligand solubility to ofhelp the the reaction oxidative products addition of thein organic copper ethers catalyst allowed to the the C-halogen recycling bond. of the The catalytic good system solubility dissolved of the inreaction glycerol products by in extractionorganic ethers of the productsallowed andthe therecycling starting of compound the catalytic to the system ether. Such dissolved recycled in catalysts glycerol by extractioncan be used of the in three products catalytic and runs. the Astarting different co ligandmpound concept to the for ether. the N-arylation Such recycled of indoles catalysts α D L1 L2 canmakes be used use in of three methyl- catalytic- -glucopyranoside runs. A different andligand glucosamine concept for theas ligands N-arylation for copper- of indoles catalyzed N-arylations, as reported by Xuan [116] and Chen [117] (Table4, entries 2 and 3). makes use of methyl-α-D-glucopyranoside L1 and glucosamine L2 as ligands for copper- Neither reaction is signiﬁcantly different from the other procedures available for the N- catalyzedarylation N of-arylations, indoles. In as the reported case of the by glucosamine Xuan [116] ligandand ChenL2, the [117] formation (Table of4, aentries radical 2 and 3). intermediateNeither reactionT4-1 was is significantly proposed, although differen thet formationfrom the ofother this intermediateprocedures hasavailable not been for the N-arylationexperimentally of indoles. veriﬁed. In the The case use ofof otherthe glucosamine natural substances ligand in L2 this, the regard formation includes of a the radical intermediateuse of N-alkyl-glucosamine T4-1 was proposed, as a sugar-basedalthough the surfactant formation [118 of], this alpha- intermediateD-galacturonic has acid not been experimentallyL3 [119], and L verified.-(-)-quebrachitol The useL4 of[120 other] as ligands natural for substances the copper-catalyzed in this regardN-arylation includes of the useindoles of N-alkyl-glucosamine and nitrogen-containing as a substances.sugar-based surfactant [118], alpha-D-galacturonic acid L3 [119], and L-(-)-quebrachitol L4 [120] as ligands for the copper-catalyzed N-arylation of indoles and nitrogen-containing substances.

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Table 4. Copper-catalyzed N-arylations of indoles. Table 4. Copper-catalyzed N-arylations of indoles. Table 4. Copper-catalyzed N-arylations of indoles.

No. of Entry Conditions indoleFG Ar/hetArFG No. ofExamplesNo. of EntryEntry ConditionsConditions No. of indoleindoleFG FG Ar/hetArAr/hetArFGFG Entry CuIConditions (10 mol%), DMSO (1 ExamplesExamples indoleFG Ar/hetArFG Examples12 Br, NO2, Br, F, NO2, 1 equiv),CuICuI (10 (10 K mol%),2 COmol%),3 (2 DMSO equiv), DMSO glyc- (1 CuI (10 mol%), DMSO (1 65–92%12 Br,OMe NO 2, Br, OMeF, NO 2, 1 equiv),(1 equiv),erol, K2CO 120 K3 (22 CO°C, equiv),3 24 h glyc- 12 12 Br, NO2, Br, F, NO2, 1 1 equiv), K2CO3 (2 equiv), ◦glyc- 65–92% Br, NO2,OMe OMe Br, F, NOOMe2, OMe (2 equiverol,), glycerol, 120 °C, 120 24 C,h 65–92%65–92% OMe OMe erol, 12024 °C, h 24 h Cu (10 mol%), L1 (20 mol%), 2 CsCu2 CO(103 mol%),(3 equiv) L1 DMSO-H (20 mol%),2O Cu (10 Cumol%), (10 mol%), L1 (20L1 mol%), 2 Cs2(20CO(1:1), mol%),3 (3 100equiv) Cs °C,2CO DMSO-H12–243 h 2O 2 2 Cs2CO3 (3 equiv) DMSO-H2O (3 equiv)(1:1), 100 DMSO-H °C, 12–242O h (1:1), 100 °C,◦ 12–24 h (1:1), 100 C, 12–24 h Cl, COMe,

Cu2O (10 mol%), L2 (20 mol%), Cl,CO COMe,2Me, Cu2O (10 mol%), L2 15 Cl,Cl, COMe, COMe, 3 Cu2CsO 2(10CO mol%),3 (2 equiv), L2 (20DMSO, mol%), CH3, CHO COCHCO2Me,2CO 2 Cu2O (10(20 mol%), mol%), L2 Cs2 (20CO 3mol%), 15 COCO2Me,2Me, 3 ◦ 86–97%15 CH , CHO 3 (2Cs equiv),2CO1203 DMSO,(2 °C, equiv), 3–24 120 DMSO, hC, 86–97%15 3CH3, CHO COCHCOCHEt OMe,CO2COEt 2 3 Cs2CO3 (2 equiv), DMSO, 86–97% CH3, CHO COCH22CO22 1203–24 °C, h 3–24 h 86–97% OMe,Et NOOMe, NO2 2 120 °C, 3–24 h Et OMe, NO2 NO2

In addition to the above-mentioned examples, other ligands containing a nitrogen In addition to the above-mentioned examples, other ligands containing a nitrogen atomIn represent addition popularto the above-mentioned choices for the copper- examplcatalyzedes, other arylationligands containing of indoles. a Nitrogennitrogen atomIn addition represent to popularthe above-mentioned choices for the exampl copper-catalyzedes, other ligands arylation containing of indoles. a nitrogen Nitrogen atomligands represent also form popular part of choices the system for the for copper- the Ncatalyzed-arylation arylationof indoles of in indoles. water (TableNitrogen 5). atomligands represent also popular form part choices of the for system the copper- for thecatalyzedN-arylation arylation of indoles of indoles. in water Nitrogen (Table 5). ligandsSchmitt alsoused form copper part bromide of the andsystem the ligandfor the L1 N -arylationfor the N-arylation of indoles of inindoles water under (Table mild 5). ligandsSchmitt also used form copper part of bromide the system and thefor ligandthe N-arylationL1 for the Nof-arylation indoles in of water indoles (Table under 5). mild Schmittreaction used conditions copper (Table bromide 5, entry and the 1) [121].ligand D L1-Glucose for the wasN-arylation used as ofthe indoles reducing under agent mild in Schmittreaction used conditions copper bromide (Table and5, entry the ligand 1) [ 121 L1]. forD-Glucose the N-arylation was used of indoles as the reducingunder mild agent reactionthis case. conditions The reaction (Table was 5,performed entry 1) [121]. in a commercially D-Glucose was available used as DL the-α -tocopherolreducing agent meth- in reactionin this conditions case. The (Table reaction 5, entry was 1) performed [121]. D-Glucose in a commercially was used as available the reducingDL-α -tocopherolagent in thisoxypolyethylene case. The reaction glycol was succinate performed solution. in a commercially It was experimentally available verifiedDL-α-tocopherol that the usemeth- of this methoxypolyethylenecase. The reaction was glycolperformed succinate in a commercially solution. It was available experimentally DL-α-tocopherol veriﬁed meth- that the oxypolyethylenea surfactant is necessary glycol succinate to achieve solution. a high yield It was of experimentallyN-arylindoles. Theverified developed that the reaction use of oxypolyethyleneuse of a surfactant glycol is succinate necessary solution. to achieve It was a high experimentally yield of N-arylindoles. verified that The the developed use of aconditions surfactant were is necessary used for to the achieve synthesis a high of 11yield N-arylindoles, of N-arylindoles. and the The tolerance developed of the reaction func- a surfactantreaction is conditions necessary were to achieve used for a high the synthesisyield of N of-arylindoles. 11 N-arylindoles, The developed and the tolerancereaction of conditionstional groups were in thisused case for wathes synthesis limited to of halogens, 11 N-arylindoles, nitrile, et hers,and the and tolerance the formyl of thegroup. func- A conditionsthe functional were used groups for the in thissynthesis case was of 11 limited N-arylindoles, to halogens, and nitrile, the tolerance ethers, andof the the func- formyl tionalsimilar groups surfactant-based in this case strategy was limited for preparing to halogens, N-arylindoles nitrile, ethers, was and reported the formyl by Liu group. in 2013 A tionalgroup. groups A in similar this case surfactant-based was limited to halogens, strategy for nitrile, preparing ethers,N and-arylindoles the formyl was group. reported A similar(Table 5,surfactant-based entry 2) [122]. The strategy reaction for conditionspreparing Nfor-arylindoles the N-arylation was reported of indoles by make Liu in use 2013 of similarby Liusurfactant-based in 2013 (Table strategy5, entry for 2) preparing [ 122]. The N-arylindoles reaction conditions was reported for the by NLiu-arylation in 2013 of (Tablethe bipyridine 5, entry 2)ligand [122]. L2 The, potassium reaction conditionsphosphate foras thethe base,N-arylation and betaine of indoles as the make surfactant. use of (Tableindoles 5, entry make 2) [122]. use ofThe the reaction bipyridine conditions ligand forL2 the, potassium N-arylation phosphate of indoles as make the base,use of and theIn contrast bipyridine to previous ligand L2 work, potassium [121], the phosphate arylation as reaction the base, must and be betaine performed as the at surfactant. 90 °C. The the betainebipyridine as the ligand surfactant. L2, potassium In contrast phosphate to previous as the work base, [121 and], the betaine arylation as the reaction surfactant. must be Inauthors contrast demonstrated to previous◦ thework tolerance [121], the of arylation the acetyl reaction group duringmust be the performed preparation at 90 of °C. ten The in- In contrastperformed to previous at 90 C. work The authors [121], the demonstrated arylation reaction the tolerance must be of performed the acetyl group at 90 °C. during The the authorsdole derivatives demonstrated under the optimized tolerance reaction of the acetyl conditions. group An during extensive the preparation series of N of-arylated ten in- authorspreparation demonstrated of ten indolethe tolerance derivatives of the under acetyl optimized group during reaction the preparation conditions. Anof ten extensive in- doleindoles derivatives was prepared under by optimized means of reaction indole arylationconditions. catalyzed An extensive by copper series iodide of N-arylated and the doleseries derivatives of N-arylated under indolesoptimized was reaction prepared conditions. by means ofAn indole extensive arylation series catalyzed of N-arylated by copper indolesphenanthroline was prepared ligand byL3 meansin 30% ofaqueous indoleL3 1,2-dimethoxyethanearylation catalyzed by (DME) copper (Table iodide 5, andentry the 3) indolesiodide was and prepared the phenanthroline by means of ligandindole arylationin 30% catalyzed aqueous by 1,2-dimethoxyethane copper iodide and (DME)the phenanthroline[123].(Table 5The, entry optimum 3 )[ligand123 ratio]. L3 The inof optimum 30%DME aqueous to ratiowater 1,2-dimethoxyethane of was DME determined to water was using determined(DME) kinetic (Table experiments, using 5, entry kinetic 3) phenanthroline ligand L3 in 30% aqueous 1,2-dimethoxyethane (DME) (Table 5, entry 3) [123].experiments, The optimum which showed ratio of that DME reactions to water performed was determined in pure water using or kinetic DME did experiments, not achieve [123]. The optimum ratio of DME to water was determined using kinetic experiments,

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which showed that reactions performed in pure water or DME did not achieve quantita- quantitativetive conversion. conversion. An alternative An alternative procedure procedure for the preparation for the preparation of N-arylindoles of N-arylindoles relies on which showed that reactions performed in pure water or DME did not achieve quantita- reliesthe reaction on the of reaction boronic of acids boronic with acids indoles with indolesin aqueous in aqueous ammonia ammonia and potassium and potassium tert-butox-tert- tive conversion. An alternative procedure for the preparation of N-arylindoles relies on butoxideide as a base as a baseunder under ligandless ligandless conditions conditions [124]. [124 To]. complete To complete the thelist listof ofN-arylationsN-arylations of the reaction of boronic acids with indoles in aqueous ammonia and potassium tert-butox- ofindoles indoles in inwater, water, it itis isnecessary necessary to to mention mention the the NN-arylation-arylation procedures procedures associated withwith ide as a base under ligandless conditions [124]. To complete the list of N-arylations of heterocyclic compounds andand amines,amines, whichwhich cancan bebe applied for the preparation ofof a limited indoles in water, it is necessary to mention the N-arylation procedures associated with number of N-arylindoles [[125–131].125–131]. heterocyclic compounds and amines, which can be applied for the preparation of a limited numberTable 5.5. Copper-catalyzed of N-arylindoles NN [125–131].-arylation-arylation ofof indolesindoles inin water.water.

Table 5. Copper-catalyzed N-arylation of indoles in water.

No. ofNo. of EntryEntry ConditionsConditions indoleindoleFGFG Ar/hetArAr/hetArFGFG ExamplesExamples No. of indole Ar/hetAr Entry CuBr2Conditions(10 mol%), L1 Br, Cl,FG F, FG CuBr2 (10 mol%), L1 (10 Examples (10 mol%), D-glucose Br, Cl, F,OMOM, OMOM, mol%),(10 mol%), D-glucosetBuONa (10 mol%), 11 11 CHO,Br, OMe, Cl, F, 1 1 CuBr2 (10 mol%), L1 (10 CHO, OMe, NONO2,2 OMe, OMe tBuONa(2 (2 equiv), equiv), TPGS-750-43–95%43–95% CH2OMOM,CN, Cl, mol%), D-glucose (10 mol%), 11 CH2CN, Cl, 1 TPGS-750-M (5 wt%), NOCHO,2 OMe OMe, NO2, OMe M (5 wt%),◦ 50 °C, 24 h tBuONa50 (2 C,equiv), 24 h TPGS-750- 43–95% NO2 OMe CH2CN, Cl, CuIM CuI(10 (5 mol%), (10wt%), mol%), 50 L2 °C, L2(20 24 mol%), h Br, Cl, (20 mol%), K PO 10 NO2 OMe 2 K3PO4 (2 equiv),3 betaine4 (2 10 – Br, Cl,COMe, COMe, F, F, 2 CuI (10(2 equiv), mol%), betaine L2 (20 mol%), 57–95% – Br, Cl, equiv.), water, 90 °C, 10 h 57–95% 10 NONO2,2 OMe, OMe 2 K3PO(24 equiv.), (2 equiv), water, betaine (2 – COMe, F, CuI (5 mol%),90 ◦C, 10 L3 h (10 mol%), 57–95% equiv.), water, 90 °C, 10 h 23 Br, CN, NOBr,2 ,Cl, OMe I, 3 KOHCuI (2 (5 equiv), mol%), DME-HL3 2O CuI (5(10 mol%), mol%), L3 KOH (10 mol%), 23 42–95% Br, CN,COMe, COMe, NO2 OMe 3 (3:7), 95 °C, 20 h 23 Br, CN, Br, Cl,Br, I,Cl, OMe I, 3 KOH(2 equiv), (2 equiv), DME-H DME-H2O 2O 42–95% NO2 42–95% COMe, NO2 OMe (3:7),(3:7), 95 95◦C, °C, 20 h20 h

The copper(I)-oxide-catalyzed N-arylation of indoles, as catalyzed using copper oxide and a pyridine N-oxide ligand L1, was reported in 2016 (Table 6, entry 1) [132]. By The copper(I)-oxide-catalyzed N-arylation of indoles, as catalyzed using copper ox- varyingThe the copper(I)-oxide-catalyzed ligands during the optimizationN-arylation of of the indoles, reaction as catalyzedconditions, using it was copper confirmed oxide ide and a pyridine N-oxide ligand L1, was reported in 2016 (Table 6, entry 1) [132]. By andthat athe pyridine presenceN-oxide of both ligand pyridineL1, wasN-oxide reported and inphenyl 2016 (Tableamide6 ,moieties entry 1) in [ 132 the]. structure By varying of varying the ligands during the optimization of the reaction conditions, it was confirmed the ligand ligands L1 during is necessary the optimization to achieve ofmaximum the reaction yields. conditions, The optimized it was reaction conﬁrmed conditions that the that the presence of both pyridine N-oxide and phenyl amide moieties in the structure of presenceare suitable of both for the pyridine preparationN-oxide of and N-aryl phenyl pyrazole, amide moietiespyrrole, inand the indazole. structure The of the reaction ligand the ligand L1 is necessary to achieve maximum yields. The optimized reaction conditions L1scopeis necessary for indoles to achieveis limited maximum to six examples. yields. The The optimized use of a reaction pyridine conditions N-oxide areligand suitable was are suitable for the preparation of N-aryl pyrazole, pyrrole, and indazole. The reaction forpresumably the preparation inspired of Nby-aryl prior pyrazole, studies pyrrole,that utilized and indazole. pyridine The N-oxide reaction ligands scope for for general indoles scope for indoles is limited to six examples. The use of a pyridine N-oxide ligand was isN-arylation limited to six[133–135]. examples. The The pyridine-based use of a pyridine ligandN-oxide L2, which ligand contains was presumably an iminopyridyl inspired presumably inspired by prior studies that utilized pyridine N-oxide ligands for general bymoiety, prior was studies used that for utilizedthe N-arylation pyridine ofN indoles-oxide in ligands DMSO for at general120 °C (TableN-arylation 6, entry [133 2) –[136].135]. N-arylation [133–135]. The pyridine-based ligand L2, which contains an iminopyridyl TheAnother pyridine-based ligand L3 that ligand containsL2, which an iminopyridyl contains an iminopyridylmoiety in its molecule moiety, was was used reported for the in moiety, was used for the N-arylation of ◦indoles in DMSO at 120 °C (Table 6, entry 2) [136]. N2021-arylation (Table 6, of entry indoles 3) [137]. in DMSO A short at 120 communicationC (Table6, entry on the 2) [copper-catalyzed136]. Another ligand N-arylationL3 that Another ligand L3 that contains an iminopyridyl moiety in its molecule was reported in containsof indoles an was iminopyridyl published moiety in 2015 in (Table its molecule 6, entry was 4). reportedCopper(I) in 2021chloride (Table with6, entry a phosphine 3) [ 137]. 2021 (Table 6, entry 3) [137]. A short communication on the copper-catalyzed N-arylation Aligand short L4 communication in DMSO was found on the to copper-catalyzed be the best combinationN-arylation for the of indolesN-arylation was of published indoles. of indoles was published in 2015 (Table 6, entry 4). Copper(I) chloride with a phosphine inThe 2015 scope (Table of the6, entryreaction 4). is Copper(I) limited to chloride aryl halides with with a phosphine electron-donating ligand L4 orin electron-neu- DMSO was ligand L4 in DMSO was found to be the best combination for the N-arylation of indoles. foundtral substituents. to be the best It should combination be noted for thethatN 4--arylationiodobenzonitrile of indoles. did The not scope react of under the reaction the opti- is The scope of the reaction is limited to aryl halides with electron-donating or electron-neu- limitedmized reaction to aryl halides conditions. with electron-donating or electron-neutral substituents. It should be tralnoted substituents. that 4-iodobenzonitrile It should be didnoted not that react 4-iodobenzonitrile under the optimized did reactionnot react conditions. under the optimized reaction conditions.

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Table 6.6. Pyridine- and phosphorous-basedphosphorous-based ligandsligands forfor thethe NN-arylation-arylation ofof indoles.indoles.

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Table 6. Pyridine- and phosphorous-based ligands for the N-arylation of indoles. No. ofNo. of EntryEntry Conditions Conditions indoleindoleFGFG Ar/hetArAr/hetArFG ExamplesExamples

Cu2O (10Cu mol%),2O (10 mol%), L1 (4 mol%), L1 (4 mol%), 6 1 Cs2CO3 (2 equiv), DMSO, 6 – NO2, OMe 1 Cs CO (2 72–95% – NO , OMe 120 °C, 20 h 2 3 72–95% 2 equiv), DMSO, No. of Entry CuI (10 mol%),Conditions◦ L2 (10 mol%), indoleFG Ar/hetArFG 120 C, 20 h Examples7 2 K2CO3 CuI(2 (10equiv), mol%), DMSO, – NO2, OMe 2 84–97% Cu O (10L2 mol%),(10 mol%), L1 (4 mol%), 120 °C, 4–16 h 7 6 1 2 Cs2CO3 K (2CO equiv),(2 equiv), DMSO, –– NO 2,, OMeOMe CuI (10 mol%),2 3 L3 (10 mol%),84–97% 72–95% 2 120 °C, 20DMSO, h 120 ◦C, 4 3 K2CO3 (1.4 equiv), DMSO, CHO OMe CuI (10 mol%),4–16 L2 h (10 mol%), 69–99 110 °C, 24CuI h (10 mol%), 7 2 K2CO3 (2 equiv), DMSO, – NO2, OMe L3 (10 mol%), CuCl (8 mol%), L4 (16 mol%), 4 84–97% 3 120 °C, 4–16K COh (1.4 8 CHOBr, OMeCl, OEt, 4 NaOH (1 2 equiv),3 DMSO, 69–99 – CuI (10 mol%),equiv), DMSO,L3 (10 mol%), 25–98% OMe 120 °C, 24 h ◦ 4 3 K2CO3 (1.4110 equiv),C, 24 h DMSO, CHO OMe 69–99 110 °C, 24CuCl h (8 mol%), L4 (16 mol%), 8 4 CuCl (8NaOH mol%), (1 L4 equiv), (16 mol%), – Br, Cl, OEt, OMe 25–98% 8 Br, Cl, OEt, 4 NaOH DMSO,(1 equiv), 120 ◦C, DMSO, – 25–98% OMe 120 °C, 24 h 24 h

Recently, a self-relaying copper(I)-catalyzed sequence was used for the preparation of indolo[1,2-a]quinazolinones S26-3 by means of the reaction of the methyl esters of 3- indolylcarboxylic acid S26-1 with 2-bromobenzamides S26-2 (Scheme 26) [138]. This reaction is sensitive to the structure of the starting indole derivative, as the use of the 3-methylindole led to the formation of the N-arylated indole S26-4 and indoloquinazolinone Recently, a self-relaying copper(I)-catalyzed sequence was used for the preparation S26-5Recently,. Fifteen indolo[1,2-a]quinazolinone a self-relaying copper(I)-catalyzed S26-3 derivatives sequence were was usedprepared for the using preparation this pro- of indolo[1,2-a]quinazolinones S26-3 by means of the reaction of the methyl esters of 3- cedure.of indolo[1,2-a]quinazolinones It is worth noting that despiteS26-3 by the means harsh of reaction the reaction conditions, of the the methyl presence esters of of a indolylcarboxylic acid S26-1 with 2-bromobenzamides S26-2 (Scheme 26) [138]. This reac- chlorine3-indolylcarboxylic atom was tolerated. acid S26-1 It withwas also 2-bromobenzamides verified that the NS26-2-arylation(Scheme of indoles26)[138 to]. form This tion is sensitive to the structure of the starting indole derivative, as the use of the 3-me- thereaction intermediate is sensitive S26-6 to is the the structure first step of in the the starting formation indole of the derivative, target compounds as the use S26-3 of the. 3- thylindole led to the formation of the N-arylated indole S26-4 and indoloquinazolinone methylindole led to the formation of the N-arylated indole S26-4 and indoloquinazolinone S26-5. Fifteen indolo[1,2-a]quinazolinone S26-3 derivatives were prepared using this pro- S26-5. Fifteen indolo[1,2-a]quinazolinone S26-3 derivatives were prepared using this procedure.cedure. It is It worth is worth noting noting that that despite despite the the harsh harsh reaction reaction conditions, conditions, the the presence presence of a chlorine atomatom waswas tolerated.tolerated. It It was was also also veriﬁed verified that that the theN-arylation N-arylation of indolesof indoles to form to form the theintermediate intermediateS26-6 S26-6is the is ﬁrstthe first step step in the in formationthe formation of the of targetthe target compounds compoundsS26-3 S26-3. .

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Scheme 26. Formal double N-arylation synthesis of indolo[1,2-a]quinazolinones S26-3 via self- relay copper catalysis. Scheme 26.SchemeFormal 26. double FormalN double-arylation N-arylation synthesis synthesis of indolo[1,2-a]quinazolinones of indolo[1,2-a]quinazolinonesS26-3 via S26-3 self-relay via self- copper catalysis. relay copper catalysis. The cobalt–copper-cocatalyzed N-arylation and alkenylation of N-heterocycles was The cobalt–copper-cocatalyzed N-arylation and alkenylation of N-heterocycles was reported by Ran (Scheme 27) [139]. The reaction conditions were optimized for the The cobalt–copper-cocatalyzedreported by Ran (Scheme N-arylation 27)[139]. and The alkenylation reaction conditions of N-heterocycles were optimized was for the alkeny- alkenylation of amides, although it was determined that these conditions could also be reported by Ranlation (Scheme of amides, 27) although[139]. The it wasreaction determined conditions that were these conditionsoptimized couldfor the also be used for used for the preparation of N-arylindoles S27-2a and S27-2b in high yields. The authors alkenylation ofthe amides, preparation although of Nit-arylindoles was determinedS27-2a thatand theseS27-2b conditionsin high yields.could also The be authors assume assume that in the first step, the Co(II) is reduced to Co(I) by means of acetylacetone. The used for the preparationthat in the ﬁrstof N step,-arylindoles the Co(II) S27-2ais reduced and S27-2b to Co(I) inby high means yields. of acetylacetone. The authors The oxidative oxidative addition is followed by the substitution of the halide ligand, which is facilitated assume that inaddition the first isstep, followed the Co by(II) is the reduced substitution to Co(I) of by the means halide of ligand, acetylacetone. which is The facilitated by the by the formation of the Cu(I)–N complex S27-6. The product of the reaction is then ob- oxidative additionformation is followed of the by Cu(I)–N the substitution complex S27-6of the. halide The product ligand, of which the reaction is facilitated is then obtained by tained by reductive elimination. The proposed mechanism was partially confirmed exper- by the formationreductive of the Cu(I)–N elimination. complex The proposed S27-6. The mechanism product of was the partially reaction conﬁrmedis then ob- experimentally. imentally. A somewhat different approach to the N-arylation of nitrogen-containing het- tained by reductiveA somewhat elimination. different The proposed approach mechanism to the N-arylation was partially of nitrogen-containing confirmed exper- heterocycles erocycles makes use of the iron-catalyzed bromination of aromatics, followed by copper- imentally. A somewhatmakes use different of the iron-catalyzed approach to the bromination N-arylation of of aromatics, nitrogen-containing followed by het- copper-catalyzed catalyzed N-arylation [140]. This approach was used for the synthesis of 1-(4-methoxy- erocycles makesN -arylationuse of the [iron-catalyzed140]. This approach bromination was used of foraromatics, the synthesis followed of 1-(4-methoxyphenyl)indole by copper- phenyl)indole in a 78% yield. catalyzed N-arylationin a 78% [140]. yield. This approach was used for the synthesis of 1-(4-methoxyphenyl)indole in a 78% yield.

Scheme 27. Cobalt–copper-cocatalyzedScheme 27. Cobalt–copper-cocatalyzedN-arylation of indoles.N-arylation of indoles.

Scheme 27. Cobalt–copper-cocatalyzed N-arylation of indoles.

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Molecules 2021, 26, 5079 26 of 44 The general copper-catalyzed N-arylation of indoles and other azoles based on C–H bond activation was reported in 2016 (Scheme 28) [141]. The developed methodology is based on N-(quinolin-8-yl)benzamidesThe general copper-catalyzed S28-1, whichN-arylation react ofwith indoles azoles and and other indoles azoles based to give on C–H ortho-substituted benzamidesbond activation S28-2 was. reportedThe methodology in 2016 (Scheme was 28used)[141 for]. Thethe developedpreparation methodology of N- aryl pyrroles, indoles,is based carbazoles, on N-(quinolin-8-yl)benzamides and pyrazoles. TheS28-1 presence, which of react a quinolin-8-yl with azoles and group indoles to give ortho-substituted benzamides S28-2. The methodology was used for the preparation facilitates the formationof N-aryl of pyrroles, the complex indoles, S28-3 carbazoles, by means and pyrazoles. of copper The coordination presence of a quinolin-8-yl to the quinolin-8-yl moiety.group The facilitates oxidation the of formation CuII to Cu of theIII forms complex complexS28-3 by S28-4 means, which of copper undergoes coordination intramolecular C–Hto thecupration. quinolin-8-yl Eight moiety. N-arylated The oxidation indoles of were CuII to prepared CuIII forms using complex thisS28-4 proce-, which dure. It was shownundergoes that benzamide intramolecular with C–H a cupration.pyrrolyl unit Eight canN-arylated be hydrolyzed indoles were into prepared ortho using- this procedure. It was shown that benzamide with a pyrrolyl unit can be hydrolyzed into substituted benzoicortho acid.-substituted The same benzoic research acid. Thegroup same showed research that group the showed methodology that the methodology developed for C–H functionalizationdeveloped for C–H reactions functionalization can be extended reactions can to bepicolinamides, extended to picolinamides, rather than rather benzamides [142]. than benzamides [142].

Scheme 28. C–H activationScheme for 28.theC–H N-arylation activation forof indoles. the N-arylation of indoles.

An alternative approach to the N-arylation of indoles makes use of 2-indolylboronic An alternativeacids approach (Scheme to 29 the)[143 N].-arylation The starting of carboxylic indoles makes acids S29-1 usereact of 2-indolylboronic with aryl bromides or acids (Scheme 29) aryl[143]. iodides The in starting the presence carboxylic of catalytic acids amounts S29-1 of copper react oxidewith andaryl potassium bromides phosphate or aryl iodides in theas presence a base. The of reported catalytic scope amounts of the reaction of copper is limited oxide to substituted and potassium phenyl iodidesphos- and phate as a base. Thebromides. reported Other scope aromatic of the andreac heteroaromatiction is limited halides to substituted were not tested. phenyl In iodides terms of the proposed mechanism, the authors assume the formation of copper carboxylate S29-4 and and bromides. Other aromatic and heteroaromatic halides were not tested. In terms of the the subsequent decarboxylation into the 2-indolyl copper reagent S29-5. The ﬁnal products proposed mechanism,S29-2 theare formedauthors via assume anion exchange, the formation oxidative of addition, copper and carboxylate reductive elimination S29-4 and steps. the subsequent decarboxylation into the 2-indolyl copper reagent S29-5. The final products S29-2 are formed via anion exchange, oxidative addition, and reductive elimination steps.

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R1 Proposed mechanism: CO2H R1 Proposed mechanism: N R1 H S29-1CO2H CuI N R1 1H N S29-3 S29-1R CuI X S29-2 R1 CO2Cu N S29-3 N 2 COH Cu R1 X R1 S29-2 R Reductive S29-4 2 R2 N 2 elimination H R1 CO2H R1 R Reductive S29-4 N RCu2 2O(10mol%) N CO H elimination H 2 K3PO4 (2 equiv), S29-1N Cu2O(10mol%) N Decarboxylation NMP, 160 °C, 12 h CO2 H K3PO4 (2 equiv), S29-1 2 Decarboxylation NMP, 160 °C, 12 h R CO2 X=Br,I 1 S29-22 52 99% R R1 X=Br,I R S29-223 examples52 99% R1 R1 Cu Selected examples: 23 examples N CuN S29-7 Oxidative H Selected examples: N Cu X N Cl Cl S29-7 Oxidativeaddition HS29-5 Cu X Cl Cl addition R1 S29-5 R1 N N N R2 Anion exchange N N N Me Me R2 NAnion exchange N X S29-6 Cu X S29-6 Cu S29-2b 87% S29-2c 19% CN S29-2b 87% S29-2c 19% 2 S29-2a 79%CN 2 R S29-2a 79% R Scheme 29. Decarboxylative N-arylation of 2-indolylcarboxylic acids. SchemeScheme 29. 29.Decarboxylative Decarboxylative N-arylation-arylation of of 2-indolylcarboxylic 2-indolylcarboxylic acids. acids.

ArguablyArguably the thethe mostmost most extensive extensive procedure procedure procedure for for for the the the preparation preparation preparation of ofN of-arylindolesN N-arylindoles-arylindoles is based is is based based ononon the the reaction reaction of ofof indolesindoles indoles with with triarylbismuth triarylbismuth triarylbismuth reagents reagents reagents (Scheme (Scheme (Scheme 30) 30 30)[144].)[ 144[144]. The]. The The reaction reaction reaction is is is catalyzedcatalyzedcatalyzed by byby coppercoppercopper acetateacetate in inin the the the presence presence presence of of ofoxygen oxygen oxygen and and and one one one equivalent equivalent equivalent of ofbase. of base. base. The The The triarylbismuthtriarylbismuthtriarylbismuth reagentsreagents reagents can can be be be prepared prepared prepared using using using the the the reaction reaction reaction of of bismuth(III)of bismuth(III) bismuth(III) trichloride trichloride trichloride with with with GrignardGrignardGrignard reagentsreagentsreagents oror by by the the chemical chemical transfor transformation transformationmation of of ofthe thethe ester ester ester or or formylor formyl formyl group group group of the of of the the correspondingcorrespondingcorresponding triarylbismuthtriarylbismuthtriarylbismuth reagents. reagents.reagents. The TheThe pr procedureprocedureocedure is issuitableis suitablesuitable for for forthe the thepreparation preparation preparation of of of highlyhighlyhighly functionalized functionalized indoles indoles because because the the the meth methodology methodologyodology can can can tolerate tolerate tolerate a variety a a variety variety of functional of of functional functional groups,groups,groups, including including aa a formyl formyl or or or ester ester ester group, group, group, as as as illustratedillustrated illustrated by by byselectedselected selected examplesexamples examples S30-2bS30-2b S30-2b–S30-––S30-S30- 2e2e2e... The The tryptophan tryptophantryptophan derivative derivative S30-2aS30-2a S30-2a waswas was alsoalso also preparedprepared prepared using using using this this this procedure. procedure. procedure. In addition, In Inaddition, addition, a series of heteroatom arylations by organobismuth reagents has been reported [145–148]. aa series series of of heteroatomheteroatom arylations arylations byby organobismuthorganobismuth reagentsreagents hashas beenbeen reportedreported [[145–148].145–148].

Scheme 30. N-arylation of indoles by means of triarylbismuth reagents. SchemeScheme 30. 30.N N-arylation-arylation of of indoles indoles by by means means of of triarylbismuth triarylbismuth reagents. reagents.

Molecules 2021, 26, x FOR PEER REVIEW 28 of 43

Molecules 2021, 26, 5079 28 of 44 An alternative approach for the preparation of (–)-aspergilazine A that uses copper- An alternativecatalyzed approach indole for N the-arylation preparation was reported of (–)-aspergilazine in 2017 (Scheme A that 31) uses [149]. copper- A direct approach to catalyzed indole(–)-aspergilazine N-arylationAn alternative was approachA reported starting for in from the2017 preparation the (Scheme tryptophan 31) of(–)-aspergilazine [149]. derivative A direct S31-4 approach A that proved uses to copper- inefficient be- (–)-aspergilazinecatalyzedcause A starting the indole expected fromN-arylation theproduct tryptophan was of reportedthe reactionderivative in 2017 S31-5 S31-4 (Scheme was proved obtained 31)[149 inefficient]. in A directonly abe- approach 66% yield. Thus, to (–)-aspergilazine A starting from the tryptophan derivative S31-4 proved inefﬁcient cause the expectedthe preparationproduct of the of reactionthe target S31-5 compound was obtained from indolein only S31-1 a 66% and yield. 2-bromoindole Thus, or 2-io- because the expected product of the reaction S31-5 was obtained in only a 66% yield. the preparation of the target compound from indole S31-1 and 2-bromoindole or 2-io- Thus,doindole the preparation S31-2 was ofaccomplished the target compound in nine steps from indolein a totalS31-1 isolatedand 2-bromoindole yield of 36%. or doindole S31-22-iodoindole was accomplishedS31-2 was in accomplished nine steps in in a ninetotal steps isolated in a totalyield isolated of 36%. yield of 36%.

Scheme 31. Total synthesis of (–)-aspergilazine A via the copper-catalyzed N-arylation of indoles. SchemeScheme 31. 31. TotalTotal synthesis of of (–)-aspergilazine (–)-aspergilazine A viaA via the the copper-catalyzed copper-catalyzedN-arylation N-arylation of indoles. of indoles. Atom-economic arylation of indoles was described in 2015 (Scheme 32) [150]. N1- Atom-economicUnsubstitutedAtom-economic arylation indoles of arylationindoles react was of with indoles described diaryliodoni was describedin 2015um (Scheme insalts 2015 in (Scheme32) the [150]. presence 32 )[N1-150 ].of N1- a catalytic Unsubstituted indoles react with diaryliodonium salts in the presence of a catalytic amount Unsubstituted amountindoles ofreact copper with iodide diaryliodoni to give umN1- saltsand C3-arylatedin the presence indoles of ina averagecatalytic isolated yields. of copper iodide to give N1- and C3-arylated indoles in average isolated yields. High amount of copper iodide to give N1- and C3-arylated indoles in average isolated yields. selectivityHigh selectivity was observed was observed for aryl-uracil for aryl-uracil iodonium triﬂatesiodoniumS32-3 triflates, affording S32-3 the, 3-aryl-1-affording the 3- High selectivityindoles-uracilaryl-1-indoles-uracil was observed conjugates for aryl-uracil conjugatesS32-4. iodoniumS32-4. triflates S32-3, affording the 3- aryl-1-indoles-uracil conjugates S32-4.

SchemeScheme 32. 32.Atom-economical Atom-economicalN-arylation N-arylation of indoles of indoles by diaryliodonium by diaryliodonium salts. salts. Scheme 32. Atom-economical N-arylation of indoles by diaryliodonium salts.

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Molecules 2021, 26, 5079 29 of 44

The combination of photocatalysis and copper-catalyzed N-arylation enabled the N- arylationThe combination of indoles of photocatalysisat room temperature and copper-catalyzed (Scheme 33)N-arylation [151]. The enabled key the stepN- in this conver- arylationsion is the of indoles photoexcitation at room temperature of a copper (Scheme complex 33)[151]. S33-3 The key. The step reaction in this conversion is also suitable for the is the photoexcitation of a copper complex S33-3. The reaction is also suitable for the preparationpreparation of N of-aryl N-aryl benzimidazoles, benzimidazoles, imidazoles, imidazoles, and carbazoles. and carbazoles.

SchemeScheme 33. 33.N-Arylation N-Arylation of indoles of indoles under mild under conditions. mild conditions. 3.4. Miscellaneous Transition-Metal-Catalyzed N–Arylation of Indoles 3.4.A Miscellaneous straightforward Transition-Metal- approach to the preparationCatalyzed of N–Arylation indolo[1,2-f]phenanthridine of Indoles derivatives S34-3A straightforwardbased on the N–arylation approach of 2-aryl-3-substituted to the preparat indolesion of S34-1indolo[1,2-f]phenanthridineusing an iridium- deriv- catalyzedatives S34-3 oxidative based [4 + on 2] annulationthe N–arylation reaction withof 2-aryl-3-substituted quinones S34-2 was reported indoles by S34-1 Guo using an irid- and Fan (Scheme 34)[152]. A series of 20 N-arylated indoles was prepared, all in satis- factoryium-catalyzed yields, under oxidative optimized [4 reaction + 2] an conditions.nulation reaction The indoles with substituted quinones at positions S34-2 was reported by 2Guo and 3and smoothly Fan (Scheme reacted under 34) optimized[152]. A reactionseries of conditions. 20 N-arylated However, indoles the reaction was is prepared, all in limitedsatisfactory for benzoquinone yields, under and 2-methylbenzoquinone. optimized reaction Other conditions. quinone derivatives,The indoles such substituted as at posi- 2-chlorobenzoquinone,tions 2 and 3 smoothly 2,5-dimethylbenzoquinone, reacted under optimize and naphthoquinone,d reaction conditions. did not furnish However, the reac- the corresponding products. The authors posited a plausible reaction mechanism on the tion is limited for benzoquinone and 2-methylbenzoquinone. Other quinone derivatives, basis of mechanistic studies. Initially, the iridium-catalyzed dual N–H/C–H bond acti- vationsuch as of S34-52-chlorobenzoquinone,is responsible for the formation2,5-dimethyl of five-memberedbenzoquinone, iridacycle and naphthoquinone,S34-6. The did not subsequentfurnish the coordination corresponding of benzoquinone products. to The the iridiumauthors complex positedS34-6 a plausibleaffords the reaction new mechanism iridacycleon the basisS34-7 ,of which mechanistic then undergoes studies. a migratory Initially, insertion the iridium-catalyzed to deliver a seven-membered dual N–H/C–H bond intermediateactivation ofS34-8 S34-5. Next, is responsible the protonolysis for of the the formation complex S34-8 of withfive-membered HOAc leads to iridacycle both S34-6. The intermediate S34-9 and the active Ir(III) catalyst S34-4. Finally, a Zn(OAc)2-promoted in- tramolecularsubsequent indolyl coordination N1-attack onof thebenz carbonyloquinone group to affords the iridium the key intermediate complex S34-6S34-10 ,affords the new whichiridacycle undergoes S34-7 a dehydration, which then reaction undergoes to deliver a the migratory final product insertionS34-11. to deliver a seven-mem- beredAn intermediate alternative approach S34-8 to. theNext,N-arylation the protonolysis of indole-2-carboxamides of the complex was developedS34-8 with HOAc leads by Kong (Scheme 35)[153]. In this reaction, zinc(II) iodide is used as a catalyst and Ag CO to both intermediate S34-9 and the active Ir(III) catalyst S34-4. Finally,2 a3 Zn(OAc)2-pro- as an oxidant en route to indolo[1,2-a]quinoxalin-6-on S35-2. The scope of the reaction is moted intramolecular indolyl N1-attack on the carbonyl group affords the key intermedi- limited to substrates with a methoxy group or halogens. The presence of the N–CH3 amide moietyate S34-10 in the, startingwhich compoundundergoes is a crucial dehydration for the success reaction of this to reaction, deliver as the no final reaction product S34-11. occurred in the case of a substrate bearing an N−H amide group or a −CO2(4-MePh) group. It was proposed that this behavior is caused by the steric effect of the N–CH3 group, which can bring the two reaction sites closer, thereby facilitating the intramolecular cyclization reaction. A plausible mechanism can be identified on the basis of controlled experiments. The reaction is initiated by the generation of the indolylzinc(II) intermediate A. The oxidation of A by Ag2CO3 delivers the resonance-stabilized radical intermediate B or C. The intermediate D is obtained via the intramolecular addition of an indole radical onto the N-aryl moiety, which is followed by oxidation and deprotonation to give the desired product S33-2a.

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SchemeScheme 34. 34.Iridium-catalyzed Iridium-catalyzed oxidative oxidative annulation annulation of 2-arylindoles of 2-arylindolesS34-1. S34-1.

An alternative approach to the N-arylation of indole-2-carboxamides was developed by Kong (Scheme 35) [153]. In this reaction, zinc(II) iodide is used as a catalyst and Ag2CO3 as an oxidant en route to indolo[1,2-a]quinoxalin-6-on S35-2. The scope of the reaction is limited to substrates with a methoxy group or halogens. The presence of the N–CH3 amide moiety in the starting compound is crucial for the success of this reaction, as no reaction occurred in the case of a substrate bearing an N−H amide group or a −CO2(4-MePh) group. It was proposed that this behavior is caused by the steric effect of the N–CH3 group, which can bring the two reaction sites closer, thereby facilitating the intramolecular cyclization reaction. A plausible mechanism can be identified on the basis of controlled experiments. The reaction is initiated by the generation of the indolylzinc(II) intermediate A. The oxidation of A by Ag2CO3 delivers the resonance-stabilized radical intermediate B or C. The intermediate D is obtained via the intramolecular addition of an indole radical onto the

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Molecules 2021, 26, 5079 31 of 44 N-aryl moiety, which is followed by oxidation and deprotonation to give the desired product S33-2a.

Scheme 35. Novel method for the N–H arylation of indole-2-carboxamides S35-1 developed. Scheme 35. Novel method for the N–H arylation of indole-2-carboxamides S35-1 developed.

4. N-Arylated Indoles as Biologically Active Substances 4. N-Arylated Indoles as Biologically Active Substances In the preceding sections, we have discussed a wide variety of procedures that can In the preceding sections, we have discussed a wide variety of procedures that can be used for the preparation of N-indoles. Such a large number of different procedures be used for the preparation of N-indoles. Such a large number of different procedures have been developed due to the near endless number of applications of N-arylindoles. have been developed due to the near endless number of applications of N-arylindoles. Among them, N-arylindoles have found applications in the field of materials chemistry. Among them, N-arylindoles have found applications in the ﬁeld of materials chemistry. For example, NFor-arylindoles example, haveN-arylindoles been proposed have beenas novel proposed dye-sensitized as novel solar dye-sensitized cells [154], solar cells [154], electrophosphorescentelectrophosphorescent diodes [155], oxygen diodes se [nsors155], oxygen[156], and sensors other [ 156things], and [157–160]. other things Pro- [157–160]. Pro- cedures for the ceduresN-arylation for theof indolesN-arylation have ofalso indoles been haveused alsofor the been preparation used for the of preparationindoles of indoles with biological withactivity. biological A number activity. of N-arylindoles A number ofhaveN-arylindoles been prepared have in beenstructure–ac- prepared in structure– tivity relationshipactivity (SAR) relationship studies in (SAR)an effort studies to verify in an the effort mechanisms to verify the of mechanismsthe biological of the biological activity of the substitutedactivity of indoles; the substituted and the indoles;determination and the of determinationthe biological activities of the biological of N- activities of arylindoles has Nalso-arylindoles been part hasof a alsolarge-scope been part synthetic of a large-scope study concerning synthetic the study preparation concerning the prepa- of N-arylindoles.ration Examples of N-arylindoles. of such works Examples include inhibitors of such works of human include neutrophil inhibitors elastase of human neutrophil (HNE) [161], centromere-associatedelastase (HNE) [161], protein-E centromere-associated (CENP-E) inhibitors protein-E [162], (CENP-E) CRTh2 inhibitorsantago- [162], CRTh2 nists [163], and antagonistsdeterminations [163 of], andcytotoxic determinations activity [164,165]. of cytotoxic Ultimately, activity a large [164,165 group]. Ultimately, of a large N-arylindoles wasgroup prepared of N-arylindoles to study their was biolog preparedical activity. to study Selected their biological examples activity. are given Selected examples in Figures 5–9. are given in Figures5–9. A series of indole derivatives, F5-1a–F5-1c and F5-2a–F5-2d, was prepared to serve as angiotensin II (Ang II) receptor 1 antagonists (Figure 5) [166]. The introduction of the aryl substituent was accomplished through nucleophilic aromatic substitution by means of the reaction of substituted indoles with 2-fluorobenzonitrile in the presence of potassium carbonate in refluxing DMF. Among the prepared N-arylindoles, the compound F5- 2b showed binding affinity to the angiotensin AT1 receptor, with an IC50 value of 1.26 ±

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0.08 nM in radioligand binding assays. The same compound also showed the strongest antihypertensive effect, with a maximum reducing response of lower than 40.62 ± 4.08 mmHg MBP at 15 mg/kg 4 h after oral administration in SHRs. The acute toxicity of compound F5-2b was determined by LD50 as 1551.71 mg/kg. Other indole derivatives have been prepared by the same group and studied as angiotensin II receptor 1 antagonists [167–170]. The examples given in Figure 5 show that a common feature of these compounds is the presence of an ortho-substituted phenyl ring with a carboxylic acid F5-3 [167,168,170] or 1,2,4-oxadiazole F5-4 [169] scaffold at position 1 of the indole unit. Simi- Molecules 2021larly,, 26, 5079 the introduction of phenyl substituents was accomplished via nucleophilic aromatic32 of 44 substitution in refluxing DMF.

O N N N R N O R N N N N N N N N NH NH

F5-1a R=nPr F5-2a R=nPr F5-1b R=nBu F5-2b R=nBu F5-1c R=nPentyl F5-2c R=nPentyl F5-2d R=nhexyl N-arylation conditions: 2-fluorobenzonitrile, K2CO3 (2.1 equiv), DMF, reflux Biological activity: Angiotensin II receptor 1 antagonists n Cl Pr CO2H Me N N N N

O PhCH2CH2NH N O O N N COOH NH

F5-3 F5-4 Molecules 2021, 26, x FOR PEER REVIEW 33 of 43

Figure 5. Selected examplesFigure 5. Selectedof bioactive examples N-arylindoles—part of bioactive N-arylindoles—part 1. 1.

The new quinoline derivatives were prepared by means of a Buchwald–Hartwig reaction, which was catalyzed using a XPhos Pd G2 catalyst and tBuONa as the base (Figure 6) [171]. A number of compounds, including the indole derivative F6-1, were prepared using this procedure. It was determined that the substance F6-1 inhibited 70% of the α- amylase at a concentration of 50 μg/mL, and it also inhibited α-glucosidase at a concentration of 50 μg/mL. Benzimidazole and indole conjugates were prepared via double copper-catalyzed C–N bond formation [172]. The selected compound F6-2 demonstrated the formation of a Nindole–Cphenyl bond by a copper(I)-iodide-catalyzed reaction in DMF at 150 °C. The substance F6-2 showed the best minimum inhibitory concentration (MIC) of 4 μg/mL against Gram-negative (E. coli, P. putida, and S. typhi) and Gram-positive (B. subtilis and S. aureus) bacteria. The antifungal activity against C. albicans and A. niger of F6-2 is represented by an MIC value of 16 μg/mL.

FigureFigure 6. 6.Selected Selected examples examples of of bioactive bioactiveN N-arylindoles—part-arylindoles—part 2. 2.

A number of indole derivatives with a 1-methylpyrazol-4-yl substituent at position 1 were investigated with respect to their inhibitory activity in relation to the autotaxin (ATX) enzyme, which is responsible for the hydrolysis of lysophosphatidylcholine (LPC) (Figure 7) [173]. The introduction of the pyrazole skeleton was performed by means of Ullman condensation with copper oxide and 1,10-phenanthroline ligand in pyridine at 110 °C under microwave conditions. A detailed SAR study showed that the indole derivative F7-1a is a potent compound with an IC50 value of 22 ± 6.9 nM in the Bis-pNPP assay and 4 ± 0.5 nM IC50 in the LPC assay. Similar results were observed for the benzoic derivative F7-1b. The crystal structure of the studied compounds indicated that the active compounds bind within the tunnel, which was described as an allosteric binding site. Both B- cell lymphoma (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1) are proteins that help with the development and survival of multiple tumor types. Therefore, Fang [174] focused on studying the properties of indole derivatives with a phenyl substituent at position 1 as compounds that exhibit potent inhibitory activity against Bcl-2. The introduction of the aryl substituents was again catalyzed by cuprous oxide, although the reactions were performed in refluxing DMF. Compound F7-2 showed the best activity against Bcl-2, with a Ki value of 0.35 ± 0.03 μM. Docking studies revealed that the active compound F7-2 binds to the active pocket of the Bcl-2 protein through a hydrogen bond with Arg143 and the π– π interaction with Ph109 and Phe101. A number of 2,3-dihydrobenzo[f][1,4]oxazepine derivatives were prepared as antagonists of the prostaglandin E2 receptor subtype 2 (EP2) [175]. The oxazepine derivative with a 4-fluoroindole substituent F7-3 showed a binding affinity of 8 nM for the hEP2 receptor and an IC50 value of 50 nM in the hEP2 cAMP assay. In addition, the compound lacked CYP inhibition at 3 μM and had a 4000-fold higher binding affinity for the hEP2 receptor when compared with hEP1, hEP3, and hEP4. The formation of a N–Caryl bond was accomplished via a CuI-catalyzed reaction in the presence of a N,N´-dimethyl-1,2-cyclohexandiamine ligand and potassium phosphate as the base in 1,4-dioxane at 110 °C.

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Ph NO2 S H X 13 HN N Cl COOH S 12 Me O O O O Cl N MeO Me N N N Me F7-1a X=N F7-1b X=CH Ph F7-2 N-arylation conditions: N-arylation conditions: 4-iodo-1-methylpyrazole Ar-I CuO (50 mol%) CuO (43 mol%) 1,10-phenanthroline (1 equiv) KOH (2.2 equiv), Cs2CO3 (2 equiv), DMF, reflux, 5 h pyridine, 110 °C, MW, 2 h Biological activity: Biological activity: Inhibitory activities on Bcl-2/Mcl-1 and Autotaxin (ATX) inhibitors anti-proliferative activity

Cl 39 O F N N NH

F7-3 O

N-arylation conditions: ArBr CuI (10 mol%) N,N´-dimethyl-1,2-cyclohexandiamine (20 mol%) K3PO4 (2.2 equiv) 1,4-dioxane, 110 °C Biological activity: Binding afinity for the EP2

Figure 7. Selected examplesFigure 7. Selected of bioactive examples N-arylindoles—part of bioactive N-arylindoles—part 3. 3.

New substituted indole-3-carbinoles, as potent anti-cancer compounds derived from indole-3-carbinol (I3C), were designed and prepared as new inhibitors of NEDD4-1 ubiquitin ligase activity (Figure 8) [176]. In this case, the N-arylation of indoles was accomplished by means of an L-proline ligand and a copper catalyst. The parent carbinol I3C reached an IC50 value of 284 μM. The introduction of a benzyl group into position 1 decreased the IC50 value to 12.3 μM, whereas the introduction of the 4-tolyl group F8-1 substantially improved the IC50 value to 2.71 μM. Protein thermal shift assays in combination with in-silico binding simulation revealed that the tested derivatives bind to the purified catalytic HECT domain of NEDD4-1. In 2018, Knerr published two papers that evaluated N-arylindoles with trifluoromethoxy and carboxamide groups as selective inhibitors of secreted phospholipase A2 type X [177,178]. The formation of an N–Caryl bond was achieved by means of copper-catalyzed Ullman condensation in the presence of piperidine-2-carboxylic acid as a ligand. The indole F8-2 exhibited the best IC50 value (0.022 μM) against sPLA2-X. The presence of a trifluoromethoxy group is the key to achieving high

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inhibitory activity. The substitution of CF3O for the methoxy group led to the IC50 value being reduced to 0.62 μM. In another two papers [179,180], the selective activity of N- arylindoles toward P-glycoprotein (P-gp) or σ2 receptor agents was studied. The indole derivative F8-3 was chosen as a good ligand for both P-glycoprotein (P-gp) and the σ2 receptor. The starting compound F8-3 was subject to SAR studies wherein the N-arylation Molecules 2021, 26, 5079 34 of 44 of indoles was performed by a copper-catalyzed reaction in the presence of zinc oxide. On the basis of these studies, the compound F8-4 as a (+)-(S)-enantiomer displayed notable nanomolar σ2 affinity [180].

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Figure 8. Selected examples of bioactive N-arylindoles—part 4. Figure 8. Selected examples of bioactive N-arylindoles—part 4. Another set of indole derivatives with a similar substitution at position 1 of the indole skeleton was reported by Tamoo [181] and Uno (Figure 9) [182]. On the basis of extensive SAR studies, it was found that F9-1 is an inhibitor of cPLA2α (with an IC50 value of 0.075 μM) [181], and indole F9-2 is a selective inhibitor of both HSP90 (IC50 = 0.069 μM) and SK- Br-3 (IC50 = 0.33 μM) [182]. The introduction of the aryl substituents was accomplished via copper-catalyzed Ullman condensation at reaction temperatures above 100 °C.

FigureFigure 9. 9.Selected Selected examples examples of of bioactive bioactiveN N-arylindoles—part-arylindoles—part 5. 5.

5. Conclusions This review article has summarized the current state-of-the-art procedures for the preparation of N-arylindoles. The syntheses of the target compounds can be accomplished in several ways. The simplest procedures are based on transition-metal-free reactions. The second approach makes use of transition-metal-catalyzed aminations of organohalogenides or organometallic compounds. The metal most commonly used for the N-arylation of indoles is arguably copper, although a number of processes use palladium and nickel catalysts. The N-arylation of indoles can be performed in an inter- or intramolecular manner in high isolated yields. Despite considerable efforts having been made to successfully accomplish N-arylation experiments, two major limitations persist. The first limitation is associated with the low tolerance of the functional groups. Only the N-arylation of indoles, which is accomplished by the effect of triorganobismuth reagents, avoids this trend. The second limitation concerns the reaction temperatures at which the N-arylations take place. In the vast majority of cases, the N-arylations are performed at high temperatures, which commonly exceed 100 °C. In some cases, the arylation reactions are also performed in refluxing DMF. However, N-arylations of indoles at room temperature are rare. Thus, the development of new catalytic systems for the N-arylation of indoles represents a new direction of development in this field. Such efforts will result in higher tolerance of the functional groups, which should streamline the development of new biologically active compounds based on substituted indoles. At the same time, efforts to lower the reaction temperature required for the N-arylation of indoles will greatly benefit the overall economic aspects of the process.

Author Contributions: Conceptualization–T.T.; writing original draft and editing–P.O., J.K., A.P, T.T. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported from the grant of Specific university research grant No A2_FCHT_2021_074 and the APC was funded by University of Chemistry and Technology Prague. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable.

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A series of indole derivatives, F5-1a–F5-1c and F5-2a–F5-2d, was prepared to serve as angiotensin II (Ang II) receptor 1 antagonists (Figure5)[ 166]. The introduction of the aryl substituent was accomplished through nucleophilic aromatic substitution by means of the reaction of substituted indoles with 2-fluorobenzonitrile in the presence of potassium carbonate in refluxing DMF. Among the prepared N-arylindoles, the compound F5-2b showed binding affinity to the angiotensin AT1 receptor, with an IC50 value of 1.26 ± 0.08 nM in radioligand binding assays. The same compound also showed the strongest antihypertensive effect, with a maximum reducing response of lower than 40.62 ± 4.08 mmHg MBP at 15 mg/kg 4 h after oral administration in SHRs. The acute toxicity of compound F5-2b was determined by LD50 as 1551.71 mg/kg. Other indole derivatives have been prepared by the same group and studied as angiotensin II receptor 1 antagonists [167–170]. The examples given in Figure5 show that a common feature of these compounds is the presence of an ortho-substituted phenyl ring with a carboxylic acid F5-3 [167,168,170] or 1,2,4-oxadiazole F5-4 [169] scaffold at position 1 of the indole unit. Similarly, the introduction of phenyl substituents was accomplished via nucleophilic aromatic substitution in refluxing DMF. The new quinoline derivatives were prepared by means of a Buchwald–Hartwig reaction, which was catalyzed using a XPhos Pd G2 catalyst and tBuONa as the base (Figure6)[ 171]. A number of compounds, including the indole derivative F6-1, were prepared using this procedure. It was determined that the substance F6-1 inhibited 70% of the α-amylase at a concentration of 50 µg/mL, and it also inhibited α-glucosidase at a concentration of 50 µg/mL. Benzimidazole and indole conjugates were prepared via double copper-catalyzed C–N bond formation [172]. The selected compound F6-2 demonstrated the formation of a Nindole–Cphenyl bond by a copper(I)-iodide-catalyzed reaction in DMF at 150 ◦C. The substance F6-2 showed the best minimum inhibitory concentration (MIC) of 4 µg/mL against Gram-negative (E. coli, P. putida, and S. typhi) and Gram-positive (B. subtilis and S. aureus) bacteria. The antifungal activity against C. albicans and A. niger of F6-2 is represented by an MIC value of 16 µg/mL. A number of indole derivatives with a 1-methylpyrazol-4-yl substituent at position 1 were investigated with respect to their inhibitory activity in relation to the autotaxin (ATX) enzyme, which is responsible for the hydrolysis of lysophosphatidylcholine (LPC) (Figure7 )[173]. The introduction of the pyrazole skeleton was performed by means of Ull- man condensation with copper oxide and 1,10-phenanthroline ligand in pyridine at 110 ◦C under microwave conditions. A detailed SAR study showed that the indole derivative F7-1a is a potent compound with an IC50 value of 22 ± 6.9 nM in the Bis-pNPP assay and 4 ± 0.5 nM IC50 in the LPC assay. Similar results were observed for the benzoic derivative F7-1b. The crystal structure of the studied compounds indicated that the active compounds bind within the tunnel, which was described as an allosteric binding site. Both B-cell lymphoma (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1) are proteins that help with the development and survival of multiple tumor types. Therefore, Fang [174] focused on studying the properties of indole derivatives with a phenyl substituent at position 1 as compounds that exhibit potent inhibitory activity against Bcl-2. The introduction of the aryl substituents was again catalyzed by cuprous oxide, although the reactions were performed in refluxing DMF. Compound F7-2 showed the best activity against Bcl-2, with a Ki value of 0.35 ± 0.03 µM. Docking studies revealed that the active compound F7-2 binds to the active pocket of the Bcl-2 protein through a hydrogen bond with Arg143 and the π–π interaction with Ph109 and Phe101. A number of 2,3-dihydrobenzo[f][1,4]oxazepine derivatives were prepared as antagonists of the prostaglandin E2 receptor subtype 2 (EP2) [175]. The oxazepine derivative with a 4-fluoroindole substituent F7-3 showed a binding affinity of 8 nM for the hEP2 receptor and an IC50 value of 50 nM in the hEP2 cAMP assay. In addition, the compound lacked CYP inhibition at 3 µM and had a 4000-fold higher binding affinity for the hEP2 receptor when compared with hEP1, hEP3, and hEP4. The formation of a N–Caryl bond was accomplished via a CuI-catalyzed reaction in the presence of a N,N0-dimethyl-1,2-cyclohexandiamine ligand and potassium phosphate as the base in 1,4-dioxane at 110 ◦C. Molecules 2021, 26, 5079 36 of 44

New substituted indole-3-carbinoles, as potent anti-cancer compounds derived from indole-3-carbinol (I3C), were designed and prepared as new inhibitors of NEDD4-1 ubiquitin ligase activity (Figure8)[ 176]. In this case, the N-arylation of indoles was accomplished by means of an L-proline ligand and a copper catalyst. The parent carbinol I3C reached an IC50 value of 284 µM. The introduction of a benzyl group into position 1 decreased the IC50 value to 12.3 µM, whereas the introduction of the 4-tolyl group F8-1 substantially improved the IC50 value to 2.71 µM. Protein thermal shift assays in combination with in-silico binding simulation revealed that the tested derivatives bind to the purified catalytic HECT domain of NEDD4-1. In 2018, Knerr published two papers that evaluated N-arylindoles with trifluoromethoxy and carboxamide groups as selective inhibitors of secreted phospholipase aryl A2 type X [177,178]. The formation of an N–C bond was achieved by means of copper- catalyzed Ullman condensation in the presence of piperidine-2-carboxylic acid as a ligand. The indole F8-2 exhibited the best IC50 value (0.022 µM) against sPLA2-X. The presence of a trifluoromethoxy group is the key to achieving high inhibitory activity. The substitution of CF3O for the methoxy group led to the IC50 value being reduced to 0.62 µM. In another two papers [179,180], the selective activity of N-arylindoles toward P-glycoprotein (P-gp) or σ2 receptor agents was studied. The indole derivative F8-3 was chosen as a good ligand for both P-glycoprotein (P-gp) and the σ2 receptor. The starting compound F8-3 was subject to SAR studies wherein the N-arylation of indoles was performed by a copper-catalyzed reaction in the presence of zinc oxide. On the basis of these studies, the compound F8-4 as a (+)-(S)-enantiomer displayed notable nanomolar σ2 affinity [180]. Another set of indole derivatives with a similar substitution at position 1 of the indole skeleton was reported by Tamoo [181] and Uno (Figure9)[182]. On the basis of extensive SAR studies, it was found that F9-1 is an inhibitor of cPLA2α (with an IC50 value of 0.075 µM)[181], and indole F9-2 is a selective inhibitor of both HSP90 (IC50 = 0.069 µM) and SK-Br-3 (IC50 = 0.33 µM)[182]. The introduction of the aryl substituents was accomplished via copper-catalyzed Ullman condensation at reaction temperatures above 100 ◦C.

5. Conclusions This review article has summarized the current state-of-the-art procedures for the preparation of N-arylindoles. The syntheses of the target compounds can be accomplished in several ways. The simplest procedures are based on transition-metal-free reactions. The second approach makes use of transition-metal-catalyzed aminations of organohalogenides or organometallic compounds. The metal most commonly used for the N-arylation of indoles is arguably copper, although a number of processes use palladium and nickel catalysts. The N-arylation of indoles can be performed in an inter- or intramolecular manner in high isolated yields. Despite considerable efforts having been made to successfully accomplish N-arylation experiments, two major limitations persist. The first limitation is associated with the low tolerance of the functional groups. Only the N-arylation of indoles, which is accomplished by the effect of triorganobismuth reagents, avoids this trend. The second limitation concerns the reaction temperatures at which the N-arylations take place. In the vast majority of cases, the N-arylations are performed at high temperatures, which commonly exceed 100 ◦C. In some cases, the arylation reactions are also performed in refluxing DMF. However, N-arylations of indoles at room temperature are rare. Thus, the development of new catalytic systems for the N-arylation of indoles represents a new direction of development in this field. Such efforts will result in higher tolerance of the functional groups, which should streamline the development of new biologically active compounds based on substituted indoles. At the same time, efforts to lower the reaction temperature required for the N-arylation of indoles will greatly benefit the overall economic aspects of the process. Molecules 2021, 26, 5079 37 of 44

Author Contributions: Conceptualization—T.T.; writing original draft and editing—P.O., J.K., A.P., T.T. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported from the grant of Specific university research grant No A2_FCHT_2021_074 and the APC was funded by University of Chemistry and Technology Prague. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest.

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