Recent Progress Concerning the N-Arylation of Indoles

This review summarizes the current state-of-the-art procedures in terms of the preparation of N-arylindoles. After a short introduction, the transition-metal-free procedures available for the N-arylation of indoles are briefly discussed. Then, the nickel-catalyzed and palladium-catalyzed N-arylation of indoles are both discussed. In the next section, copper-catalyzed procedures for the N-arylation of indoles are described. The final section focuses on recent findings in the field of biologically active N-arylindoles.


Introduction
Heterocyclic compounds are cyclic compounds that each contain either a heteroatom or a number of heteroatoms. Among the most important groups of heterocyclic compounds are the aromatic heterocyclic compounds. Well-known examples of such compounds include pyridine, pyrrole, thiophene, and furan. Indoles occupy a unique position within the field of heterocyclic compounds. An indole is a condensed compound that is composed of a benzene and pyrrole core. The importance of indoles and their derivatives is illustrated by the examples shown in Figure 1. Tryptophan is an aromatic essential amino acid, and sattazolin [1] and umifenovir [2] are indole derivatives with antiviral effects. Narylated indoles also belong to the group of important indole derivatives. An example of such a compound is sertindole, which is used as an antipsychotic drug [3]. Due to the significant biological activity of the indole derivatives, much attention has been paid to the modification of the indole unit [4][5][6][7][8].

Introduction
Heterocyclic compounds are cyclic compounds that each contain either a heteroatom or a number of heteroatoms. Among the most important groups of heterocyclic compounds are the aromatic heterocyclic compounds. Well-known examples of such compounds include pyridine, pyrrole, thiophene, and furan. Indoles occupy a unique position within the field of heterocyclic compounds. An indole is a condensed compound that is composed of a benzene and pyrrole core. The importance of indoles and their derivatives is illustrated by the examples shown in Figure 1. Tryptophan is an aromatic essential amino acid, and sattazolin [1] and umifenovir [2] are indole derivatives with antiviral effects. N-arylated indoles also belong to the group of important indole derivatives. An example of such a compound is sertindole, which is used as an antipsychotic drug [3]. Due to the significant biological activity of the indole derivatives, much attention has been paid to the modification of the indole unit [4][5][6][7][8]. The significant biological activity exhibited by sertindole has inspired the search for new procedures for the preparation of N-arylindoles. Every indole contains a pyrrole core, of heteroatoms in furan and thiophene to form stable derivatives o are not feasible. In some cases, phospholes can be P-arylated t phospholes [9], although the reactivity of the phosphole is affect [10][11][12][13]. By contrast, pyrroles can be very easily arylated at posit In addition, the dearomatizations of pyrroles are important [18-2 be expected even in the case of indole arylations. The typical app of amines, including nitrogen-containing heteroaromatic compou transition-metal-catalyzed reactions (Scheme 1). In these cases, U 25], Buchwald-Hartwig amination [26][27][28], and Chan-Lam cou quently used. A common feature of these procedures is the react nohalides or boronic acids in the presence of a transition metal c atively large number of N-arylation reactions of indoles have be decade. However, to the best of our knowledge, only a few review the preparation of N-arylindoles [32][33][34]. Thus, we decided to su that have been used for the preparation of N-arylindoles over th of the present review is limited to works that focused on the N otherwise significantly contributed to this field. Scheme 1. Transition-metal-catalyzed approaches to N-arylamines.

Transition-Metal-Free N-Arylation of Indoles
The preparation of N-arylindoles without transition metal ca ried out using benzynes. This approach was first reported in 201 study, the starting indole S2-1 was treated with 2-bromoacetoph ence of t BuOK to produce N-phenylindole S2-3 in a 66% yield. T accounts for the formation of a benzyne intermediate (S2-6) and enolate S2-4. The scope of the reaction is limited to the indole S Wu published another benzyne-involving route to functionalize trast, furnishes mainly C3-arylated indole derivatives, along wi side-products [36]. Scheme 1. Transition-metal-catalyzed approaches to N-arylamines.

Transition-Metal-Free N-Arylation of Indoles
The preparation of N-arylindoles without transition metal catalysts can be easily carried out using benzynes. This approach was first reported in 2018 (Scheme 2) [35]. In this study, the starting indole S2-1 was treated with 2-bromoacetophenone (S2-2) in the presence of t BuOK to produce N-phenylindole S2-3 in a 66% yield. The proposed mechanism accounts for 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]. Intermolecular nucleophilic aromatic substitution can also be used to prepare Nylindoles (Scheme 5). This concept for the preparation of N-arylindoles is usually bas on the reaction of aryl fluorides with indoles under basic conditions. Diness et al. dev oped two procedures for the preparation of N-arylindoles. In the first procedure, the action of pentafluorobenzene with an indole in the presence of t BuONa afforded N-aryl dole S5-2, which was then used for the preparation of pentasubstituted benzene (Sche 5, Diness's N-arylation of indoles) [42]. The analogous reaction with a halogenated a mate containing only one fluorine atom proceeded under harsh reaction conditions, illustrated by the selected synthesis of indole S5-3. However, the overall reaction sco was limited to three examples of N-arylated indoles [43]. Similar reaction conditions w used for the preparation of bis N-arylindoles with structures represented by the ind S5-5 (Scheme 5, Chang´s N-arylation of indoles). The prepared N-arylindoles were p ymerized, and their optical and electrochemical properties and thermal stability were d termined [44]. The results summarized in Scheme 5 indicate that the use of nucleoph aromatic substitution for the preparation of N-arylindoles proceeds best in the case pentafluorobenzenes. This conclusion was confirmed by the work of Zhang [45], who p pared a series of tetrafluorophenylbenzenes through the reaction of indoles with pe tafluorobenzenes in the presence of sodium hydroxide under mild reaction conditio (Scheme 5, Zhang´s N-arylation of indoles). Similar reaction conditions (KOH, DMSO, 1 °C, 24 h) were used by Hua to prepare a series of N-arylated indoles (23 compounds, 2 87% isolated yields) [46].
In addition to the above-mentioned procedures for the transition-metal-free arylati of indoles by means of intermolecular nucleophilic aromatic substitution, other pro dures have also been used to achieve limited N-arylation of indoles as parts of gene Intermolecular nucleophilic aromatic substitution can also be used to prepare Narylindoles (Scheme 5). This concept for the preparation of N-arylindoles is usually based on the reaction of aryl fluorides with indoles under basic conditions. Diness et al. developed two procedures for the preparation of N-arylindoles. In the first procedure, the reaction of pentafluorobenzene with an indole in the presence of t BuONa afforded N-arylindole S5-2, which was then used for the preparation of pentasubstituted benzene (Scheme 5, Diness's N-arylation of indoles) [42]. The analogous reaction with a halogenated aromate containing only one fluorine atom proceeded under harsh reaction conditions, as illustrated by the selected synthesis of indole S5-3. However, the overall reaction scope was limited to three examples of N-arylated indoles [43]. Similar reaction conditions were used for the preparation of bis N-arylindoles with structures represented by the indole S5-5 (Scheme 5, Chang's N-arylation of indoles). The prepared N-arylindoles were polymerized, and their optical and electrochemical properties and thermal stability were determined [44]. The results summarized in Scheme 5 indicate that the use of nucleophilic aromatic substitution for the preparation of N-arylindoles proceeds best in the case of pentafluorobenzenes. This conclusion was confirmed by the work of Zhang [45], who prepared a series 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]. The organocatalytic preparation of N-aryl carbazoles and indoles was reported in 2020 (Scheme 6) [51]. The reaction between the azonaphthalene S6-2 and N-nucleophiles was catalyzed by chiral phosphoric acid derivatives. Although the majority of reported N-arylations have been 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. Scheme 5. Intermolecular nucleophilic aromatic substitution for the synthesis of N-arylindoles.
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].
The organocatalytic preparation of N-aryl carbazoles and indoles was reported in 2020 (Scheme 6) [51]. The reaction between the azonaphthalene S6-2 and N-nucleophiles was catalyzed by chiral phosphoric acid derivatives. Although the majority of reported Narylations have been 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. A different approach to the N-arylation of indoles, which involves aza-Michael addition and aromatization, was reported in 2018 (Scheme 7) [52]. The developed methodology is based on the reaction of azoles with cyclohexa-2,4-dienones in the presence of a catalytic amount of scandium triflate in acetonitrile. The procedure can be used for the regioselective preparation of N-aryl pyrazoles, 1,2,4-triazoles, benzimidazoles, and 1,2,3benzotriazoles in high yields. In the case of substituted indoles, the low selectivity of the arylation reaction was observed. Thus, 3-methylindole S7-1a reacted with the starting dienone to form a mixture of C2-and N-arylated indoles S7-2a and S7-3a. By contrast, 3ethylindole S7-1b exclusively gave N-arylindole S7-2b in a 75% yield. The observed reactivity was not explained. The transition-metal-free synthesis of N-arylindoles S8-3 from 1,2-allenic ketones S8-2 and variously substituted indoles S8-1 via a Cs2CO3-promoted tandem benzannulation reaction has recently been demonstrated by Li et al. (Scheme 8) [53]. The substrate scope with respect to both indoles S8-1a and S8-1b and allenic ketones S8-2 is quite broad. Interestingly, the C2-substituted indoles were either unreactive or reacted poorly under the reaction conditions, likely due to steric hindrance. A mechanism that involves a series of Michael additions followed by cyclization and benzannulation may be operative, as proposed by the authors. A different approach to the N-arylation of indoles, which involves aza-Michael addition and aromatization, was reported in 2018 (Scheme 7) [52]. The developed methodology is based on the reaction of azoles with cyclohexa-2,4-dienones in the presence of a catalytic amount of scandium triflate in acetonitrile. The procedure can be used for the regioselective preparation of N-aryl pyrazoles, 1,2,4-triazoles, benzimidazoles, and 1,2,3-benzotriazoles in high yields. In the case of substituted indoles, the low selectivity of the arylation reaction was observed. Thus, 3-methylindole S7-1a reacted with the starting dienone to form a mixture of C2-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. A different approach to the N-arylation of indoles, which involves aza-Michae tion and aromatization, was reported in 2018 (Scheme 7) [52]. The developed met ogy is based on the reaction of azoles with cyclohexa-2,4-dienones in the presenc catalytic amount of scandium triflate in acetonitrile. The procedure can be used f regioselective preparation of N-aryl pyrazoles, 1,2,4-triazoles, benzimidazoles, and benzotriazoles in high yields. In the case of substituted indoles, the low selectivity arylation reaction was observed. Thus, 3-methylindole S7-1a reacted with the st dienone to form a mixture of C2-and N-arylated indoles S7-2a and S7-3a. By contr ethylindole S7-1b exclusively gave N-arylindole S7-2b in a 75% yield. The observed tivity was not explained.

Scheme 7. Synthesis of N-arylindoles via an aza-Michael addition and aromatization sequen
The transition-metal-free synthesis of N-arylindoles S8-3 from 1,2-allenic keton 2 and variously substituted indoles S8-1 via a Cs2CO3-promoted tandem benzannu reaction has recently been demonstrated by Li et al. (Scheme 8) [53]. The substrate with respect to both indoles S8-1a and S8-1b and allenic ketones S8-2 is quite bro terestingly, the C2-substituted indoles were either unreactive or reacted poorly und reaction conditions, likely due to steric hindrance. A mechanism that involves a se Michael additions followed by cyclization and benzannulation may be operative, a posed by the authors. The transition-metal-free synthesis of N-arylindoles S8-3 from 1,2-allenic ketones S8-2 and variously substituted indoles S8-1 via a Cs 2 CO 3 -promoted tandem benzannulation reaction has recently been demonstrated by Li et al. (Scheme 8) [53]. The substrate scope with respect to both indoles S8-1a and S8-1b and allenic ketones S8-2 is quite broad. Interestingly, the C2-substituted indoles were either unreactive or reacted poorly under the reaction conditions, likely due to steric hindrance. A mechanism that involves a series of Michael additions followed by cyclization and benzannulation may be operative, as proposed by the authors.

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 t BuOLi in 1,4dioxane at 100 °C. As illustrated by selected examples S9-3a-S9-3h, the yields of the Narylindoles 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 catalyst was explained by the competitive coordination of heteroaryl halide during the Narylation reaction.

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 t BuOLi in 1,4dioxane 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 catalyst was explained by the competitive coordination of heteroaryl halide during the N-arylation reaction.
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 1,1bis(bis(alkyl/aryl)phosphino)ferrocene ligands (L X ) and Ni(COD) 2 . The electron-poor ligand L CF3 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 L X variants, including L iPr , L Cy , L Ph , L CF3 , L OMe , and L Me . The amination of 4-chloroquinaldine with the ligand L Ph represents the first room-temperature N-arylation of an indole. In addition, ligands with ortho-substituted phenyl (L o-tol and L 1-nap ), a sterically demanding dialkylphosphino group (L tBu ), and difuranylphosphino variants (L fur ) proved ineffective under the studied conditions. The comparable catalytic performance of L Ph , L CF3 , and L OMe 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. thyl 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 catalyst was explained by the competitive coordination of heteroaryl halide during the Narylation reaction. Different catalytical systems for the N-arylation of indoles were studied by Stradiott [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 a kylamines and indole in the presence of ten structurally diverse 1,1′-bis(bis(a kyl/aryl)phosphino)ferrocene ligands (L X ) and Ni(COD)2. The electron-poor ligand L C 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 indol with 4-chlorobenzonitrile proceeded efficiently with several L X variants, including L iP L Cy , L Ph , L CF3 , L OMe , and L Me . The amination of 4-chloroquinaldine with the ligand L Ph rep resents the first room-temperature N-arylation of an indole. In addition, ligands with o tho-substituted phenyl (L o-tol and L 1-nap ), a sterically demanding dialkylphosphino grou (L tBu ), and difuranylphosphino variants (L fur ) proved ineffective under the studied cond tions. The comparable catalytic performance of L Ph , L CF3 , and L OMe in the studied nicke catalyzed N-arylations suggests that the electronic perturbations arising from a ylphosphine substitution do not significantly affect the behavior of nickel in this branc of chemistry. A different procedure for N-arylation is based on the reaction of amines or heterocy clic compounds with phenols (Scheme 11) [56]. Phenols are reluctant to react during cross coupling reactions, so the starting phenol is converted into a cyanuric acid ester S11-4 vi the reaction with cyanuric chloride (TCT) in 1,4-dioxane in the presence of a base. Th conditions for the formation of the cyanuric acid ester S11-4 were obtained through ex tensive optimization. For example, the N-arylation of indole S11-1 with activated pheno S11-4 was performed using the NiCl2(dppf) catalytic system to give the N-arylated indol A different procedure for N-arylation is based on the reaction of amines or heterocyclic compounds with phenols (Scheme 11) [56]. Phenols are reluctant to react during crosscoupling reactions, so the starting phenol is converted into a cyanuric acid ester S11-4 Molecules 2021, 26, 5079 9 of 44 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 NiCl 2 (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. The nickel-catalyzed decarbonylation of substituted N-acyl indoles S12-1 represent another approach for the preparation of N-arylated indoles (Scheme 12) [57]. Two condi tions were optimized for the Ni(0)-catalyzed decarbonylation of the starting indoles. Firs stoichiometric amounts of Ni(cod)2 and PCy3 preferred quantitative decarbonylation at 8 °C (Condition A). Second, catalytic decarbonylation was achieved through the use of th 1,2-ethanediylbis[dicyclohexyl]phosphine (dcype) ligand at 180 °C (Condition B). Condi tion B proved to be suitable for N-acylindoles bearing an electron withdrawing group whereas Condition A was suitable for N-acylindoles bearing an acyl group with electron neutral and electron-rich substituents. Selected examples S12-2a-S12-2f indicate that thi method tolerates esters, nitriles, and the ketone functional group. In addition to benzoi acid derivatives, this method has proven suitable for the formation of N-alkenylindole S12-2e and N-heteroarylindoles S12-2f. Scheme  Recently, the use of NiO nanoparticles for the N-arylation of indoles by means of th reaction of boronic acids with indoles in the presence of NiO nanoparticles as a catalys has been reported [58]. Pure NiO nanoparticles were prepared using the quercetin-medi ated (F2-1, Figure 2) hydrothermal method. The nickel-catalyzed decarbonylation of substituted N-acyl indoles S12-1 represents another approach for the preparation of N-arylated indoles (Scheme 12) [57]. Two conditions were optimized for the Ni(0)-catalyzed decarbonylation of the starting indoles. First, stoichiometric amounts of Ni(cod) 2 and PCy 3 preferred quantitative decarbonylation at 80 • C (Condition A). Second, catalytic decarbonylation was achieved through the use of the 1,2-ethanediylbis[dicyclohexyl]phosphine (dcype) ligand at 180 • C (Condition B). Condition B proved to be suitable for N-acylindoles bearing an electron withdrawing group, whereas Condition A was suitable for N-acylindoles bearing an acyl group with electronneutral and electron-rich substituents. Selected examples S12-2a-S12-2f indicate that this method tolerates esters, nitriles, 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. The nickel-catalyzed decarbonylation of substituted N-acyl indoles S12-1 represents another approach for the preparation of N-arylated indoles (Scheme 12) [57]. Two conditions were optimized for the Ni(0)-catalyzed decarbonylation of the starting indoles. First, stoichiometric amounts of Ni(cod)2 and PCy3 preferred quantitative decarbonylation at 80 °C (Condition A). Second, catalytic decarbonylation was achieved through the use of the 1,2-ethanediylbis[dicyclohexyl]phosphine (dcype) ligand at 180 °C (Condition B). Condition B proved to be suitable for N-acylindoles bearing an electron withdrawing group, whereas Condition A was suitable for N-acylindoles bearing an acyl group with electronneutral and electron-rich substituents. Selected examples S12-2a-S12-2f indicate that this method tolerates esters, nitriles, 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. Recently, the use of NiO nanoparticles for the N-arylation of indoles by means of the reaction of boronic acids with indoles in the presence of NiO nanoparticles as a catalyst has been reported [58]. Pure NiO nanoparticles were prepared using the quercetin-mediated (F2-1, Figure 2) hydrothermal method. Recently, the use of NiO nanoparticles for the N-arylation of indoles by means of the reaction of boronic acids with indoles in the presence of NiO nanoparticles as a catalyst has been reported [58]. Pure NiO nanoparticles were prepared using the quercetin-mediated (F2-1, Figure 2) hydrothermal method. In addition to the above-mentioned nickel-based cat of indoles, the use of nickel catalysts F3-1 [59], F3-2 [60], F with a polymeric triazine-phosphite ligand [63] for the re with electrophiles has also been reported ( Figure 3). A u tion of N-aryl amines and indoles makes use of the nicke nation of carboxylic acid esters [64]. However, such proc oped for the N-arylation of amines, whereas the N-arylat for only a limited number of indole derivatives. Similarly to the palladium-catalyzed arylation of py 3-arylated indoles can also be observed in the palladiu 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. 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.

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][66][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 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.

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][66][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 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.
boxylic acids S13-1 with diaryliodonium salts S13-2 and determined that N1/C2 or C2/C arylations of indoles can be performed with high regioselectivity. The reaction allows th introduction of variously substituted biphenyls. The proposed key intermediates for bot C2/C3 and N1/C2 arylation, S13-5 and S13-6, show that the N-arylation of indoles is th first step in N1/C2 arylation. However, the C3 arylation of the starting material occurs firs 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. A different approach for the preparation of diarylated indoles was reported in 2020 (Scheme 14) [69]. Muller et al. used 5-bromoindole to prepare diarylated indoles via sequential Suzuki reaction and Buchwald-Hartwig amination. The Suzuki reaction was performed first to avoid any side reactions. The subsequent amination reaction uses the same catalytic system as the Suzuki reaction, although potassium carbonate is used instead of CsF. Selected examples S14-2a and S14-2b illustrate how the Suzuki reaction of bromoindole S14-1 with 1-naphthylboronic acid gives worse yields of the indole S14-2b than the Buchwald-Hartwig amination with naphthyl bromide. This approach is also suitable for the preparation of diarylated carbazoles and 10H-phenothiazines. A different approach for the preparation of diarylated indoles was reported in 2020 (Scheme 14) [69]. Muller et al. used 5-bromoindole to prepare diarylated indoles via sequential Suzuki reaction and Buchwald-Hartwig amination. The Suzuki reaction was performed first to avoid any side reactions. The subsequent amination reaction uses the same catalytic system as the Suzuki reaction, although potassium carbonate is used instead of CsF. Selected examples S14-2a and S14-2b illustrate how the Suzuki reaction of bromoindole S14-1 with 1-naphthylboronic acid gives worse yields of the indole S14-2b than the Buchwald-Hartwig amination with naphthyl bromide. This approach is also suitable for the preparation of diarylated carbazoles and 10H-phenothiazines. An alternative approach to N-arylated indoles utilizes reactions the substituted indole S15-1 with substrates with activated C-O and C-N bonds. Selected examples are presented in Scheme 15. In some cases, the palladium-catalyzed reaction of quaternary ammonium salts with indoles in the presence of potassium tert-butoxide can be used to prepare N-arylated indoles, although the reported scope of the reaction is limited to the preparation of four simple N-arylindoles, S15-4. However, the synthesis of N-alkylated indoles by means of this approach is convenient [70]. Additionally, tosylates are sufficiently reactive for the preparation of N-arylindoles. In this way, a large group of quinazolines S15-2 were prepared in high isolated yields, although similar nonaflates do not react under the developed reaction conditions [71]. A similar approach for the synthesis of N-arylindoles S15-3 was reported in 2018 by Kwong, albeit with a significantly narrower scope [72]. An alternative approach to N-arylated indoles utilizes reactions the substituted indole S15-1 with substrates with activated C-O and C-N bonds. Selected examples are presented in Scheme 15. In some cases, the palladium-catalyzed reaction of quaternary ammonium salts with indoles in the presence of potassium tert-butoxide can be used to prepare Narylated indoles, although the reported scope of the reaction is limited to the preparation of four simple N-arylindoles, S15-4. However, the synthesis of N-alkylated indoles by means of this approach is convenient [70]. Additionally, tosylates are sufficiently reactive for the preparation of N-arylindoles. In this way, a large group of quinazolines S15-2 were prepared in high isolated yields, although similar nonaflates do not react under the developed reaction conditions [71]. A similar approach for the synthesis of N-arylindoles S15-3 was reported in 2018 by Kwong, albeit with a significantly narrower scope [72].

Scheme 15. Palladium-catalyzed N-arylation of indoles via the reactions with substrates with activated C-O and C-N bonds.
A hydrogen-transfer-mediated cross-coupling reaction can also be used for the preparation of N-arylindoles (Scheme 16) [73]. The starting material, as represented by the structure of substituted indolines S16-1, reacts with 2-naphthols and their derivatives in the presence of Pd/C and sodium methoxide. Optimized conditions were applied to prepare 27 indole derivatives S16-2 with a naphthyl group at position 1. The reaction can tolerate, for example, an ester and a hydroxy functional group. However, 1-naphthols do not react under the optimized reaction conditions, as illustrated in Scheme 16. The proposed mechanism assumes the formation of active catalyst S16-5 by means of the reaction of Pd(0) with indoline. The resultant palladium catalyst S16-5 subsequently hydrogenates 2-naphthol S16-6 to form the intermediate S16-7. The final reaction product is formed by the condensation of intermediate S16-7 with indoline S16-1a, followed by palladium-mediated dehydrogenation. A hydrogen-transfer-mediated cross-coupling reaction can also be used for the preparation of N-arylindoles (Scheme 16) [73]. The starting material, as represented by the structure of substituted indolines S16-1, reacts with 2-naphthols and their derivatives in the presence of Pd/C and sodium methoxide. Optimized conditions were applied to prepare 27 indole derivatives S16-2 with a naphthyl group at position 1. The reaction can tolerate, for example, an ester and a hydroxy functional group. However, 1-naphthols do not react under the optimized reaction conditions, as illustrated in Scheme 16. The proposed mechanism assumes the formation of active catalyst S16-5 by means of the reaction of Pd(0) with indoline. The resultant palladium catalyst S16-5 subsequently hydrogenates 2-naphthol S16-6 to form the intermediate S16-7. The final reaction product is formed by the condensation of intermediate S16-7 with indoline S16-1a, followed by palladium-mediated dehydrogenation. A hydrogen-transfer-mediated cross-coupling reaction can also be used for the preparation of N-arylindoles (Scheme 16) [73]. The starting material, as represented by the structure of substituted indolines S16-1, reacts with 2-naphthols and their derivatives in the presence of Pd/C and sodium methoxide. Optimized conditions were applied to prepare 27 indole derivatives S16-2 with a naphthyl group at position 1. The reaction can tolerate, for example, an ester and a hydroxy functional group. However, 1-naphthols do not react under the optimized reaction conditions, as illustrated in Scheme 16. The proposed mechanism assumes the formation of active catalyst S16-5 by means of the reaction of Pd(0) with indoline. The resultant palladium catalyst S16-5 subsequently hydrogenates 2-naphthol S16-6 to form the intermediate S16-7. The final reaction product is formed by the condensation of intermediate S16-7 with indoline S16-1a, followed by palladium-mediated dehydrogenation. The two-step one-pot procedure for the preparation of N-arylindoles relies on the 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 indoles S17-3 must be carried out at 200 • C. Running the same cyclisation reaction at 140 • C exclusively produces indoline derivatives S17-2b and intermediates. In the next step, the arylation of the resulting indole S17-2a is performed using the same catalytic system at 180 • C. The two-step one-pot procedure for the preparation of N-arylindoles relies on the 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 indoles S17-3 must be carried out at 200 °C. Running the same cyclisation reaction at 140 °C exclusively produces indoline derivatives S17-2b and intermediates. In the next step, the arylation of the resulting indole S17-2a is performed using the same catalytic system at 180 °C.
S17-1 S17-2a S17- 3  A similar approach for the preparation of N-arylated indoles was reported by Stradiotto (Scheme 18) [75]. In this case, the starting alkynes S18-1 reacts with ammonia to form indole-based intermediates S18-3. In the next step, the N-arylation of the resulting indole is performed using the same catalytic system in the presence of potassium tertbutoxide. This procedure led to the preparation of 13 indole derivatives. From the selected examples S18-2a-S18-2e, it is evident that the N-arylation of indoles also tolerates orthodisubstituted aryl halides. The reaction conditions for the N-arylation of indoles developed in relation to the two-step one-pot procedure can also be used for the N-arylation of independently prepared indoles. 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], or magnetic Fe3O4 nanoparticles [79]. Scheme 19 illustrates the immobilization of the Scheme 17. Palladium-catalyzed one-pot synthesis of N-arylated indoles.
A similar approach for the preparation of N-arylated indoles was reported by Stradiotto (Scheme 18) [75]. In this case, the starting alkynes S18-1 reacts with ammonia to form indole-based intermediates S18-3. In the next step, the N-arylation of the resulting indole is performed using the same catalytic system in the presence of potassium tert-butoxide. This procedure led to the preparation of 13 indole derivatives. From the selected examples S18-2a-S18-2e, it is evident that the N-arylation of indoles also tolerates ortho-disubstituted aryl halides. The reaction conditions for the N-arylation of indoles developed in relation to the two-step one-pot procedure can also be used for the N-arylation of independently prepared indoles. The two-step one-pot procedure for the preparation of N-arylindoles relies on the 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 indoles S17-3 must be carried out at 200 °C. Running the same cyclisation reaction at 140 °C exclusively produces indoline derivatives S17-2b and intermediates. In the next step, the arylation of the resulting indole S17-2a is performed using the same catalytic system at 180 °C.
S17-2b 91% S17-2c 82% S17-1 S17-2a S17- 3  A similar approach for the preparation of N-arylated indoles was reported by Stradiotto (Scheme 18) [75]. In this case, the starting alkynes S18-1 reacts with ammonia to form indole-based intermediates S18-3. In the next step, the N-arylation of the resulting indole is performed using the same catalytic system in the presence of potassium tertbutoxide. This procedure led to the preparation of 13 indole derivatives. From the selected examples S18-2a-S18-2e, it is evident that the N-arylation of indoles also tolerates orthodisubstituted aryl halides. The reaction conditions for the N-arylation of indoles developed in relation to the two-step one-pot procedure can also be used for the N-arylation of independently prepared indoles. 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], or magnetic Fe3O4 nanoparticles [79]. Scheme 19 illustrates the immobilization of the 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], or magnetic Fe 3 O 4 nanoparticles [79]. Scheme 19 illustrates the immobilization of the palladium catalyst on the surface of SBA-15 through the coordination of palladium to the amidoxime group [76]. The major advantages offered by immobilized catalysts are their recyclability and reusability. This was demonstrated by reusing the immobilized catalyst in five catalytic cycles [76]. palladium catalyst on the surface of SBA-15 through the coordination of palladium to the amidoxime group [76]. The major advantages offered by immobilized catalysts are their recyclability and reusability. This was demonstrated by reusing the immobilized catalyst in five catalytic cycles [76].

Copper-Catalyzed N-Arylation of Indoles
Ligand-free cross-coupling reactions can be considered economical and geous due to the cost reductions associated with the designed chemical transfor In addition, indole N-arylations have been the subjects of ligandless experimenta This approach for the preparation of N-aryl azoles, including N-arylindoles, was by Teo in 2011 (Scheme 21) [91]. The reaction of unsubstituted indoles with ary in the presence of catalytic amounts of copper oxide and tetrabutylammonium (TBAB) as phase-transfer catalysts in water gave N-arylindoles S21-2 in high yields. Only aryl iodides can be used for the reaction, because the use of the corres bromides leads to significantly lower isolated yields of the target compounds, S developed reaction conditions can also be used for the N-arylation of imidazole, 7-azaindole, and indazole. Alternatively, 5 mol% of copper(II) sulphate has been catalyze indole and azole N-arylation in the presence of sodium hydroxide at 1 dimethyl sulfoxide [92].  Table 1. In most cases, nanocatalysts catalyze the N-arylation of indol ligandless conditions. An exception to this concerns the preparation of N-arylin the presence of 1,10-phenanthroline as a ligand, which is catalyzed by electrospu oxide nanoparticles [93] and ceria-supported copper [94] (Table 1, entries 1 and copper-based nanocatalysts include CuO nanoflakes (CuO NFs@MP) prepared b ing copper(II) chloride with fruit waste [95] and CuO nanoparticles, which are eas able by reducing copper(II) acetate by means of water extraction from fresh Ro fruits [96] (Table 1, entries 3 and 4). The structures of both nanocatalysts were det using physicochemical methods, including X-ray diffraction, Fourier transform spectroscopy, field emission scanning electron microscopy, and others. However ing of their ability to catalyze the N-arylation of indoles is limited to only a fe

Copper-Catalyzed N-Arylation of Indoles
Ligand-free cross-coupling reactions can be considered economical and advantageous due to the cost reductions associated with the designed chemical transformations. In addition, indole N-arylations have been the subjects of ligandless experimental setups. This approach for the preparation of N-aryl azoles, including N-arylindoles, was reported by Teo in 2011 (Scheme 21) [91]. The reaction of unsubstituted indoles with aryl iodides in the presence of catalytic amounts of copper oxide and tetrabutylammonium bromide (TBAB) as phase-transfer catalysts in water gave N-arylindoles S21-2 in high isolated yields. Only aryl iodides can be used for the reaction, because the use of the corresponding bromides leads to significantly lower isolated yields of the target compounds, S20-2. The developed reaction 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].

Copper-Catalyzed N-Arylation of Indoles
Ligand-free cross-coupling reactions can be considered economical and advantageous due to the cost reductions associated with the designed chemical transformations. In addition, indole N-arylations have been the subjects of ligandless experimental setups. This approach for the preparation of N-aryl azoles, including N-arylindoles, was reported by Teo in 2011 (Scheme 21) [91]. The reaction of unsubstituted indoles with aryl iodides in the presence of catalytic amounts of copper oxide and tetrabutylammonium bromide (TBAB) as phase-transfer catalysts in water gave N-arylindoles S21-2 in high isolated yields. Only aryl iodides can be used for the reaction, because the use of the corresponding bromides leads to significantly lower isolated yields of the target compounds, S20-2. The developed reaction 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].  Table 1. In most cases, nanocatalysts catalyze the N-arylation of indoles under ligandless conditions. An exception to this concerns the preparation of N-arylindoles in the presence of 1,10-phenanthroline as a ligand, which is catalyzed by electrospun copper oxide nanoparticles [93] and ceria-supported copper [94] (Table 1, entries 1 and 2). Other copper-based nanocatalysts include CuO nanoflakes (CuO NFs@MP) prepared by reducing copper(II) chloride with fruit waste [95] and CuO nanoparticles, which are easily available by reducing 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, Table 1. In most cases, nanocatalysts catalyze the N-arylation of indoles under ligandless conditions. An exception to this concerns the preparation of N-arylindoles in the presence of 1,10-phenanthroline as a ligand, which is catalyzed by electrospun copper oxide nanoparticles [93] and ceria-supported copper [94] (Table 1, entries 1 and 2). Other copper-based nanocatalysts include CuO nanoflakes (CuO NFs@MP) prepared by reducing copper(II) chloride with fruit waste [95] and CuO nanoparticles, which are easily available by reducing 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).  An alternative route to N-arylindoles is based on the two-step N-arylation of indoles starting from either indolines, S22-1a, or indoline carboxylic acids, S22-1b (Scheme 22) [101]. The reaction of the starting compounds S22-1a and S22-1b with predominantly aryl iodides is catalyzed by a recyclable nano-copper oxide catalyst. Based on the available literature, the authors assume that the preparation of the target compounds S22-2 starts with the aromatization of indolines into indoles, followed by N-arylation. During this  An alternative route to N-arylindoles is based on the two-step N-arylation of indoles starting from either indolines, S22-1a, or indoline carboxylic acids, S22-1b (Scheme 22) [101]. The reaction of the starting compounds S22-1a and S22-1b with predominantly aryl iodides is catalyzed by a recyclable nano-copper oxide catalyst. Based on the available literature, the authors assume that the preparation of the target compounds S22-2 starts with the aromatization of indolines into indoles, followed by N-arylation. During this  An alternative route to N-arylindoles is based on the two-step N-arylation of indoles starting from either indolines, S22-1a, or indoline carboxylic acids, S22-1b (Scheme 22) [101]. The reaction of the starting compounds S22-1a and S22-1b with predominantly aryl iodides is catalyzed by a recyclable nano-copper oxide catalyst. Based on the available literature, the authors assume that the preparation of the target compounds S22-2 starts with the aromatization of indolines into indoles, followed by N-arylation. During this 5 CNT-CuO (5 mol%), t BuONa (3 equiv An alternative route to N-arylindoles is based on the two-step N-arylation of indoles starting from either indolines, S22-1a, or indoline carboxylic acids, S22-1b (Scheme 22) [101]. The reaction of the starting compounds S22-1a and S22-1b with predominantly aryl iodides is catalyzed by a recyclable nano-copper oxide catalyst. Based on the available literature, the authors assume that the preparation of the target compounds S22-2 starts with the aromatization of indolines into indoles, followed by N-arylation. During this 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.
Copper catalysts and nitrogen ligands represent a popular combination for crosscoupling 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, although the reactions were carried out in DMF at 130 • C (Table 2, entry 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 crosscoupling 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, although the reactions were carried out in DMF at 130 °C (Table 2, entry 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 crosscoupling 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, although the reactions were carried out in DMF at 130 °C (Table 2, entry 5) [106]. The scope of this N-arylation is limited to the preparation of N-arylindoles. 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 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 Narylated indoles S23-3 than the palladium-catalyzed cyclization (Pd(OAc) 2 , BINAP, K 2 CO 3 , toluene, reflux, 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 Narylated 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[1,2a]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 palladiumcatalyzed 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]. dium-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].

Scheme 24. Diverse synthesis of heterocyclic compounds from the Ugi adducts S24-2.
N,N′-Dimethylethylenediamine (DMEDA) is a popular ligand for use in the coppercatalyzed N-arylation of indoles. Lim used stoichiometric amounts of copper oxide for the arylation of indoles in pyridine (Table 3, entry 1) [110]. Unfortunately, the reaction scope is limited to the preparation of indoles with an ethoxycarbonyl group at position 2 of the indole moiety. An interesting route for the preparation of functionalized N-arylindoles was reported in 2013 (Table 3, entry 2) [111]. In their study, Ham and Kim developed the chemoselective arylation of halogen aryltrifluoroborates to form functionalized organotrifluoroborates. Only two indole derivatives were prepared by this procedure (in 72% and 73% yields, respectively). The presence of a trifluoroborate group in the structure of Narylindoles can be used in the Suzuki reaction to prepare N-arylindoles with more complex substituents at position 1 [111]. The complementary method for the N-arylation of indoles was performed under similar reaction conditions (Table 3, entries 3 and 4) [112,113].  (Table 3, entry 1) [110]. Unfortunately, the reaction scope is limited to the preparation of indoles with an ethoxycarbonyl group at position 2 of the indole moiety. An interesting route for the preparation of functionalized N-arylindoles was reported in 2013 (Table 3, entry 2) [111]. In their study, Ham and Kim developed the chemoselective arylation of halogen aryltrifluoroborates to form functionalized organotrifluoroborates. Only two indole derivatives were prepared by this procedure (in 72% and 73% yields, respectively). The presence of a trifluoroborate group in the structure of N-arylindoles can be used in the Suzuki reaction to prepare N-arylindoles with more complex substituents at position 1 [111]. The complementary method for the N-arylation of indoles was performed under similar reaction conditions (Table 3, entries 3 and 4) [112,113].  Dichotomies during the arylations of 3-substituted indoles S25-1a and S25-1b were reported by Schnürch (Scheme 25) [114]. The starting indole, which featured a Boc-protecting group, reacted with arylboronic acids in the presence of a palladium catalyst and one equivalent of copper acetate to give 2-arylindoles S25-3a-S25-3c in moderate yields. The formation of N-arylindoles was not observed in this case. The low yields of indoles S25-3a, S25-3b, and S25-3c were explained by the inferior steric requirements for substitution at position 2. Changing the catalytic system to ferric chloride with a DMEDA ligand led to the formation of N-arylated indoles S25-4a-S25-4e in high yields. N-arylation can also be performed in the case of unprotected indole S25-1b, although in this case a catalytic amount of copper iodide with a DMEDA ligand and cesium fluoride as a base had to be used.  Dichotomies during the arylations of 3-substituted indoles S25-1a and S25-1b were reported by Schnürch (Scheme 25) [114]. The starting indole, which featured a Boc-protecting group, reacted with arylboronic acids in the presence of a palladium catalyst and one equivalent of copper acetate to give 2-arylindoles S25-3a-S25-3c in moderate yields. The formation of N-arylindoles was not observed in this case. The low yields of indoles S25-3a, S25-3b, and S25-3c were explained by the inferior steric requirements for substitution at position 2. Changing the catalytic system to ferric chloride with a DMEDA ligand led to the formation of N-arylated indoles S25-4a-S25-4e in high yields. N-arylation can also be performed in the case of unprotected indole S25-1b, although in this case a catalytic amount of copper iodide with a DMEDA ligand and cesium fluoride as a base had to be used.  Dichotomies during the arylations of 3-substituted indoles S25-1a and S25-1b were reported by Schnürch (Scheme 25) [114]. The starting indole, which featured a Boc-protecting group, reacted with arylboronic acids in the presence of a palladium catalyst and one equivalent of copper acetate to give 2-arylindoles S25-3a-S25-3c in moderate yields. The formation of N-arylindoles was not observed in this case. The low yields of indoles S25-3a, S25-3b, and S25-3c were explained by the inferior steric requirements for substitution at position 2. Changing the catalytic system to ferric chloride with a DMEDA ligand led to the formation of N-arylated indoles S25-4a-S25-4e in high yields. N-arylation can also be performed in the case of unprotected indole S25-1b, although in this case a catalytic amount of copper iodide with a DMEDA ligand and cesium fluoride as a base had to be used.
Dichotomies during the arylations of 3-substituted indoles S25-1a and S25-1b were reported by Schnürch (Scheme 25) [114]. The starting indole, which featured a Boc-protecting group, reacted with arylboronic acids in the presence of a palladium catalyst and one equivalent of copper acetate to give 2-arylindoles S25-3a-S25-3c in moderate yields. The formation of N-arylindoles was not observed in this case. The low yields of indoles S25-3a, S25-3b, and S25-3c were explained by the inferior steric requirements for substitution at position 2. Changing the catalytic system to ferric chloride with a DMEDA ligand led to the formation of N-arylated indoles S25-4a-S25-4e in high yields. N-arylation can also be performed in the case of unprotected indole S25-1b, although in this case a catalytic amount of copper iodide with a DMEDA ligand and cesium fluoride as a base had to be used. A series of N-arylation reactions using ligands or reagents obtained from natural 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 the commonly used solvents DMF and DMSO. A common feature of N-arylation reactions performed in glycerol, DMF, and DMSO is the high reaction temperature. The authors hypothesize that one equivalent of DMSO acts as a ligand to help the oxidative addition of the copper catalyst to the C-halogen bond. The good solubility of the reaction products in organic ethers allowed the recycling of the catalytic system dissolved in glycerol by extraction of the products and the starting compound to the ether. Such recycled catalysts can be used in three catalytic runs. A different ligand concept for the N-arylation of indoles makes use of methyl-α-D-glucopyranoside L1 and glucosamine L2 as ligands for coppercatalyzed N-arylations, as reported by Xuan [116] and Chen [117] (Table 4, entries 2 and 3). Neither reaction is significantly different from the other procedures available for the N-arylation of indoles. In the case of the glucosamine ligand L2, the formation of a radical intermediate T4-1 was proposed, although the formation of this intermediate has not been experimentally verified. The use of other natural substances in this regard includes the use of N-alkyl-glucosamine as a 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.

Scheme 25. Dichotomies in the transition-metal-catalyzed arylation of substituted indoles.
A series of N-arylation reactions using ligands or reagents obtained from natural 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 the commonly used solvents DMF and DMSO. A common feature of N-arylation reactions performed in glycerol, DMF, and DMSO is the high reaction temperature. The authors hypothesize that one equivalent of DMSO acts as a ligand to help the oxidative addition of the copper catalyst to the C-halogen bond. The good solubility of the reaction products in organic ethers allowed the recycling of the catalytic system dissolved in glycerol by extraction of the products and the starting compound to the ether. Such recycled catalysts can be used in three catalytic runs. A different ligand concept for the N-arylation of indoles makes use of methyl-α-D-glucopyranoside L1 and glucosamine L2 as ligands for coppercatalyzed N-arylations, as reported by Xuan [116] and Chen [117] (Table 4, entries 2 and 3). Neither reaction is significantly different from the other procedures available for the Narylation of indoles. In the case of the glucosamine ligand L2, the formation of a radical intermediate T4-1 was proposed, although the formation of this intermediate has not been experimentally verified. The use of other natural substances in this regard includes the use of N-alkyl-glucosamine as a 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.  In addition to the above-mentioned examples, other ligands containing a nitrogen atom represent popular choices for the copper-catalyzed arylation of indoles. Nitrogen ligands also form part of the system for the N-arylation of indoles in water (Table 5). Schmitt used copper bromide and the ligand L1 for the N-arylation of indoles under mild reaction conditions (Table 5, entry 1) [121]. D-Glucose was used as the reducing agent in this case. The reaction was performed in a commercially available DL-α-tocopherol methoxypolyethylene glycol succinate solution. It was experimentally verified that the use of a surfactant is necessary to achieve a high yield of N-arylindoles. The developed reaction conditions were used for the synthesis of 11 N-arylindoles, and the tolerance of the functional groups in this case was limited to halogens, nitrile, ethers, and the formyl group. A similar surfactant-based strategy for preparing N-arylindoles was reported by Liu in 2013 (Table 5, entry 2) [122]. The reaction conditions for the N-arylation of indoles make use of the bipyridine ligand L2, potassium phosphate as the base, and betaine as the surfactant. In contrast to previous work [121], the arylation reaction must be performed at 90 °C. The authors demonstrated the tolerance of the acetyl group during the preparation of ten indole derivatives under optimized reaction conditions. An extensive series of N-arylated indoles was prepared by means of indole arylation catalyzed by copper iodide and the phenanthroline ligand L3 in 30% aqueous 1,2-dimethoxyethane (DME) ( Table 5, entry 3) [123]. The optimum ratio of DME to water was determined using kinetic experiments,  In addition to the above-mentioned examples, other ligands containing a nitrogen atom represent popular choices for the copper-catalyzed arylation of indoles. Nitrogen ligands also form part of the system for the N-arylation of indoles in water (Table 5). Schmitt used copper bromide and the ligand L1 for the N-arylation of indoles under mild reaction conditions (Table 5, entry 1) [121]. D-Glucose was used as the reducing agent in this case. The reaction was performed in a commercially available DL-α-tocopherol methoxypolyethylene glycol succinate solution. It was experimentally verified that the use of a surfactant is necessary to achieve a high yield of N-arylindoles. The developed reaction conditions were used for the synthesis of 11 N-arylindoles, and the tolerance of the functional groups in this case was limited to halogens, nitrile, ethers, and the formyl group. A similar surfactant-based strategy for preparing N-arylindoles was reported by Liu in 2013 (Table 5, entry 2) [122]. The reaction conditions for the N-arylation of indoles make use of the bipyridine ligand L2, potassium phosphate as the base, and betaine as the surfactant. In contrast to previous work [121], the arylation reaction must be performed at 90 °C. The authors demonstrated the tolerance of the acetyl group during the preparation of ten indole derivatives under optimized reaction conditions. An extensive series of N-arylated indoles was prepared by means of indole arylation catalyzed by copper iodide and the phenanthroline ligand L3 in 30% aqueous 1,2-dimethoxyethane (DME) (  In addition to the above-mentioned examples, other ligands containing a nitrogen atom represent popular choices for the copper-catalyzed arylation of indoles. Nitrogen ligands also form part of the system for the N-arylation of indoles in water (Table 5). Schmitt used copper bromide and the ligand L1 for the N-arylation of indoles under mild reaction conditions (Table 5, entry 1) [121]. D-Glucose was used as the reducing agent in this case. The reaction was performed in a commercially available DL-α-tocopherol methoxypolyethylene glycol succinate solution. It was experimentally verified that the use of a surfactant is necessary to achieve a high yield of N-arylindoles. The developed reaction conditions were used for the synthesis of 11 N-arylindoles, and the tolerance of the functional groups in this case was limited to halogens, nitrile, ethers, and the formyl group. A similar surfactant-based strategy for preparing N-arylindoles was reported by Liu in 2013 (Table 5, entry 2) [122]. The reaction conditions for the N-arylation of indoles make use of the bipyridine ligand L2, potassium phosphate as the base, and betaine as the surfactant. In contrast to previous work [121], the arylation reaction must be performed at 90 °C. The authors demonstrated the tolerance of the acetyl group during the preparation of ten indole derivatives under optimized reaction conditions. An extensive series of N-arylated indoles was prepared by means of indole arylation catalyzed by copper iodide and the phenanthroline ligand L3 in 30% aqueous 1,2-dimethoxyethane (DME) ( Table 5, entry 3) [123]. The optimum ratio of DME to water was determined using kinetic experiments, In addition to the above-mentioned examples, other ligands containing a nitrogen atom represent popular choices for the copper-catalyzed arylation of indoles. Nitrogen ligands also form part of the system for the N-arylation of indoles in water (Table 5). Schmitt used copper bromide and the ligand L1 for the N-arylation of indoles under mild reaction conditions (Table 5, entry 1) [121]. D-Glucose was used as the reducing agent in this case. The reaction was performed in a commercially available DL-α-tocopherol methoxypolyethylene glycol succinate solution. It was experimentally verified that the use of a surfactant is necessary to achieve a high yield of N-arylindoles. The developed reaction conditions were used for the synthesis of 11 N-arylindoles, and the tolerance of the functional groups in this case was limited to halogens, nitrile, ethers, and the formyl group. A similar surfactant-based strategy for preparing N-arylindoles was reported by Liu in 2013 (Table 5, entry 2) [122]. The reaction conditions for the N-arylation of indoles make use of the bipyridine ligand L2, potassium phosphate as the base, and betaine as the surfactant. In contrast to previous work [121], the arylation reaction must be performed at 90 • C. The authors demonstrated the tolerance of the acetyl group during the preparation of ten indole derivatives under optimized reaction conditions. An extensive series of N-arylated indoles was prepared by means of indole arylation catalyzed by copper iodide and the phenanthroline ligand L3 in 30% aqueous 1,2-dimethoxyethane (DME) ( Table 5, entry 3) [123]. The optimum ratio of DME to water was determined using kinetic experiments, which showed that reactions performed in pure water or DME did not achieve quantitative conversion. An alternative procedure for the preparation of N-arylindoles relies on the reaction of boronic acids with indoles in aqueous ammonia and potassium tertbutoxide as a base under ligandless conditions [124]. To complete the list of N-arylations of indoles in water, it is necessary to mention the N-arylation procedures associated with heterocyclic compounds and amines, which can be applied for the preparation of a limited number of N-arylindoles [125][126][127][128][129][130][131]. which showed that reactions performed in pure water or DME did not achieve quantitative conversion. An alternative procedure for the preparation of N-arylindoles relies on the reaction of boronic acids with indoles in aqueous ammonia and potassium tert-butoxide as a base under ligandless conditions [124]. To complete the list of N-arylations of indoles in water, it is necessary to mention the N-arylation procedures associated with heterocyclic compounds and amines, which can be applied for the preparation of a limited number of N-arylindoles [125][126][127][128][129][130][131]. 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 varying the ligands during the optimization of the reaction conditions, it was confirmed that the presence of both pyridine N-oxide and phenyl amide moieties in the structure of the ligand L1 is necessary to achieve maximum yields. The optimized reaction conditions are suitable for the preparation of N-aryl pyrazole, pyrrole, and indazole. The reaction scope for indoles is limited to six examples. The use of a pyridine N-oxide ligand was presumably inspired by prior studies that utilized pyridine N-oxide ligands for general N-arylation [133][134][135]. The pyridine-based ligand L2, which contains an iminopyridyl moiety, was used for the N-arylation of indoles in DMSO at 120 °C (Table 6, entry 2) [136]. Another ligand L3 that contains an iminopyridyl moiety in its molecule was reported in 2021 (Table 6, entry 3) [137]. A short communication on the copper-catalyzed N-arylation of indoles was published in 2015 (Table 6, entry 4). Copper(I) chloride with a phosphine ligand L4 in DMSO was found to be the best combination for the N-arylation of indoles. The scope of the reaction is limited to aryl halides with electron-donating or electron-neutral substituents. It should be noted that 4-iodobenzonitrile did not react under the optimized reaction conditions. which showed that reactions performed in pure water or DME did not achieve quantitative conversion. An alternative procedure for the preparation of N-arylindoles relies on the reaction of boronic acids with indoles in aqueous ammonia and potassium tert-butoxide as a base under ligandless conditions [124]. To complete the list of N-arylations of indoles in water, it is necessary to mention the N-arylation procedures associated with heterocyclic compounds and amines, which can be applied for the preparation of a limited number of N-arylindoles [125][126][127][128][129][130][131]. Table 5. Copper-catalyzed N-arylation of indoles in water. 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 varying the ligands during the optimization of the reaction conditions, it was confirmed that the presence of both pyridine N-oxide and phenyl amide moieties in the structure of the ligand L1 is necessary to achieve maximum yields. The optimized reaction conditions are suitable for the preparation of N-aryl pyrazole, pyrrole, and indazole. The reaction scope for indoles is limited to six examples. The use of a pyridine N-oxide ligand was presumably inspired by prior studies that utilized pyridine N-oxide ligands for general N-arylation [133][134][135]. The pyridine-based ligand L2, which contains an iminopyridyl moiety, was used for the N-arylation of indoles in DMSO at 120 °C (Table 6, entry 2) [136]. Another ligand L3 that contains an iminopyridyl moiety in its molecule was reported in 2021 (Table 6, entry 3) [137]. A short communication on the copper-catalyzed N-arylation of indoles was published in 2015 (Table 6, entry 4). Copper(I) chloride with a phosphine ligand L4 in DMSO was found to be the best combination for the N-arylation of indoles. The scope of the reaction is limited to aryl halides with electron-donating or electron-neutral substituents. It should be noted that 4-iodobenzonitrile did not react under the optimized reaction conditions. 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 varying the ligands during the optimization of the reaction conditions, it was confirmed that the presence of both pyridine N-oxide and phenyl amide moieties in the structure of the ligand L1 is necessary to achieve maximum yields. The optimized reaction conditions are suitable for the preparation of N-aryl pyrazole, pyrrole, and indazole. The reaction scope for indoles is limited to six examples. The use of a pyridine N-oxide ligand was presumably inspired by prior studies that utilized pyridine N-oxide ligands for general N-arylation [133][134][135]. The pyridine-based ligand L2, which contains an iminopyridyl moiety, was used for the N-arylation of indoles in DMSO at 120 • C ( Table 6, entry 2) [136]. Another ligand L3 that contains an iminopyridyl moiety in its molecule was reported in 2021 (Table 6, entry 3) [137]. A short communication on the copper-catalyzed N-arylation of indoles was published in 2015 (Table 6, entry 4). Copper(I) chloride with a phosphine ligand L4 in DMSO was found to be the best combination for the N-arylation of indoles. The scope of the reaction is limited to aryl halides with electron-donating or electron-neutral substituents. It should be noted that 4-iodobenzonitrile did not react under the optimized reaction conditions.  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 3indolylcarboxylic 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 S26-5. Fifteen indolo[1,2-a]quinazolinone S26-3 derivatives were prepared using this procedure. It is worth noting that despite the harsh reaction conditions, the presence of a chlorine atom was tolerated. It was also verified that the N-arylation of indoles to form the intermediate S26-6 is the first step in the formation of the target compounds S26-3.  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 3indolylcarboxylic 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 S26-5. Fifteen indolo[1,2-a]quinazolinone S26-3 derivatives were prepared using this procedure. It is worth noting that despite the harsh reaction conditions, the presence of a chlorine atom was tolerated. It was also verified that the N-arylation of indoles to form the intermediate S26-6 is the first step in the formation of the target compounds S26-3.

Conditions
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 3methylindole 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 procedure. It is worth noting that despite the harsh reaction conditions, the presence of a chlorine atom was tolerated. It was also verified that the N-arylation of indoles to form the intermediate S26-6 is the first step in the formation of the target compounds S26-3. s 2021, 26,  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 alkenylation of amides, although it was determined that these conditions could also be used for the preparation of N-arylindoles S27-2a and S27-2b in high yields. The authors assume that in the first step, the Co (II) is reduced to Co (I) by means of acetylacetone. The oxidative addition is followed by the substitution of the halide ligand, which is facilitated by the formation of the Cu(I)-N complex S27-6. The product of the reaction is then obtained by reductive elimination. The proposed mechanism was partially confirmed experimentally. A somewhat different approach to the N-arylation of nitrogen-containing heterocycles makes use of the iron-catalyzed bromination of aromatics, followed by coppercatalyzed N-arylation [140]. This approach was used for the synthesis of 1-(4-methoxyphenyl)indole in a 78% yield. 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 alkenylation of amides, although it was determined that these conditions could also be used for the preparation of N-arylindoles S27-2a and S27-2b in high yields. The authors assume that in the first step, the Co (II) is reduced to Co (I) by means of acetylacetone. The oxidative addition is followed by the substitution of the halide ligand, which is facilitated by the formation of the Cu(I)-N complex S27-6. The product of the reaction is then obtained by reductive elimination. The proposed mechanism was partially confirmed experimentally. A somewhat different approach to the N-arylation of nitrogen-containing heterocycles makes use of the iron-catalyzed bromination of aromatics, followed by copper-catalyzed N-arylation [140]. This approach was used for the synthesis of 1-(4-methoxyphenyl)indole in a 78% yield. The cobalt-copper-cocatalyzed N-arylation and alkenylation of N-heterocycles reported by Ran (Scheme 27) [139]. The reaction conditions were optimized fo alkenylation of amides, although it was determined that these conditions could al used for the preparation of N-arylindoles S27-2a and S27-2b in high yields. The au assume that in the first step, the Co (II) is reduced to Co (I) by means of acetylacetone oxidative addition is followed by the substitution of the halide ligand, which is facili by the formation of the Cu(I)-N complex S27-6. The product of the reaction is the tained by reductive elimination. The proposed mechanism was partially confirmed e imentally. A somewhat different approach to the N-arylation of nitrogen-containing erocycles makes use of the iron-catalyzed bromination of aromatics, followed by cop catalyzed N-arylation [140]. This approach was used for the synthesis of 1-(4-meth phenyl)indole in a 78% yield. 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)benzamides S28-1, which react with azoles and indoles to give ortho-substituted benzamides S28-2. The methodology was used for the preparation of N-aryl pyrroles, indoles, carbazoles, and pyrazoles. The presence of a quinolin-8-yl group facilitates the formation of the complex S28-3 by means of copper coordination to the quinolin-8-yl moiety. The oxidation of Cu II to Cu III forms complex S28-4, which undergoes intramolecular C-H cupration. Eight N-arylated indoles were prepared using this procedure. It was shown that benzamide with a pyrrolyl unit can be hydrolyzed into ortho-substituted benzoic acid. The same research group showed that the methodology developed for C-H functionalization reactions can be extended to picolinamides, rather than benzamides [142].

FOR PEER REVIEW 26 of 43
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)benzamides S28-1, which react with azoles and indoles to give ortho-substituted benzamides S28-2. The methodology was used for the preparation of Naryl pyrroles, indoles, carbazoles, and pyrazoles. The presence of a quinolin-8-yl group facilitates the formation of the complex S28-3 by means of copper coordination to the quinolin-8-yl moiety. The oxidation of Cu II to Cu III forms complex S28-4, which undergoes intramolecular C-H cupration. Eight N-arylated indoles were prepared using this procedure. It was shown that benzamide with a pyrrolyl unit can be hydrolyzed into orthosubstituted benzoic acid. The same research group showed that the methodology developed for C-H functionalization reactions can be extended to picolinamides, rather than benzamides [142]. An alternative approach to the N-arylation of indoles makes use of 2-indolylboronic acids (Scheme 29) [143]. The starting carboxylic acids S29-1 react with aryl bromides or aryl iodides in the presence of catalytic amounts of copper oxide and potassium phosphate as a base. The reported scope of the reaction is limited to substituted phenyl iodides and bromides. Other aromatic and heteroaromatic halides were not tested. In terms of the proposed mechanism, the authors assume the formation of copper carboxylate S29-4 and 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. An alternative approach to the N-arylation of indoles makes use of 2-indolylboronic acids (Scheme 29) [143]. The starting carboxylic acids S29-1 react with aryl bromides or aryl iodides in the presence of catalytic amounts of copper oxide and potassium phosphate as a base. The reported scope of the reaction is limited to substituted phenyl iodides and bromides. Other aromatic and heteroaromatic halides were not tested. In terms of the proposed mechanism, the authors assume the formation of copper carboxylate S29-4 and 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. Arguably the most extensive procedure for the preparation of N-arylindoles is based on the reaction of indoles with triarylbismuth reagents (Scheme 30) [144]. The reaction is catalyzed by copper acetate in the presence of oxygen and one equivalent of base. The triarylbismuth reagents can be prepared using the reaction of bismuth(III) trichloride with Grignard reagents or by the chemical transformation of the ester or formyl group of the corresponding triarylbismuth reagents. The procedure is suitable for the preparation of highly functionalized indoles because the methodology can tolerate a variety of functional groups, including a formyl or ester group, as illustrated by selected examples S30-2b-S30-2e. The tryptophan derivative S30-2a was also prepared using this procedure. In addition, a series of heteroatom arylations by organobismuth reagents has been reported [145][146][147][148]. Arguably the most extensive procedure for the preparation of N-arylindoles is based on the reaction of indoles with triarylbismuth reagents (Scheme 30) [144]. The reaction is catalyzed by copper acetate in the presence of oxygen and one equivalent of base. The triarylbismuth reagents can be prepared using the reaction of bismuth(III) trichloride with Grignard reagents or by the chemical transformation of the ester or formyl group of the corresponding triarylbismuth reagents. The procedure is suitable for the preparation of highly functionalized indoles because the methodology can tolerate a variety of functional groups, including a formyl or ester group, as illustrated by selected examples S30-2b-S30-2e. The tryptophan derivative S30-2a was also prepared using this procedure. In addition, a series of heteroatom arylations by organobismuth reagents has been reported [145][146][147][148]. Arguably the most extensive procedure for the preparation of N-arylindoles is based on the reaction of indoles with triarylbismuth reagents (Scheme 30) [144]. The reaction is catalyzed by copper acetate in the presence of oxygen and one equivalent of base. The triarylbismuth reagents can be prepared using the reaction of bismuth(III) trichloride with Grignard reagents or by the chemical transformation of the ester or formyl group of the corresponding triarylbismuth reagents. The procedure is suitable for the preparation of highly functionalized indoles because the methodology can tolerate a variety of functional groups, including a formyl or ester group, as illustrated by selected examples S30-2b-S30-2e. The tryptophan derivative S30-2a was also prepared using this procedure. In addition, a series of heteroatom arylations by organobismuth reagents has been reported [145][146][147][148]. An alternative approach for the preparation of (-)-aspergilazine A that uses coppercatalyzed indole N-arylation was reported in 2017 (Scheme 31) [149]. A direct approach to (-)-aspergilazine A starting from the tryptophan derivative S31-4 proved inefficient because the expected product of the reaction S31-5 was obtained in only a 66% yield. Thus, the preparation of the target compound from indole S31-1 and 2-bromoindole or 2-iodoindole S31-2 was accomplished in nine steps in a total isolated yield of 36%. An alternative approach for the preparation of (-)-aspergilazine A that uses coppercatalyzed indole N-arylation was reported in 2017 (Scheme 31) [149]. A direct approach to (-)-aspergilazine A starting from the tryptophan derivative S31-4 proved inefficient because the expected product of the reaction S31-5 was obtained in only a 66% yield. Thus, the preparation of the target compound from indole S31-1 and 2-bromoindole or 2-iodoindole S31-2 was accomplished in nine steps in a total isolated yield of 36%. Scheme 31. Total synthesis of (-)-aspergilazine A via the copper-catalyzed N-arylation of indoles.
Atom-economic arylation of indoles was described in 2015 (Scheme 32) [150]. N1 Unsubstituted indoles react with diaryliodonium salts in the presence of a catalyti amount of copper iodide to give N1-and C3-arylated indoles in average isolated yield High selectivity was observed for aryl-uracil iodonium triflates S32-3, affording the 3 aryl-1-indoles-uracil conjugates S32-4. The combination of photocatalysis and copper-catalyzed N-arylation enabled the Narylation of indoles at room temperature (Scheme 33) [151]. The key step in this conversion is the photoexcitation of a copper complex S33-3. The reaction is also suitable for the preparation of N-aryl benzimidazoles, imidazoles, and carbazoles.
Molecules 2021, 26, x FOR PEER REVIEW The combination of photocatalysis and copper-catalyzed N-arylation enable arylation of indoles at room temperature (Scheme 33) [151]. The key step in this sion is the photoexcitation of a copper complex S33-3. The reaction is also suitabl preparation of N-aryl benzimidazoles, imidazoles, and carbazoles.

Miscellaneous Transition-Metal-Catalyzed N-Arylation of Indoles
A straightforward approach to the preparation of indolo[1,2-f]phenanthridin atives S34-3 based on the N-arylation of 2-aryl-3-substituted indoles S34-1 using ium-catalyzed oxidative [4 + 2] annulation reaction with quinones S34-2 was rep Guo and Fan (Scheme 34) [152]. A series of 20 N-arylated indoles was prepare satisfactory yields, under optimized reaction conditions. The indoles substituted tions 2 and 3 smoothly reacted under optimized reaction conditions. However, tion is limited for benzoquinone and 2-methylbenzoquinone. Other quinone der such as 2-chlorobenzoquinone, 2,5-dimethylbenzoquinone, and naphthoquinone furnish the corresponding products. The authors posited a plausible reaction me on the basis of mechanistic studies. Initially, the iridium-catalyzed dual N-H/Cactivation of S34-5 is responsible for the formation of five-membered iridacycle S3 subsequent coordination of benzoquinone to the iridium complex S34-6 affords iridacycle S34-7, which then undergoes a migratory insertion to deliver a seve bered intermediate S34-8. Next, the protonolysis of the complex S34-8 with HO to both intermediate S34-9 and the active Ir(III) catalyst S34-4. Finally, a Zn(OA moted intramolecular indolyl N1-attack on the carbonyl group affords the key in ate S34-10, which undergoes a dehydration reaction to deliver the final product S Scheme 33. N-Arylation of indoles under mild conditions.

Miscellaneous Transition-Metal-Catalyzed N-Arylation of Indoles
A straightforward approach to the preparation of indolo[1,2-f]phenanthridine derivatives S34-3 based on the N-arylation of 2-aryl-3-substituted indoles S34-1 using an iridiumcatalyzed oxidative [4 + 2] annulation reaction with quinones S34-2 was reported by Guo and Fan (Scheme 34) [152]. A series of 20 N-arylated indoles was prepared, all in satisfactory yields, under optimized reaction conditions. The indoles substituted at positions 2 and 3 smoothly reacted under optimized reaction conditions. However, the reaction is limited for benzoquinone and 2-methylbenzoquinone. Other quinone derivatives, such as 2-chlorobenzoquinone, 2,5-dimethylbenzoquinone, and naphthoquinone, did not furnish the corresponding products. The authors posited a plausible reaction mechanism on the basis of mechanistic studies. Initially, the iridium-catalyzed dual N-H/C-H bond activation of S34-5 is responsible for the formation of five-membered iridacycle S34-6. The subsequent coordination of benzoquinone to the iridium complex S34-6 affords the new iridacycle S34-7, which then undergoes a migratory insertion to deliver a seven-membered intermediate S34-8. Next, the protonolysis of the complex S34-8 with HOAc leads to both intermediate S34-9 and the active Ir(III) catalyst S34-4. Finally, a Zn(OAc) 2 -promoted intramolecular indolyl N1-attack on the carbonyl group affords the key intermediate S34-10, which undergoes a dehydration reaction to deliver the final product S34-11.
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 Ag 2 CO 3 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-CH 3 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 −CO 2 (4-MePh) group. It was proposed that this behavior is caused by the steric effect of the N-CH 3 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 Ag 2 CO 3 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. 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. N-aryl moiety, which is followed by oxidation and deprotonation to give the desired product S33-2a.

N-Arylated Indoles as Biologically Active Substances
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 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. For example, N-arylindoles have been proposed as novel dye-sensitized solar cells [154], electrophosphorescent diodes [155], oxygen sensors [156], and other things [157][158][159][160]. Procedures for the N-arylation of indoles have also been used for the preparation of indoles with biological activity. A number of N-arylindoles have been prepared in structure-activity relationship (SAR) studies in an effort to verify the mechanisms of the biological activity of the substituted indoles; and the determination of the biological activities of Narylindoles has also been part of a large-scope synthetic study concerning the preparation of N-arylindoles. Examples of such works include inhibitors of human neutrophil elastase (HNE) [161], centromere-associated protein-E (CENP-E) inhibitors [162], CRTh2 antagonists [163], and determinations of cytotoxic activity [164,165]. Ultimately, a large group of N-arylindoles was prepared to study their biological activity. Selected examples are given in Figures 5-9.
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 ±

N-Arylated Indoles as Biologically Active Substances
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 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. For example, N-arylindoles have been proposed as novel dye-sensitized solar cells [154], electrophosphorescent diodes [155], oxygen sensors [156], and other things [157][158][159][160]. Procedures for the N-arylation of indoles have also been used for the preparation of indoles with biological activity. A number of N-arylindoles have been prepared in structureactivity relationship (SAR) studies in an effort to verify the mechanisms of the biological activity of the substituted indoles; and the determination of the biological activities of N-arylindoles has also been part of a large-scope synthetic study concerning the preparation of N-arylindoles. Examples of such works include inhibitors of human neutrophil elastase (HNE) [161], centromere-associated protein-E (CENP-E) inhibitors [162], CRTh2 antagonists [163], and determinations of cytotoxic activity [164,165]. Ultimately, a large group of N-arylindoles was prepared to study their biological activity. Selected examples are given in  been prepared by the same group and studied as angiotensin II receptor 1 antagonists [167][168][169][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. 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 t BuONa 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 αamylase 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 N indole -C phenyl 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) (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  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 sub- 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 Narylindoles 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 ( 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.

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 organohalogeni-  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 AT 1 receptor, with an IC 50 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 LD 50 as 1551.71 mg/kg. Other indole derivatives have been prepared by the same group and studied as angiotensin II receptor 1 antagonists [167][168][169][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. 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 t BuONa 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 N indole -C phenyl 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) (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 IC 50 value of 22 ± 6.9 nM in the Bis-pNPP assay and 4 ± 0.5 nM IC 50 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 IC 50 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-C aryl 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.
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 IC 50 value of 284 µM. The introduction of a benzyl group into position 1 decreased the IC 50 value to 12.3 µM, whereas the introduction of the 4-tolyl group F8-1 substantially improved the IC 50 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 A 2 type X [177,178]. The formation of an N-C aryl bond was achieved by means of coppercatalyzed Ullman condensation in the presence of piperidine-2-carboxylic acid as a ligand. The indole F8-2 exhibited the best IC 50 value (0.022 µM) against sPLA 2 -X. The presence of a trifluoromethoxy group is the key to achieving high inhibitory activity. The substitution of CF 3 O for the methoxy group led to the IC 50 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 σ 2 receptor agents was studied. The indole derivative F8-3 was chosen as a good ligand for both P-glycoprotein (P-gp) and the σ 2 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 σ 2 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 ( Figure 9) [182]. On the basis of extensive SAR studies, it was found that F9-1 is an inhibitor of cPLA 2α (with an IC 50 value of 0.075 µM) [181], and indole F9-2 is a selective inhibitor of both HSP90 (IC 50 = 0.069 µM) and SK-Br-3 (IC 50 = 0.33 µM) [182]. The introduction of the aryl substituents was accomplished via copper-catalyzed Ullman condensation at reaction temperatures above 100 • C.

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.