molecules Review Review RecentRecent ProgressProgress Concerningconcerning the the NN-Arylation-Arylation of of Indoles Indoles Petr Oeser, Jakub Koudelka, Artem Petrenko and Tomáš Tobrman * Petr Oeser, Jakub Koudelka , Artem Petrenko and Tomáš Tobrman * Department of Organic Chemistry, University of Chemistry and Technology, 16628 Prague, Czech Republic; [email protected] of Organic (P.O.); Chemistry, [email protected] University of Chemistry (J.K.); [email protected] and Technology, 16628 (A.P.) Prague, Czech Republic; [email protected]* Correspondence: (P.O.); [email protected] [email protected] (J.K.); [email protected] (A.P.) * Correspondence: [email protected] Abstract: This review summarizes the current state-of-the-art procedures in terms of the prepara- Abstract:tion of N-arylindoles.This review summarizesAfter a short the intr currentoduction, state-of-the-art the transition-metal procedures-free in procedures terms of the available preparation for oftheN N-arylindoles.-arylation of After indoles a short are briefly introduction, discussed. the Th transition-metal-freeen, the nickel-catalyzed procedures and palladium-catalyzed available for the NN-arylation-arylation ofof indoles are brieflyboth discussed. discussed. In Then,the next the section, nickel-catalyzed copper-catalyzed and palladium-catalyzed procedures for the NN-arylation-arylation ofof indolesindoles areare bothdescribed. discussed. The final In the sectio nextn section,focuses copper-catalyzedon recent findings procedures in the field forof bio- the Nlogically-arylation active of indolesN-arylindoles. are described. The final section focuses on recent findings in the field of biologically active N-arylindoles. Keywords: N-arylation; indole; Buchwald–Hartwig amination; Ullmann condensation; Chan–Lam Keywords:coupling N-arylation; indole; Buchwald–Hartwig amination; Ullmann condensation; Chan– Lam coupling 1. Introduction 1. Introduction Heterocyclic compounds are cyclic compounds that each contain either a heteroatom Heterocyclic compounds are cyclic compounds that each contain either a heteroatom or a number of heteroatoms. Among the most important groups of heterocyclic com- orpounds a number are ofthe heteroatoms. aromatic heterocyclic Among the comp mostounds. important Well-known groups of heterocyclicexamples of compounds such com- Citation: Oeser, P.; Koudelka, J.; arepounds the aromaticinclude pyridine, heterocyclic pyrrole, compounds. thiophene, Well-known and furan. Indoles examples occupy of such a unique compounds position Petrenko,Citation: A.;Oeser, Tobrman, P.; Koudelka, T. Recent J.; includewithin the pyridine, field of pyrrole, heterocyclic thiophene, compounds. and furan. An Indolesindole is occupy a condensed a unique compound position within that is Petrenko, A.; Tobrman, T. Recent Progress Concerning the N-Arylation thecomposed field of heterocyclicof a benzene compounds. and pyrrole Ancore. indole The isimportance a condensed of indoles compound and thattheir is derivatives composed Progress ConcerningMolecules 2021 the 26 of a benzene and pyrrole core. The importance of indoles and their derivatives is illustrated of Indoles. , , 5079. is illustrated by the examples shown in Figure 1. Tryptophan is an aromatic essential https://doi.org/10.3390/N-Arylation of Indoles. Molecules by the examples shown in Figure1. Tryptophan is an aromatic essential amino acid, amino acid, and sattazolin [1] and umifenovir [2] are indole derivatives with antiviral ef- molecules261650792021, 26, 5079. https://doi.org/ and sattazolin [1] and umifenovir [2] are indole derivatives with antiviral effects. N- fects. N-arylated indoles also belong to the group of important indole derivatives. An ex- 10.3390/molecules26165079 arylated indoles also belong to the group of important indole derivatives. An example ample of such a compound is sertindole, which is used as an antipsychotic drug [3]. Due Academic Editors: David StC Black of such a compound is sertindole, which is used as an antipsychotic drug [3]. Due to the to the significant biological activity of the indole derivatives, much attention has been andAcademic Naresh Editors: Kumar David StC Black significant biological activity of the indole derivatives, much attention has been paid to the paid to the modification of the indole unit [4–8]. and Naresh Kumar modification of the indole unit [4–8]. Received: 31 July 2021 H Accepted:Received: 1831 AugustJuly 2021 2021 N Published:Accepted: 2218 August 2021 O N Published: 22 August 2021 Publisher’s Note: MDPI stays neutral O N Publisher’s Note: MDPI stays neu- with regard to jurisdictional claims in CO2H Me2N tral with regard to jurisdictional published maps and institutional affil- CO2Et NH2 OH HO Cl iations.claims in published maps and institu- tional affiliations. N N Br N SPh N H H Me tryptofan (+)-sattazolin umifenovir (arbidol) Copyright: © 2021 by the authors. F Copyright: © 2021 by the authors. Li- Licensee MDPI, Basel, Switzerland. sertindole censee MDPI, Basel, Switzerland. This article is an open access article This article is an open access article FigureFigure 1.1. SelectedSelected examplesexamples ofof importantimportant indoleindole derivatives.derivatives. distributed under the terms and distributed under the terms and con- conditions of the Creative Commons ditions of the Creative Commons At- TheThe significantsignificant biologicalbiological activityactivity exhibitedexhibited byby sertindolesertindole hashas inspiredinspired thethe searchsearch forfor Attribution (CC BY) license (https:// tribution (CC BY) license (http://crea- newnew procedures for for the the preparation preparation of of N-arylindoles.N-arylindoles. Every Every indole indole contains contains a pyrrole a pyrrole core, creativecommons.org/licenses/by/ tivecommons.org/licenses/by/4.0/). core, so it can be expected that the N-arylation of indoles will proceed in a similar manner 4.0/). Molecules 2021, 26, x. https://doi.org/10.3390/xxxxx www.mdpi.com/journal/molecules Molecules 2021, 26, 5079. https://doi.org/10.3390/molecules26165079 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 43 so it can be expected that the N-arylation of indoles will proceed in a similar manner to the N-arylation of pyrroles. Among the group of aromatic heterocyclic compounds with one heteroatom, pyrrole is unique in terms of its reactivity. Unlike pyrrole, modifications of heteroatoms in furan and thiophene to form stable derivatives of the starting compound are not feasible. In some cases, phospholes can be P-arylated to form pentasubstituted phospholes [9], although the reactivity of the phosphole is affected by its low aromaticity Molecules 2021, 26, 5079 2 of 44 [10–13]. By contrast, pyrroles can be very easily arylated at position 1 [14,15] or 2 [16,17]. In addition, the dearomatizations of pyrroles are important [18–22]. Similar reactivity can to the N-arylation of pyrroles. Among the group of aromatic heterocyclic compounds withbe expected one heteroatom, even pyrrole in isthe unique case in termsof indole of its reactivity. arylations. Unlike pyrrole,The typical modifi- approach for the N-arylation cationsof amines, of heteroatoms including in furan nitrogen-containing and thiophene to form stable derivativesheteroaromatic of the starting compounds, involves the use of compound are not feasible. In some cases, phospholes can be P-arylated to form penta- substitutedtransition-metal-catalyzed phospholes [9], although the reactions reactivity of the (Scheme phosphole is1). affected In these by its lowcases, Ullman condensation [23– aromaticity25], Buchwald–Hartwig [10–13]. By contrast, pyrroles amination can be very easily[26–28], arylated and at position Chan–Lam 1 [14,15] coupling [29–31] are all fre- or 2 [16,17]. In addition, the dearomatizations of pyrroles are important [18–22]. Similar reactivityquently can used. be expected A common even in the case feature of indole arylations.of these The procedures typical approach is for the the reaction of amines with orga- Nnohalides-arylation of amines, or boronic including nitrogen-containingacids in the presence heteroaromatic of compounds,a transition involves metal catalyst and a base. A rel- the use of transition-metal-catalyzed reactions (Scheme1). In these cases, Ullman conden- sationatively [23–25 large], Buchwald–Hartwig number of amination N-arylation [26–28], and reactions Chan–Lam couplingof indoles [29–31] have are been reported over the last alldecade. frequently However, used. A common to featurethe best of these of proceduresour knowledge, is the reaction only of amines a few with review articles have addressed organohalides or boronic acids in the presence of a transition metal catalyst and a base. A relativelythe preparation large number of ofN-arylation N-arylindoles reactions of indoles[32–34]. have beenThus, reported we overdeci theded last to summarize the procedures decade.that have However, been to the used best of ourfor knowledge, the preparation only a few review of N articles-arylindoles have addressed over the past decade. The scope the preparation of N-arylindoles [32–34]. Thus, we decided to summarize the procedures thatof havethe beenpresent used for review the preparation is limite of N-arylindolesd to works over the that past decade. focused The scope on the N-arylation of indoles or ofotherwise the present review significantly is limited to workscontributed that focused to on this the N field.-arylation of indoles or otherwise significantly