140 years ago Adolf von Baeyer proposed the structure of a heteroaromatic compound which revolutionized organic and medical chemistry: indole. After more than a century, indole itself and the complexity of naturally occurring indole derivatives continue to inspire and influence developments in synthetic chemistry. In particular, the ubiquitous presence of indole rings in pharmaceuticals, agrochemicals, and functional materials are testament to the ever increasing interest in the design of mild and efficient synthetic routes to functionalized indole derivatives. This Review emphasizes the achievements in the selective catalytic functionalization of indoles (C-C bond-forming processes) over the last four years.

Breaking the taboo: The direct use of allylic alcohols in catalytic and enantioselective Friedel–Crafts alkylation is described for the first time in the presence of chiral gold complexes. This intramolecular Friedel–Crafts reaction was used to prepare a broad range of functionalized tetrahydrocarbazoles (see scheme; X=Me, F, Br, Cl, OMe; R=Me, Et, tBu; R′=H, Me).

Vor 140 Jahren schlug Adolf von Baeyer die Struktur für eine heteroaromatische Verbindung vor, die die organische und medizinische Chemie nachhaltig veränderte: Indol. Nach mehr als einem Jahrhundert beeinflussen Indol selbst, ebenso wie natürliche Indolderivate, weitgehend die Entwicklung in der Synthesechemie. Vor allem die allgegenwärtige Präsenz des Indolrings in pharmazeutischen und agrochemischen Verbindungen sowie seine Verwendung in der Materialchemie sind ausschlaggebend für das anhaltende Interesse an der Entwicklung von neuen milden und effizienten Synthesestrategien für funktionalisierte Indolderivate. Dieser Aufsatz fasst die Fortschritte hinsichtlich der selektiven katalytischen Funktionalisierung von Indolen (durch C‐C‐Kupplung) aus den vergangenen vier Jahre zusammen.

The preparation of enantiomerically pure compounds has become a stringent requirement for pharmaceutical synthesis. [1] In this context, asymmetric catalysis is probably the most attractive procedure for the synthesis of active pharmaceutical ingredients (APIs) due to environmental, operational, and economic benefits.3,4-Dihydropyrazino[1,2-a]indol-1(2H)-ones 1 (see Scheme 1) have attracted much attention due to the broad scope of their biological activities (that is, their antifungal properties, noncompetitive antihistamine activity, and specific inhibition of serotonergic receptors).[2] Moreover, recent patents reported the effectiveness of the corresponding 1,2,3,4-tetrahydropyrazino[1,2-a]indoles 2 (Scheme 1) as antiobesity agents and in the treatment and prevention of noninsulin-dependent diabetes. [3] From these studies, the importance of the absolute configuration of the stereocenters on the pharmacological activity emerged clearly. Moreover, since the piperazine compounds 2 are readily obtainable from 1,[3] the development of an effective stereoselective synthetic route to pyrazino-indol-1-ones 1 would be extremely valuable. The use of chiral pools and the resolution of racemates are the only synthetic routes to 1 and 2 to date. [3][4][5] During our ongoing research addressing the functionalization of polycyclic indoles, [6] we recently communicated an efficient Pd-catalyzed approach to tetrahydro-b-carbolines through regio-and enantioselective C3-allylic nucleophilic alkylation (up to 97 % ee).[7] Unfortunately, all our attempts to exploit such an approach to perform enantioselective indolyl-N1 ring-closing reactions were unsuccessful. Herein, we describe the first highly enantioselective synthesis of molecular motifs of type 1 through a phase-transfer-catalyzed [8] aza-Michael addition.[9]The employment of a metal-free approach [10] stems from our recent findings on the intramolecular base-catalyzed synthesis of 1, from readily available precursors 3 (Scheme 2).[11] However, the use of Lewis acid catalysis in the present ring-closing reaction failed, probably due to the poor electrophilic character of the a,b-unsaturated ester and to low catalyst turnover as a result of starting material/ product inhibition (that is, a metallo-poisoning effect exerted by the strongly coordinating amide group). Searching for an enantioselective variant, we firstly turned our attention to chiral organic bases such as the Cinchona alkaloids and sparteine, which gave disappointing results in the cyclizations of 3 a (X = H; toluene, reflux, 48 h, 0 % ee). We reasoned that the unsatisfactory stereoinduction could be ascribable to the formation of flexible and not sufficiently tight ion pairs between the ammonium salt of the quinuclidine ring and the nucleophilic indolate intermediate (Figure 1 a).

Ein Tabu gebrochen: Die erste erfolgreiche direkte Verwendung von Allylalkoholen in katalytischen und enantioselektiven Friedel‐Crafts‐Alkylierungen gelang in Gegenwart chiraler Goldkomplexe. Diese intramolekulare Friedel‐Crafts‐Reaktion machte eine Vielzahl an funktionalisierten Tetrahydrocarbazolen zugänglich (siehe Schema; X=Me, F, Br, Cl, OMe; R=Me, Et, tBu; R′=H, Me).