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.

Catalytic Functionalization of Indoles in a New Dimension

Alkylation reactions represent an important organic transformation to form C–C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various carbon–hydrogen bonds (addition of C–H bonds across olefins) using regular olefins or 1,3-dienes up to May 2016. According to the mode of activation, the Review is divided into two sections: alkylation via C–H activation and alkylation via olefin activation.

Transition-Metal-Catalyzed C–H Alkylation Using Alkenes

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

Katalytische Funktionalisierung von Indolen in einer neuen Dimension

The use of p-activated alcohols in catalytic Friedel–Crafts alkylation (FCA) reactions has become a well-known and eco-sustainable reality. A large number of Lewis and Brønsted–Lowry acid catalyzed benzylation/allylation/propargylation procedures has been documented, and they allow rapid access to structural complexity in the realm of aromatic compounds. Despite efficiency, the formation of positively charged intermediates in FCA with alcohols (SN1-type mechanism) makes the stereocontrol of the process a challenging task that has not yet been overcome. As a matter of fact, at present only a handful of reports addressing such an issue have been documented. As a part of our program directed toward the development of innovative catalytic and stereoselective methodologies for the synthesis of polycyclic aromatic compounds, we describe herein the first example of direct activation of allylic alcohols in enantioselective catalytic Friedel–Crafts allylic alkylations of indoles. The methodology allows 1vinyland 4-vinyltetrahydrocarbazoles (THCs) to be readily prepared in a highly enantioselective manner. Our working hypothesis deals with the choice of a suitable chiral Lewis acid promoter, which is capable of efficiently activating the hydroxy group as a leaving group without the formation of an allylic carbocationic species (SN1-type mechanism) that would preclude any stereochemical control in the course of the reaction. Guidelines for searching for a suitable catalyst came from the intrinsic “chelating” architecture of the allylic alcohol featuring a soft p-base center (C=C bond) and a hard s-base unit (hydroxy group) that are adjacent to each other. Cationic late-transition-metal complexes (e.g. Pt, Ag, Au), which feature dual function (i.e. sand p-acidity), appeared suitable candidates to obtain conformationally rigid adducts between the FC precursors and the catalyst. In this context, chelating (monometallic catalyst) or single-point (bimetallic catalyst) interactions were envisioned (Figure 1).

Enantioselective gold-catalyzed allylic alkylation of indoles with alcohols: an efficient route to functionalized tetrahydrocarbazoles.

The indole framework represents a key structural motif in a large number of biologically active natural products and pharmaceutical compounds. Consequently, modifications on the indole structure, including the development of enantioselective variants, have triggered increasing interests. Because of the inherent nucleophilic characteristics of indole compounds, their reactions preferentially take place at the C3-position of the ring system. As a result, the majority of enantioselective reactions of indoles focus on the C3-selective addition of electron-rich indoles to electrophilic imines, epoxides, carbonyl compounds, a,b-unsaturated carbonyl compounds, and nitroalkenes etc., thus leading to the formation of diversely structured enantioenriched C3-functionalized indole derivatives. Recently, the enantioselective synthesis of C2-substituted indoles has also been realized through the asymmetric alkylation of 4,7-dihydroindoles and subsequent oxidation. In sharp contrast to the progress in enantioselective alkylation at the C3or C2-positions, the asymmetric Nalkylation of indoles has been underdeveloped: probably because of the privileged C3-chemoselectivity of indole compounds. The limited examples include the palladiumcatalyzed N-allylic alkylation of 3-substituted indoles developed by Trost et al. and the enantioselective intramolecular aza-Michael addition of tethered indole-2-carboxylates under chiral phase-transfer catalysis developed by Bandini et al. Indeed, N-alkylated indoles have been applied as useful intermediates for the synthesis of polyheterocycles and occur widely among natural products and biologically active pharmaceuticals (Scheme 1). For example, mitomycin C exhibits potent antitumour activity and is used clinically in the treatment of certain cancers. Yuremamine, which was recently isolated from the stem bark of Mimosa hostilis, shows hallucinogenic and psychoactive effects. Pyrrolo[3,2,1-ij]quinoline derivatives are active antihistamines and inhibitors of leukotriene, and they offer the possibility of a novel multimediator approach to the treatment of allergic diseases. Therefore, it would be extremely desirable to develop effective protocols to access optically pure N-alkylated indoles. Recently, the allylic alkylation of Morita-Baylis–Hillman (MBH) adducts catalyzed by a metal-free organic Lewis base has emerged as an attractive strategy to prepare multifunctional compounds. Our research group has also reported that modified cinchona alkaloids are outstanding catalysts for the asymmetric allylic alkylation of a,a-dicyanoolefins with MBH carbonates. We anticipated that, as outlined in Scheme 2, the deprotonation of the acidic NH group of the

Haoxi Huang

Papers

A highly strained planar-chiral platinacycle for catalytic activation of internal olefins in the Friedel-Crafts alkylation of indoles.

Ein hoch gespannter planar‐chiraler Platinacyclus zur katalytischen Aktivierung interner Olefine bei Friedel‐Crafts‐Alkylierungen von Indolen