SummaryThe development of efficient Friedel–Crafts alkylations of arenes and heteroarenes using only catalytic amounts of a Lewis acid has gained much attention over the last decade. The new catalytic approaches described in this review are favoured over classical Friedel–Crafts conditions as benzyl-, propargyl- and allyl alcohols, or styrenes, can be used instead of toxic benzyl halides. Additionally, only low catalyst loadings are needed to provide a wide range of products. Following a short introduction about the origin and classical definition of the Friedel–Crafts reaction, the review will describe the different environmentally benign substrates which can be applied today as an approach towards greener processes. Additionally, the first diastereoselective and enantioselective Friedel–Crafts-type alkylations will be highlighted.

Dedicated to Professor Gerhard Quinkert on the occasion of his 80th birthdayThe application of chiral Brønsted acids in metal-free enantioselective catalysis is increasing rapidly.[1] Within the last two years the first highly enantioselective transformations have been developed in which chiral Brønsted acids function as biomimetic catalysts. The central role performed by the Brønsted acids in such reactions is the activation of the electrophile by catalytic protonation, thereby enabling them to react with a nucleophile. In this manner it has been possible to realise enantioselective transformations with aldimines and ketoimines using chiral Brønsted acids such as binol phosphates [Eq. (1)]. [2][3][4][5] In these transformations a proton is initially transferred from the Brønsted acid to an aldimine or ketoimine to form an intermediary chiral ion pair which subsequently reacts with a nucleophile to form the corresponding amine and the regenerated Brønsted acid. Within this field of chiral ion pair catalysis, only aldimines and ketoimines have been activated to date. More recently, however, we have been successful in the activation of both the electrophile and the nucleophile in a new double Brønsted acid catalyzed reaction.[5] In these reactions the simultaneous and co-operative activation of the aldimine by the chiral binol phosphate *BH [Eq. (1)], and the carbonyl nucleophile by an achiral Brønsted acid [Eq. (2)], result in the desired products.[5]The enantioselective Brønsted acid catalyzed activation of a "pure" carbonyl compound using a chiral binol phosphate has not previously been described. Here we report for the first time the development of such a reaction: a Brønsted acid catalyzed enantioselective Nazarov cyclization. The Nazarov reaction belongs to the group of electrocyclic reactions and is one of the most versatile methods for the synthesis of fivemembered rings, which are the key structural elements of numerous natural products.[6] In general, the Nazarov cyclization can be catalyzed by Brønsted or Lewis acids. However, only a few asymmetric variations have been described, of which most require the use of large amounts of chiral metal complexes. [7] Building on our previous results, [3][4][5] we decided to examine a metal-free Nazarov reaction catalyzed by a binol phosphate. This would not only be the first example of a Brønsted acid catalyzed, enantioselective, electrocyclic reaction but would additionally provide a simple and direct route to optically pure cyclopentenones.We assumed that the catalytic protonation of a divinylketone A by the binol phosphate (*BH) would result in the formation of an adduct B, which consisted of a cyclopentadienyl cation and a phosphate anion (Scheme 1). Subsequent conrotatory 4p electrocyclization would lead to oxyallyl cation C which, through the elimination of a proton, would form enolate D. Successive protonation of this enolate should then result in the formation of cyclopentenone E and the regenerated Brønsted acid catalyst *BH.At the outset of our experiment...

Asymmetric alkylations of electron-rich arenes such as indoles are of great importance for the synthesis of many natural products and pharmaceuticals.[1] Hence, different approaches have been undertaken to develop catalytic enantioselective additions of indoles to a,b-unsaturated carbonyl compounds. To date, these have been based on the application of chiral transition-metal complexes [2] or secondary amines, the latter of which function through covalent activation, forming intermediary iminium ions. [3] In this context the use of b,g-unsaturated a-keto esters is of particular interest since they not only exhibit a higher reactivity but also can be functionalized readily to the corresponding amino acids or a-hydroxy acids.Given the frequent occurrence of the indole core structure in biologically active substances and natural products [4] together with the possibility of activating carbonyl functionalities with chiral Brønsted acids, [5][6] the development of an enantioselective, metal-free, noncovalently catalyzed Friedel-Crafts alkylation of indoles appeared to be of great significance. This would not only be the first example of such an organocatalyzed transformation, but more importantly it would give simple and direct access to optically pure a-keto and a-amino acids. We report here on the development of such a reaction, a highly enantioselective Brønsted acid catalyzed addition of indoles to a,b-unsaturated carbonyl compounds.In continuing studies on the Bønsted acid catalyzed asymmetric Nazarov cyclization of divinyl ketones [5] [Eq. (1)], we assumed that an enantioselective FriedelCrafts alkylation of indoles through the noncovalent activation of a-keto esters using N-triflylphosphoramides [Eq. (2)] should also be feasible. Therefore, our investigations started with the examination of the Brønsted acid catalyzed addition of N-methylindole (1 a) to the a-keto ester 2 a. While no reaction was observed when weak Brønsted acids, such as carbonic acids or diphenyl phosphate, were used, catalytic amounts of N-triflylphosphoramide 5 a resulted in product formation. However, in addition to the desired 1,4-addition product 3 a, the bisindole 4 a was isolated as the main product (Scheme 1).The Lewis or Brønsted acid catalyzed formation of bisindoles starting from aldehydes, ketones, and 1,2-diketones is well known, [7] and several naturally occurring alkaloids contain this structural element.[8] However, the remarkable regioselectivity observed in the reaction of indoles with b,gunsaturated a-keto esters favoring the 1,2-addition with the generation of bisindole 4 a has not previously been reported. Figure 1 shows the X-ray crystal structure of 4 a. In contrast to all previously reported bisindoles, 4 a exhibits atropisomerism as a result of the rotation barrier about the bonds to the quaternary carbon bond. The bisindole atropisomers are not only observed in the X-ray crystal structure but can also be Scheme 1. Brønsted acid catalyzed reaction of N-methylindole (1 a) with a-keto ester 2 a to form bisindole 4 a.

A widely applicable triazole‐substituted chiral aryl iodide is described as catalyst for enantioselective oxidation reactions. The introduction of a substituent in ortho‐position to the iodide is key for its high reactivity and selectivity. Besides a robust and modular synthesis, the main advantage of this catalyst is the excellent performance in a plethora of mechanistically diverse enantioselective transformations, such as spirocyclizations, phenol dearomatizations, α‐oxygenations, and oxidative rearrangements. DFT‐calculations of in situ generated [hydroxy(tosyloxy)iodo]arene isomers give an initial rational for the observed reactivity.

Recently, chiral highly acidic Brønsted acids have emerged as powerful catalysts for enantioselective C-C and C-X bond-forming reactions. Their strong acidity renders them valuable tools for the activation of imines, carbonyl compounds, and other weakly basic substrates. As a result, new perspectives are opened and highly stereoselective transformations based on the concept of chiral contact-ion-pair catalysis can be realized. This Minireview gives an overview of the design and application of these new organocatalysts and presents recent results in this rapidly growing field.