Friedel-Crafts alkylation chiral catalysts

Pseudo-C3-symmetrical trisoxazoline copper(II) complexes prove to be excellent catalysts in the Friedel-Crafts alkylation of indoles with alkylidene malonates (Eq. 7.13). Water tolerance of chiral catalyst trisoxazoline/Cu(OTf)2 was examined, and it was found that the addition of up to 200 equivalents of water relative to the catalyst in /,vo-butyl... 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

The concept of a diastereoselective Friedel-Crafts alkylation of a-chiral benzyl alcohols was first examined by Bach and coworkers [62, 63]. The initial protocol required stoichiometric amounts of strong Brpnsted acids like HBF4 and was followed by a more valuable methodology in which catalytic amounts of AuC L were employed for the diastereoselective functionalization of chiral benzyl alcohols [64], Beside arenes, allyl silanes, 2,4-pentanediones and silyl enol ethers have been used as nucleophiles. Depending on the diastereodiscriminating group and on the catalyst (Brpnsted or Lewis acid), the authors observed either the syn or the anti diastereoisomer as the major product. 

Chiral bis-sulfonamides 162-163 are a new group of organo catalysts for the enantioselective Friedel-Crafts alkylation of indoles to nitroolefins. The hy-... 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

Jorgensen and co-workers employed chiral bis-sulfonamide catalyst 27, a proven ligand for metal-based asymmetric catalysis, for the Friedel-Crafts alkylations of N-methylindoles (24) using -substituted nitroolefins [52]. Using optimized conditions, 2 mol% 27 gave the desired indole alkylation products of substituted aryl and heteroaryl nitroolefins in moderate to high yields (20-91%) and moderate enantiopurities (13-63% ee Scheme 6.3). Aliphatic -substitution... 

An enantioselective Friedel-Crafts alkylation of pyrroles with /V-acylimincs has been reported <070L4065>. The reactions were run in the presence of chiral phosphoric acids. A novel C-H bond activation procedure was developed for the preparation of heteroarylamides including pyrrole-3-carboxamides <07CL872>. The reactions involved imine-substituted pyrroles, isocyanate electrophiles, and a rhenium catalyst. 

The Friedel-Crafts alkylation and acylation reactions have become important methods for the synthesis of substituted furans. The most useful reactions employ chiral catalysts to generate products in good yield and with high... 

Nitroalkenes are not the only substrates employed as electrophiles in these conjugate Friedel-Crafts alkylations using chiral phosphoric acids as catalysts. In fact, the first reports in this field were focused on the reaction of indoles with p,y-unsaturated ot-ketoesters as Michael acceptors, which underwent clean... 

Enantioselective Friedel-Crafts alkylation reactions were performed between substituted indoles and methyl trifluoropyruvate, using a chiral nonracemic ( -symmetric 2,2 -bipyridyl copper triflate complex as catalyst. The active copper(II) catalyst was... 

From a mechanistic viewpoint, asymmetric Friedel-Crafts alkylation (AFCA) reactions are similar to the historical version, with the chiral additives responsible for triggering and controUing the overall aromatic C—H replacement. Interestingly, covalent (organocatalysis) or noncovalent (metal catalysis) interactions can take place between catalysts and electrophiles during the enantiodis-criminating step of the reaction course (Fig. 5.1). 

Friedel-Craft Alkylation Conjugated Additions. In the last decade, several methodologies have been developed to enantios-electively alkylate the Al-methylindole via a conjugated addition. One of them uses an a./S-unsaturated acylphosphonate as electrophile and a scandium(III) PyBox as chiral catalyst. After the Michael addition, the phosphonate moiety is directly converted into an ester by adding the corresponding alcohol in the presence of DBU. The desired product is isolated in 88% yield and 98% ee (eq... 

Besides performing diastereoselective reactions using chiral staring materials, optically active catalyst-controlled enantioselective Friedel-Crafts alkylation [31] can also be served as an alternative to provide chiral products. Great advances have been demonstrated in this hot field within the last decade. Generally, three strategies have been success-fnlly ntilized to achieve catalytic asymmetric Friedel-Crafts alkylation. The first one involves the nse of chiral Lewis acids, where a chiral ligand is coordinated to the Lewis acid. 

The enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes is one of the most important carbon-bond-forming reactions for the preparation of biologically active compounds, such as indole alkaloids [39], Although several chiral catalysts have been investigated for the reaction, the enantioselectivities are not always satisfactory. Akiyama and coworkers developed a highly enantioselective Friedel-Crafts reaction of nitroalkenes 77 with indoles 75 using chiral phosphoric acid Ih (Scheme 11.21) [40]. They found that the addition of molecular... 

In 2011, Hermeke and Toy synthesized phosphonium ion-tagged chiral phosphoric acids 117 and 118 bearing a BINAP core and examined them as recoverable organocatalysts in Friedel-Crafts alkylation of indoles [55], The phosphonium tag position in the catalysts was cmcial for the reaction outcome. Compound 117 with the tags at positions 3 and 3 of phosphoric acid, where they served as spaceblocking groups, failed to catalyze the reactions. However, a shift of the phosphonium ion groups to positions 6 and 6 produced efficient and enantioselective... 

In 2007, Melchiorre and coworkers [27] reported a dual catalyst system based on the combination of chiral primary amine and N-protected amino acid. The combinational chiral counteranion led to the first example of highly enantioselective Friedel-Crafts alkylation of indoles 80 with simple a,P-unsaturated ketones 79 (Scheme 43.16). The N-protected amino acid had a beneficial effect on the... 

In 2009, Cai et al. reported a cascade olefin cross-metathesis/intramolecular Friedel-Crafts alkylation for the construction of polycyclic indoles 133 (Scheme 5.89) [90], A Ru complex (134)/chiral Brpnsted acid [(S)-135] binary system was used in this relay catalysis. Recently, the same group reported an enantioselective intramolecular aza-Michael addition of indoles using a similar binary catalyst system (Scheme 5.90) [91]. 

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

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