Enantioselectivity Friedel-Crafts alkylation

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate <06OL2115>. 

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

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. 

Enantioselective Friedel-Crafts alkylation of A -benzylpyrrole and 5-nitroindole with benzoylhydrazones 504 promoted by a simple strained silacycle reagent 505 gives 2- and 3-derivatives 506 and 507, respectively (Scheme 102) <2005JA2858>. Indole itself provides the corresponding product with significantly reduced enantioselectivity (ee 24%). 

Very recently, the enantioselective Friedel-Crafts alkylation of the simple phenols 157 with trifluoropyruvate was also accomplished by using the bifunctional quinidine... 

The alcohol group also works as an alternative functionality in thiourea catalysts. Catalytic enantioselective Friedel-Crafts alkylation of indoles with nitroalkanes using alcohol-... 

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... 

In the case of indole itself, the conjugate addition product was formed in excellent yield (97%) and in good enantiomeric excess (59% ee). According to the authors, this was the first report of the use of a chiral nonracemic 2,2 -bipyridyl ligand in catalytic and enantioselective Friedel-Crafts alkylation reactions. 

Scheme 2 Enantioselective Friedel-Crafts alkylations and further transformations...

A catalytic enantioselective Friedel-Crafts alkylation of indole with /3,y-unsaturated a-ketoesters was developed. By changing metals (samariiun and silver), the... 

This phosphoric acid derived from (i )-BINOL was also applied by Akiyama et al. as an organocatalyst to promote the highly enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes, generating the corresponding Friedel-Crafts adducts with high yields and excellent enantioselectivities of up to 94% ee for a broad range of substrates in the presence of 3-A molecular sieves (Scheme 10.2). ... 

Itoh, J. Fuchibe, K. Akiyama, T. Chiral Phosphoric Acid Catalyzed Enantioselective Friedel-Crafts Alkylation of Indoles with Nitroalkenes Cooperative Effect of 3 A Molecular Sieves. Angew. Chem. Int. Ed. 2008, 47, 4016-4018. 

Enantioselective Friedel-Crafts alkylation of indoles with a,P-unsaturated acyl phosphonates was investigated in the presence of bis(oxazolinyl)pyridine-scandium triflate complexes [151]. The intermediate -indolyl acyl phosphonates were converted to the corresponding methyl esters by direct addition of methanol and DBU (1,8-diazobicyclo [5.4.0] undec-7-ene) to the reaction mixture. Various acyl phosphonates and indole derivatives gave the alkylated products in moderate to good yields with high to excellent enantioselectivities (Scheme 12.57). It was also shown that the reaction was quenched by morpholine to give the corresponding amide, and that electron-rich 3-dimethylaminoanisole was also an effective nucleophile in this reaction. 

SCHEME 10.24 Enantioselective Friedel-Crafts alkylation catalyzed by a chiral copper complex. 

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. 

On the other hand, Lee showed that 28 could activate N-sulfonyl imines through hydrogen-bonding interaction and could function as an efficient Br0nsted acid catalyst for the highly enantioselective Friedel-Crafts alkylation of indoles with the imines (Scheme 7.55) [83]. It was essential to wash the catalyst with dilute hydrochloric acid followed by water and brine prior to use to attain sufficient reactivity. 

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... 

Extending the application of his strained silacycle reagents, Leighton et al. published a procedure for the enantioselective Friedel-Crafts alkylation with benzoyl hydrazones, catalyzed by a simple chiral silane Lewis acid. The enantiopure silanes were prepared in bulk in a single step from (S,S)- or (k,k)-pseudoephedrine and PhSiCls. After use in the catalytic reaction the pseudoephedrine was recovered in nearly quantitative yield during the workup. Scheme 16.16 shows the best example, in which by employing enantiopure silane 23 a 92% yield and 90% ee of the product was obtained in 48 h [62]. 

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... 

Scheme 22.35 Phosphonium ion-tagged chiral phosphoric acids 117 and 118 and their use in enantioselective Friedel-Crafts alkylations of indole derivatives.

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