Friedel-Crafts alkylation of indoles with nitroalkenes

3 Friedel-Crafts alkylation of indoles with nitroalkenes 

Computational study of the origin of enantioselection revealed a bifunctional mechanism of the substrate activation that also followed 

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Lin JH, Zhang CP, Zhu ZQ et al (2009) A novel pyrrohdinium ionic liquid with 1,1,2,2-tetra-fluoro-2-(l,l,2,2-tetrafluoroethoxy)ethanesulfonate anion as a recyclable reaction medium and efficient catalyst for Friedel-Crafts alkylations of indoles with nitroalkenes. J Fluorine Chem 130 394-398... 

Friedel-Crafts alkylation of indole with nitroalkenes was also effected by chiral phosphoric acid 21i (Equation 10.42) [88]. 

Scheme 4.52 Enantioselective conjugate Friedel-Crafts alkylation of indoles with nitroalkenes.

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. 

Ricci et al studied a series of thiourea catalysts for the Friedel-Crafts alkylation of aromatic and heteroaromatic compounds with nitroalkenes. They have succeeded in developing the Friedel-Crafts alkylation of indoles with nitroalkenes for the first time by means of a novel thiourea catalyst (13) (Scheme 2.48) [101]. The authors proposed the bifunctional nature of the thiourea catalyst, where thiourea activates the nitro group and at the same time the free alcoholic function interacts with the indole proton through a weak hydrogen bond, directing the attack of the incoming nucleophile on the Si face of the nitroalkene (Figure 2.18). 

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... 

Akiyama and coworkers extended the scope of electrophiles applicable to asymmetric Brpnsted acid catalysis with chiral phosphoric acids to nitroalkenes (Scheme 57). The Friedel-Crafts alkylation of indoles 29 with aromatic and aliphatic nitroalkenes 142 in the presence of BINOL phosphate (7 )-3r (10 mol%, R = SiPhj) and 3-A molecular sieves provided Friedel-Crafts adducts 143 in high yields and enantioselectivities (57 to >99%, 88-94% ee) [81]. The use of molecular sieves turned out to be critical and significantly improved both the yields and enantioselectivities. 

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... 

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