Phosphoric acids, enantioselection Friedel-Crafts alkylation

In 2004, Terada and coworkers reported the first asymmetric phosphoric acid-catalyzed Friedel-Crafts alkylation (Scheme 8). Aldimines 11 reacted with commercially available 2-methoxy furan (20) in the presence of BINOL phosphate (/ )-3q (2 mol%, R = S.S-MeSj-C Hj) to provide access to A-Boc-protected 2-furyl amines 21 in high yields (80-96%) and enantioselectivities (86-97% ee) [19]. 

Subsequently, the chiral phosphoric acid catalyzed Friedel-Crafts alkylation attracted much attention and became the subject of comprehensive investigations. In particular, the reaction with indole was investigated extensively because it provided pharmacologically important 3-substituted indole derivatives in enantio-merically enriched forms. The groups of You [35], Terada [36], and AntUla [37] almost simultaneously developed a highly enantioselective Friedel-Crafts reaction of indoles 75 with aromatic imines 74 (Scheme 11.20). Interestingly, their reactions... 

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. 

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 reactions using metal-based chiral catalysts or chiral organocatalysts have been investigated extensively because the reactions directly provide alkylated arenes, a pharmacologically important substructure, in optically active forms. The chiral phosphoric acid catalyzed Friedel-Crafts reaction was first accomplished via the activation of imines but, currently, the scope of the electrophilic components has been broadened to include the Michael addition to nitroalkenes, a, 3-unsaturated carbonyl compounds, and so on. 

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... 

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

In conjunction with their Friedel-Crafts alkylation, Terada et al. found phosphoric acid (R)-3m (2 mol%, R = 9-anthryl) bearing a bulky 9-anthryl group to mediate the asymmetric Friedel-Crafts-type reaction of a-diazoester 22a with iV-acylated aldimines 26 (Scheme 10). a-Diazo-P-amino esters 27 were obtained in moderate yields (62-89%) and very good enantioselectivities (91-97% ee) [20],... 

Moreover, phosphoric acid (5)-3r (5 mol%, R = SiPhj) bearing a bulky triphe-nylsilyl group turned out to be a suitable catalyst for the asymmetric Friedel-Crafts alkylation of iV-alkyl pyrroles 31 with M-benzoyl-protected aldimines 32 (Scheme 12) [23]. 2-Pyrrolyl amines 33 were obtained in high yields (66-97%) and moderate to high enantioselectivities (42 to >99% ee). 

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. 

As mentioned above, a range of enantioselective transformations have been established using chiral phosphoric acids via the activation of imines and related nitrogen-substituted substrates. In contrast, the activation of carbonyl compounds, including a,P-unsaturated carbonyl compounds, by chiral phosphoric acids has been limited. In 2008, Zhou, He, and coworkers achieved the asymmetric Friedel-Crafts alkylation reaction of indole derivatives with 1,3-diaryl a,p-unsaturated... 

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... 

The same authors used the chiral phosphoric acid (300) in enantioselective asymmetric Friedel-Crafts alkylation reaction of indoles (324) with 3-sub-stituted 3-hydroxyisoindolin-l-ones (325) in synthesising 3,3-disubstituted isoindolin-l-ones (326), in excellent chemical yields (up to 99%) and with good to excellent enantioselectivities (up to 95% ee) (Scheme 85). ... 

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