Friedel-Crafts alkylation cascade reactions

Xiao et al. developed a highly enantioselective, copper-catalyzed Friedel-Crafts alkylation/A7-hemiacetalization cascade reaction of indoles. Indole 184 was allowed to react with ester 185 to furnish fused indole 186 in excellent yield, diastereoselectivity, and enantioselectivity. Indole 186 was further elaborated to complete a formal synthesis of analogs of flinderoles B and C (13AG(I)3250). 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

Wang elegantly demonstrated the potentiality of chiral diarylprolinol ether 54 in the synthesis of chromanes 56 via enantioselective Michael-type Friedel-Crafts alkylation/cychzation cascade synthetic sequence between 5a and a,p-unsaturated aldehydes 37a [30a]. Under optimal conditions, moderate diastereoselectivity and high enantioselectivity were obtained. Differently, phenol was found unreactive (Scheme 5.17a). The same team years later documented also the activity of a rosin-derived tertiary amine-thiourea 55 in similar process involving 1- and 2-naphthols and P,y-unsaturated a-ketoesters 25 (Scheme 5.17b) [30b]. A proposed model of the enantiodiscrimi-nating step of the reaction is also provided by the authors (58). 

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. 

Methyl-l-phenylhept-3-yne-2,6-diol undergoes a one-pot three-step cascade reaction with alkyl and aryl aldehydes to provide 2,4-dihydro-lH-benzo[ isochromans.This two-component cascade reaction promoted by Bp3-OEt2 involves an alkynyl-Prins cyclization, Friedel-Crafts arylation, and dehydrative aromatization (130L4070). Other Prins cascade cycliza-tions of 2-arylethylbut-3-en-l-ol with aliphatic and aromatic aldehydes occur in the presence of Sc(OTf)3 andp-TsOH to prepare trans-fused hexa-hydro-1 H-benzo[ isochromans in good yields and excellent selectivity (Scheme 44) (13EJ01993). 

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