Friedel-Crafts reaction cascade

Similar substituted quinolines can be efficiently obtained starting from N-alltylaniline (including glycine) derivatives by reaction with alkenes in the presence of FeCls (10 mol%) and TEMPO oxoammonium tetrafluoroborate salt (2 equiv.) as the oxidant in dichloromethane (DCM) at 60 °C. Interestingly, the same quinolines can be obtained starting from anilines, ethyl glyoxalate and alkenes, in a one-pot multi-component reaction, under similar conditions.  

---

In the same year, Enders and coworkers reported an asymmetric one-pot, two-step synthesis of substituted isoindolines 159 in the presence of chiral A-triflyl phosphoramide (R)-Ae (10 mol%, R = d-NO -C H ) (Scheme 67) [87]. The cascade was triggered by a Brpnsted acid-catalyzed aza-Friedel-Crafts reaction of indoles 29 and A-tosyliminoenoates 160 followed by a DBU-mediated aza-Michael cyclization of intermediates 161 to afford the isoindolines 159 in high yields (71-99%) and short reaction times (10 min to 4 h) along with good enantioselectivities (52-90% ee). Longer reaction times (16 h to 10 days) caused increasing formation of the bisindole byproduct 162 (Scheme 68) along with amplified optical purity of isoindolines 159. 

Moreover, Friedel-Crafts reactions have been applied as a crucial step in multicomponenti as well as multistep cascade reactions. These approaches have considerable importance from the economic and environmental point of view since they allow the building of fargef compounds with great structural complexity through a one-pot process. 

Cascades Initiated by Conjugate Friedel-Crafts Reaction... 

Scheme 7.40 A representative example of the Friedel-Crafts/chlorination cascade reaction.

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

MacMillan and co-workers [79] pioneered the development of entirely organo-catalyzed cascade reactions. In his seminal report, iminium-catalyzed Friedel-Crafts reactions were followed by enamine-catalyzed a-chlorinations (Scheme 13.40). In this same report, an iminium-catalyzed conjugate reduction was followed by an enamine-catalyzed a-chlorination (not shown). In both of these cascade reactions, a single catalyst was used for both the iminium- and enamine-mediated reactions. Alternatively, MacMillan demonstrated that it was possible to use one catalyst for an iminium-catalyzed conjugate reduction and a different catalyst for an enamine-catalyzed a-fluorination (Scheme 13.40) [79]. Such cycle-specific cascade reactions allow access to both the anti (shown) and syn diastereomers of the product simply by using the opposite enantiomer of the catalyst for one of the two reactions in the cascade. 

A triflic acid-catalysed cascade cyclization of arenyl 1,7-enynes apparently proceeds through acetylene-cation cyclization followed by Friedel-Crafts reaction (Scheme 38)7 ... 

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

Ruthenium/Br0nsted Acid System The tandem isomerization/Friedel-Crafts reaction of aUylamides reported by Sorimachi and Terada was another early example of a cascade catalysis procedure using Brpnsted acid and metal salts as catalysts (Scheme 2.93) [127]. With the promotion of the ruthenium catalyst 342, the aUylamides isomerized to enamide X32, which was then tautomerized by a Brpnsted acid (343 or 344) to form imine X33 then the electron-enriched aromatic substrates 341 attacked the Brpnsted acid-activated imine intermediates to afford Friedel-Crafts products 345 in up to 91% yield. 

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. 

Finally, there is also a relevant example of an intermolecular conjugate Friedel-Crafts/electrophilic amination cascade developed very recently by Melchiorre in which 2-methyl-IH-indole reacted with a variety of a,p-unsatu-rated aldehydes and dialkyl azodicarboxylates in the presence of a primary amine catalyst, leading to the formation of a family of products containing two contiguous stereocenters, one of them a quaternary one (Scheme 7.43). This reaction started with the conjugate addition of 2-methyl-lH-indole to the enal... 

---