Conjugate Friedel-Crafts

Brmnsted-Lewis Superacids. Conjugate Friedel-Crafts acids prepared from ptotic and Lewis acids, such as HCl—AlCl and HCl—GaCl ate, indeed, supetacids with an estimated value of —15 to —16 and ate effective catalysts in hydrocarbon transformation (217). 

Carbocations formed through protonation of alkenes by proton acids are usually assumed as intermediates in alkylation with alkenes. Metal halides, when free of protic impurities, do not catalyze alkylation with alkenes except when a cocatalyst is present. It was shown that no neat conjugate Friedel-Crafts acids such as HA1C14 or HBF4 are formed from 1 1 molar compositions in the absence of excess HC1 or HF, or another proton acceptor.163-166 In the presence of a proton acceptor (alkene), however, the Lewis acid halides—hydrogen halide systems are readily able to generate carbocations ... 

Positional isomerization occurs similarly as during alkylation with alkyl halides. HF and H2S04, which are weaker catalysts than the conjugate Friedel-Crafts acids, however, do not bring about ready positional isomerization of the alkylated products. Rearrangement in the side chain always takes place before the attachment of the substituent to the aromatic ring when these catalysts are used. 

The conjugate Friedel Crafts alkylation is a powerful strategy for the chemical modification of electron-rich aromatic substrates allowing the building up of complex structures, which is very often the synthetic tool of choice when preparing a highly substituted heterocyclic compound. Developments in... 

Scheme 3.23 Enantioselective conjugate Friedel-Crafts alkylations using itnidazoli-dinone catalysts.

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

On the other hand, 2-naphthols have been used with different success as Michael donors in conjugate Friedel Crafts reactions with nitroalkenes and related substrates (Scheme 4.53). For example, cinchonine-derived thiourea 72b was identified as an excellent promoter for the reaction of a wide variety of 2-naphthols and nitroolefins, providing excellent yields and enantioselectivities. Remarkably, the more challenging p-alkyl substituted nitroalkenes were also found to undergo the reaction in a highly stereoselective way and with comparable yields to those obtained when nitrostyrene derivatives were employed. 

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... 

Scheme 4.56 Enantioselective conjugate Friedel-Crafts reaction of indoles with p,y-unsaturated-a-ketoesters.

To end this section, it has to be mentioned that there is a single example of a conjugate Friedel Crafts alkylation involving enones as Michael acceptors. In particular, a camphor-based sulfonic acid (94) has been used as catalyst in the reaction of indoles with chalcones (Scheme 4.57). It has also to be noted that the best conditions involved the use of catalyst 94 together with an ionic liquid (l-butyl-3-methyl-l//-imidazolium bromide BmimBr). However, although excellent yields were obtained for a set of different substrates tested, the enantioselectivities remained in rather low values. 

Cascades Initiated by Conjugate Friedel-Crafts Reaction... 

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... 

Scheme 7.43 Cascade conjugate Friedel-Crafts/electrophilic amination using a,P-disubstituted aldehydes.

Scheme 2.113 Asymmetric conjugate Friedel-Crafts addition of pyrrols to enals...

Scheme 14.7 Catalytic asymmetric conjugate Friedel-Crafts-type addition of indoles to enones catalysed by primaiy amine Cinchona catalysts, and reaction transition state.

Conjugate Friedel-Crafts Acids (HBr AIBr3, HCkAICb, Etc.)... 

When alkenes are used as the alkylating agent, the catalysts are metal halides with hydrogen halide or water as cocatalyst or protic acids. Similarly, conjugate Friedel-Crafts acids such as HAICI4 or HBF4 show catalytic activity only in the presence of excess HCl or HF (eq. 59). The transformation is usually assumed to take place with the participation of carbocations formed through protonation of alkenes by proton acids. 

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