Conjugate Friedel-Crafts Reactions

Several organocatalytic variants for the conjugate addition of electron-rich aromatic substrates to electron-deficient olefins have been reported in the last few years which apply the concept of activation of the electrophile by hydrogen-bonding interactions. In this context, chiral bifunctional thiourea ent-91 has been employed as an excellent promoter for the enantioselective conjugate 

The use of iV-alkyl indoles can therefore be considered as a more challenging situation in this reaction because these compounds are unable to interact with a secondary Bronsted basic site present at the structure of the bifunctional 

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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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. 

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

Cascades Initiated by Conjugate Friedel-Crafts Reaction... 

In contrast to the saturated azlactones, the Friedel-Crafts reaction of 2-substituted-4-arylidene-5-oxazolones is quite complex and may follow several different courses, often concurrently, depending on both reaction conditions and structural variations in the arylidene ring. This behavior is readily interpreted in terms of the a,)S-unsaturated carbonyl moiety and the cross-conjugated system containing nitrogen, both of which provide potential reaction sites in addition to the lactone carbonyl group. The reaction has been investigated " ... 

Asides from the application of imines on conjugate addition reactions, Deng [87, 88] reported the first asymmetric chiral thiourea catalyzed Friedel-Crafts reaction of indoles with iV-tosyl imines (Scheme 35). The reaction was receptive to various aromatic, heteroaromatic, and aliphatic imines in good yield and high enantioselec-tivity (Scheme 36). 

Enantiomerically pure chloro-ester 26 was needed for an investigation into the stereochemistry of the Friedel-Crafts reaction. Disconnecting the ester we reach the one piece of carbon skeleton and see that it has a 1,3-diX relationship 27. However we need a carbonyl group and an ester 28 should ensure conjugate addition of chloride to 29. 

There are few studies on the metal triflate-catalyzed addition of pyrroles to a, 1-unsaturated compounds <2001 AGE 160, 2001TL8063>. The Friedel-Crafts reaction of homochiral pyrrole derivatives 450 with a,P-unsatu-rated esters catalyzed by metal triflates furnished conjugated addition products 451 in good yields without racemiza-tion (Equation 107) <2004S2574>. The addition worked regioselectively at C-5 of pyrrole. The best yields were obtained by using yttrium triflate and methyl 4-phenyl-2-oxobut-3-enoate. The diastereoisomers were separated by column chromatography. 

You may be surprised that thiophene is the least reactive of the three but this is because the p orbital of the lone pair of electrons on sulfur that conjugates with the ring is a 3p orbital rather than the 2p orbital of N or O, so overlap with the 2p orbitals on carbon is less good. Both furan and thiophene undergo more or less normal Friedel-Crafts reactions though the less reactive anhydrides are used instead of acid chlorides, and weaker Lewis acids than AICI3 are preferred. 

The electrophilicity index also accounts for the electrophilic activation/deactivation effects promoted by EW and electron-releasing substituents even beyond the case of cycloaddition processes. These effects are assessed as responses at the active site of the molecules. The empirical Hammett-like relationships found between the global and local electrophilicity indexes and the reaction rate coefficients correctly account for the substrate selectivity in Friedel-Crafts reactions, the reactivity of carbenium ions, the hydrolysis of esters, the reactivity at the carbon-carbon double bonds in conjugated Michael additions, the philicity pattern of carbenes and the superelectrophilicity of nitronium, oxonium and carboxonium ions. This last application is a very promising area of application. The enhanced electrophilicity pattern in these series results from... 

The application of the aliphatic Friedel-Crafts reaction (chapter 5) to alkynes is a stereoselective approach to vinyl-lithiums that forms a bridge between the Shapiro reaction and the next section-hydrometallation. Acid chlorides 64 react with alkynes under Lewis acid catalysis to give E-P-chloroenones -65 stereoselectively. The chlorine can be replaced by more reactive iodine by conjugate substitution.11... 

The corresponding ketones 76 can be made by aliphatic Friedel-Crafts reactions between an acid chloride and acetylene using A1C13 as catalyst. Under these conditions chloride adds to the acetylenic ketone to give the P-chloroenone 77 directly. These compounds are converted into the sulfides 78 by conjugate substitution13 and are used as vinyl cation equivalents in the next section. 

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