Conjugate Friedel-Crafts alkylation

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.

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... 

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. 

The elfectiveness of imidazolidinone of type 11 was confirmed by successful application to a broad range of chemical transformations, including cycloadditions, conjugate additions, Friedel-Crafts alkylations, Mukaiyama-Michael additions, hydrogenations, cyclopropanations, and epoxidations. A summary of these enantio-selective iminium catalyzed processes is provided by reaction subclass. 

We have found that intramolecular Friedel-Crafts alkylations of conjugated dienones permit the efficient preparation of functionalized hydrophenanthrenes (Equation 5.1).21 Since this represents a new strategy for the synthesis of 6,6,6-fused tricycles, we sought to demonstrate its utility through the total syntheses of miltirone (56) and two closely related diterpenoids sageone (57), which possesses significant antiviral activity,22 and arucadiol (58), 23... 

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. 

As indicated from computational studies, the catalyst-activated iminium ion MM3-2 was expected to form with only the (E)-conformation to avoid nonbonding interactions between the substrate double bond and the gem-dimethyl substituents on the catalyst framework. In addition, the benzyl group of the imidazolidinone moiety should effectively shield the iminium-ion Si-face, leaving the Re-face exposed for enantioselective bond formation. The efficiency of chiral amine 1 in iminium catalysis was demonstrated by its successful application in several transformations such as enantioselective Diels-Alder reactions [6], nitrone additions [12], and Friedel-Crafts alkylations of pyrrole nucleophiles [13]. However, diminished reactivity was observed when indole and furan heteroaromatics where used for similar conjugate additions, causing the MacMillan group to embark upon studies to identify a more reactive and versatile amine catalyst. This led ultimately to the discovery of the second-generation imidazolidinone catalyst 3 (Fig. 3.1, bottom) [14],... 

We see here a situation exactly analogous to one we have encountered several times before in 1,2- and 1,4-addition to conjugated dienes (Sec. 8.22), in Friedel-Crafts alkylation of toluene (Sec. 12.11), and in sulfonation of phenols (Problem 24.13, p. 803). At low temperatures the controlling factor is rate of reaction, at high temperatures, position of equilibrium,... 

We can kill two birds with one stone here both problems common to the Friedel-Crafts alkylation are solved when the acylation is used instead. Firstly, the product of the acylation is a ketone the reaction introduces a deactivating, electron-withdrawing, conjugating carbonyl group to the ring, so the product is less reactive than the starting material. Reaction will stop cleanly after one acylation. Here s benzene reacting with propionyl chloride. 

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. 

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