Conjugate Friedel Crafts Alkylation Reaction

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 

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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. 

In the case of indole itself, the conjugate addition product was formed in excellent yield (97%) and in good enantiomeric excess (59% ee). According to the authors, this was the first report of the use of a chiral nonracemic 2,2 -bipyridyl ligand in catalytic and enantioselective Friedel-Crafts alkylation reactions. 

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. 

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],... 

So far, most of the reactions presented in the book that are useful in synthesis have made C-O, C-N, or C-halogen bonds and only a few (Wittig, Friedel-Crafts, and reactions of cyanides and alkynes) make C-C bonds. This limitation has severely restricted the syntheses that we can discuss in this chapter. This is by design as we wanted to establish the idea of synthesis before coming to more complicated chemistry. The next four chapters introduce the main C-C bond-forming reactions in the chemistry of enols and enolates. You met these valuable intermediates in Chapter 21 but now you are about to see how they can be alkylated and acylated and how they add directly to aldehydes and ketones and how they do conjugate addition to unsaturated carbonyl compounds. Then in Chapter 30 we return to a more general discussion of synthesis and develop a new approach in the style of the last synthesis in this chapter. 

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. 

The Friedel-Crafts alkylation is one of the oldest synthetic methodologies known. The catalytic asymmetric version of the reaction [311] enables the preparation of important chiral building blocks. Electron-rich aromatic and heteroaromatic compounds have been productively used in organocatalyzed enantioselective inter- and intramolecular Friedel-Craft-[312] type conjugate additions over different Michael acceptors such as, a,p-unsaturated aldehydes, a,P-unsaturated ketones, nitroole-fins, and a,p-unsaturated acyl phosphonates. 

Furans represent an important class of electron-rich heterocycles which are useful intermediates in synthetic chemistry and are broadly found as structural motifs of many natural products and pharmaceutically important substances [333]. Since furans are generally less nucleophilic than indoles and pyrroles, their catalytic enantioselective Friedel-Crafts-type conjugate addition has been much less developed so far. Very recently Harada et al. have developed a catalytic system able to achieve good enantioselectivities in the Friedel-Crafts alkylation of electron-rich furans with acychc a,p-unsaturated ketones [334]. As depicted in Scheme 2.117, a//o-threonine-derived oxazaborolidinone 190 (10 mol%) in the presence of V,V-dimethyl benzylamine (10 mol%) as cocatalyst in ether at -40°C, is an efficient catalytic system for the reaction affording the corresponding functionalized furans with good yields and enantioselectivities. 

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