Regioselectivity Friedel-Crafts alkylation

S. L. Schreiber et al. carried out the total synthesis of the potent cytotoxin (+)-tri-0-methyl dynemicin A methyl ester. The key step was a regioselective Friedel-Crafts alkylation of an extremely sensitive aromatic enediyne with 3-bromo-4,7-dimethoxyphthalide. The coupling of these two fragments took place in the presence of silver triflate at 0 °C in 1 minute, and after methylation, gave a 1 1 mixture of diastereomers in 57% yield. 

Hoseini-Sarvari M and Parhizgar G. Regioselective Friedel-Crafts alkylation of indoles with epoxides using nano MgO. Green Chem. Lett. Rev. 2012 5(3) 439-449. 

Other methods for the regioselective SN2-opening of vinyloxiranes include intramolecular enolate addition for formation of cyclohexane systems [135, 136] and Friedel-Crafts alkylations [49, 137, 138]. 

Figure 17.50 shows how a benzyl alkoxide can be reduced in this way. Here, the reduction is part of the synthesis of an alkylated aromatic system. The target molecule contains a primary alkyl group. It is not possible to introduce this alkyl group by way of a Friedel-Crafts alkylation into the ortho-position of anisole in a regioselective fashion and without rearrangements (see Section 5.2.5). 

Phenols are such good nucleophiles that protonated carbonyl compounds functionalize two phenol molecules. The first phenol molecule is attacked in an Ar-SE reaction by the carboxonium ion formed in an equilibrium reaction. Subsequently, the second equivalent of phenol becomes the substrate of a Friedel-Crafts alkylation. The electrophile is the benzyl cation that is formed from the initially obtained benzyl alcohol and the acid. Protonated acetone is only a weak electrophile for electronic and steric reasons It contains two electron-donating and relatively large methyl groups on the electrophilic C atom. Therefore, it attacks phenol regioselectively in the para and not at all in the less favored ortho position (Figure 5.25). The benzyl cation formed there-... 

The f-butylated naphthalene derivative (18 equation 49) is of interest as an intermediate for the synthesis of fungicides. Tetrahydronaphthalene derivatives, such as (20), have been evaluated as antifertility agents. Sugita et al. have studied the AlCb-catalyzed Friedel-Crafts alkylation of benzene with l-phenyl-2-propanol and 2-phenyl-1-propanol in the presence of additives, such as CuCb, CU2CI2 and decalin. Highly regioselective formation of 1,1-diphenylpropane was observed with Cu or Cu chloride as the additive. Some pertinent results of synthetic value are shown in Scheme 5. The addition of decalin diminished the alkylation reaction to give Ae reduction product 1-phenylpropane. 

The next step is a simple electrophilic attack by another molecule of formaldehyde on the alkene - in other words a simple Prins reaction 215 - showing the regioselectivity we expect to produce the secondary benzylic cation 216. The second molecule of formaldehyde has added onto the opposite side from the first. The resulting cation is perfectly placed for an intramolecular Friedel-Crafts alkylation 216 of the benzene ring. This is again a stereoselective reaction giving the more stable anti diastereoisomer 214. This sequence involves three successive C-C bondforming reactions and the stereochemistry is simply controlled by the preference for the more stable anti product. 

A simple example of electrophilic substitution is the VUsmeier formylation with DMF and POCI3, showing that indole has similar reactivity, if different regioselectivity, to pyrrole. If the 3-position is blocked, reaction occurs at the 2-position and this at first seems to suggest that it is aU right after all to take the electrons the wrong way round the five-membered ring. This intramolecular Friedel—Crafts alkylation is an example. 

Limited alkyl groups can be regioselectively introduced on the corannulene core by Friedel-Crafts alkylation. For example, five sterically congested ieri-butyl... 

Before explaining the previous data, it is important to understand why 54 is formed in the Friedel-Crafts alkylation reaction. This means that the reactivity of benzene derivatives must be addressed. If 54 is formed by a reaction of 53, then 53 must react with the intermediate carbocation more quickly than benzene. Why does 53 react more quickly than benzene In addition, this discussion must address the question of why polyalkylation is a problem but polyacylation is not. The answers to these questions will also explain the regioselectivity of the reaction. 

In nature, the alkylation of aromatic rings most commonly proceeds using 5-adenosyhnethionine ( SAM, 31a) as the source of an electrophilic methyl group. Such alkylations are catalyzed by C-methyltransferase enzymes and are analogous to Friedel-Crafts alkylations. Two C-methyl-transferases, NovO and CouO (from Streptomyces spheroides and Streptomyces rishiriensis, respectively), have been expressed in recombinant E. coli and have been shown to have a synthetically useful substrate scope. Not only are they able to catalyze the regioselective alkylation of various coumarins 32 (X=0), 2-quinolones 32 (X=NH), and naphthalenediols 34-36, but in addition, they are able to accept nonnatural cofactors 31b-f in place of SAM and so can transfer various alkyl groups other than methyl to the substrates (Scheme 32.4) [26]. 

Representative Electrophilic Aromatic Substitution Reactions of Benzene 457 Mechanistic Principles of Electrophilic Aromatic Substitution 458 Nitration of Benzene 459 Sulfonation of Benzene 461 Halogenation of Benzene 462 Biosynthetic Halogenation 464 Friedel-Crafts Alkylation of Benzene Friedel-Crafts Acylation of Benzene Synthesis of Alkylbenzenes by Acylation-Reduction 469 Rate and Regioselectivity in Electrophilic Aromatic Substitution 470 Rate and Regioselectivity in the Nitration ofToluene 472... 

Among the wide variety of organic reactions in which zeolites have been employed as catalysts, may be emphasized the transformations of aromatic hydrocarbons of importance in petrochemistry, and in the synthesis of intermediates for pharmaceutical or fragrance products.5 In particular, Friede 1-Crafts acylation and alkylation over zeolites have been widely used for the synthesis of fine chemicals.6 Insights into the mechanism of aromatic acylation over zeolites have been disclosed.7 The production of ethylbenzene from benzene and ethylene, catalyzed by HZSM-5 zeolite and developed by the Mobil-Badger Company, was the first commercialized industrial process for aromatic alkylation over zeolites.8 Other typical examples of zeolite-mediated Friedel-Crafts reactions are the regioselective formation of p-xylene by alkylation of toluene with methanol over HZSM-5,9 or the regioselective p-acylation of toluene with acetic anhydride over HBEA zeolites.10 In both transformations, the p-isomers are obtained in nearly quantitative yield. 

Gold-catalyzed direct C-H functionalizations enable the formation of polyalkylated arenes under mild conditions. In many cases, branched products are obtained. Two mechanisms are thought to operate with electron-rich arenes, an S si2-type mechanism via Au(lll) leads to the linear product. The branched product is obtained via a Friedel-Craft-type alkylation. A silver salt is often added and is believed to generate a more electrophilic Au(m) species. Often regioselectivities are poor and symmetric arenes are employed. Intramolecular variants as well as Michael additions are also known (Equations (72)-(74)).71,71a,71b... 

As mentioned before, alkyl radicals and acyl radicals have a nucleophilic character therefore, radical alkylation and acylation of aromatics shows the opposite reactivity and selectivity to polar alkylation and acylation with the Friedel-Crafts reaction. Thus, alkyl radicals and acyl radicals do not react with anisole, but may react with pyridine. Eq. 5.1 shows the reaction of an alkyl radical with y-picoline (1). The nucleophilic alkyl radical reacts at the 2-position of y-picoline (1), where electron density is lower than that of the 3-position. So, 2-alkyl-4-methylpyridine (2) is obtained with complete regioselectivity. When pyridine is used instead of y-picoline, a mixture of 2-alkylpyridine and 4-alkylpyridine is obtained. Generally, radical alkylation or radical acylation onto aromatics is not a radical chain reaction, since it is just a substitution reaction of a hydrogen atom of aromatics by an alkyl radical or an acyl radical through the addition-elimination reaction. Therefore, the intermediate adduct radical (a complex) must be rearomatized to form a product and a hydrogen atom (or H+ and e ). Thus, this type of reactions proceeds effectively under oxidative conditions [1-6]. 

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