Friedel-Crafts-like reactions

The statine-like moiety in one of the first drugs, saquinovir (23-8), comprises a transition state mimic for the cleavage of phenylalanylprolyl and tyrosylprolyl sequences. Constmction starts with the protection of the amino group of phenylalanine as its phthaloyl derivative (Phth) by reaction with phthalic anhydride this is then converted to acid chloride. The chain is then extended by one carbon using a Friedel-Crafts-like reaction. The required reagent (21-2) is prepared by reaction of the enolate obtained from the /7A-silyl ether (21-3) of glyoxylic acid and lithio... 

This synthesis of 1,2,3,4-tetraphenylnaphthalene (7) demonstrates the transient existence of benzyne (5), a hydrocarbon that has not been isolated as such. The precursor, diphenyliodonium-2-carboxylate (4), is heated in an inert solvent to a temperature at which it decomposes to benzyne, iodobenzene, and carbon dioxide in the presence of tetraphenylcyclo-pentadienone (6) as trapping agent. The preparation of the precursor (4) illustrates oxidation of a derivative of iodobenzene to an iodonium salt (2) and the Friedel-Crafts-like reaction of the substance with benzene to form the diphenyliodonium salt (3). Neutralization with ammoniuim hydroxide then liberates the precursor, inner salt (4), which, when obtained by crystallization from water, is the monohydrate. 

Figure 2.52 In a Friedel-Crafts-like reaction, the hexachlorofullerene CeoCis may be converted into a pentaarylated product.

Scheme 4 Derivatization of squaric acid by Friedel-Crafts-like reaction an example [46]...

A chalcogen spacer at a boron atom can be added by a Friedel-Crafts-like reaction. To do this, elemental sulphur or the corresponding chalcogen chloride is used, with aluminium(III)... 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Figure 16.10 Biosynthesis of phylloquinone (vitamin K-j) from 1,4-dihydroxynaphthoic acid. The key step that joins the 20-carbon phytyl side chain to the aromatic ring is a Friedel-Crafts-like electrophilic substitution reaction.

The thermodynamic stabilities of phenonium ions relative to the parent have been determined in the gas phase by measuring the position of the equilibrium between (46) and (47)7 The results followed a Yukawa-Tsuno relationship with a p value of -12.6 and an r+ value of 0.62, the general behaviour being more like benzenium ions than benzyl cations, with tt-delocalization less effective than in benzyl cations. A theoretical study of the elimination of molecular H2 from the benzenium ion C6H7+ shows that the barrier to this process appears to be very small.The gas-phase Friedel-Crafts alkylation reaction of CF3C6L6+ (L = H or D) with C2L4 is accompanied by isotopic scrambling, which has been used to elucidate the mechanism of this process. A theoretical calculation shows that the lifetime of triplet phenyl cation must be very short. ... 

In 1977, an article from the authors laboratories [9] reported an TiCV mediated coupling reaction of 1-alkoxy-l-siloxy-cyclopropane with aldehydes (Scheme 1), in which the intermediate formation of a titanium homoenolate (path b) was postulated instead of a then-more-likely Friedel-Crafts-like mechanism (path a). This finding some years later led to the isolation of the first stable metal homoenolate [10] that exhibits considerable nucleophilic reactivity toward (external) electrophiles. Although the metal-carbon bond in this titanium complex is essentially covalent, such titanium species underwent ready nucleophilic addition onto carbonyl compounds to give 4-hydroxy esters in good yield. Since then a number of characterizable metal homoenolates have been prepared from siloxycyclopropanes [11], The repertoire of metal homoenolate reactions now covers most of the standard reaction types ranging from simple... 

For the purposes of this review, we include probe molecules that can be either directly adsorbed or formed in situ. Examples of the latter case are carbenium ions and related electrophilic species. We will also consider several important heteroatom-substituted carbenium ions and heteroatom analogs of carbenium ions. Acylium ions are the intermediates in Friedel-Crafts acylation reactions (96). The most simple, stable acylium ion is the acetylium ion, 1, and others are formally derived by replacing the methyl group with other R groups. Oxonium ions, formed by alkylation of an ether, resemble carbenium ions but are in fact onium ions in terms of their structures. Their stabilization requires strongly acidic media, and like carbenium ions, oxonium ions have been proposed as intermediates in a... 

The Robinson annelation is by no means the only ionic reaction that makes six-membered rings. Six-membered rings form easily so trapping a Nazarov intermediate (chapter 35) makes good sense. The Friedel-Crafts-like disconnection 18 suggests a most unlikely cation 19 until we realise that it would be formed in the Nazarov cyclisation of the dienone 20 whose synthesis is discussed in the workbook. 

Acetylenes are also reported to undergo intramolecular Friedel-Crafts-like alkylation as shown in Eq. (204) [489]. The reaction occurred regioselectively with respect to both epoxide and acetylene moieties and this was rationalized by the chelation structure involving the titanium metal as depicted. The facile preparation of a func-... 

Carbonyl groups form complexes or intermediates with Lewis acids like AICI3, BF3, and SnCl4. For example, in the Friedel-Crafts acylation reaction in nonpolar solvents, an aluminum chloride complex of an acid chloride is often the acylating agent. Because of the basicity of ketones, the products of the acylation reaction are also complexes. For more detail on electrophilic aromatic substitution, see Section 7. 

The comparison of results obtained with different methods could be extended to other classes of reactions. There is a considerable wealth of results for several classes of reactions with simple mechanisms, like Sjv2, S l, ET reactions, which are the favourite examples selected by theoreticians to test new models. There is a rapid increase in the number of reactions for which a comparison among different methods is possible, and there is also an increase in the complexity of the studied mechanisms. We quote, as examples, Menshutkin and Friedel-Craft s reactions, Claisen s rearrangement, Diels-Alder s and other pericyclic reactions. 

Microencapsulated Sc(OTf)3 has shown considerable promise for both batch and flow reactions in those procedures in which the reaction was recirculated through columns containing the reagent. This reagent was found to be more reactive than the monomeric Lewis acid. One example is the TMS-mediated Michael reaction shown in Figure 3.25. Microencapsulated Sc(OTf)3 was also found to be useful for Mannich reactions, Michael additions, and Friedel-Crafts—like acylations [51]. 

Besides only as green reaction media, ionic liquids as dual green solvents and catalysts are also widely used in acylation reactions, especially C-acylation. Benzophenone and its derivatives are important fine chemicals or intermediates in dyes, pharmaceuticals, and other chemical industries. Li et al. have studied the Friedel-Crafts acylation reactions using ionic liquids like BMlMCl-FeClj, BMIMCI-AICI3, and BMIMCl-ZnCl as dual catalyst-solvent to synthesize benzophenone and its derivatives. They found that BMIMCl-FeCl3 showed much higher catalytic activity than that observed for the other two ionic liquids, and in conventional organic... 

---