Friedel-Crafts synthesis with

The Friedel-Crafts synthesis with acyl chlorides and anhydrides can be applied to all aromatic hydrocarbons and to many heterocyclic compounds, in particular to thiophene, furan, and pyrrol derivatives. Pyridine does not react,531,532 and hydrocarbons carrying electron-attracting substituents react with difficulty or not at all. 

The Friedel-Crafts synthesis with cyclic ethers such as oxirane has been discussed on page 937. 

Friedel-Crafts synthesis with thioacid chlorides... 

Synthesis This route has been carried out successfully (Rec. Trav. Chem., 1958, 77, 854). Note that no AICI3 is needed for Friedel-Crafts alkylation with easily formed t-alkyl compounds. 

Cydopentane reagents used in synthesis are usually derived from cyclopentanone (R.A. Ellison, 1973). Classically they are made by base-catalyzed intramolecular aldol or ester condensations (see also p. 55). An important example is 2-methylcydopentane-l,3-dione. It is synthesized by intramolecular acylation of diethyl propionylsucdnate dianion followed by saponification and decarboxylation. This cyclization only worked with potassium t-butoxide in boiling xylene (R. Bucourt, 1965). Faster routes to this diketone start with succinic acid or its anhydride. A Friedel-Crafts acylation with 2-acetoxy-2-butene in nitrobenzene or with pro-pionyl chloride in nitromethane leads to acylated adducts, which are deacylated in aqueous acids (V.J. Grenda, 1967 L.E. Schick, 1969). A new promising route to substituted cyclopent-2-enones makes use of intermediate 5-nitro-l,3-diones (D. Seebach, 1977). 

An ingenious synthesis of 1-arylisoindolcs has been developed by Vebor and Lwowski, based upon the reaction of an o-phthalimido-methylbenzophenone (41, R = aryl) with hydrazine (Table IV). The benzophenone is prepared by a Friedel-Crafts reaction with o-phthalimidomethylbenzoyl chloride (40). The mechanism of isoindole formation can be represented sehematically by a sequence involving attack by hydrazine at the imide to give the ring-opened hj drazide (42), followed by cyclization to phthalazine-l,4-dione (44) with displacement of the o-aminomethylbenzophenone (43). Intramolecular condensation of the latter can lead, via the isoindolenine... 

Based on petrochemicals, linear alkyl benzene sulfonates (LAS) are the most important surfactants. First description can be found in patents from the mid-1930s [2] using Fischer-Tropsch synthesis and Friedel-Crafts reactions. With the beginning of the 1950s the importance of the class of surfactants rose. The main use is in household and cleaning products. 

Friedel-Crafts alkylations are among the most important reactions in organic synthesis. Solid acid catalysts have advantages in ease of product recovery, reduced waste streams, and reduction in corrosion and toxicity. In the past, people have used (pillared) clays (18), heteropolyacids (19) and zeohtes (20) for Friedel-Craft alkylations, with mixed success. Problems included poor catalyst stabihty and low activity. Benzylation of benzene using benzyl chloride is interesting for the preparation of substitutes of polychlorobenzene in the apphcation of dielectrics. The performance of Si-TUD-1 with different heteroatoms (Fe, Ga, Sn and Ti) was evaluated, and different levels of Fe inside Si-TUD-1 (denoted Fei, Fe2, Fes and Feio) were evaluated (21). The synthesis procedure of these materials was described in detail elsewhere (22). 

B. The Phthaleins.—If two molecules of a phenol and one molecule of phthalic anhydride are caused to interact under the conditions which prevail during the Friedel-Crafts synthesis (Chap. IX. p. 342), the tendency of the ketone first formed to combine with a second molecule of the phenol outweighs condensation to the anthraquinone derivative in this way are formed the phthaleins, discovered by Baeyer in 1871. This process may be discussed by taking phenolphthalein as an example. 

Regardless of whether the Pd-catalyzed coupling or alkyne metathesis is utilized to make PAEs, the critical step is the synthesis of the diiodoarene monomers. In this section some of the more interesting syntheses are showcased. The synthesis of dipropynyldi-tert-butylnaphthalene is shown in Scheme 5. Starting from naphthalene, Friedel-Crafts alkylation with 2-chloro-2-methylbutane gives a mixture of two di-tert-butylnaphthalenes that are separated by crystallization. Iodination of the correct isomer is followed by a Pd-catalyzed coupling of propyne to the diiodide to give the desired l,5-dipropynyl-3,8-di-tert-butyl-naphthalene [56] ready for ADIMET. 

Aminophenols from anilines, 35, 2 Anhydrides of aliphatic dibasic acids, Friedel-Crafts reaction with, 5, 5 Anion-assisted sigmatropic rearrangements, 43, 2 Anthracene homologs, synthesis of, 1, 6 Anti-Markownikoff hydration of alkenes, 13, 1... 

The synthesis of the right-hand fragment of ziprasidone started with a Wolff-Kishner reduction of isatin 43 to give the oxmdole 44 (Scheme 14). Friedel-Crafts acylation with chloroacetyl chloride afforded aryl ketone 45, which was reduced with triethylsilane in trifluoroacetic acid to the phenethyl chloride 46. The two fragments were joined by alkylation of 40 with 46 in the presence of Nal and Na2CO3 to give ziprasidone (4) in low yield. The yield of the coupling step was improved dramatically when the reaction was conducted in water (Scheme 15). 

An alternative focus based on known antitumor activity of adriamycin-type systems stimulated the synthesis of the aza-anthraquinones 599 and 600 (Scheme 177) (84CC897). Thus, synergistic chloro-oxazoline directed metalation of 597 with methyllithium followed by treatment with 2,5-dimethoxybenzaldehyde and acid-promoted cyclization provided the lactone 598. Radical bromination and base-induced hydrolysis gave an intermediate keto acid which, upon Friedel-Crafts cyclization with methanesulfonic acid, led to the aza-anthraquinone 599 in modest yield. The azanaphthacene dione 600 was prepared by an analogous series of reactions starting with 597. 

The synthesis of rofecoxib can be achieved by several different routes (Drugs Fut., 1998). A highly efficient synthesis for rofecoxib was recently described (Therien et al., 2001). As illustrated in Scheme 79, acetophenon (i) is prepared according to the literature, by Friedel-Crafts acylation with thioanisole. Oxidation with MMPP (magnesium monoperoxyphthalate hexahydrate) affords the sulfone (ii), which is reacted with bromine in chloroform in the presence of a trace amount of AICI3, to give (iii). Bromoketone (iii) is than coupled and cyclized in a second step, one-pot procedure with phenylacetic acid. Firstly, the mixture of bromoacetophenone (iii) and phenylacetic acid in acetonitrile is treated with... 

An approach to the synthesis of a prostaglandin intermediate began with 2-furanacetonitrile (71JOC3191). Friedel-Crafts acylation with pimelic half-ester acid chloride and Wolff-Kishner reduction of the product with concomitant hydrolysis of the nitrile group to acid yielded the diester (78) on diazomethane treatment. Ring opening of the furan by a standard procedure yielded a diketo diester (79) which on refluxing in aqueous methanolic potassium carbonate underwent hydrolysis and cyclization to the diacid (80 Scheme 19). 

The synthesis of fluotrimazole starts from m-xylene. Peroxide catalyzed perchlorination converts this to m-trichloromethyl-benzo-trichloride. m-Trichloromethyl-benzotrifluoride is then obtained by selective chlorine/fluorine exchange. This key product is also readily accessible on a technical scale by conproportionation of the two corresponding m-trihalomethyl-benzotrihalogenides. Friedel-Crafts reaction with benzene leads to trifluoromethyl-tritylchloride, which reacts smoothly with 1,2,4-triazole in polar solvents to give fluotrimazole. 

At the time the chemistry of (OC)9Co3CCO+PF6 was being developed (27, SO), another route to this novel acylium ion was found in these laboratories (31, 32). This discovery was a result of our intention to adapt the Friedel-Crafts synthesis of benzylidynetricobalt nonacarbonyl complexes of Dolby and Robinson (15) to the preparation of alkyl derivatives of methylidynetricobalt nonacarbonyl, whose general preparation was not well in hand. The reaction chosen for investigation was the aluminum chloride-induced interaction of tetraalkyltin compounds with ClCCo3(CO)9 In analogy to a known ketone synthesis (33),... 

The first step in the Friedel-Crafts synthesis is formation of an electrophile capable of electrophilic substitution in the aromatic ring. Such an electrophile (or cation) is generated from an alkyl halide by its reaction with a Lewis acid, in this case boron trifluoride. Boron trifluoride... 

These diketones with different aryl groups at the ends were needed for a photochemical experiment. The compounds could be prepared by successive Friedel-Crafts acylations with a diacid dichloride but the yields were poor. Why is this a bad method Suggest a better synthesis. 

There are two main synthetic routes to naphthalene the Haworth synthesis and a Diels-Alder approach. In the Haworth synthesis (Scheme 12.1), benzene is reacted under Friedel-Crafts conditions with succinic anhydride (butanedioic anhydride) to produce 4-oxo-4-phenylbutanoic acid, which is reduced with either amalgamated zinc and HCl (the Clemmensen reduction) or hydrazine, ethane-1,2-diol and potassium hydroxide (the Wolff-Kischner reaction) to 4-phenylbutanoic acid. Ring closure is achieved by heating in polyphosphoric acid (PPA). The product is 1-tetraione and reduction of the carbonyl group then gives 1,2,3,4-tetrahydronaphthalene (tetralin). Aromatization is achieved by dehydrogenation over a palladium catalyst. 

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