Ketone synthesis by Friedel Crafts reaction

Ketone synthesis by Friedel-Crafts reaction, 12, 16, 62 Knoevenagel reaction, 10, 58... 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel-Crafts reaction, thiadiazole acetic acid derivatives and halo ketones via the Amdt-Eistert synthesis and carbinols by hydride reduction (68AHC(9)107). The dialkylcadmium conversion of acid chlorides into ketones fails in the... 

Tetrahydrobenzo[6]thiophen-4-one (103) may be prepared from y-(2-thienyl)butyric acid by cyclization with phosphoric acid854 or by Friedel-Crafts cyclization of the corresponding acid chloride.194, 355.358 j s 5-methyl,357 2-ethyl,194 2-isopropyl,358 2- and 3-tert-butyl,359 2,3-dimethyl,360 2-ethyl-3-methyl,360 and 2-bromo 354 derivatives and diethyl 4,5,6,7-tetrahydrobenzo[6]thiophene-4,5-di-carboxylate861 may be prepared similarly. 4,5,6,7-Tetrahydrobenzo-[6]thiophen-7-one (104)357 362,863 and its 5- and 6-methyl 357 and 2-chloro 362 derivatives are obtained from the appropriately substituted y-(3-thienyl)butyric acid, A recent patent 364 describes the vapor phase cyclization of y-(2-thienyl)butyric acid to 103. Ketones (103 and 104) are useful intermediates for the synthesis of 4- and 7-substituted benzo[6]thiophenes, respectively their reactions are discussed in Section VI, B, 4. 

A stereospecific synthesis of (S)-(—)-cathinone that utilizes the Friedel-Crafts reaction has been described (3/7). Reaction of the acid chloride obtained from /V-(methoxycarbonyl)-L-alanine (10) in benzene by A1C13 catalysis provided the N-protected a-amino ketone 11 with retention of chiralty 11 was deprotected by hydrolysis with potassium hydroxide. A more recently published method (408)... 

Shudo and coworkers have reported that 0,0-diprotonated nitroalkenes (16) behave as novel electrophilic species which can efficiently alkylate aromatics such as benzene, anisole, chlorobenzene, naphthalene, etc. under extremely mild conditions (equation 28). The reaction enables the synthesis of a-arylated ketones (17) which are difficult to synthesize by conventional Friedel-Crafts reactions. 

Ketone (23) is clearly made by a Friedel-Crafts reaction, but how are we to make the starting diol (24) Looking back at our guidelines for aromatic synthesis (Chapter 3) we find that a good strategy is to use available starting materials with such ortho substitution patterns already established and an obvious candidate here is salicylic acid (25). 

Both methods have been used to make adrenaline analogues. The broncho-dilator Metaproterenol (34) can be made from the a-keto aldehyde (3S) by familiar methods. Our new a-oxidation makes aryl ketone (36) a suitable starting material, though the hydroxyl groups will need protection during the oxidation.The strategy of a-oxidation appeals here because of the easy synthesis of ArCOMe by the Friedel-Crafts reaction. 

An aqueous Friedel-Crafts reaction has also been used in polymer synthesis. The acid-catalyzed polymerization of benzylic alcohol and fluoride functionality in monomeric and polymeric fluorenes was investigated in both organic and aqueous reaction media. Polymeric products are consistent with the generation of benzylic cations that participate in electrophilic aromatic substitution reactions. Similar reactions occurred in a water-insoluble Kraft pine lignin by treatment with aqueous acid. A Bisphenol A-type epoxy resin is readily emulsified in aqueous medium with an ethylene oxide adduct to a Friedel-Crafts reaction product of styrene and 4-(4-cumyl)phenol as emulsifier.Electrophilic substitution reaction of indoles with various aldehydes and ketones proceeded smoothly in water using the hexamethylenetetramine-bromine complex to afford the corresponding Z A(indolyl)methanes in excellent yields.InFs-catalyzed electrophilic substitution reactions of indoles with aldehydes and ketones are carried out in water.Enzymatic Friedel-Crafts-type electrophilic substitution reactions have been reported. ... 

Improved method for preparation of 173 is reported by Wang and Gu (Scheme 12.29). It comprises of four-step synthesis of 179, conversion of acid into 5-2-(5-fluoropyrimidin-4-yl)propionyl chloride, Friedel-Crafts reaction to obtain ketone 180, and the reaction with 1-methyl-17/-1,2,4-triazole under basic condition. 

The approach to haplophytine proposed by Fukuyama and Tokuyama et al. did not rely on the synthesis of aspidophytine previously reported [75]. One of the main synthetic problems was the connection of the left-hand segment to the indole moiety of aspidophytine. Retrosynthetically, Fischer indole synthesis of the fully elaborated left-hand fragment 186 and the tricychc ketone 187 gave haplophytine. 186 was generated through oxidative skeletal rearrangement from precursor 188, which was accessible from indole 189 by Friedel-Crafts alkylation. Optically active ketone 187 was assembled through a stereoselective intramolecular Mannich reaction from aldehyde 190 (Scheme 33). 

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