Ketones, 2-arylated Friedel-Crafts reaction

Another version of the Friedel-Crafts reaction uses acyl halides instead of alkyl halides and yields aryl ketones... 

Answer Ester disconnection gives a tertiary alcohol (4S), Of the three possible Grignard disconnections, (a) is most helpful as it requires the Mannich product (49) of an aryl ketone (50) available by the Friedel-Crafts reaction. 

FRIEDEL-CRAFTS REACTION. Aluminum chloride anhydrous, introduced by Friedcl and Crafts, is used as reagent, generally in CS solution to avoid rise in temperature, for the preparation of (I) aryl-alkyl hydrocarbons, (2) di- and triphenylmethane and derivatives, and (3) aryl-alkyl and diaryl ketones, Other chlorides, such as those of zinc, irun(lll), and liniiV), are often effective in certain cases. 

Friedel-Crafts reaction with an aromatic compound to yield an aryl ketone (Sec. 16.3)... 

Alkylation of aryl halides (method 76) and phenols (method 106) is discussed elsewhere as is the application of the Friedel-Crafts reaction to the synthesis of ketones (method 178) and carboxylic acids (method 273)-Nitro and alkoxy groups also have been present on the aromatic nucleus during alkylations. ... 

Three common procedures are available for the transformation of aldehydes and ketones to hydrocarbons (1) reduction by zinc and hydrochloric acid (Clemmensen), (2) reduction by hydrazine in the presence of a base (Wolff-Kishner), and (3) catalytic hydrogenation. In view of the complicated mixtures obtained by the polyalkylation of benzene by the Friedel-Crafts reaction (method 1), reduction of alkyl aryl ketones is the most reliable method for the preparation of di- and poly-alkylbenzenes. 

Friedel-Crafts reaction of arenes with a-chloro-a-(methylthio)acetophenones [19], When A -phenylbenzimidoyl chlorides are aroylated with an aryl halide in the presence of a catalytic amount of an azoliuni salt (such as 1,3-dimethylimidazolium iodide) and sodium hydride, followed by acid treatment in TUF, unsymmetrical benzils can be isolated in 80-92% yields [201. Added to this method is the sequence ketone enaminoketone a-diketone, which cleaves a carbon-carbon double bond in the final stage by photooxygenation [21]. 

The Willgerodt reaction is frequently used to convert alkyl aryl ketones, which are synthesized easily by the Friedel-Crafts reaction, into aryl alkanoic acids with or without isolation of the intermediate thiomor-pholides [499, 504, 1170] (equation 416). 

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. 

In chapter 16 we shall discover that vinyl-copper reagents can be prepared with stereochemical control over double bond geometry and acylated directly with acid chlorides. We shall also meet vinyl silanes and see how they too can be acylated with acid chlorides. In this chapter we shall consider only the acylation of alkenes themselves with acid chlorides, that is the aliphatic Friedel-Crafts reaction.15 The normal Friedel-Crafts reaction 66 combines an aromatic compound with an acid chloride and a Lewis acid to give a cation 67 which loses a proton to give an aryl ketone 68. 

Alkylation solves the awkward problem of how to make aryl ketones of the pattern 151, awkward because the Friedel-Crafts reaction doesn t work with this substitution pattern. Alkylation of a nitroalkane with the benzylic halide 149 does work well and the product 150 can be oxidised to the ketone32151. Reactions with aldehydes work even with masked aldehydes33 like dihydropyran to give 154 and hence the ketone 155 with a 1,2-substitution pattern after hydrolysis.34 More vigorous conditions give nitroalkenes 145 from aldehydes and these will be very useful later as a2 reagents. 

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. 

The Friedel-Crafts acylation reaction, named after the French and American chemists who discovered it, used to prepare aryl ketones, is catalyzed by the Lewis acid aluminum chloride. Although aluminum chloride is a catalyst, it must be used (in Friedel-Crafts reactions) in stoichiometric amounts, as the portion of aluminum chloride that is catalytically inactive strongly binds to the product. Because aluminum chloride is corrosive and difficult to handle and must be destroyed when the reaction is complete, chemists continue to seek more environmentally friendly catalysts for this reaction. 

Optically pure (R)-2-chloropropionic acid (90) is available by diazotization of L-alanine in 6n HCl [31]. Using the corresponding acid chloride 91 as an acylating agent, Friedel-Crafts reaction with isobutylbenzene produces aryl ketone 92 with an enantiomeric purity of 85%. 

TfOH protonates nitroalkenes, even nitroethylene, to give N,N-dihydroxyiminium carbenium ions, which react with arenes to give arylated oximes. This overall process provides a route to a-aryl methyl ketones from 2-nitropropene (eq 11) and constitutes a versatile synthetic method for the preparation of a-arylated ketones, otherwise difficult to s)Tithesize by the conventional Friedel-Crafts reaction. 

Tertiary benzamides can be efficiently metallated at the ortho position by Bu Li at -78 °C in the presence of TMEDA the aryl-lithium derivatives thus produced react well with a range of electrophiles. Of particular relevance to this section of the Report is their reaction with ketones leading to the phthalide derivatives (56). 3-Aryl-3-methylphthalides (57) are available from a Friedel-Crafts reaction between o-acetylbenzoyl chloride and arenes using stannic chloride as Lewis acid. ° A total synthesis of the phthalide derivative iso-ochracinic acid (58) has been reported. ... 

Havens and Reimer have used carbon-13 NMR measurements to study the sequence distribution in a series of aryl ether ketone copolymers [41]. These copolymers were based on terephthaloyl chloride (T), 1,4-diphenoxy-benzene (B), and diphenyl ether (E) and were prepared by a Friedel-Crafts reaction using either HF/BF3 or buffered AICI3 as the catalyst. The copolymers formed are comprised of T units alternating with either E or B units. 

Another category of reductions involves aryl ketones. The Friedel-Crafts acylation reaction reacts benzene with an acid chloride such as butanoyl chloride (49) to give an aryl ketone, 50. Complete removal of the oxygen from this ketone constitutes a method to make straight-chain arenes, which cannot be prepared via Friedel-Crafts alkylation (see Section 21.3.2). At least two classical methods are used to accomplish this reaction, which is formally a reduction. If 50 is treated with zinc metal in HCl, the product is 1-phenylbutane, 105. This acidic reduction involves a mineral acid such as HCl and an active metal, and it is called the Clemmensen reduction. 

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