Ketones from Friedel-Crafts acylation

Clemmensen Reduction (Review) The Clemmensen reduction commonly converts acylbenzenes (from Friedel-Crafts acylation, Section 17-1 IB) to alkylbenzenes, but it also works with other ketones and aldehydes that are not sensitive to acid. The carbonyl compound is heated with an excess of amalgamated zinc (zinc treated with mercury) and hydrochloric acid. The actual reduction occurs by a complex mechanism on the surface of the zinc. 

The main product, C, comes from the addition of both these electrophiles, but which adds first The ketone in A is meta-directing but the t-butyl group in B is para-directing. Product C has a par. relationship and must come from Friedel-Crafts acylation of B with the acylium cation. 

Aldehydes and ketones can be reduced to hydrocarbons by the action (a) of amalgamated zinc and concentrated hydrochloric acid, the Clemmensen reduction or (b) of hydrazine, NH2NH2, and a strong base like KCm or potassium teh-butoxide, the Wolff-Kishner reduction. These are particularly important when applied to the al faTryl ketones obtailTed from Friedel-Crafts acylation, since this reaction sequence permits, indirectly, the attachment of straight alkyl chains to the benzene ring. For example ... 

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. 

Friedel-Crafts acylation reactions usually involve the interaction of an aromatic compound with an acyl halide or anhydride in the presence of a catalyst, to form a carbon-carbon bond [74, 75]. As the product of an acylation reaction is less reactive than its starting material, monoacylation usually occurs. The catalyst in the reaction is not a true catalyst, as it is often (but not always) required in stoichiometric quantities. For Friedel-Crafts acylation reactions in chloroaluminate(III) ionic liquids or molten salts, the ketone product of an acylation reaction forms a strong complex with the ionic liquid, and separation of the product from the ionic liquid can be extremely difficult. The products are usually isolated by quenching the ionic liquid in water. Current research is moving towards finding genuine catalysts for this reaction, some of which are described in this section. 

The Friedel-Crafts acylation reaction has also been performed in iron(III) chloride ionic liquids, by Seddon and co-workers [96]. An example is the acetylation of benzene (Scheme 5.1-66). Ionic liquids of the type [EMIM]Cl/FeCl3 (0.50 < X(FeCl3) < 0.62) are good acylation catalysts, with the added benefit that the ketone product of the reaction can be separated from the ionic liquid by solvent extraction, provided that X(FeCl3) is in the range 0.51-0.55. 

Compounds 1 and 2 were identified by FTIR and 13C-NMR. The 13C proton decoupled spectra for 1 and 2 are dominated by signals ranging from 62 to 195 ppm. The 13C chemical shift assignments were made based on comparisons with 4,4 -(hexafluoroisopropylidene)diphenol and from calculations based on substituted benzenes and naphthalenes.15 The 13C-NMR spectrum clearly showed that the Friedel-Crafts acylation of 1 by 4-fluorobenzoyl chloride yielded the 1,4-addition product exclusively. The 13C chemical shifts for 2 are listed in Table 8.1. The key structural features in the FTIR spectrum of2 include the following absorptions aromatic C-H, 3074 cnr1, ketone C=0, 1658 cm-1, aromatic ether Ar—0—Ar, 1245 cm-1, and C—F, 1175 cm-1. 

Further investigation on the chemistry of the very potent diuretic drug ethacrinic acid W led to a compound that retained the high potency of the parent with reduced propensity for causing side effects, such as loss of body potassium and retention of uric acid. Friedel-Crafts acylation of dichioroanisole with phenyl acetyl chloride gives ketone 10. This is then reacted in a variant of the Mannich reaction which involves the aminal from dimethyl-... 

A ketone can also be formed with a Friedel-Crafts acylation. The process requires an acid chloride and an aromatic compound. An aldehyde can t be formed by this procedure because the appropriate acid chloride, formyl chloride (HCOCl), is unstable and decomposes to carbon monoxide and hydrogen chloride. Figure 10-12 illustrates the preparation of acetophenone from benzene and acetyl chloride. 

In the Mukaiyama aldol additions of trimethyl-(l-phenyl-propenyloxy)-silane to give benzaldehyde and cinnamaldehyde catalyzed by 7 mol% supported scandium catalyst, a 1 1 mixture of diastereomers was obtained. Again, the dendritic catalyst could be recycled easily without any loss in performance. The scandium cross-linked dendritic material appeared to be an efficient catalyst for the Diels-Alder reaction between methyl vinyl ketone and cyclopentadiene. The Diels-Alder adduct was formed in dichloromethane at 0°C in 79% yield with an endo/exo ratio of 85 15. The material was also used as a Friedel-Crafts acylation catalyst (contain-ing7mol% scandium) for the formation of / -methoxyacetophenone (in a 73% yield) from anisole, acetic acid anhydride, and lithium perchlorate at 50°C in nitromethane. 

A considerable difference between Friedel-Crafts alkylation and acylation is the amount of the Lewis acid necessary to induce the reaction. Friedel-Crafts alkylation requires the use of only catalytic amounts of the catalyst. Lewis acids, however, form complexes with the aromatic ketones, the products in Friedel-Crafts acylations, and the catalyst is thus continuously removed from the system as the reaction proceeds. To achieve complete conversion, therefore, it is necessary to use an equimolar amount of Lewis acid catalyst when the acylating agent is an acyl halide. Optimum yields can be obtained using a 1.1 molar excess of the catalyst. With... 

Furyl ketones can be easily obtained by Friedel-Crafts acylation of furans. They can also be obtained from derivatives of furan-2-carboxylic acid such as the amides, nitriles and chlorides by literature reactions. The 3-furyl ketones are also obtained by similar methods. 

Fluorobenzene is prepared from aniline by the Schiemann reaction, shown in Section 22.18. Aniline is, of course, prepared from benzene via nitrobenzene. Friedel-Crafts acylation of fluorobenzene has been carried out with the results shown and gives the required ethyl p-fluorophenyl ketone as the major product. 

Friedel-Crafts acylations (see Chapter 2) are used to prepare aromatic ketones. The preparation of acetophenone from benzene and acetyl chloride is a typical Friedel-Crafts acylation. 

An alternative is FGI back to the ketone 67 and hence the a-bromoketone 68 that can be made from the ketone 69 itself by methods discussed earlier in this chapter. The ketone 69 is clearly made by some sort of Friedel-Crafts acylation, but how are we to make the diol 70 In chapter 3 we said that a good strategy to make ort/io-disubstituted aromatic compounds was to start with an... 

The tertiary alcohol is an obvious place to disconnect. Rejecting the poor disconnection of one carbon atom 20a, we have a choice between 20b and 20c giving one of two ketones 23 or 24 and Grignard reagents made from one of two halides 22 or 25. We can easily make 22 and 24 by halogenation or Friedel-Crafts acylation of toluene. But what about 23 and 25 ... 

On the other hand, rare-earth trifluoromethanesulfonates (rare earth triflate, RE(OTf)3) have been found to work efficiently as Lewis acids even in aqueous media or in the presence of amines [4], A catalytic amount of RE(OTf)3 enables several synthetically useful reactions, for example aldol, Michael, allylation, Mannich, Diels-Alder reactions, etc., to proceed. It has also been demonstrated that a small amount of RE(OTf)3 is enough to complete the reactions and that RE(OTf)3 can easily be recovered from the reaction mixture and can be reused. A key to accomplishing the catalytic processes was assumed to be the equilibrium between Lewis acids and Lewis bases, for example water, carbonyl compounds, and amines, etc. A similar equilibrium was expected between Lewis adds and aromatic ketones, and, thus, RE(OTf)3-catalyzed Friedel-Crafts acylation was investigated [5]. 

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