Friedel-Crafts acylation Wolff-Kishner reduction

Another method for reduction proceeds under basic conditions and treats 50 with hydrazine (NH2NH2) and potassium hydroxide (KOH). An aqueous workup produces 105. This is called the Wolff-Kishner reduction (mentioned in Chapter 19, Section 19.4.1). By using either the Clemmensen or the Wolff-Kishner procedure, straight-chain arenes such as 105 can be produced in a two-step procedure Friedel-Crafts acylation followed by reduction. Indeed, this two-step procedure is usually the preferred route to synthesize straight-chain arenes. 

Friedel-Crafts acylation followed by Clemmensen or Wolff-Kishner reduction is a standard sequence used to introduce a primary alkyl group onto an aromatic ring... 

Several methods are available to supplement the phenol alkylations described above. Primary alkylphenols can be produced using the more traditional Friedel-Crafts reaction. Thus an -butylphenol can be synthesized direcdy from a butyl haUde, phenol, and mild Lewis acid catalyst. Alternatively, butyryl chloride can be used to acylate phenol producing a butyrophenone. Reduction with hydrazine (a Wolff-Kishner reduction) generates butylphenol. 

Friedel-Crafts acylation of dibenzothiophene with succinic anhydride is known to occur in the 2-position, yielding y-oxo-2-dibenzothiophene-but3Tic acid (135a). Subsequent Wolff-Kishner reduction and internal cyclization yields 7-keto-7,8,9,10-tetrahydrobenzo[6]naphtho[2,3-d]thio-phene (136a). - This reaction has been extended to 4-methyldibenzo-... 

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 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 key here is to recognize that an ethyl substituent can be introduced by Friedel-Crafts acylation followed by a Clemmensen or Wolff-Kishner reduction step later in the synthesis. If the chlorine is introduced prior to reduction, it will be directed meta to the acetyl group, giving the correct substitution pattern. 

Aryl alkyl ketones are readily prepared by the Friedel-Crafts acylation process (see Section 6.11.1, p. 1006) and their Clemmensen reduction constitutes a more efficient procedure for the preparation of monoalkylbenzenes than the alternative direct Friedel-Crafts alkylation reaction (see below). Alternatively aldehydes and ketones may be reduced to the corresponding hydrocarbon by the Wolff-Kishner method which involves heating the corresponding hydrazone or semicarbazone with potassium hydroxide or with sodium ethoxide solution. 

Alternatively, benzene could have been subjected to Friedel-Crafts acylation with benzoyl chloride to give benzophenone. Clemmensen or Wolff-Kishner reduction of benzophenone would then furnish diphenylmethane. 

The orientation is right attack is para to one of the methoxy groups and ortho to the methyl. The substrate for the Friedel-Crafts acylation reaction, 3,4-dimethoxytoluene, is prepared from compound A by a Clemmensen or Wolff-Kishner reduction. Compound A cannot be acylated directly because it bears a strongly deactivating —CH substituent. 

The desired sequence may be carried out by a Friedel-Crafts acylation, followed by Clemmensen or Wolff-Kishner reduction of the ketone. 

The Friedel-Crafts Alkylation may give polyalkylated products, so the Friedel-Crafts Acylation is a valuable alternative. The acylated products may easily be converted to the corresponding alkanes via Clemmensen Reduction or Wolff-Kishner Reduction. 

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 ... 

When cyclic anhydrides are used as one component, the Friedel-Crafts acylation provides a means of adding a new ring to an aromatic compound. One illustration is shown here. Note that only the ketone is reduced in the Clemmensen reduction step. The carboxylic acid is unaffected. The same result can be achieved using the Wolff-Kishner reduction. 

If carbocation rearrangements are likely, then Friedel-Crafts acylation followed by Wolff-Kishner or Clemmensen reduction should be used to incorporate a primary alkyl group. 

Synthetic Applications of Friedel-Crafts Acylations The Clemmensen and Wolff-Kishner Reductions 683... 

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