Haworth syntheses tetralone

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-tetralone and reduction of the carbonyl group then gives 1,2,3,4-tetrahydronaphthalene (tetralin). Aromatization is achieved by dehydrogenation over a palladium catalyst. 

The Haworth synthesis of tetralone derivatives has found substantial utility in natural product and small molecule synthesis. Zubaidha and co-workers performed the Haworth reaction on 2-methylanisole (15) to yield 18 as an intermediate in the synthesis of ( )-heritol (19), a potent itchthyotoxin. Beginning with 15, acylation to yield 16 is followed by the Clemmensen reduction to produce 17. Subsequent intramolecular Friedel-Crafts acylation results in the formation of tetralone 18. Ferraz and coworkers have also synthesized 18 in the same manner as an intermediate for the synthesis of ( )-mutisianthol (20), a potential antitumor agent. In addition, this substrate 18 has been used for the synthesis of various a-tetralols as substrates for enzymatic resolution studies. ... 

The Haworth synthesis has also found substantial utility in materials synthesis. Within this area, Rheingold and co-workers were able to synthesize rigid spacer-chelators using a monobrominated tetralone prepared under modified Haworth conditions. Following / ara-acylation of bromobenzene (40) under vigorous conditions to yield 41, reduction under modified Wolflf-Kishner conditions is followed by cyclization to give 42. 

A further example is given below illustrating the use of a dibasic anhydride (succinic anhydride) the succinoylation reaction is a valuable one since it leads to aroyl carboxylic acids and ultimately to polynuclear hydrocarbons. This general scheme of synthesis of substituted hydrocarbons through the use of succinic anhydride is sometimes called the Haworth reaction. Thus a-tetralone (see below) may be reduced by the Clemmensen method to tetralin (tetrahydronaphthalene) and the latter converted into naphthalene either catal3d.ically or by means of sulphur or selenium (compare Section, VI,33). 

Reaction of succinic anhydride with benzene in the presence of anhydrous aluminium chloride (slightly over two equivalents see above) yields 3-benzoylpropanoic acid. This may be reduced by the Clemmensen method in the presence of a solvent (toluene) immiscible with the hydrochloric acid to 4-phenylbutanoic acid. Cyclisation to a-tetralone (Expt 6.123) is then effected smoothly by treatment with hot polyphosphoric acid. This reaction sequence represents the first stages in the Haworth procedure for the synthesis of polycyclic aromatic hydrocarbons (see Section 6.1.4, p. 839). 

The Haworth reaction is a classical method for the synthesis of tetralone, beginning with benzene and succinic anhydride. The three-step protocol involves a Friedel-Crafts acylation, followed by reduction of the arylketone, and an intramolecular Friedel-Crafts acylation. The tetralone analog may be further reduced and dehydrogenated to form new aromatic species, in what is known as the Haworth phenanthrene synthesis. 

Although the modem Haworth reaction is more commonly used to form tetralone analogs, the reaction sequence first targeted the synthesis of phenanthrene and its derivatives. The original protocol used by Robert Downs Haworth in 1932 involved the reaction of naphthalene (1) with succinic anhydride (2) and aluminum chloride to form nearly equal quantities of naphthoylpropionic acids 3 and 4. 

The tetralone derivatives produced by the Haworth reaction are important synthetic intermediates. However, in Haworth s original work, his efforts were directed toward the synthesis of phenanthrene fi-om naphthalene. Thus the synthesis of tetralone derivative 12 by the standard Haworth conditions is followed by a Clemmensen " or Wolff-Kishner reduction of the ketone... 

The Haworth phenanthrene synthesis has been extensively used in the synthesis of derivatives of chrysene,an environmental pollutant which exhibits tumorigenic and mutagenic properties. For example Harvey and coworkers treated 61 with succinic anhydride under Friedel-Crafts conditions to produce 62. Reduction of the ketoacid under Wolff-Kishner conditions is followed by esterification to yield 63. Dehydrogenation of 63 is followed by saponification to yield carboxylic acid 64. Intramolecular Friedel-Crafts acylation produces tetralone derivative 65, which undergoes carbonyl reduction and dehydrogenation to produce 66. 

The Haworth phenanthrene synthesis was also employed for the preparation of naphthalene intermediates toward the synthesis of novel HMG-CoA reductase inhibitors/ The usual Haworth procedure was followed to secure tetralone 67. Hydride reduction of the carbonyl produced 68, which on dehydration to 69, was subsequently dehydrogenated with DDQ to provide naphthalene 70. A related procedure was used in the same work to replace the C-7 methyl with a chlorine atom. 

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