Haworth syntheses

Synthesis of naphthalene from benzene Haworth synthesis... 

The method has been applied to the synthesis of a range of substituted phenanthrenes and has the merit that it involves fewer steps than, for example, the Haworth synthesis. Good results are not always obtained, however, when some electron-withdrawing substituents (e.g. N02, Me CO) are present. 

Fig. 5.34. Steps 1-3 of the five-step Haworth synthesis of substituted naphthalenes.

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

Although it is possible to synthesize anthracene in a number of ways using Friedel-Crafts methodology, the usual routes involve either an adaptation of the Haworth synthesis of naphthalene or a Dicls-Alder reaction using naphtho-l,4-quinone as the dienophile. 

There are two major routes to phenanthrene, both of which can be used to prepare substituted derivatives. In the Haworth synthesis (Scheme 12.11), reaction of naphthalene with succinic anhydride yields an oxobut-anoic acid which is reduced under Clemmensen conditions to the butanoic acid. Cyclization in sulfuric acid and reduction of the resulting ketone is followed by dehydrogenation over palladium-on-carbon to phenanthrene. Alkyl or aryl derivatives can be obtained by treatment of the intermediate ketone with a Grignard reagent prior to dehydration and oxidation. 

As an example, let us look at just one method used to make certain naphthalene derivatives the Haworth synthesis (developed by R. D. Haworth at the University of Durham, England). Figure 30.2 (p. 987) shows the basic scheme, which would yield naphthalene itself (not, of course, actually prepared in this way). 

There are two major routes to phenanthrene, both of which can be used to prepare substituted derivatives. In the Haworth synthesis (Scheme... 

Other references related to the Haworth synthesis are cited in the literature. ... 

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. ... 

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