2-Hydroxyacetophenones

C. Insoluble in water, soluble in organic solvents. Flavone occurs naturally as dust on the flowers and leaves of primulas. It has been prepared from o-hydroxyacetophenone and benzaldehyde. 

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

Phenyl-3,6-dihydro-l,3,4-oxadiazin-2-one (50) is a high temperature blowing agent used primarily for polycarbonates (qv). It is prepared by the reaction of a-hydroxyacetophenone and methyl carbazate (52), made from hydrazine and dimethyl carbonate (175) ... 

Production is by the acetylation of 4-aminophenol. This can be achieved with acetic acid and acetic anhydride at 80°C (191), with acetic acid anhydride in pyridine at 100°C (192), with acetyl chloride and pyridine in toluene at 60°C (193), or by the action of ketene in alcohoHc suspension. 4-Hydroxyacetanihde also may be synthesized directiy from 4-nitrophenol The available reduction—acetylation systems include tin with acetic acid, hydrogenation over Pd—C in acetic anhydride, and hydrogenation over platinum in acetic acid (194,195). Other routes include rearrangement of 4-hydroxyacetophenone hydrazone with sodium nitrite in sulfuric acid and the electrolytic hydroxylation of acetanilide [103-84-4] (196). 

The Eries rearrangement of phenol esters gives a mixture of 2- and 4-acylphenols (56). The reaction is cataly2ed by Lewis acids such as aluminum chloride or by Brmnsted acids like hydrogen fluoride. This reaction is used in the production of 4-hydroxyacetophenone [99-93-4] a raw material for... 

The sulfonate ester of o-hydroxyacetophenone oximes, when treated with pyridine, are similarly converted into a benzoxazole, but cyclize to a 1,2-benzisoxazole when treated with aqueous KOH <73JCS(P1)2220, 71T711). 

Heating of the ( )-oximes of o-hydroxyacetophenones produced 1,2-benzisoxazoles as the predominant product, while thermolysis of the (Z)-oximes yielded only minor amounts of 1,2-benzisoxazoles 67AHC(8)277, 73IJC541). 

The treatment of 2-hydroxyacetophenone with hydroxylamine-O-sulfonic acid in dilute aqueous base produced 3-methyl-1,2-benzisoxazole. The mechanism was reported to be a C(2)—C(3) ring closure via intermediate (560) (Scheme 171). Salicylaldehyde failed to cyclize with dilute base, but with 20% KOH and hydroxylamine-O-sulfonic acid the transformation to 1,2-benzisoxazole succeeded (76MI41600). Kemp and Woodward isolated an oxime sulfonate (561) from salicylaldehyde and hydroxylamine-O-sulfonic acid and the subsequent decomposition gave 1,2-benzisoxazole in 95% yield (65T3019). 

Since two quaternary atoms and four CH atoms appear in the C NMR spectrum, the latter with a benzenoid coupling constant of 7-9 Hz, this is a disubstituted benzene ring, and the C signal with 5c = 162.2 fits a phenoxy C atom. The keto carbonyl (5c = 204.9) and methyl (5c = 26.6) resonances therefore point to an acetyl group as the only meaningful second substituent. Accordingly, it must be either o- or m-hydroxyacetophenone A or B the para isomer would show only four benzenoid C signals because of the molecular symmetry. 

The AFO reaction has seen very few variations since it was first reported in 1934. However, the most significant modification was reported in 1958 by Ozawa and further elaborated by Smith and others. Prior to this modification the intermediate chalcones were purified and then subjected to hydrogen peroxide in a basic medium. With the modification, the chalcone was generated in situ, from an aldehyde and a hydroxyacetophenone, and then allowed to react with aqueous hydrogen peroxide in the presence of sodium hydroxide to deliver the flavonol. Smith and coworkers conducted a limited study to examine the scope and limitations of this modification.Flavonols were delivered in 51-67% however, no flavonols were isolated with highly reactive aldehydes such as p-nitrobenzaldehyde and when 2-hydroxy-4-methoxyacetophenone was used. 

The mechanism of the K-R reaction has been studied by several groups. " However, the mechanism proposed by Baker and Szell appears to be the most likely pathway. Szell and coworkers agreed with the original mechanism postulated by Baker based on product isolation, spectroscopy and kinetic studies. The o-hydroxyacetophenone 4 is first acylated... 

A modification of the K-R reaction was introduced by Mozingo. This method involved reacting an o-hydroxyacetophenone with an ester in the presence of metallic sodium to form a 1,3-diketone. Treatment of the diketone with an acid then delivered the chromone via an intramolecular cyclization reaction. This method was applied to the preparation of 2-ethylchromone (21). 0-hydroxyarylketone 22 was allowed to react with ethyl propionate (23) in the presence of sodium metal.The resulting sodium enolate was then quenched with acetic acid to deliver the 1,3-diketone 24. Upon heating 24 in glacial acetic acid and hydrochloric acid, 2-ethylchromone (21) was delivered in 70-75% overall yield. 

In the area of medicinal chemistry, Haemers and coworkers synthesized a series of 4 -hydroxy-3-methoxyflavones that exhibited antiviral activity against poliomyelitis and rhinoviruses. A representative number of compounds is shown below. First, O-hydroxyacetophenones 61 were converted to the corresponding flavones 64 using standard conditions in yields of 74-92%. Cleavage of the benzyloxy groups of 64 was then achieved under acidic conditions to deliver the requisite flavones 65. 

On the other hand, 1,1,1-trisubstituted alkanes behave similarly to aldehydes, yielding pyrjdium salts (128) with identical substituents in positions 2 and 6. Thus, Dorofeenko and co-workers condensed 2 moles of acetophenone with 1 mole of benzotrichloride in the presence of perchloric acid obtaining 2,4,6-triphenjdpjTylium perchlorate with 1 mole of ethyl orthoformate, they obtained 2,6-diphenyl-pyrylium perchlorate (57) from o-hydroxyacetophenone, ortho-formic ester and perchloric acid, 4-ethoxybenzopyrylium perchlorate was formed. 

Further work in this area showed that only one of the cou-marin rings was needed for biologic activity. Condensation of the hydroxyacetophenone, 4, with diethyl carbonate affords 4-hydroxycoumarin (2). The reaction may involve the 3-ketoester (5) cyclization of this would afford 2. Alternately, the reagent may first give the 0-acyl derivative cyclization as above will give the same product. Michael condensation of the coumarin with benzalacetone (6) affords the anticoagulant warfarin (named after its place of origin Wisconsin Alumni Research Foundation,... 

In much the same vein, condensation of the difunetional o-hydroxyacetophenone 64 with diethyl... 

In semiindustrial synthesis, to achieve better yields, it is possible to omit (A), by directly preparing the ester (B) by reaction of p-hydroxy acetophenone on ethyl 2-bromoacetate in the presence of potassium carbonate in butanone. The yield of ester is 90%, and elimination of excess of p-hydroxyacetophenone is effected by washing with sodium hydroxide. 

How would you prepare /n-hydroxyacetophenone from benzene, using a diazonium replacement reaction in your scheme ... 

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