2-Hydroxyacetophenone, reaction with

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,... 

The Knoevenagel reaction between o-hydroxyaryl aldehydes and ketones and substituted acetonitriles affords high yields of 3-substituted coumarins in aqueous alkaline media <96H(43)1257>, whilst 4-hydroxycoumarins have been elaborated to pyrano [3,2-c]benzopyran-5-ones by reaction with aromatic aldehydes and malononitiile <96P148>. The imine (10) resulting from the complex reaction of o-hydroxyacetophenone with malononitrile undergoes a 1,5-tautomeric shift in solution <96JCS(P1)1067>. 

The use of mesitoic acid esters has again been successfully employed by Burrows and Topping (1975) in the elucidation of intramolecular carbon acid participation. Under basic aqueous conditions, 2-acetylphenyl mesitoate [41] hydrolyses to yield mesitoic acid and 2-hydroxyacetophenone, reacting with intramolecular catalysis via the monoanion of the ketonic hydrate (see p. 192). However, in 47.5% aqueous ethanol containing potassium hydroxide, the reaction products from l-acetyl-2-naphthyl mesitoate [45] were found... 

An interesting conversion of 2,6-dimethylpyran -4-one (408) into 7-methyl-5-phenylchromone (410) is achieved by reaction with the anion of acetophenone and cycliz-ation of the 2-hydroxyacetophenone (409) (77AP744). 

Aromatic esters may be used to aroylate the dianions derived from 1,3-diketones by reaction with potassium amide (60JOC538). Not only are acetyl and benzoyl acetones suitable for reaction, but alicyclic diketones and 2-hydroxyacetophenone are also acceptable. Cycliz-ation of the triketones occurs in cold sulfuric acid, presumably via the enolic form and the hemiacetal (Scheme 132). 

Hydroxyacetophenone reacts with DMF under Vilsmeier conditions to yield chromone-3-carbaldehyde (72LA(765)8). The reaction appears to be generally applicable, various substituents being acceptable in the aromatic ring (74T3553). Furthermore, acetylhydroxy-naphthalenes yield the corresponding benzochromones, and the pyranochromone (452) is formed from the appropriately substituted coumarin. 

Salicylic acid derivatives serve a similar purpose to 2-hydroxyacetophenones in a number of chromone syntheses, acting as a precursor of the 1,3-diketone fragment. For instance, a Claisen reaction between methyl 2-methoxybenzoate and acetone takes place in the presence of sodium to give the diketone. Demethylation occurs on reaction with hydriodic acid with concomitant ring closure to the chromone (00CB1998). The corresponding naphthol derivatives are a source of benzochromones (52JOC1419). 

In an unusual modified chromone synthesis, enaminones formally derived from o-hydroxyacetophenone react with selenium oxychloride prior to cyclisation resulting in the formation of Se-bridged bischromones. Various reactions at Se are described, including fission of an Se-Se bond, leading to chromone-3-seleninic acid (95JHC43). 

Trost and coworkers recently reported that these dinuclear zinc complexes catalyze Mannich reactions with unmodified aromatic hydroxy ketones as donors with excellent enantioselectivity [18]. Mannich-type reactions between an N-para-meth-oxyphenyl (PMP)-protected a-ethyl glyoxalate and hydroxyacetophenone in the presence of a catalytic amount of catalyst 5a afford the desired N-PMP protected amino acid derivative in 76 % yield with a dr of 7 1 and 95 % ee (Eq.5). 

Chromone. A convenient procedure for the preparation of chromone (4) involves the reaction of 2-hydroxyacetophenone (I) with dimethylformamide dimethyl acetal (2) in refluxing xylene with continuous distillation of the methanol formed. The enaminoketone (3) formed in this way is cyclized to chromone by treatment with aqueous sulfuric acid at 100°. 

The use of ethyl [2-13C]acetoacetate instead of diethyl [2-t3CJmafonafe in the condensation reaction with 4H-pyran-4-one afforded ethyl 4-hydroxy[1 -13C]benzoate in 87% yield. In this case, 1.1 equiv of 4H-pyran-4-one and 1.1 equiv of potassium tert-butoxide were optimal. The addition of catalytic amounts of the base was not satisfactory. Ethyl [2-13C]acetoacetate was prepared from ethyl (2-13C]acetate as described for diethyl [2-13C]matonate.16 The maximum yield for this reaction on a 10-mmol scale was only 70% after distillation. 4H-Pyran-4-one reacted with nitromethane and potassium tert-butoxide (each 1.1 equiv) to afford 4-nitrophenol in 75% yield after purification by flash chromatography. This gives easy access to 4-nitro[4-13C]phenol. With 2,4-pentanedione, the condensation with 4H-pyran-4-one under the same reaction conditions gave 4-hydroxyacetophenone in 45-50% yield after purification. 

Optically active P-hydroxysulfoximines which catalyze the asymmetric borane reduction of ketones [110], also catalyze the same reaction with sodium borohydride/trimethylsilyl chloride system as reducing agent [126]. Reduction of a protected a-hydroxyacetophenone afforded the alcohol with 90% ee. 

Hollinshead [32] used polymer-bound enones for the synthesis of highly functionalized pyrrolidines. 3-Hydroxyacetophenone was immobilized on chlorinated Wang resin and transformed into polymer-bound enones upon a Knoevenagel reaction with aldehydes. Pyrrolidines were then formed in the addition of azomethinylides, generated from imines, LiBr and DBU (Fig. 6.24). 

Etherification of 4-hydroxyacetophenone in dimethyl sulphoxide containing potassium carbonate by the slow addition of methyl (S)-2-chloropropionate over 30 mins, and reaction with stirring during 6 hours at ambient temperature (with introduction of more potassium carbonate over a further 5 hours) gave methyl (R)-2-(4-acetylphenoxy)propionate (enantiomeric excess, 86%). 

A pyrazolobenzoxazine derivative has been synthesised from an alkoxycarbonylhydrazone of 2-hydroxyacetophenone by further reaction with methyl salicylate. Thus, the hydrazone in tetrahydrofuran was first treated with excess lithium diisopropylamide in THF at OX to generate a dianion which was then reacted with methyl salicylate. Acidification of the mixture after 2 hours followed by refluxing afforded the produrd in 86% yield ref. 94). 

Coumarins, Isocoumarins, and a-Pyrones.—A two-step conversion of 2-hydroxyacetophenones into coumarins by a Wittig reaction with ethoxycarbo-... 

Paracetamol is used in broad spectrum of arthritic and rheumatic conditions linked with musculoskeletal pain, headaches, neuralgias and dysmenorrhea. It is generally prepared from p-nitrophenol by reduction (Sn + HCl) followed by reaction with acetic anhydride-acetic acid mixture. Alternatively it is obtained by the Beckmann rearrangement of oxime of p-hydroxyacetophenone. 

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. 

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. 

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