Hydroxyacetophenone derivatives

A novel acetophenone-4-O-glucoside named nauplathizine was isolated as an active constituent from the antibacterial acetone extract of the aerial parts of Nauplius aquaticus (L.) [245]. The dichloromethane extract of underground parts of Calea uniflora Less, exhibited antifungal activities [246]. Four />-hydroxyacetophenone derivatives were isolated as the main compounds. Some of them showed antifungal activity, with MIC values between 500 and 1000 pg/ml against pathogenic Candida spp. and dermatophytes. 

TABLE 14.2 Zig-zag Variations of the Affinity of Hydroxyacetophenone Derivatives for the Human Peripheral Neutrophils. Inhibition of H LTB4 Binding at 0.1 mM. °... 

Aminocyclohexenones, easily accessible from 3-acetyl-2,6-dimethyJpyrone and seconds amines, are converted in good yield to 2-amino-6-hydroxyacetophenone derivatives (equation 229). 

Boyd and Robertson763 describe a synthesis providing a good yield of 4-hydr-oxycoumarins from o-hydroxyacetophenone derivatives and diethyl carbonate ... 

The 2-hydroxyacetophenone derivative depicted, formed spontaneously from a tetraketone precursor in the presence of silica, itself derived in turn by ozonolysis of 3,6-dihydroindan-1-one acetal, has been regiospecifically recyclised with potassium hydroxide to 1,8-dihydroxy-3-methylnaphthalene (ref.75). 

Table 12.1 Zig-zag variations of the affinity of hydroxyacetophenone derivatives for the human peripheral neutrophils. Inhibition of pH] LTB4 binding at 0.1mlvF°...

Bohlmann, F., C. Zdero, L. Fiedler, H. Robinson, and R.M. King A labdane derivative from Chromolaena collina and a j 7-hydroxyacetophenone derivative from Stomatanthes corumbensis. Phytochem. 20, 1141 (1981). 

This problem prompted the development of second-generation photoinitiators for radical polymerization, which do not possess benzylic H atoms, such as a,a-dimethoxy-a-phenylacetophenone (1), a,a-diethoxyacetophenone (2), and the a-hydroxyacetophenone derivatives (3) and (4). These photoinitiators undergo photocleavage, in an analogous manner to benzoin ethers, as shown by various studies, " including free-radical trapping and laser flash photolysis. 

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,... 

Hydroxyacetophenone [23] and benzophenone derivatives [24] N-containing glycolate esters [25]... 

Partial hydrolysis of a potentially heptadentate Schiff-base tripodal ligand derived from tris-(2-aminoethyl)amine and 2-hydroxyacetophenone, induced by copper(II) salts, was reported and the final copper(II) complex (377) was characterized.333 Using salicylaldehyde as a co-ligand, with a copper(II) complex (378), catalytic epoxidation was demonstrated 334... 

Reaction of 2-hydroxyacetophenones in the Hurd-Mori reaction led to a range of 4-(o-hydroxyaryl)-l,2,3-thiadia-zoles 56. Subsequent treatment of these derivatives with base and an alkyl halide led to the formation of 2-benzofuransulfanyl derivatives 57 (Scheme 6) <2000T3933>. 

Both phenylhydrazones and imines derived from 5-halogeno-2-hydroxyacetophenones 510 were cyclized to the corresponding 4-methylene-substituted l,3-benzoxazin-2-ones 194 and 511 on treatment with 0.5 or O.bequiv of triphosgene under mild conditions (Scheme 96) <2003X8163, 2004SC71>. In the similar reactions of arylhydra-zones of 2-hydroxyacetophenones with 1 equiv of triphosgene, spiro-l,3-benzoxazine dimers were formed <2002JCM473>. 

The above process is applicable to almost all hydroxyalde-hydes in which the hydroxyl and carbonyl groups occupy ortho or para positions relatively to each other 1 in the latter case derivatives of hydroquinone are produced. When the hydroxyl and carbonyl groups occupy the meta position with respect to each other, no reaction takes place, as is also the case with certain ortho and para compounds containing nitro groups and iodine atoms. o-Hydroxyacetophenone and />-hydroxyaceto-phenone are also capable of yielding catechol and hydroquinone respectively under the above conditions. 

Oxovanadium(IV) complexes with (97) and (98) derived from alkyl aminoalcohols and Hsal or o-hydroxyacetophenone (and substituted derivatives), respectively, have been prepared as well as VOz+ complexes with (99) derived from 2-hydrazinoethanol and Hsal and substituted Hsal. Most of these and some properties are summarized in Table 42. Generally the complexes were prepared by adding an alcoholic solution of the SB, either previously obtained as a solid or prepared in situ, to alcoholic vanadyl acetate. The mixture is normally refluxed for several hours and the precipitates are collected by filtration as they are not soluble they are not recrystallized. 

The furanoid ring in benzo[6 ]furan is susceptible to attack by oxidants. Permanganate and chromic acid give derivatives of 2-hydroxybenzoic acid with compounds unsubstituted at the 3-position, but compounds with a 3-methyl or a 3-aryl substituent give derivatives of 2-hydroxyacetophenone or 2-hydroxybenzophenone. Ozonolysis of benzo[6]furan affords 2-hydroxybenzoic acid, 2-hydroxybenzaldehyde and some catechol produced via its diformate. Before the advent of NMR spectroscopy these methods were used in structural elucidation of benzofuranoid natural products, as in the case of O-methyleuparin (Scheme 26). 

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). 

The coumarin is probably derived from the initial acylated hydroxyacetophenone which, in addition to undergoing a Baker-Venkataraman rearrangement, may cyclize through an intramolecular aldol condensation. Elimination of water then gives rise to the coumarin (Scheme 161). 

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). 

Aminofiavones are also available from chalcones derived from 5-acetamino-2-hydroxyacetophenone (57JOC304). Oxidation by selenium dioxide leads to 6-acetaminoflavones which may be deacetylated to the 6-amino compound, whilst alkaline hydrogen peroxide affords the corresponding flavonols (461) in a typical Algar-Flynn-Oyamada reaction (64CB610). 

Hydroxyacetophenone and related compounds are attractive precursors of chromanones, most notably in the synthesis of their 2-phenyl derivatives. Being adjacent to the carbonyl group, the methyl group of the acetophenone is activated and forms a carbanion on treatment with base. Subsequent condensation with a carbonyl compound which lacks an a-hydrogen atom leads to a 1,3-dicarbonyl or an enone system which readily cyclizes to a chromanone. Thus, methyl formate affords the chromanone (591) (53MI22400) and formaldehyde has been used in the synthesis of 3-methylchroman-4-one from o-hydroxypropiophenone (68T949). 

This route may be extended to the synthesis of flavylium salts through the reaction of an orthoformate with C-acyl derivatives of o-hydroxyacetophenone (72JOU2250). During this synthesis small amounts of 2,6-di-(2-hydroxyaryl)pyrylium salts are produced. If an excess of o-hydroxyketone is used in the reaction, the 2,6-diarylpyrylium salt becomes the major product (73JOU399). 

As reported in the literature, the acylation of aromatic hydrocarbons can be carried out by using zeolites as catalysts and carboxylic acids or acyl chlorides as acylating agents. Thus toluene can be acylated by carboxylic acids in the liquid phase in the presence of cation exchanged Y-zeolites (ref. 1). The acylation of phenol or phenol derivatives is also reported. The acylation of anisole by carboxylic acids and acyl chlorides was obtained in the presence of various zeolites in the liquid phase (ref. 2). The acylation of phenol by acetic acid was also carried out with silicalite (ref. 3) or HZSM5 (ref. 4). The para isomer has been generally favoured except in the latter case in which ortho-hydroxyacetophenone was obtained preferentially. One possible explanation for the high ortho-selectivity in the case of the acylation of phenol by acetic acid is that phenylacetate could be an intermediate from which ortho-hydroxyacetophenone would be formed intramolecularly. 

NMR studies have been mainly applied to elucidating the structural features of Schilf bases in solution. These studies are mainly concerned with SchiiT bases derived from benzaldehyde and its substituents, / -diketones, o-hydroxyacetophenones and o-hydroxyacetonaphthones. They were devoted to obtaining an insight into the keto-enol equilibrium (Scheme 1), syn and anti isomerism and steric distortions in different kinds of solvents. Relevant data and results are described in the following sections. 

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