Phenol ethers cyclization

Reaction of the potassium salt of salicylaldehyde with chlo-roacetone affords first the corresponding phenolic ether aldol cyclization of the aldehyde with the ketonic side chain affords the benzofuran (1). Reduction of the carbonyl group by means of the Wolf-Kischner reaction affords 2-ethyl-benzofuran. Friedel-Crafts acylation with anisoyl chloride proceeds on the remaining unsubstituted position on the furan ring (2). The methyl ether is then cleaved by means of pyridine hydrochloride (3). lodina-tion of the phenol is accomplished by means of an alkaline solution of iodine and potassium iodide. There is thus obtained benziodarone (4)... 

A direct synthesis of cyclic quinone imine acetals has been accomplished by the treatment of substituted phenol ethers bearing an alkyl azido side chain with IBTA (Eq. 39) [96JCS(CC)1491]. The cyclization reaction proceeds smoothly in polar and low nucleophilic solvents such as CF3CH2OH and (CF3)2CH0H in the presence of 10% MeOH. 

Only a few benzo derivatives are known, and most of them have the oxygen attached to the aromatic rings, i.e. they are cyclic phenol ethers or esters. 3,4,5,6-Tetrahydro-2H-1-benzoxocin (136), mentioned above, can also be obtained by cyclization of o-(bromopentyl)phenol (139) with base. The cyclization is rapid in DMSO and does not require high dilution conditions. The yield of (136) is 30% the alkenyl phenol (140) is obtained in 57% yield (74JOC2598). The latter product is formed by an intramolecular E2 reaction and thus is independent of the concentration of (139). In 75% ethanol solution, more of (136) is formed (64%) and less of (140) (35%), even though the rate of cyclization is much lower than in DMSO (75JA4960). 

Boger and co-workers performed a detailed study on the effect of substrate structural features on the 17-membered ring macrolactamization. It was found that the substituent at the remote C4 aryl position had a profound effect on the rate and yield of the cyclization. Substrates bearing either a free phenol or no substituent were found to cyclize more efficiently, whereas those bearing methyl or benzyl ethers cyclized considerably less efficiently (Table 1)J5 ... 

A closely related reaction involves that between a saturated acyl halide and a phenol or phenolic ether. A necessary feature of the acid chloride is that it contains a bromine atom at C-2 which allows formation of a double bond during the reaction by loss of bromide. Normal Friedel-Crafts conditions are employed in the first step which leads to an o-hydroxyphenyl 2-bromoalkyl ketone (589). In boiling diethylaniline, hydrogen bromide is lost and the resulting acrylophenone spontaneously cyclizes to the chromanone <24LA(439)132). 

Oxidative Cyclization of Substituted Phenols and Phenol Ethers. . 103... 

Intramolecular oxidative cyclizations in the appropriately substituted phenols and phenol ethers provide a powerful tool for the construction of various practically important polycyclic systems. Especially interesting and synthetically useful is the oxidation of the p-substituted phenols 12 with [bis(acyloxy)iodo]-arenes in the presence of an appropriate external or internal nucleophile (Nu) leading to the respective spiro dienones 15 according to Scheme 6. It is assumed that this reaction proceeds via concerted addition-elimination in the intermediate product 13, or via phenoxenium ions 14 [18 - 21]. The recently reported lack of chirality induction in the phenolic oxidation in the presence of dibenzoyltar-taric acid supports the hypothesis that of mechanism proceeding via phenoxenium ions 14 [18]. The o-substituted phenols can be oxidized similarly with the formation of the respective 2,4-cyclohexadienone derivatives. 

A novel hypervalent iodine-induced direct intramolecular cyclization of a-(aryl)alkyl-jS-dicarbonyl compounds 33 has been recently reported (Scheme 15) [30]. Both meta- and para-substituted phenol ether derivatives containing acyclic or cyclic 1,3-dicarbonyl moieties at the side chain undergo this reaction in a facile manner affording spirobenzannulated compounds 34 that are of biological importance. 

Instead of amino-ketones, compounds may be used which are capable of forming amino-ketones as intermediates. Thus, if phenols and phenol ethers are acylated with y- or 8-amino acids in the presence of polyphosphoric acid, the intermediate amino-ketones cyclize to 2-aryl-z31-pyrrolines or 2-aryl-J -piperideines95 (Scheme 1). 

Not only phenols but also their 0-silyl derivatives and phenol ethers reacted similarly. In 0-silylated phenols bearing an aminoquinone moiety at their para-position BTI oxidation resulted in the formation of cyclized products in high yield [21] ... 

Intramolecular reaction with nucleophilic groups can also lead to heterocycles. For example, good yields of 3-acylbenzofurans result from cyclization caused by intramolecular substitution of the tertiary amino group by a phenol formed by cleavage of a phenol ether by boron tribromide251 (equation 182). 0-Hydroxy benzyl alcohols were used to obtain 4//-chromenes by their reaction with 4-morpholino-3-buten-2-one in acetic acid-acetic anhydride187. 

Pyrolysis of tri-, tetra-, and penta-chlorobenzenes affords mixtures of chlorinated dibenzofurans and dibenzo-p-dioxins, " and chlorinated diphenyl ethers cyclize in the presence of palladium acetate to polychloro-dibenzofurans/ The action of malononitrile on tetrahydroxy-p-benzoquinone leads to the benzo-difuran (79), contrary to a previous report/ The acid-catalysed condensation of quinones with phenols has been studied p-benzoquinone and resorcinol, for example, afford compound (80)/ Naphtho[2,3- >]furan-4,9-diones (81 R = Me or Ph R = Ac, Bz, C02Et, or CN) are obtained from 2,3-dichloronaphtho-1,4-quinone and compounds R COCHaR in DMF that contains potassium fluoride/ The action of mineral acids on p-benzoquinone produces a mixture of complex benzofurans, which includes (82) and (83)/ Bases convert the ben-zofuranone (84) into the tetrameric compound (85), contrary to an earlier... 

Kita Y, Egi M, Ohtsubo M, Saiki T, Okajima A, Takada T, Tohma H (1999) Hypervalent iodine(III)-induced intramolecular cyclization reaction of substituted phenol ethers with an alkyl azido side-chain a novel and efficient synthesis of quinone imine derivatives. Chem Pharm Bull 47 241-245... 

Anodic coupling of vinyl ethers, phenols and phenol ethers is claimed to be promising for the synthesis of natural products and medicaments, e.g. cyclization of methoxybiben ls in LiCIOJAlN Dimethoxydihydrofuran, a sales product... 

Additional examples of intramolecular oxidative coupling of phenolic ethers include the oxidative biaryl coupling of various N-substituted 1-benzyltetrahydroisoquinolines 313 to the corresponding aporphines 314 [374], the oxidative cyclization of 3,4-dimethoxyphenyl 3,4-dimethoxyphenylacetate (315) leading to the seven-membered lactone 316 [375] and the conversion of phenol ether derivatives 317 into the products of... 

General Procedure for the Enantioselective Cyclization of Geranyl Phenol Ether Promoted by the BINOL-SnCU Complex... 

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