Cyclization reactions phenol ethers

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. 

Pyridinium chloride (]PyH]Cl) has also been used in a number of cyclization reactions of aryl ethers (Scheme 5.1-4) [4,18]. Presumably the reaction initially proceeds by dealkylation of the methyl ether groups to produce the corresponding phenol. 

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). 

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). 

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. 

DAIB and BTIB oxidations of phenols proceed through aryloxyiodane 129 and/or aryloxenium ion 130 intermediates and are quite useful for the preparation of quinones, quinol ethers, and quinone acetals (e.g., Scheme 39) (88TL677, 92MI2, 93JCS(P1)1891, 01OR327). When phenols bearing nucleophilic side chains are used as substrates, such oxidations provide fertile ground for the assembly of heterocyclic structures. This can be accomplished by oxidative-cyclization reactions of different types. 

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. 

A dramatic cesium effect was found by Weber in the case of the synthesis of the tetrabenzo crown ether 31, which is of interest for applications in ionselective electrodes [39]. The cyclization reactions starting from the cesium phenolate obtained from 29 and the tosylate 30 under high dilution conditions in DMF led to 31 in 37 % yield. This is a dramatic improvement of the formerly obtained yield of only 6 % in the system KOH/ -butanol/ethanol/DMF [40]. 

Model 20 was also treated with 2,6-xylenol, 1,5-anhydrocellobiitol, amylose, and amines none of these substances cansed mnch fragmentation cyclization reactions dominated [131]. The resnlts indicate that condensation reactions between the QM 21 and phenolates or carbohydrates are much slower than fragmentation reactions of 20 with snlhde or AHD. The addition of amines to soda cooks of 20 provided little additional model fragmentation instead, vinyl ethers (23) were observed in substantial amonnts. 

The most popular ring closure methods to prepare the benzoaza-crowns are (1) ring closure to form two aliphatic C—O bonds (ester or ether) by a 1 1 cyclization reaction (method S) (2) ring closure to form two phenolic... 

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... 

In addition to the ruthenium SNAr chemistry discussed in Section 11.7.2, an analogous copper-assisted S Ar cyclization reaction of a boronic acid and a phenol has been reported to construct biaryl ethers 146 (Scheme 11.19). Specifically, this functionality was then incorporated into MMP inhibitors. The mild conditions were shown to tolerate amides and esters in the substrate, although the presence of an additional phenol resulted in only trace product. Some other transformations involving copper mediation are presented in Section 11.8. 

Nearly every substitution of the aromatic ring has been tolerated for the cyclization step using thermal conditions, while acid-promoted conditions limited the functionality utilized. Substituents included halogens, esters, nitriles, nitro, thio-ethers, tertiary amines, alkyl, ethers, acetates, ketals, and amides. Primary and secondary amines are not well tolerated and poor yield resulted in the cyclization containing a free phenol. The Gould-Jacobs reaction has been applied to heterocycles attached and fused to the aniline. 

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