Reactions of Phenolic Ethers

Since the alkyl group, usually the methyl, is used for the protection of the phenolic group, the reactions described in this section effectively extend the synthesis of phenols already described. Thus some of the syntheses from phenolic ethers in the last part of the preceding section would also appear to be equally an aspect of the reactions of phenolic ethers. The general reactions 

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Total Synthesis via Oxidation Reactions of Phenol Ether... 

Intramolecular nucleophilic substitution reactions of phenol ether derivatives induced by activated iodine(III) reagents such as PIFA-TMSOTf and PIFA-BF3 Et20 [Eq. (7) - (11)] have been applied to total or formal synthesis of various types of bioactive natural products. 

K. V. Rao and T. R. Seshadri. Proc. Indian Acad. Sci. 30A, 30-3 (1949). UV chelation and color reaction of phenolic ethers with nitric acid. 

Friedel-Crafts catalyst. Iron serves as a satisfactory catalyst for the reaction of phenolic ethers with f-butyi chloride.5... 

A similar SET mechanism involving cation-radical intermediates 30 has also been confirmed for the reactions of phenolic ethers with diaryliodonium salts in hexafluoroisopropanol [215], The use of fluoroal-cohols as solvents in these reactions is explained by their unique ability to stabilize the aromatic cation-radicals [107],... 

Scheme 8.2 PIFA-Induced CDC reaction of phenol ether derivatives and proposed reaction pathway.

Allyl phenyl ether is pre pared by the reaction of phenol with allyl bromide as described in Section 24 11... 

Depending on the ring substituent, trifluoromethoxyben2enes can be made by the sequential chlorination—fluorination of anisole(s) (351—354). A one-step process with commercial potential is the BF (or SbF2)-cataly2ed reaction of phenol with carbon tetrachloride/hydrogen fluoride (355). Aryl trifluoromethyl ethers, which may not be accessible by the above routes,may be made by fluorination of aryl fluoroformates or aryl chlorothioformates with sulfur tetrafluoride (348) or molybdenum hexafluoride (356). 

Pyridinium chloride ([PyHjCl) has also been used in a number ofcyclization reactions of aryl ethers (Scheme 5.1-4) [4, 18]. Presumably the reaction initially proceeds by deallcylation of the methyl ether groups to produce the corresponding phenol. The mechanism of the cyclization is not well understood, but Pagni and Smith have suggested that it proceeds by nucleophilic attack of an Ar-OH or Ar-0 group on the second aromatic ring (in a protonated form) [4]. 

Azo coupling reactions with phenol ethers give in some cases the expected arylazo-phenol ether. In others, however, hydrolysis of the ether bond is observed and the arylazophenol is isolated. This ambiguity has, to the best of our knowledge, never been investigated systematically. 

The final coal product in the MeOH/KOH experiments was 20%-25% soluble in the methanol. When the methanol was removed, the resultant product was a room temperature liquid with the properties described in Table V. Apparently the polymethylphenol fraction is formed by the cleavage of phenolic ethers and subsequent methyla-tion by the CO that is present in the reaction mixture as a result of methanol decomposition. The methylation reaction has been observed before for similar systems (3). 

Other procedures include zinc-dust distillation, not generally useful except for exhaustive degradation of phenols to hydrocarbons, and various sodium and liquid ammonia cleavages of phenol ethers.3-7 These latter reactions lack generality and are often unpredictable. They require conditions too harsh for... 

It is clear that O-alkylation is favoured over C-alkylation with the heterogeneous system. Homogeneous BF3 reactions generally favour C-alkylation due to the rearrangement of the ether. The selectivity of the heterogeneous system towards ether formation is further illustrated by the reaction of phenol with... 

Low molecular weight aromatic ethers have been prepared principally by the condensation of phenolate salts with aromatic halides 82). The Ullmann condensation (81), which employs copper or its salts as catalysts has been used in most cases in the laboratory. Recently a modification of the Ullmann condensation which consists of heating copper (1) oxide, the free phenol, and the aromatic halide in s-collidine has been reported (3). This method is recommended for alkali-sensitive aromatic compounds. In addition, reaction of phenolate salts with copper (1) oxide and the aromatic halide in boiling N,N-dimethyl formamide is described. When the halogen is activated by electronegative groups as in -chloroni-... 

Table 5—Summary of Electrophilic Substitution Reactions of Phenol, Diphenyl Ether, and Anisole... 

The available rate data for the substitution reactions of phenol, diphenyl ether, and anisole are summarized in Table 5. The elucidation of the reactivity of phenol is hindered by its partial conversion in basic media into the more reactive phenoxide anion. Because of the high reaction velocity of phenol and the even greater reactivity of phenoxide ion the relative rates are difficult to evaluate. Study of the bromination of substituted phenols (Bell and Spencer, 1959 Bell and Rawlinson, 1961) by electrochemical techniques suitable for fast reactions indicates the significance of both reaction paths even under acidic conditions. 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

In the intermolecular mode, this reaction has been utilized for the preparation of products 28 from various nucleophiles, including C-nucleophiles (e. g. (3-dicarbonyl compounds). A similar reaction in the intramolecular mode provides a powerful synthetic tool for the preparation of various polycyclic compounds via oxidative biaryl coupling [21,27 - 30]. Several examples of these C-C bond forming reactions are shown in Schemes 13-15. Specifically, various dibenzoheterocyclic compounds 30 have been prepared by the oxidation of phenol ether derivatives 29 with [bis(trifluoroacetoxy)iodo]benzene in the presence of BF3-etherate in dichloromethane (Scheme 13) [27-29]. 

Carboxonium-carbenium dications have also been proposed in the reactions of aryl ethers, phenols, and naphthols, with superacids. When 2-naphthol is reacted with an excess of AICI3 (3 equivalents) and cyclohexane, the product of ionic hydrogenation is observed in 59% yield (eq 15).24 This conversion is thought to occur by double protonation of the 2-naphthol ring to give the dication 48, which is capable of abstracting hydride from cyclohexane. Similar intermediates are formed by the reactions of HF-SbFs with naphthyl ethers (eq 16).25... 

Onodera et al. [8] examined the applicability of isotachophoresis to the identification and determination of chlorinated mono- and dicarboxylic acids in chlorinated effluents. Four electrolyte systems for the separation of acids were evaluated. The potential unit values in each system were determined for the chlorinated acids. A mechanism for the reaction of phenol with hypochlorite in dilute aqueous solutions is suggested, based on results from the isotachophoretic analysis of diethyl ether extracts taken from phenol treated with hypochlorite. 

Phenol itself can be arylated multiply around the oxygen up to five times by use of excess bromobenzene (Eq. 4) [8]. The use of a less polar solvent such as o-xylene is important no reaction of phenol occurs in DMF. The lack of hexa-arylated product may be attributed to steric reasons. When the 2- and 6-positions of phenol are masked by fert-butyl groups, the 4-position is arylated (Eq. (5) and path b in Scheme 3) [10]. It is worth noting that a diaryl ether is formed by reductive elimination of the alkoxyarylpalladium intermediate when a bulky phosphine ligand is used (path d) [11]. 

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