Phenolic ethers preparation

Several derivatives of phenols have been found to be especially suited for hydrogenolysis by catalytic hydrogenation. Phenol ethers prepared by the reaction of phenols with l-phenyl-5-chlorotetrazole or with 2-chlorobenzoxazole are hydrogenolyzed over 5% palladium on carbon or over platinum oxide, but not over Raney nickel. The hydrogenations are run at 35 °C in benzene, ethanol or tetrahydrofuran, and give 35-89% yields of the corresponding hydrocarbons. The reaction sequence is exemplified by conversion of phenylphenols to biphenyls (equation 77). 

The Gattermann-Koch formylatioii was found unsuited to the preparation of aldehydes from phenols and phenol ethers such aldehydes may be obtained by Gatteimann s aldehyde reaction. 

The tetrahydropyranyl ether, prepared from a phenol and dihydropyran (HCl/ EtOAc, 25°, 24 h), is cleaved by aqueous oxalic acid (MeOH, 50-90°, 1-2 h). ... 

Zn, HOAc, 25°, 1 h, 88-96% yield. Phenacyi andp-bromophenacyl ethers of phenols are stable to 1 % ethanolic alkali (reflux, 2 h), and to 5 N sulfuric acid in ethanol-water. The phenacyi ether, prepared from /3-naphthol, is cleaved in 82% yield by 5% ethanolic alkali (reflux, 2 h). 

A carbonyl group cannot be protected as its ethylene ketal during the Birch reduction of an aromatic phenolic ether if one desires to regenerate the ketone and to retain the 1,4-dihydroaromatic system, since an enol ether is hydrolyzed by acid more rapidly than is an ethylene ketal. 1,4-Dihydro-estrone 3-methyl ether is usually prepared by the Birch reduction of estradiol 3-methyl ether followed by Oppenauer oxidation to reform the C-17 carbonyl function. However, the C-17 carbonyl group may be protected as its diethyl ketal and, following a Birch reduction of the A-ring, this ketal function may be hydrolyzed in preference to the 3-enol ether, provided carefully controlled conditions are employed. Conditions for such a selective hydrolysis are illustrated in Procedure 4. 

Oxidative reactions frequently represent a convenient preparative route to synthetic intermediates and end products This chapter includes oxidations of alkanes and cycloalkanes, alkenes and cycloalkenes, dienes, aromatic fluorocarbons, alcohols, phenols, ethers, aldehydes and ketones, carboxylic acids, nitrogen compounds, and organophosphorus, -sulfur, -selenium, -iodine, and -boron compounds... 

The azidomethyl ether, used to protect phenols and prepared by the displacement of azide on the chloromethylene group, is cleaved reductively with LiAH4 or by hydrogenolysis (Pd-C, H2). It is stable to strong acids, permanganate, and free-radical brominations. ... 

The tetrahydropyranyl ether, prepared from a phenol and dihydropyran (HCl/EtOAc, 25°, 24 h) is cleaved by aqueous oxalic acid (MeOH, 50-90°, 1-2 h). Tonsil, Mexican Bentonite earth, HSZ Zeolite, and H3[PW,204o] have also been used for the tetrahydropyranylation of phenols. The use of [Ru(ACN)3(triphos)](OTf)2 in acetone selectively removes the THP group from a phenol in the presence of an alkyl THP group. Ketals of acetophenones are also cleaved. ... 

The key structural features of compound 1 are the chiral cis-diaryl benzox-athiin fused ring system, two phenols, and one phenol ether linkage with the pyrrolidinylethanol. Originally, SERM 1 was prepared by medicinal chemists from a key ketone intermediate 5 shown in Scheme 5.1. Compound 5 was prepared in four steps with rather low yield [4a], Among these steps, the high temperature de-methylation step and the use of extremely toxic MOM-C1 were not particularly suitable for scale-up. The ketone 5 was then brominated with PhMe3NBr3 (PTAB) and coupled with thiophenol 7 to produce adduct 8. The key step of the synthesis was the conversion of adduct 8 to cis-diaryl benzoxathiin 9 under the Kursanov-Parne reaction conditions (TFA/Et3SiH). This novel reaction allowed the formation... 

Of the substituted phenol ethers the amino-derivatives of anisole (anisidine) and phenetole (pkenetidine) may be mentioned. They are prepared from the nitrophenols by alkylation and subsequent reduction of the nitro-group. 

A. Preparation of the Phenolic Ether p-(l-Phenyl-5-tetrazolyl-oxy)biphenyl. In a 1-1. round-bottomed flask fitted with an efficient condenser is placed a magnetic bar for stirring. Seventeen grams (0.1 mole) of p-phenylphenol, 18.1 g. (0.1 mole) of... 

Dissolve 0 01 mol of the phenolic ether in 10 ml. of warm chloroform, and also (separately) 0-01 mol of picric acid plus 5 per cent, excess (0 -241 g.) in 10 ml. of chloroform. Stir the picric acid solution and pour in the solution of the phenolic ether. Set the mixture aside in a 100 ml beaker and allow it to crystallise. Recrystallise the picrate from the minimum volume of chloroform. In most cases equally satisfactory results may be obtained by conducting the preparation in rectified spirit (95 per cent. C2H5OH). The m.p. should be determined immediately after recrystallisation. It must be pointed out, however, that the picrates of aromatic ethers suffer from the disadvantage of being comparatively unstable and may undergo decomposition during recrystallisation. 

A particularly useful chromene synthesis involves the thermal rearrangement in an inert solvent of aryl propargyl ethers (33) (62CPB926,63CPB1042) which are conveniently prepared from a phenol and a chloroalkyne. An indication of the ease of cyclization is apparent from the presence of chromene in the ethers prepared in this manner. 

Cleavage conditions for alkyl benzyl ethers prepared from acid-labile benzyl alcohols are similar to those for the corresponding benzyl esters (Table 3.30). Aryl benzyl ethers, however, are generally cleaved more easily by acidolysis than esters or alkyl ethers. Phenols etherified with hydroxymethyl polystyrene, for instance, can even be released by treatment with TFA (Entry 1, Table 3.31). It has also been shown that Wang resin derived phenyl ethers are less stable than Wang resin derived esters towards refluxing acetic acid [29]. Alternatively, boron tribromide may be used to cleave aryl ethers from hydroxymethyl polystyrene [573],... 

GATTERMANN ALDEHYDE SYNTHESIS. Preparation of aldehydes of phenols, phenol ethers, or heterocyclic compounds hy treatment of the aromatic substrate with hydrogen cyanide and hydrochloric acid in the presence of Lewis acid catalysts. 

The pure o- and m-compounds can be prepared in a similar manner, (iv.) Instead of the hydrocarbons the phenol ethers which react with great ease can be employed the same rules as to position apply. 

An aqueous solution of the substance is gently warmed, when a vigorous evolution of nitrogen occurs, and a dark coloured oil, smelling strongly of phenol, separates. It can be extracted with ether and tested for phenol (see Preparation 352). 

Dialkyl sulfates can replace the halogen derivatives, and this modification is especially useful for the preparation of phenolic ethers ... 

The Gatterman-Koch formylation is unsuitable for the preparation of aldehydes from phenols and phenolic ethers owing to the formation of complexes with the Lewis acid. 

Phenolic ketones may be prepared by the Hoesch acylation reaction, which may be regarded as an extension of the Gattermann aldehyde synthesis (Section 6.10.1, p. 990). The procedure involves reaction of a nitrile with a phenol (or phenolic ether) in the presence of zinc chloride and hydrogen chloride best results are usually obtained with polyhydric phenols or their ethers, as for example in the preparation of phloroacetophenone (Expt 6.125). The formation of phenolic ketones by means of the Fries rearrangement of phenolic esters with aluminium chloride is discussed on p. 976. 

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]. 

Under similar conditions, the phenanthro-fused thiazoles, isoxazoles and pyrimidines 32 (Scheme 14) can be prepared by oxidative coupling of the respective phenol ethers 31 [31,32]. 

Kita and co-workers have developed a concise and high-yielding procedure for preparing the pyrroloiminoquinone derivatives (158), which are key precursors of antitumor marine alkaloids, makaluvamine D (54), I (55), and M (56), from the phenol ether derivatives (157) bearing an alkylazido side chain using PIFA-TMSOTf [122] (Scheme 30). 

Williamson synthesis of phenyl alkyl and dialkyl ethers. Phenols react with alkyl halides in 20% aqueous NaOH containing 1 equiv. of this surfactant at 80° to form phenolic ethers in 85-97% yield. There is no reaction in the absence of CTAB. This procedure is not useful for preparation of dialkyl ethers from alcohols and alkyl halides. Instead, the alkyl chloride, alcohol, a trace of water, and CTAB are heated in THF at 70° with NaOH (2 equiv.). 

Bushby has examined the FeCl3-mediated oxidation of hexyl-protected (Hex) phenol ether units in the preparation of triphenylene-based liquid crystals [63]. This strategy allows the formation of unsymmetrically substituted products 75a-l (Table 18) [64]. The use of methanol in the work-up is critical in order to obtain the products in good yield. If the protecting group on the phenol component is isopropyl (74m), the coupling reaction occurs to give the unprotected phenols 76a-c directly (Scheme 17) [65]. 

---