Phenolic ethers reduction

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. 

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)... 

Reduction of phenols, phenolic ethers, or phenolic esters... 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

The inertness of phenols and phenoxy phenols toward Na/liq. NH3 can be attributed to the fact that phenols are powerful proton-donors in this system, and resistance of the resultant anions toward reduction is believed to result from stabilization by resonance (10). While alkylation of low-rank coals before treatment with Na/liq. NH3 therefore offers means for establishing the presence of phenoxy phenol ethers in them, an alternative is afforded by the observation that some phenols can be reduced by concentrated solutions of lithium (11). If this latter reaction also reduces phenoxy phenols in coal, a second treatment should then cause ether-cleavage. 

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. 

Dissolving metal reductions of the benzene rings are especially important with functional derivatives of benzene such as phenols, phenol ethers and carboxylic acids (pp. 80, 82,93 and 140). 

The o-fluoro-nitroarene was attached to TentaGel resin as a phenolic ether 73 via a modified Wang-type linker. Following aminolysis of 73, reduction of the intermediate nitroaniline to di-aniline 74 proceeded poorly... 

Step 6. The catecholic and phenolic ethers were removed by treatment with hydrobromic acid. Benzyl ethers are frequently removed by reduction (e.g. hydrogenation) but reduction, of course, would not remove the methyl ether. The mechanism of the deprotection is shown below. 

The anethole ring has two functional groups - an ether and a hydrocarbon side chain with a double bond. The ether is synthesized first - by a Williamson ether synthesis from phenol and CH3I. The hydrocarbon side chain results from a Friedel-Crafts acylation of the ether. Reduction of the ketone, bromination and dehydrohalogenation are used to introduce the double bond. 

Sodium-Ammonia-Ethanol. The combination of sodium with liquid ammonia and ethanol is commonly employed in the Birch reduction (of phenol ethers), which see. 

Synthesis of the alkaloids trilobine and obaberine, containing the diphenyl ether linkages, have been accomplished from (5)-(+)-(0)-benzyl-8-bromo-A -benzoylnorarmepavine (80) by Ullmann condensation with the phenolic amide (81) followed by reductive debenzylation to give the phenolic ether (82). ... 

The phenolic aromatic ring is deactivated by deprotonation, which allows the selective reduction of the phenol ether system in the presence of a phenol90. 

O-Demethylation has been observed as well as, or instead of, nucleophilic displacement on reaction of 3,4,5-chloro/methoxy pyridazines and 4,5-chloro/methoxy-2-methyl-3(2//)-py-ridazinones with morpholine (e.g.. Scheme 63). Demethylation was observed at all ring positions, but usually adjacent to chlorine or a carbonyl group, and A -methylmorpholine was isolated, consistent with demethylation rather than hydrolysis. The demethylation can also occur with other primary and secondary amines such as diethylamine, butylamine, and piperidine, but not with pyrrolidine and aniline <87H(26)1 >. 3-Phenolic ethers of pyridazines are resistant to reductive cleavage of the aryl ether bond under the conditions of phase transfer catalytic hydrogenolysis <82T3775>. 

Birch reduction of 12-methoxypodocarpa-8,l l,13-trien-19-ol has been investigated and methods have been developed for converting the C-12 ketones into C-13 ketones. An alternative approachhas been used to transpose the aromatic oxygen function from C-12 to C-13. The best route involved mononitration of methyl podocarpate (57), reduction of the nitrophenol toluene-p-sulphonate (58) to an amine (59) with stannous chloride and then Raney nickel, and finally diazotization with isopentenyl nitrite in cold acidic methanol to atTord the phenol ether. 

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