Phenols Birch 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. 

Occasionally we have found iron contaminants in aromatic steroids that have not been adequately purified. The methylation of a phenolic steroid with methyl sulfate and alkali is often carried out just prior to a Birch reduction and iron in the tap water precipitates with the steroid during the... 

Direct Electron Transfer. We have already met some reactions in which the reduction is a direct gain of electrons or the oxidation a direct loss of them. An example is the Birch reduction (15-14), where sodium directly transfers an electron to an aromatic ring. An example from this chapter is found in the bimolecular reduction of ketones (19-55), where again it is a metal that supplies the electrons. This kind of mechanism is found largely in three types of reaction, (a) the oxidation or reduction of a free radical (oxidation to a positive or reduction to a negative ion), (b) the oxidation of a negative ion or the reduction of a positive ion to a comparatively stable free radical, and (c) electrolytic oxidations or reductions (an example is the Kolbe reaction, 14-36). An important example of (b) is oxidation of amines and phenolate ions ... 

The isolated double bonds in the dihydro product are much less easily reduced than the conjugated ring, so the reduction stops at the dihydro stage. Alkyl and alkoxy aromatics, phenols, and benzoate anions are the most useful reactants for Birch reduction. In aromatic ketones and nitro compounds, the substituents are reduced in preference to the Dissoiving-Memi... 

Catalytic hydrogenation of benzo [6]thiophene (mainly to ethylbenzene) has been studied in the presence of a molybdenum trisulfide catalyst.40 Birch reduction of benzo[6]thiophene 428 429 and its 5-methyl derivative428 affords 2-ethyl- and 2-ethyl-4-methylthio-phenol, respectively. 

The phenolic hydroxy group is deprotected in the course of the Birch reduction, so it must again be protected. 

Since the phenolic hydroxy group is deacetylated during the Birch reduction it must once again be acetylated in a third step. 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

Regioselectivity of the Birch reductive alkylation of polysubstituted biaryls is affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced and then alkylated, whereas phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated on the second ring, provided that the acidic proton has been removed prior to the Li-NH3 reduction.300... 

Q Predict the products of oxidation and reduction of the aromatic ring, including hydrogenation, chlorination, and Birch reduction. Predict the products of the oxidation of phenols. 

Studies aimed at the synthesis of the tetracyclic steroid skeleton from dehydro-abietic acid have centred, in their initial stages, on transformations of the C-13 isopropyl group. The full paper describing the conversion of methyl 12-acetyl-abieta-8,ll,13-trien-18-oate into methyl 13-hydroxypodocarpa-8,ll,13-trien-18-oate by nitrodeacylation and dealkylation reactions, has appeared. Birch reduction of the methyl ether of the phenol afforded the a/5-unsaturated ketone (56) which is a useful synthetic intermediate. Methods for the conversion of podocarpic acid into the a) -unsaturated ketones (57 R = CO2H and CHjOAc) have been investigated reduction of the ester (58 R = C02Me) with lithium in liquid ammonia, which was accompanied by decarboxylation, gave only a... 

The total synthesis of the 7(8 lla)oheo-steroid (128) has been achieved by two different routes. The shorter approach (Scheme 10) involves a four-step synthesis of the triketone (124) from (122), followed by stepwise cyclization to (126) and reduction to the tetracyclic phenol (127a). Birch reduction of ring a of (127b) then gave the )Sy-ethylenic keto-derivative (128). ... 

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

Birch reduction of aromatic ethers is well known to afford alicyclic compounds such as cyclohexadienes and cyclohexenones, from which a number of natural products have been synthesized. Oxidation of phenols also affords alicyclic cyclohexadienones and masked quinones in addition to C—C and/or C—O coupled products. All of them are regarded as promising synthetic intermediates for a variety of bioactive compounds including natural products. However, in contrast to Birch reduction, systematic reviews on phenolic oxidation have not hitherto appeared from the viewpoint of synthetic organic chemistry, particularly natural products synthesis. In the case of phenolic oxidation, difficulties involving radical polymerization should be overcome. This chapter demonstrates that phenolic oxidation is satisfactorily used as a key step for the synthesis of bioactive compounds and their building blocks. 

Selective Birch reductions were investigated with a number of electron-rich fused pyrrole substrates <05JOC2054>. Deprotonation of phenol 79 followed by treatment of phenoxide 80 with sodium metal in ammonia gave 81. The same reaction with the corresponding 7-methoxy derivative gave a mixture that contained over-reduced products. 

Birch reduction of phenols [1, 56, before references]. Although free phenols are regarded as generally not reducible under Birch conditions, Fried eta . 1 noted some reduction in the case of 2-hydroxy-7-methoxyfluorene (1). They then noted that if the concentration of lithium is increased from 1.5 to 4 M essentially complete reduction of the phenolic ring occurs. Thus estrone (4) furnishes (5) in 75% yield. 

Although one successful synthesis of equilin from equilenin methyl ether has been reported, Birch reductions of such substrates are non-selective, since reduction of both aromatic rings occurs. Use of the free phenol in such reductions, however, has neatly overcome these difficulties. Formation of the naphthoxide ion prior to Birch reduction with lithium-ammonia at — 70 °C has resulted in high yields of equilin. Surprisingly, further reduction of equilin 17-dimethylketal... 

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. 

As outlined in Scheme 6, isovanillin (35) was converted to aryl iodide 36 via MOM-protection, protection of the aldehyde, and subsequent iodination. Hydrolysis of the acetal and Wittig olefination delivered phenol 37 after exposure of the intermediate aldehyde to methanolic hydrochloric acid. Epoxide 41, the coupling partner of phenol 37 in the key Tsuji-Trost-reaction, was synthesized from benzoic acid following a procedure developed by Fukuyama for the synthesis of strychnine [62]. Birch reduction of benzoic acid with subsequent isomerization of one double bond into conjugation was followed by esterification and bromohydrin formation (40). The ester was reduced and the bromohydrin was treated with base to provide the epoxide. Silylation concluded the preparation of epoxide 41, the coupling partner for iodide 37, and both fragments were reacted in the presence of palladium to attain iodide 38. 

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