Aromatic Birch reduction

Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1. Tetrahedron 1986, 42, 6354. Cornprehensice Organic Synthesis 1991, voJ. 8, 107. 

Akhrem, A. A. Reshetova, I. G. Titov, Yu. A. 1972, Birch Reduction of Aromatic Compound, Plenum New York... 

Metal-ammonia-alcohol reductions of aromatic rings are known as Birch reductions, after the Australian chemist Arthur J Birch who demonstrated their usefulness begin nmg m the 1940s... 

Birch reduction (Section 11 11) Reduction of an aromatic nng to a 1 4 cyclohexadiene on treatment with a group I metal (Li Na K) and an alcohol in liquid ammonia Boat conformation (Section 3 7) An unstable conformation of cyclohexane depicted as... 

In the presence of a proton source, the radical anion is protonated and further reduction occurs (the Birch reduction Part B, Section 5.5.1). In general, when no proton source is present, it is relatively difficult to add a second electron. Solutions of the radical anions of aromatic hydrocarbons can be maintained for relatively long periods in the absence of oxygen or protons. 

The steroidal total synthesis intermediate (18) contains an aromatic ring of the type found in 5-methoxytetralin, a compound which undergoes Birch reduction slowly. As a consequence, compound (18) is reduced with... 

The A-ring of the 17-ol (25) derived from equilenin 3-methyl ether is reduced rapidly under Birch reduction conditions, since the 1,4-positions are unsubstituted. The B-ring is reduced at a much slower rate, as is characteristic of aromatic compounds in which 1,4-reduction can occur only if a proton enters an alkylated position. Treatment of (25) with sodium and t-butyl alcohol in ammonia reduces only the A-ring to afford the corresponding 1,4-dihydro compound in over 85% yield.On the other hand,... 

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. 

The term Birch reduction was originally applied to the reduction of aromatic compounds by alkali metals and an alcohol in ammonia. In recent years many chemists have used the term to include all metal-ammonia reductions, whether an alcoholic proton source is present or not. The author prefers to use the term Birch reduction to designate any reduction carried out in ammonia with a metal and a proton donor as or more acidic than an alcohol, since Birch customarily used such a proton donor in his extensive pioneering work. The term metal-ammonia reduction is best reserved for reductions in which ammonia is the only proton donor present. This distinction in terminology emphasizes the importance of the acidity of the proton donor in the reduction process. 

Krapcho and Bothner-By made additional findings that are valuable ii understanding the Birch reduction. The relative rates of reduction o benzene by lithium, sodium and potassium (ethanol as proton donor) wer found to be approximately 180 1 0.5. In addition, they found that ben zene is reduced fourteen times more rapidly when methanol is the protoi donor than when /-butyl alcohol is used. Finally, the relative rates of reduc tion of various simple aromatic compounds by lithium were deteiTnined these data are given in Table 1-2. Taken together, the above data sho that the rate of a given Birch reduction is strikingly controlled by the meta... 

Various other observations of Krapcho and Bothner-By are accommodated by the radical-anion reduction mechanism. Thus, the position of the initial equilibrium [Eq. (3g)] would be expected to be determined by the reduction potential of the metal and the oxidation potential of the aromatic compound. In spite of small differences in their reduction potentials, lithium, sodium, potassium and calcium afford sufficiently high concentrations of the radical-anion so that all four metals can effect Birch reductions. The few compounds for which comparative data are available are reduced in nearly identical yields by the four metals. However, lithium ion can coordinate strongly with the radical-anion, unlike sodium and potassium ions, and consequently equilibrium (3g) for lithium is shifted considerably... 

A major advance in the art of effecting Birch reductions was the discovery by Wilds and Nelson that lithium reduced aromatic steroids much more efficiently than had hitherto been possible with sodium or potassium. The superiority originally was attributed to the somewhat higher reduction potential of lithium as compared to the other alkali metals. Later work showed that the following explanation is more probable. ... 

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... 

A remarkable feature of the Birch reduction of estradiol 3-methyl ether derivatives, as well as of other metal-ammonia reductions, is the extreme rapidity of reaction. Sodium and -butyl alcohol, a metal-alcohol combination having a comparatively slow rate of reduction, effects the reduction of estradiol 3-methyl ether to the extent of 96% in 5 minutes at —33° lithium also effects complete reduction under the same conditions as is to be expected. Shorter reaction times were not studied. At —70°, reduction with sodium occurs to the extent of 56 % in 5 minutes, although reduction with lithium is virtually complete (96%) in the same time. (The slow rates of reduction of compounds of the 5-methoxytetralin type is exemplified by 5-methoxy-tetralin itself with sodium and f-butyl alcohol reduction occurs to the extent of only 50% in 6 hours vs. 99+% with lithium.) The iron catalyzed reaction of sodium with alcohols must be very fast since it competes so well with the rapid Birch reduction. One cannot compensate for the presence of iron in a Birch reduction mixture containing sodium by adding additional metal to extend the reaction time. The iron catalyzed sodium-alcohol reaction is sufficiently rapid that the aromatic steroid still remains largely unreduced. 

Many aromatic steroids submitted to the Birch reduction contain hydroxyl groups which are deprotonated to the corresponding alkoxides during the reduction, particularly if a tertiary alcohol is used as the proton donoi. The steroidal alkoxides and the one derived from the proton donor often precipitate and cause foaming of the reaction mixture, as was noted by Wilds and Nelson. These alkoxides can be kept in solution by adding an excess of the proton donor alcohol to the mixture the alcohol also assists in dissolving the starting hydroxylic steroid. A particularly useful reaction medium for hydroxylic steroids contains ammonia, tetrahydrofuran and -butyl alcohol in the volume ratio of 2 1 (Procedure 2, section V). This mixture... 

Reduction of a conjugated enone to a saturated ketone requires the addition of two electrons and two protons. As in the case of the Birch reduction of aromatic compounds, the exact order of these additions has been the subject of study and speculation. Barton proposed that two electrons add initially giving a dicarbanion of the structure (49) which then is protonated rapidly at the / -position by ammonia, forming the enolate salt (50) of the saturated ketone. Stork later suggested that the radical-anion (51), a one electron... 

The crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

Sodium, liquid ammonia. The utility of this method depends on the nature of the substituents on the aromatic ring. Rings containing electron-withdrawing groups will be reduced, as in the classic Birch reduction. 

The reduction of aromatic compounds 1 by alkali metals in liquid ammonia in the presence of an alcohol is called the Birch reduction, and yields selectively the 1,4-hydrogenated product " 2. 

For the Birch reduction of mono-substituted aromatic substrates the substituents generally influence the course of the reduction process. Electron-donating substituents (e.g. alkyl or alkoxyl groups) lead to products with the substituent located at a double bond carbon center. The reduction of methoxybenzene (anisole) 7 yields 1-methoxycyclohexa-1,4-diene 8 ... 

The elaboration of a method for the reduction of aromatic rings to the corresponding dihydrobenzenes under controlled conditions by A. J. Birch opened a convenient route to compounds related to the putative norprogesterone. This reaction, now known as the Birch reduction,is typified by the treatment of... 

This procedure is illustrative of the general method of reduction of aromatic compounds by alkali metals in liquid ammonia known as the Birch reduction. The theoretical and preparative aspects of the Birch reduction have been discussed in excellent reviews,4-4... 

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