The Birch Reduction

We saw in Section 9.10 that the combination of a Group 1 metal and liquid ammonia is a powerful reducing system capable of reducing alkynes to trans alkenes. In the presence of an alcohol, this same combination reduces arenes to nonconjugated dienes. Thus, treatment of benzene with sodium and methanol or ethanol in liquid ammonia converts it to 1,4-cyclohexadiene. 

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

The Birch reduction not only provides a method to prepare dienes from arenes, which cannot be accomplished by catalytic hydrogenation, but also gives a nonconjugated diene system rather than the more stable conjugated one. 

Step 1 An electron is transferred from sodium (the reducing agent) to the n system of the aromatic ring. The prodnct is an anion radical. 

Step 2 The anion radical is a strong base and abstracts a proton from methanol. 

Alkyl-substituted arenes give 1,4-cyclohexadienes in which the alkyl group is a substituent on the donble bond. 

PROBLEM 11.5 A single organic product was isolated after Birch reduction of p-xylene. Suggest a reasonable structure for this substance. 

The mechanism by which the Birch reduction of benzene takes place (Mechanism 11.1) is analogous to the mechanism for the metal-ammonia reduction of alkynes. It involves a sequence of four steps in which steps 1 and 3 are single-electron transfers from the metal and steps 2 and 4 are proton transfers from the alcohol. 

The regioselectivity of Birch reduction of aikoxy-substituted benzenes is the same as for a Iky I benzenes. What did Arthur Birch isoiate when he carried out the foiiowing reaction over 

As in Mechanism 9.1 for the reduction of alkynes by Group 1 metals, the sodium dissociates in liquid ammonia to its Na ion and an electron, both of which are solvated by ammonia. These solvated electrons are represented in the equation as e am). 

The mechanism of the Birch reduction (shown next) is similar to the sodium/liq-uid ammonia reduction of alkynes to rram-alkenes (Section 9-9C). A solution of sodium in liquid ammonia contains solvated electrons that can add to benzene, forming a radical anion. The strongly basic radical anion abstracts a proton from the alcohol in the solvent, giving a cyclohexadienyl radical. The radical quickly adds another solvated electron to form a cyclohexadienyl anion. Protonation of this anion gives the reduced product. 

The Birch reduction involves twice adding a solvated electron, followed by a proton, to the aromatic ring. Preceding step Formation of solvated electrons in the ammonia solution. 

A carbon hearing an elecfron-wifhdrawing carbonyl group is reduced 

---

Analysis The strategy for any modem syntheses of these compounds would be based on the Diels-Alder reaction or the Birch reduction ... 

Synthesis Since we can make both compounds from the same intermediate 395A, we ll use the Birch reduction route ... 

In polycyclic systems the Birch reduction of C—C double bonds is also highly stereoselective, e.g. in the synthesis of the thermodynamically favored trans-fused steroidal skeletons (see p. 104 and p. 278). 

The Birch reductions of C C double bonds with alkali metals in liquid ammonia or amines obey other rules than do the catalytic hydrogenations (D. Caine, 1976). In these reactions regio- and stereoselectivities are mainly determined by the stabilities of the intermediate carbanions. If one reduces, for example, the a, -unsaturated decalone below with lithium, a dianion is formed, whereof three different conformations (A), (B), and (C) are conceivable. Conformation (A) is the most stable, because repulsion disfavors the cis-decalin system (B) and in (C) the conjugation of the dianion is interrupted. Thus, protonation yields the trans-decalone system (G. Stork, 1964B). 

Section 1111 An example of a reaction m which the ring itself reacts is the Birch reduction The ring of an arene is reduced to a nonconjugated diene by treatment with a Group I metal (usually sodium) m liquid ammonia m the presence of an alcohol... 

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 Y appendage of 2-cyclohexenone 191 cannot be directly disconnected by an alkylation transform. (y-Extended enolates derived from 2-cyclohexenones undergo alkylation a- rather than y- to the carbonyl group). However, 191 can be converted to 192 by application of the retro-Michael transform. The synthesis of 192 from methoxybenzene by way of the Birch reduction product 193 is straightforward. Another synthesis of 191 (free acid) is outlined in... 

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 application of the Birch reduction to ethers of estradiol by A. J. Birch opened up the area of 19-norsteroids to intensive research. The major Birch reduction product is an enol ether which affords either a 3-keto-A -or a 3-keto-A -19-norsteroid depending upon the hydrolysis conditions. Various 19-norsteroids have been found to have useful clinical activity compounds (30), (31), and (32) are oral contraceptive agents and compound (33) has been used as an oral anabolic agent. Several of these compounds were prepared on an industrial scale for a number of years by the Birch reduction of estradiol derivatives. 

The Birch reduction of a benzenoid compound involves the addition of two electrons and two protons to the ring. The order in which these additions occur has been the subject of both speculation and study. Several reviews of the subject are available and should be consulted for details. The present discussion is concerned with summarizing data that is relevant to understanding the reaction from the preparative point of view. For convenience, reaction intermediates are shown without indicating their solvation by liquid ammonia. This omission should not obscure the fact that such solvation is largely responsible for the occurrence of the Birch reduction. 

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... 

Bates and his associates have found that cyclohexadienyl carbanion itself protonates at the central carbon atom from three to eight times as rapidly as at a terminal one, but the conditions involved were different from those encountered in a Birch reduction. Since the Birch reduction of many 3-meth-oxyestra-l,3,5(10)-triene derivatives affords 1,4-dihydro compounds in yields approaching 90%, the cyclohexadienyl carbanions involved in these reductions must protonate about eighteen times faster at the central carbon atom than at a terminal one. 

TABLE 1-5 Effect of Iron on the Birch Reduction of Estradiol 3-Methyl Ether by Lithium, Sodium and Potassium" ... 

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. 

Our current knowledge of the Birch reduction makes clear that the reaction is a complex one, especially with regard to the various factors that determine... 

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... 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

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... 

Estrone methyl ether (100 g, 0.35 mole) is mixed with 100 ml of absolute ethanol, 100 ml of benzene and 200 ml of triethyl orthoformate. Concentrated sulfuric acid (1.55 ml) is added and the mixture is stirred at room temperature for 2 hr. The mixture is then made alkaline by the addition of excess tetra-methylguanidine (ca. 4 ml) and the organic solvents are removed. The residue is dissolved in heptane and the solution is filtered through Celite to prevent emulsions in the following extraction. The solution is then washed threetimes with 500 ml of 10 % sodium hydroxide solution in methanol to remove excess triethyl orthoformate, which would interfere with the Birch reduction solvent system. The heptane solution is dried over sodium sulfate and the solvent is removed. The residue is satisfactory for the Birch reduction step. Infrared analysis shows that the material contains 1.3-1.5% of estrone methyl ether. The pure ketal may be obtained by crystallization from anhydrous ethanol, mp 99-100°. Acidification of the methanolic sodium hydroxide washes affords 10-12 g of recovered estrone methyl ether. 

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. 

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... 

Reaction of estrone methyl ether with methyl Grignard reagent followed by Birch reduction and hydrolysis of the intermediate enol ether affords the prototype orally active androgen in the 19-nor series, normethandrolone (69). ° (Note that here again the addition of the methyl group proceeded stereoselectively by approach from the least hindered side.) The preparation of the ethyl homolog starts by catalytic reduction of mestranol treatment of the intermediate, 70, under the conditions of the Birch reduction and subsequent hydrolysis of the intermediate enol ether yields norethandrolone (71). ... 

Apparently, 1,4-dihydrobenzoic acid has been prepared only by the Birch reduction of benzoic acid, as illustrated by the present procedure.2 3... 

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... 

---