Sodium Birch reduction

The less hindered f/ans-olefins may be obtained by reduction with lithium or sodium metal in liquid ammonia or amine solvents (Birch reduction). This reagent, however, attacks most polar functional groups (except for carboxylic acids R.E.A. Dear, 1963 J. Fried, 1968), and their protection is necessary (see section 2.6). 

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... 

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,... 

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 competing reaction in any Birch reduction is reaction of the alkali metal with the proton donor. The more acidic the proton donor, the more rapid IS the rate of this side reaction. Alcohols possess the optimum degree of acidity (pKa ca. 16-19) for use in Birch reductions and react sufficiently slowly with alkali metals in ammonia so that efficient reductions are possible with them. Eastham has studied the kinetics of reaction of ethanol with lithium and sodium in ammonia and found that the reaction is initially rapid, but it slows up markedly as the concentration of alkoxide ion in the mixture... 

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. ... 

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. 

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. 

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. 

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 ... 

Many expensive reductions such as the Birch reduction of naphthalene to isotetralin, benzene to cyclohexene, with metallic sodium and liquid ammonia, or reduction with LiAlHa, can generally be carried out electrochemically at much lower cost and under safe conditions. Electrochemical processes allow fluorinations to be carried out without using fluorine gas. Conducting polymers have been made by electrochemical processes which operate under ambient conditions, and the polymer can be synthesized, doped and shaped in film form in a single step. 

Dissolving-Metal Reduction of Aromatic Compounds and Alkynes. Dissolving-metal systems constitute the most general method for partial reduction of aromatic rings. The reaction is called the Birch reduction,214 and the usual reducing medium is lithium or sodium in liquid ammonia. An alcohol is usually added to serve as a proton source. The reaction occurs by two successive electron transfer/proto-nation steps. 

Benkeser, R. A. etal., Tetrahedron Lett., 1984, 25, 2089-2092 The use of calcium in 1,2-diaminoethane as a safer substitute for sodium or lithium in liquid ammonia for the improved Birch reduction of aromatic hydrocarbons is described in detail. 

The second approach (224-226) employs O-methylhexadehydroyohimbine (420), prepared from spiroindeno-2-(l -tetrahydro-0-carboline)-l-onederivative 416 by photolysis and subsequent reduction, as the key intermediate. The side product (418) of the photolysis was also utilized for the preparation of 420 via subsequent phosphoryl chloride treatment and sodium borohydride reduction. Birch reduction of 420 resulted in enol ether 421, which could be transformed to 15,16-didehydroyohimbinone (410), prepared previously by Szantay et al. (74, 221) as a universal precursor of the synthesis of yohimbine-type alkaloids. 

A solution of lithium, sodium, potassium or calcium in liquid ammonia can reduce a wide variety of unsaturated groups. Thus when aromatic rings are reduced by such metals in liquid ammonia, non-conjugated cyclohexadienes are produced. The reaction is called Birch reduction. 

At the outset of our studies of the reactivity of I and II, it was necessary to investigate claims that tertiary henzamides were inappropriate substrates for the Birch reduction. It had been reported that reduction of A,A-dimethylbenzamide with sodium in NH3 in the presence of tert-butyl alcohol gave benzaldehyde and a benzaldehyde-ammonia adduct. We formd that the competition between reduction of the amide group and the aromatic ring was strongly dependent on reaction variables, such as the alkali metal (type and quantity), the availability of a proton source more acidic than NH3, and reaction temperature. Reduction with potassium in NH3-THF solution at —78 °C in the presence of 1 equiv. of tert-butyl alcohol gave the cyclohexa-1,4-diene 2 in 92% isolated yield (Scheme 3). At the other extreme, reduction with lithium in NH3-THF at —33 °C in the absence of tert-butyl alcohol gave benzaldehyde and benzyl alcohol as major reaction products. ... 

The Birch reduction of dibenzofuran is reported to give 1,4-dihydro-dibenzofuran. The electrochemical reduction of dibenzofuran by solvated electrons is reported to produce a dihydrodibenzofuran and a tetrahydro-dibenzofuran, both of unspecified structure. Treatment of dibenzofuran with W-7 Raney nickel in boiling methanol gave a moderate yield of trans-2-phenylcyclohexanol, whereas treatment of dibenzofuran with Raney nickel alloy and aqueous sodium hydroxide gave a low yield of 2-biphenylol. ... 

Alkylation of the enolate of a carboxylic acid, formed as an intermediate in the Birch reduction of an aromatic acid, has been successfully exploited in synthesis, e.g., in the synthesis of gibberellic acid. A model compound 24 was reduced with sodium in diethyl ether-liquid ammonia and the resulting carbanion was alkylated with iodomethane to give 25 in ca. 80% yield87. 

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 (5-10), where sodium directly transfers an electron to an aromatic ring. An example from this chapter is found in the bimolecular reduction of ketones (9-62), where again it is... 

Thienyimethanol (360a) underwent allylic rearrangement to 4-hydroxy-2//-pyran (2) with oxalic acid at 20°C for 6 days.341 2-Thienylmethylamine (360b) with nitrous acid (Demyanov reaction) gave a mixture of 360a and 2.3 An 86% yield of a mixture of 2,6-di-te/ -bu tyl-2//- and 4//-thiopyrans 362 and 363 was obtained when 2,5-dihydrothiophene ketone 361 (readily accessible by Birch reduction of 2-pivaIoyl-5-ter/-butylthiophene) was reduced with zinc and sodium hydroxide in the presence of trimethylsilyl chloride.286... 

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