Lithium 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). 

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). 

Birch reduction of indole with lithium metal in THF in the presence of trimethylsilyl chloride followed by oxidation with p-benzoquinone gave l,4-bis(trimethylsilyl)indoIe (106). This is readily converted in two steps into l-acetyl-4-trimethylsilylindole. Friedel-Crafts acylation of the latter compound in the presence of aluminum chloride yields the corresponding 4-acylindole (107) (82CC636). 

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. 

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. 

For the reduction of conjugated enones to saturated alcohols, Procedure 5 (section V) may be modified by adding methanol in place of ammonium chloride a sufficient excess of lithium is present to effect reduction of the intermediate saturated ketone to the alcohol. Procedure 2 (section V) for effecting Birch reductions is also useful for reduction of conjugated enones to saturated alcohols. Thus, 17-ethyl-19-nortestosterone affords crude 17a-ethyl-5a-estrane-3) ,17) -diol of mp 174-181°, reported mp 181-183°, in quantitative yield. 

When double bonds are reduced by lithium in ammonia or amines, the mechanism is similar to that of the Birch reduction (15-14). ° The reduction with trifluoro-acetic acid and EtsSiH has an ionic mechanism, with H coming in from the acid and H from the silane. In accord with this mechanism, the reaction can be applied only to those alkenes that when protonated can form a tertiary carbocation or one stabilized in some other way (e.g., by a OR substitution). It has been shown, by the detection of CIDNP, that reduction of a-methylstyrene by hydridopenta-carbonylmanganese(I) HMn(CO)5 involves free-radical addition. ... 

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. 

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. ... 

Because dianion formation appears to be more important when lithium rather than potassium is used, many of the Birch reductions and reduction-alkylations of I and II that have been developed utilize potassium as the reducing metal. Piperylene is added prior to the alkylation reagent to consume any remaining metal and thereby prevent reduction of the alkylation reagent. In the event that the alkylation reagent is unstable to strong bases (e.g. homoallylic and arylethyl halides) LiBr is added to reduce the basicity of the reaction medium. 

FIGURE 17a. Alternative routes for vinylogous birch reductive cleavage of cinnamyl ether promoted by lithium naphthalenide. Reprinted with permission from Reference 22. Copyright 1996 American Chemical Society... 

The superfluous bromine is then removed by reduction with zinc in acetic acid (26-1). The 20 ketone is next protected against the strongly reducing conditions in the subsequent step by conversion to the ethylene glycol acetal (26-2). Birch reduction with lithium in liquid ammonia in the presence of ethanol proceeds as usual to the dihydrobenzene (26-3). Treatment of this last product with mineral acid serves to hydrolyze both the enol ether at the 3 position and the acetal at the... 

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