Conjugated Birch reduction

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). 

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

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... 

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. 

Ordinary alkenes are usually unaffected by Birch-reduction conditions, and double bonds may be present in the molecule if they are not conjugated with the ring. However, phenylated alkenes, internal alkynes (p. 1009), and conjugated alkenes (with C=C or C=0) are reduced under these conditions. 

Note that (30) is the only possible Birch reduction product in which both electron-donating groups are on double bonds. Vigorous acid hydrolysis moves the double bond into conjugation. 

Non-conjugated enone (31) is clearly a Birch reduction product from ether (33). Grlgnard disconnection leaves aldehyde (34), and FGA reveals a condensation product from (35). 

Go, finally, (38) must be the Birch reduction product, derived from (44) via (45). This time base was used to move the double bond into conjugation. Synthesis ... 

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... 

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. 

In contrast to the ester enolates, the a.O-carboxylic dianions are intrinsically more reactive and their use in conjugate reactions is thus limited. Typically, a-substituted-a.O-carboxylic dianions add exclusively to a,(3-unsaturated esters155a and nitroalkenes,155b while additions to ot,(3-enones are sensitive to the substitution pattern of the enones.155c>d Notable is the conjugate addition of dihydrobenzoic acid dianions (207), from Birch reduction of benzoic acids, to oi,3-unsaturated esters (Scheme 77).155e... 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

Reduction of substituted benzenes with sodium (or lithium) in liquid ammonia in the presence of a proton source (such as methanol, ethanol, etc.) leads to a substituted, non-conjugated cyclohexadiene as a result of 1,4-addition of hydrogen (the Birch reduction).16 With benzene the product is cyclohexa-1,4-diene as a result of the following mechanistic pathway. 

Non-conjugated dienes isomerize during complexation to afford tricarbonyliron-coordinated conjugated dienes. This isomerization has been applied to a wide range of substituted cyclohexa-1,4-dienes available by Birch reduction from aromatic... 

It turned out that the Birch reduction of 76 R=Me had already been done in 1958 by the standard sodium in liquid ammonia procedure but gave a low yield ( 20%) of the conjugated ketone as the first compound isolated.14 Guillou and her team improved on this by using lithium and r-BuOH at low temperature to give 78 in nearly quantitative yield.15 The reductive amination needed only NaBH4 in MeOH at room temperature and gave 78% of the enol ether of 73 from which the synthesis of 72 was completed. 

We have to choose between making a five-membered ring 28 or a six-membered ring 27 and we shall choose the latter since it offers more possibilities. Disconnection at the branchpoint gives synthon 20 that can simply be an alkyl halide. The nucleophilic synthon 29 could be an enolate providing we move the alkene out of conjugation 30 and this leads back to a Birch reduction product. 

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