Birch reduction enone

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. 

Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone oxidation of the alcohol at 17 leads to dione Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group... 

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). 

With an effective strategy for construction of the diazofluorene established, we set out to prepare the coupling partners required for synthesis of (—)-kinamycin F (6). The synthesis of the enone 117 began with meta-cresol (128, Scheme 3.23). Silylation formed the silyl ether 119 in nearly quantitative yield. Birch reduction of the silyl ether 119 formed the cyclohexadiene derivative 129 in excellent yield. Asymmetric dihydroxylation [52] of 129 occurred regioselectively to afford the... 

Birch reduction of the norgetrel intermediate 5 oil owed by hydrolysis of the enol ether gives the enone oxidation of the alcohol at 17 leads to dione 7. Fermentation of that intermediate in the presence of the mold PeniciIlium raistricky serves to introduce a hydroxyl group at the 15 position W. Acetal formation with neopentyl glycol affords the protected ketone which consists of a mixture of the A and A isomers (2 ) hindrance at position 17 ensures selective reaction of the 3 ketone. The... 

Birch reduction, followed by acid treatment and addition of diazomethane leads to the A9(11)-enone 159 in 41% yield. Then, the double bond is hydrogenated and, by using PhSeCl and hydrogen hydroperoxide, the double bond A13 is formed. Treatment of the enone with lithium disopropylcuprate-dimethyl sulfide complex gives an intermediate enolate that is trapped again using PhSeCl. Enone 160 is obtained via oxidative elimination (62%). 

Birch reduction of enones provides for a number of useful synthetic applications ... 

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 third is partial or total reduction of an aromatic ring. Any catalogue lists a vast number of available substituted benzene rings. Saturated compound 8 can obviously be made by total reduction of 9 but it may not be obvious that partial reduction (Birch) allows the enone 11 also to be made from 9. Birch reduction is the only new method here so we shall revise the Robinson and the Diels-Alder and concentrate on Birch. 

Reduction of benzocyclobutenes.J Birch reduction of 1, available from m-hydroxybenzaldehyde, provides the enone 2 after hydrolysis of the intermediate. This enone is a useful precursor to the cyclobutane monoterpenes grandisol (4) and lineaton (5). 

Another approach for annulation at the less substituted carbon is to first form the kinetic enolate using one of several methods (e.g., LDA, Birch reduction of an enone, conjugate addition of an organocuprate to an enone) followed by reaction with MVK and cyclization. 

The normal Birch reduction is most interesting when applied to aromatic ethers 209 or acids 213. The addition of two electrons may make a dianion in which the charges keep away from the ether 210 but conjugate with the acid 214. Protonation of 210 gives the enol ether 211 and hence the non-conjugated enone 212. The dianion 214 has a proton which transfers to the less stable anion leaving the enolate 215 that can be alkylated to give 216. None of these compounds is chiral and there appears to be little scope for asymmetric induction. 

C, Synthesis.—Atisine and Veatchine Types. Zalkow and co-workers developed syntheses of intermediates potentially transformable into atisine-type alkaloids, starting with podocarpic acid. The general approach is illustrated by a synthesis" of an ajaconine degradation product. Methyl O-methyl-7-keto-podocarpate (56) was reduced to the diol, which was converted by Birch reduction to dienone (57). The diene diol diacetate from this was converted to the 7,8-epoxide. Boron trifluoride converted this to the non-conjugated enone (58) which isomerised and... 

Further examples of Birch reductions of aromatic ethers are listed in Table 8. Ketones, as well as enones, are also reduced under the Birch reaction conditions (entries 4-6). 

Addition of an alkyl group at C17 initially involves conditions fairly similar to those used in the Birch reduction of enones. A solution of the steroid in liquid ammonia and some inert co-solvent is first treated with lithium metal (Scheme 6.20). The resulting anion 20-1 is then quenched with an alkyl halide instead of the alcohol usually employed in Birch reductions. The anion at C17 then displaces the halogen, in the case at hand iodide, from the alkyl group to form a carbon-carbon bond and the 17a-methyl derivative 20-2. 

At first, the enone 23 was catalytically reduced to afford almost exclusively a cis fused ketone which was expected from the preceding examples. Birch reduction gave cis and trans products in a ratio of ca. 5 4 (13). In general six-membered ring ketones produce trans products preferentially under Birch reduction conditions. In this case the trans product was not the preferred product and the ratio did not change when several different conditions were tried. Thus Birch reduction followed by carboxylation with carbon dioxide of the enolate and methylation afforded the ester, whose ratio of the cis and trans products was ca. 

The simplest example of this type of transformation, a type of reversed Birch reduction, is the conversion of cydohex-2-enone to phenyl ethyl ether in 93% yield by treatment with 2 equivalents of the ethoxy dichlorovanadium compound, VCHOEQCIj under an oxygen atmosphere which resulted in a faster reaction rather than with nitrogen or in a toluene solution (ref.72). 

An interesting conversion of an erythrinan (9) into a -erythroidine derivative (12) has been reported (Scheme 1). Birch reduction of (9) followed by hydrolysis gave a good yield of the conjugated enone (10), which upon successive treatment with benzaldehyde, ozone, hydrogen peroxide, and diazomethane provided the... 

Model studies showed that Birch reduction of 6-substituted a-picolines and hydrolysis of the intermediate bisenamines yield 1, S-diketones, which can cyclize to enones A and/or B. In fact, literature precedent and experience with 1,4-diketones favored cyclization mode B (e.g., jasmone). However, the model studies showed substantial and in some cases predominant cyclization to A. 

Birch reduction of the bisketal of 54 to the enone 55, followed by Eschenmoser cleavage of the derived epoxyketone with aminodiphenylaziridine, yielded the acetylide 56. Ring B was formed by aldol condensation, hydrolysis of the acetylene to the methyl ketone, and selective ketalization to give 57. The extensive manipulation of protecting groups resulted in a somewhat unsatisfactory overall yield of 14%. 

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