Unsaturated ketone metal-ammonia reduction

In the presence of acids (e.g. ethanol) sufficiently strong to protonate the enolate anion, however, the ketone is generated in the reducing medium and is reduced further to the saturated alcohol. The formation of enolate anions such as 63 during metal-ammonia reduction of a,p-unsaturated ketones is shown by their ready trapping with electrophiles such as iodomethane. 

In a study of electron-transfer reactions. House has examined the stabilities of the anion radicals derived from a number of y-cyclopropyl-ap-unsaturated ketones. It would appear that for the conversion of substrates containing the unit depicted by (240) into (241) a rearrangement rate in excess of 10 s is necessary in order to detect the anion radical intermediate present in metal-ammonia reductions. A rate of ca. 10 s is likewise required in lithium dimethylcuprate reactions. ... 

BIRCH hOCKEL - BENKESER Reduction Reduction ol aromatics, unsaturated ketones coniugated dienes by alkali metals in liquid ammonia or amines... 

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. 

The stereochemistry of the photocycloadducts can be predicted from the result of a dissolving metal reduction of the same ,/)-unsaturated ketone. For example, sodium/ammonia reduction of 3,4-dimethylcydohexenone yielded trans- and cis-dimethylcyclohexanone 37 in a ratio of 84 16, which was similar to the ratio of the two photocycloadducts 38 (80 20) [33b, 42],... 

The main methods of reducing ketones to alcohols are (a) use of complex metal hydrides (b) use of alkali metals in alcohols or liquid ammonia or amines 221 (c) catalytic hydrogenation 14,217 (d) Meerwein-Ponndorf reduction.169,249 The reduction of organic compounds by complex metal hydrides, first reported in 1947,174 is a widely used technique. This chapter reviews first the main metal hydride reagents, their reactivities towards various functional groups and the conditions under which they are used to reduce ketones. The reduction of ketones by hydrides is then discussed under the headings of mechanism and stereochemistry, reduction of unsaturated ketones, and stereochemistry and selectivity of reduction of steroidal ketones. Finally reductions with the mixed hydride reagent of lithium aluminum hydride and aluminum chloride, with diborane and with iridium complexes, are briefly described. 

The reduction of a carbon-carbon multiple bond by the use of a dissolving metal was first accomplished by Campbell and Eby in 1941. The reduction of disubstituted alkynes to c/ s-alkenes by catalytic hydrogenation, for example by the use of Raney nickel, provided an excellent method for the preparation of isomerically pure c -alkenes. At the time, however, there were no practical synthetic methods for the preparation of pure trani-alkenes. All of the previously existing procedures for the formation of an alkene resulted in the formation of mixtures of the cis- and trans-alkenes, which were extremely difficult to separate with the techniques existing at that time (basically fractional distillation) into the pure components. Campbell and Eby discovered that dialkylacetylenes could be reduced to pure frani-alkenes with sodium in liquid ammonia in good yields and in remarkable states of isomeric purity. Since that time several metal/solvent systems have been found useful for the reduction of C=C and C C bonds in alkenes and alkynes, including lithium/alkylamine, ° calcium/alkylamine, so-dium/HMPA in the absence or presence of a proton donor,activated zinc in the presence of a proton donor (an alcohol), and ytterbium in liquid ammonia. Although most of these reductions involve the reduction of an alkyne to an alkene, several very synthetically useful reactions involve the reduction of a,3-unsaturated ketones to saturated ketones. ... 

A wide variety of a. -unsaturated ketones have been reduced to saturated ketones, usually in good yield, by metal solutions, mainly in liquid ammonia.The reduction is applicable to compounds with any degree of substitution on the double bond. Although only 2 equiv. of these metals are required for the conversion of an enone to a saturated ketone, it is often convenient to employ the metal in excess. A suspension of lithium bronze (Li4NH3) in ether allows the employment of the metal in stoichiometric amounts. Proton donors are often employed to reduce competing side reactions, such as dimerization. The presence of proton donors in the medium may lead to the conversion of an a,p-unsaturated ketone to the saturated alcohol, but at least 4 equiv. of metal must obviously be present for this type of reduction to take place. 

Dissolving metal reduction of a,(3-unsaturated ketones regiospecifically produces enolates that, on removal of ammonia, may be reacted with electrophiles. 

The total synthesis of galbulimima alkaloid GB 13 was accomplished by L.N. Mander and co-workers. The Birch reduction of a complex intermediate was necessary in order to prepare a cyclic a,p-unsaturated ketone. The treatment of the substrate with lithium metal in liquid ammonia first resulted in a quantitative reductive decyanation of the C6a cyano group. The addition of excess ethanol to the reaction mixture reduced the aromatic ring to the corresponding enol ether that was hydrolyzed in a subsequent step to afford the unsaturated ketone. 

Birch reduction of ct,ft-unsaturated ketones. House et al.e have reported an extended study of the reduction of cyclic ct,/3-unsaturated ketones of the type (1) with sodium or lithium in HMPT as compared with reduction with the same metals in liquid ammonia. In general, use of HMPT somewhat favors formation of the less stable epimer, for example (3). The factors which seem to favor formation of... 

Isolated carbon-carbon double bonds are not normally reduced by dissolving metal reducing agents. Reduction is possible when the double bond is conjugated, because the intermediate anion can be stabilized by electron delocalization. The best reagent is a solution of an alkali metal in liquid ammonia, with or without addition of an alcohol - the so-called Birch reduction conditions. Under these conditions conjugated alkenes, a,p-unsaturated ketones and even aromatic rings can be reduced to dihydro derivatives. 

Reduction with Alkali Metals, Various methods of reduction using alkali metals have come into use in total steroid synthesis in liquid ammonia, in ammonia with the addition of alcohols (Birch reduction), and in alcohols. The working procedures and mechanisms of these reactions have been discussed in appropriate reviews [87-89] in general, they take place through the formation of anions or anion-radicals with their subsequent protonation. As a rule, in these reactions isolated double bonds are not reduced the sequence of reduction of other unsaturated groupings is as follows a, -unsaturated ketones > slyrene or stilbene double bonds > aromatic rings. Each of these cases has its own stereochemical problems, which are discussed below on the basis of suitable examples. 

Other Unsaturated Alcohols. An improved procedure that has been reported recently for the preparation and utilization of alkali-metal acetylides in liquid ammonia allows the ethynation of sensitive carbonyl compounds to be carried out, in good yield, to give propargylic alcohols. The reduction of ap-acetylenic ketones to (S propargyl alcohols of high enantiomeric purity can be performed with NB-Enantrane (27) [cf. (6) earlier], which is derived from nopol benzyl ether as a low-cost alternative to (—)-a-pinene. a-Allenic alcohols have been prepared by the new routes shown in Schemes... 

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