Dissolving metal conjugate reduction

As the synthetic value38 of regiospecifically generated enolates became apparent in the 1960s, new methods were discovered and developed to prepare them. Dissolving metal conjugate reduction of a,3-... 

The reduction of conjugated dienes by dissolving metals is not extensively reported. This method appears to be nonselective, giving rise to a mixture of the expected olefins and polyolefins as by-products". 

Double bonds conjugated with benzene rings are reduced electrolytically [344] (p. 23). Where applicable, stereochemistry can be influenced by using either catalytic hydrogenation or dissolving metal reduction [401] (p. 24). Indene was converted to indane by sodium in liquid ammonia in 85% yield [402] and acenaphthylene to acenaphthene in 85% yield by reduction with lithium aluminum hydride in carbitol at 100° [403], Since the benzene ring is not inert toward alkali metals, nuclear reduction may accompany reduction of the double bond. Styrene treated with lithium in methylamine afforded 25% of 1-ethylcyclohexene and 18% of ethylcyclohexane [404]. 

Various examples of the use of dissolving metal reduction on exocyclic double bonds, conjugated either with another C —C double bond53 or a carbonyl group,54 have been reported. For example, reaction of 2,6,6-trimethyltricyclo[5-4.0.0I,5]undec-7-en-9-one with lithium metal in liquid ammonia gave, after trapping of the intermediate enolate, 2,6,6-trimethyl-9-tri-fyloxy[5.4.0.015]undec-8-enc (3).53... 

Although Smh is more chemoselective than traditional dissolving metal reagents, it does react with sulfoxides, epoxides, the conjugated double bonds of unsaturated ketones, aldehydes and esters, alkyl bromides, iodides and p-toluenesulfonates. It does not, however, reduce carboxylic acids, esters, phosphine oxides or alkyl chlorides. In common with most dissolving metal systems, ketones with an a-hetero substituent suffer loss of the substituent rather than reduction of the carbonyl group. ... 

DISSOLVING METAL REDUCTION AND RELATED REACTIONS OF NONCONJUGATED AND CONJUGATED ALDEHYDES AND KETONES... 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

Catalytic hydrogenation of an enone would not be chemoselective if an isolated double bond were also present in the molecule. However, isolated double bonds are inert to dissolving metal reduction. On the other hand, a variety of functional groups are reduced with alkali metals in liquid ammonia. These include alkynes, conjugated dienes, allylic, or benzylic halides and ethers. 

The cyclohexenone system generated by the Robinson annulation can be elaborated into a wide variety of synthetically useful structures via alkylation, conjugate addition, reduction, deconjugation, reductive deoxygenation, dissolving metal reduction, hydrogenation, etc. 

Carbon—carbon double bonds which are conjugated to other multiple bonds can also be reduced selectively by dissolving metals. For example, in the selective reduction of ergosterol (7) the distribution of the regioisomers depends on the hydroxy substituent, as well as on the solvent and the metal employed 1 °. Excellent yields of the (ran. -fused product 8 are obtained when sodium in /erf-butyl alcohol/tetrahydrofuran is used. Only a trace of the epimeric civ-product, formed as a result of / -face protonation, is found. The isolated double bond is not affected under the reaction conditions. 

The developments described above were predicated upon the expectation based on less highly substituted examples that the dissolving metal reduction of 35 would likewise result in regioselective rupture of the central bond of the three-membered ring conjugated to the carbonyl. No guidance was available to insure that the second cyclopropane would be insulated from electron transfer chemistry or that the a-pivaloyloxymethyl group would survive intact. Once the experiment... 

Acrylonitrile (2) has also been used for heterocycle formation from p-diketone substrates. Conjugate addition of 185 to acrylonitrile produced 186 with previously reported conditions,2 and cyclization under hydrolytic conditions generated the corresponding lactam 187 (Scheme 15).65 Dissolving metal reduction provided the trans ring fused product 188, which was subsequently converted to 189. Reduction of 189 completed the synthesis of the Lycopodium alkaloid ( )-Na-methyl-A p-acetylphlegmarine (190) as a mixture of 4 diastereomers. 

Birch reduction is a partial reduction of aromatic compounds by electron transfer from dissolving metals—usually Na in liquid ammonia or Li in ethylamine—in the presence of a weak proton donor—usually an alcohol. The reaction behaves as if dianion (30) were an intermediate, giving non-conjugated dienes (31). Electron-donating substituents repel the anions (32) to give products like (33). whilst electron-withdrawing substituents attract the anions (34), to give products like (35). 

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