Aldehydes dissolving metal reduction

Both disubstituted alkynes (Chapter 3.3, this volume) and isolated terminal double bonds may be reduced by alkali metals in NH3, but isolated double bonds are usually stable to these conditions. However, 16,17-secopregnanes (10 equation 8) afford mixtures of cyclization products (11) and (12) in 61% to 80% yield with Na naphthalenide-THF, Na-NHs-THF, Na-THF or Li-NHs-THF. With Na-NHa-THF-r-butyl alcohol, a 91% yield of a 72 28 mixture of (11) (12) (R = Me) is obtained. This type of radical cyclization of alkenes and alkynes under dissolving metal reduction conditions to form cyclopentanols in the absence of added proton donors is a general reaction, and in other cases it competes with reduction of the carbonyl group. Under the conditions of these reactions which involve brief reaction times, neither competitive reduction of a terminal double bond nor an alkyne was observed. However, al-lenic aldehydes and ketones (13) with Li-NHs-r-butyl alcohol afford no reduction products in which the diene system survives. ... 

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

On a related front, the reactions of carbonyl compounds with metaliated derivatives of 2-methylthia-zoline furnish adducts (85). Although the initial nucleophilic addition occurs smoothly with a wide variety of aldehydes and ketones, the intermediate P-hydroxythiazolines (85) suffer thermal reversion upon attempted purification by distillation. Moreover, attempted cleavage of the corresponding P-hydroxythia-zolidines, which are readily produced from (85) upon dissolving metal reduction (Al-Hg), leads to the formation of p-hydroxy aldehydes only in simple systems numerous complications arising from dimerization, dehydration and retroaldol processes of the products usually intervene. Consequently it is necessary to protect the initial 1,2-adducts (85 = H) as the corresponding 0-methoxymethyl ether... 

A ketone or aldehyde is reduced to an alcohol by reaction with sodium or lithium metal in liquid ammonia, in the presence of ethanol. This is called a dissolving metal reduction and it proceeds by an alkoxy-radical known as a ketyl. 

A variety of ketones or aldehydes may be reduced to an alcohol using dissolving metal reduction. Alcohols other than ethanol are used as solvents, and low boiling amines such as methylamine or dimethylamine can be used in place of ammonia. Other alkali metals such as lithium or calcium also work. Lithium in a mixture of methylamine and ethanol, and calcium metal in methylamine may also be used in these reduction reactions, primarily on large-scale reactions such as those found in industrial laboratories or factories. 

Dissolving metal reductions works very well with aldehydes and ketones, but alkenes are not readily reduced under the same conditions. For example, 1-hexene is reduced to hexane in only 41% yield with Na/MeOH/liquid NHg.14 Alkynes, on the other hand, are reduced to alkenes in good yield using dissolving metal conditions, and the experimental evidence shows that the -alkene is the major product. In a typical example, 4-octyne (60) is treated with sodium in liquid ammonia, and oct-4 -ene (64) is isolated in 90% yield. None of the Z-alkene is observed in this reaction. The reaction with sodium in liquid ammonia is an electron transfer process similar to that observed with ketones and aldehydes, but how is the E geometry of the alkene product explained ... 

Benzene was introduced in Chapter 5 (Section 5.10). Chapter 21 will discuss many benzene derivatives, along with the chemical reactions that are characteristic of these compounds. In the context of dissolving metal reductions of aldehydes, ketones, and alkynes, however, one reaction of benzene must be introduced. When benzene (65) is treated with sodium metal in a mixture of liquid ammonia and ethanol, the product is 1,4-cyclohexadiene 66. Note that the nonconjugated diene is formed. The reaction follows a similar mechanism to that presented for alkynes. Initial electron transfer from sodium metal to benzene leads to radical anion 67. Resonance delocalization as shown shordd favor the resonance contributor 67B due to charge separation. 

The equation below illustrates the application of dissolving-metal reduction in the synthesis of the sex pheromone of the spruce budworm, which is the most destructive pest to the spruce and fir forests of North America. The pheromone lure is employed at hundreds of sites in the United States and Canada as part of an integrated pest-management strategy (Section 12-17). The key reaction is reduction of 11-tetradecyn-l-ol to the corresponding trans alkenol. Subsequent oxidation to the aldehyde completes the synthesis. 

In dissolving-metal ester reduction, the ester carbonyl is believed to accept an electron to form a radical oxyanion 37 (Scheme 12.12). Chelation with a lithium counterion then ensues to produce a tertiary radical 38 which then captures a second electron to become a carbanion. Protonation of 39 next yields 40, whose fate is to collapse to aldehyde 41. Another multiple electron transfer/protonation sequence subsequently yields the product alcohol 46. 

Dissolving metals have been used as reducing agents in organic synthesis for well over a century and for many years metal-alcohol or metal amalgam-water systems were the principal methods employed for the reduction of aldehydes and ketones to primary and secondary alcohols, respectively. The same reagents were employed for the reduction of imines and oximes to the corresponding amines. Catalytic hy-... 

The reduction of various substrates by dissolving metals in alcoholic and aqueous media is a very old procedure in synthetic organic chemistry. In addition to aldehydes, ketones, imines and other unsaturated nitrogen compounds, many other functional groups are reduced under these conditions. Historically, the most common reduction conditions were Na in ethanol, and the reductions were carried out by adding the metal to a solution of the substrate in alcohol and the reaction mixture was heated at reflux for varying periods of time. Other reduction systems included Na-Hg amalgam in water or alcohols and, for easily reduced compounds such as aldehydes and aromatic ketones, Zn-NaOH or Fe-acetic acid have been used. ... 

The metal-NHs reductions of carbonyl groups are exceedingly fast reactions for the reaction of acetone with an ammoniated electron the rate is 9 x 10 M" s". Although many, particularly older, published experimental procedures for the metal-NHs reduction of ketones employ prolonged reaction times with excess metal, these conditions are unnecessarily harsh. The reactions of carbonyl compounds with metals in NH3 are effectively instantaneous and by using short reaction times it appears that reduction of terminal alkenes and disubstituted alkynes can be avoided.In addition to the functional groups mentioned above, alcohols, amines and ethers, other than epoxides, are usually stable to reductions of aldehydes and ketones by dissolving metals. " ... 

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. ... 

In conclusion, nitriles may be reduced electrochemically or with dissolving metal to produce amines. Nonetheless, such reactions must be used with caution. In addition to competitive decyanation, aldehyde or 2,4,6-trialkyIhexahydro-l,3,5-triazine formation and reductive dimerization are waiting to overwhelm the unwary. 

Several related reactions involve reduction of cyclic carboxylic acid derivatives to masked aldehydes which resist further reduction but can be converted into the required aldehydes by acid hydrolysis. In a series of papers, it was established that carboxylic acids could be converted into dihydro-1,3-thiazines or dihydro-1,3-oxazines which could be reduced by NaBH4 in weakly acidic ethanol. Thus, as shown in Scheme 20, dihydro-1,3-thiazines (41) were reduced to tetrahydro-1,3-thiazines (42) in yields of 66-84%. The resulting tetrahydro compounds could be hydrolyzed to aldehydes by aqueous acid. - In a later publication, these workers showed that there was little evidence for ring opening during reduction and that other methods of reduction e.g. hydrogenation over Pt, Pd or Rh or use of dissolving metals such as Zn, Sn or Na) were totally unsuccessful. In closely similar work, reduction of 5,6-dihydro-4W-... 

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. 

The traditional Reformatsky reaction involves the conversion of a a-haloester to a a-organozinc ester in the presence of zinc metal and an initiator such as I2 or 1,2-diiodoethane (the initiator is necessary to remove the layer of zinc oxide). The resulting organozinc reagent then reacts with an aldehyde or ketone to deliver a p-hydroxy ester. Other zinc sources such as Rieke zinc , dissolving lithium reductions with... 

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