Reductions of Carbonyl Groups

We should now look in detail at reductions of carbonyl compounds, and in doing so we shall introduce a few more specialized reducing agents. Then we will come back to the other type of reduction in the salmefamol synthesis—catalytic hydrogenation. 

We don t need to spend much time on this—sodium borohydride, which you met in Chapter 6, does it very well. Sodium borohydride will reduce only in protic solvents (usually ethanol or methanol) or in the presence of electrophilic metal cations such as Li or Mg2 (LiBH4 can be used in THF, for example). The mechanism follows a course which can be represented like this. 

The essence of the reaction is the transfer of a hydrogen atom with two electrons (called hydride transfer, although no hydride ion is involved) from boron to carbon. The developing 

Li AIH4 is often the best reagent, and gives alcohols by the mechanism we discussed in Chapter 10 (p. 217). As a milder alternative (needed because LiAlH4 has caused countless fires through careless handling), lithium borohydride in alcoholic solution will reduce esters—in fact, it has useful selectivity for esters over acids or amides that LiAlH4 does not have. Sodium borohydride reduces most esters only very slowly. 

The best reagent for this is borane, BH3. Borane is, in fact, a gas with the structure B2H6, but it can be tamed as a liquid by complexing it with ether (Et20), THF, or dimethyl sulfide (DMS, Me2S). 

Alcohols are easily accessible by reduction of carbonyl compounds, such as aldehydes, ketones or carboxylic acid derivatives. While aldehydes, ketones and esters have been frequently used in microwave-assisted reductions, there have been no reports about the use of microwave technology in the reduction of nitriles or amides. 

Borohydrides and reagents derived therefrom are preferred over the use ofaluminium hydrides, for economic and safety considerations and the much higher ease to handle 

We shall use this synthesis as a basis for discussion on chemoselectivity in reductions. In the first step, sodium borohydride leaves the black carbonyl group of the ester untouched while it reduces the ketone (in yellow) in the last step, lithium aluminium hydride reduces the ester (in black). These chemoselectivities are typical of these two most commonly used reducing agents borohydride can usually be relied upon to reduce an aldehyde or a ketone in the presence of an ester, while lithium aluminium hydride will reduce almost any carbonyl group. 

Each reduction gives an alcohol, apart from the reduction of an amide with LiAlH4, which gives an amine, which we shall explain next. We shall return to the salmefamol synthesis later to explain the reductions with hydrogen gas catalysed by palladium. 

According to the substrate and conditions, the reaction stops at the ketyl stage or continues to the alcohol, the pinacol, or the cyclized structures when adequate functionalities are present. 

An example of this type of reduction is that of benzaldehyde to 1-d-benzyl alcohol by a copper-aluminum alloy in the presence of deuterium oxide and sodium carbonate.Huffman et al observed that the stereoselectivity of camphor reduction is the same either sonochemically in THF or silently in liquid ammonia with the usual three alkali metals (Eq. 13),106 

The authors analyze the results to exclude a mechanism involving the ketone dianion. From a practical viewpoint, the sonochemical reductions in THF occur in 0.5-1 h, making this procedure much easier than the reductions in liquid ammonia. Quinones and a-diketones are reduced by zinc and TMSCl (Fig. 17).i07 

The yields are not always improved, but the acceleration with respect to the silent process is ca. 10-fold. As expected, the process occurs more efficiently in THF than in diethyl ether, due to a higher cavitation energy. From benzil, a minor change in the isomeric ratio is observed in the sonochemical reaction. Various aromatic ketones are reduced to alcohols with aluminum in liquid ammonia.The competing pinacolization is suppressed by addition of ammonium chloride. 

105 Tsukinoki, T. Ishimoto, K. Tsuzuki, H. Mataka, S. Tashiro, M. /. Labelled Compd. Radiopharm. 1993,33, 987-990. 

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Enzyme catalyzed reductions of carbonyl groups are more often than not com pletely stereoselective Pyruvic acid for example is converted exclusively to (5) (+) lactic acid by the lactate dehydrogenase NADH system (Section 15 11) The enantiomer... 

The well-known reduction of carbonyl groups to alcohols has been refined in recent studies to render the reaction more regioselective and more stereoselective Per-fluorodiketones are reduced by lithium aluminum hydride to the corresponding diols, but the use of potassium or sodium borohydride allows isolation of the ketoalcohol Similarly, a perfluoroketo acid fluonde yields diol with lithium aluminum hydnde, but the related hydroxy acid is obtainable with potassium borohydnde [i f] (equations 46 and 47)... 

The dynamic resolution of an aldehyde is shown in Figure 8.40. The racemization of starting aldehyde and enantioselective reduction of carbonyl group by baker s yeast resulted in the formation of chiral carbon centers. The enantiomeric excess value of the product was improved from 19 to 90% by changing the ester moiety from the isopropyl group to the neopentyl group [30a]. 

Other examples of microalgae-catalyzed reductions of carbonyl groups are summarized below and shown in Fig. 2 ... 

Reduction of carbonyl groups Terpene and aromatic aldehydes (lOOppm) were reduced by microalgae. In a series of chlorinated benzaldehyde, m - or p-chlorobenzaldehyde reacted faster than the o-derivative. Due to toxicity, the substrate concentrations are difficult to increase. Asymmetric reductions of ketones by microalgae were reported. Thus, aliphatic " and aromatic " ketones were reduced. 

Reduction of carbon-carbon double bond Microalgae easily reduce carbon-carbon double bonds in enone. Usually, the reduction of carbonyl group and carbon-carbon double bond proceeds concomitantly to afford the mixture of corresponding saturated ketone, saturated alcohol, and unsaturated alcohol because a whole cell of microalgae has two types of reductases to reduce carbonyl and olefinic groups. The use of isolated reductase, which reduces carbon-carbon double bond chemoselectively, can produce saturated ketones selectively. 

Although single-electron-transfer (SET) processes would be expected to be important in reactions that use metals as reagents, this type of process has also been recognized in the reduction of carbonyl groups that involve 1,4-dihydronicotinamide derivatives . Recent work by Oae and coworkers" has shown that an SET process is operative in the reduction of dibenzothiophene S-oxide by l-benzyl-l,4-dihydronicotinamide when the reaction is catalyzed by metalloporphins. The reaction is outlined in equation (18), but the study gave results of much more mechanistic than synthetic value. This type of study is relevant to understanding biochemical mechanisms since it is known that methionine sulphoxide is reduced to methionine by NADPH when the reaction is catalyzed by an enzyme isolated from certain yeasts . 

Chelation Control. The stereoselectivity of reduction of carbonyl groups can be controlled by chelation when there is a nearby donor substituent. In the presence of such a group, specific complexation among the substituent, the carbonyl oxygen, and the Lewis acid can establish a preferred conformation for the reactant. Usually hydride is then delivered from the less sterically hindered face of the chelate so the hydroxy group is anti to the chelating substituent. 

The Wolff-Kishner reaction175 is the reduction of carbonyl groups to methylene groups by base-catalyzed decomposition of the hydrazone of the carbonyl compound. It is thought that alkyldiimides are formed and then collapse with loss of nitrogen.276... 

In the fine chemical industry, reduction of carbonyl groups mainly relies on the use of complex metal hydrides sodium dihydrobis-(2-methoxyethoxy)-aluminate, commercialized as RedAl or Vitride is one of the most used (4). 

Asymmetric synthesis of spiroketalic pheromones is also reported, in which the asymmetric reduction of carbonyl group is carried out with baker s yeast (Scheme 4.22).160... 

There are also voices critical of the rTCA cycle Davis S. Ross has studied kinetic and thermodynamic data and concludes that the reductive, enzyme-free Krebs cycle (in this case the sequence acetate-pyruvate-oxalacetate-malate) was not suitable as an important, basic reaction in the life evolution process. Data on the Pt-catalysed reduction of carbonyl groups by phosphinate show that the rate of the reaction from pyruvate to malate is much too low to be of importance for the rTCA cycle. In addition, the energy barrier for the formation of pyruvate from acetate is much too high (Ross, 2007). 

Hydrogenase Reduction of carbonyl groups, Unsaturated fatty adds,... 

Dehydrogenase catalyzes enantioselective reduction of carbonyl groups. 

TiCl4 promotes reduction of carbonyl groups or acetals with R3SiH or R3SnH (Scheme 24) Other hydride sources are also effective.91 ... 

The importance of reactions with complex, metal hydrides in carbohydrate chemistry is well documented by a vast number of publications that deal mainly with reduction of carbonyl groups, N- and O-acyl functions, lactones, azides, and epoxides, as well as with reactions of sulfonic esters. With rare exceptions, lithium aluminum hydride and lithium, sodium, or potassium borohydride are the... 

For the reduction of carbonyl groups or the oxidation of alcohols in the presence of C-C double and triple bonds, MPVO catalysts seem to be the best choice with respect to selectivity for the carbonyl group, as reductions with com-... 

BINAP (40a) was first reported as a ligand in an enantioselective hydrogenation in 1980 [172], and provides good selectivity for the reductions of dehydroamino acid derivatives [173], enamides, allylic alcohols and amines, and a,p-unsaturated acids [4, 9, 11, 12, 174, 175]. The fame of the ligand system really came with the reduction of carbonyl groups with ruthenium as the metal [11, 176]. The Rh-BINAP systems is best known for the enantioselective isomerizations... 

The prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

The balance between biocatalytic and other, organometallic-based, methodology is heavily biased in favour of the latter section when considering reduction reactions of importance in synthetic organic chemistry. Two areas will be described to illustrate the point, namely the reduction of carbonyl groups and the reduction of alkenes, not least since these points of focus complement experimental work featured later in the book. 

Enzyme reductions of carbonyl groups have important applications in the synthesis of chiral compounds (as described in Chapter 10). Dehydrogenases are enzymes that catalyse, for example, the reduction of carbonyl groups they require co-factors as their co-substrates. Dehydrogenase-catalysed transformations on a practical scale can be performed with purified enzymes or with whole cells, which avoid the use of added expensive co-factors. Bakers yeast is the whole cell system most often used for the reduction of aldehydes and ketones. Biocatalytic activity can also be used to reduce carbon carbon double bonds. Since the enzymes for this reduction are not commercially available, the majority of these experiments were performed with bakers yeast1 41. 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Conjugate reduction.1 This stable copper(I) hydride cluster can effect conjugate hydride addition to a,p-unsaturated carbonyl compounds, with apparent utilization of all six hydride equivalents per cluster. No 1,2-reduction of carbonyl groups or reduction of isolated double bonds is observed. Undesirable side reactions such as aldol condensation can be suppressed by addition of water. Reactions in the presence of chlorotrimethylsilane result in silyl enol ethers. The reduction is stereoselective, resulting in hydride delivery to the less-hindered face of the substrate. 

Aluminium isopropoxide is a specific reagent for the reduction of carbonyl group to hydroxyl group. Since it reduces the carbonyl group in presence of other reducible groups like nitro or a double bond which remain unaffected, aluminium isopropoxide is largely employed for the reduction of unsaturated aldehydes and ketones. 

Reduction of carbonyl groups using tetra-n-butylammonium borohydride... 

The stereoselectivity of reduction of carbonyl groups is effected by the same combination of steric and stereoelectronic factors which control the addition of other nucleophiles, such as enolates and organometallic reagents to carbonyl groups. A general discussion of these factors on addition of hydride is given in Section 3.10 of Part A. 

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