Aldehydes metal hydride reductions

Org Prep Proc Int 21 4S1 (1989) (metal hydride reduction of acids and derivatives to aldehydes)... 

When a proton source such as ethanol is used, sodium reduces esters, aldehydes and ketones to alcohols and the reduction is known as Bouveault-Blanc reduction s . But metal hydride reduction of carbonyl compounds gives higher yields of alcohols. 

Problem 20.5 What aldehyde or ketone is needed to prepare each alcohol by metal hydride reduction ... 

Now, everyone with a rudimentrary background on metal hydride reductions knows that a formal addition of the elements M-H to the C=0 bond takes place at a first stage. There is no reason to believe that anything different occurs to a close relative of carbonyls such as the hydrazone group upon exposure to boron hydride. On that account, the postulation of structure IV is as reasonable as the metal alkoxides that have always been proposed for analogous reductions of aldehydes and ketones (see Scheme 8.1). 

METAL HYDRIDE REDUCTIONS OF AROMATIC ALDEHYDES AND KETONES 313... 

Aldehydes and ketones show expected behavior. Metal hydride reductions yield the corresponding alcohols and aldehyde oxidations furnish the corresponding acids. 

The hydride ion is a very strong base (pAT of hydrogen > 40) and hydride transfer to electrophihc centres in non-enzyme-catalysed reactions usually requires H either to be pushed off , as in metal hydride reductions or the Cannizzaro reaction, or to be pulled off by strong electrophiles, such as carbonium ions or bromine. The Cannizzaro reaction is another good example of how reaction at one centre in a molecule may completely modify the properties of an adjacent potential reaction site. Hydride transfer from an aldehyde group is thermodynamically unfavourable... 

The key step in the metal hydride reduction of an aldehyde or a ketone is the transfer of a hydride ion from the reducing agent to the carbonyl carbon to form a tetrahedral carbonyl addition intermediate. In the reduction of an aldehyde or a ketone to an alcohol, only the hydrogen atom attached to carbon comes from the hydride-reducing agent the hydrogen atom bonded to oxygen comes from the water added to hydrolyze the metal alkoxide salt. 

Metal hydride reduction of esters is difficult to stop at the intermediate aldehyde stage, and the usual result is further reduction to the primary alcohol (Fig. 18.37). Either LiAlH4 or LiBH4 (hut not NaBH4, which will not reduce esters) is the reagent of choice. 

A series of papers on the metal hydride reduction of aldehydes and ketones, - and some other functional groups, has demonstrated the importance of the metal ion for example, y " is indispensable in the lithium aluminium hydride reduction of many ketones in aprotic solvents, through transition state (46), and reaction is prevented by the specific lithium complexing cryptand (47). 

For most laboratory scale reductions of aldehydes and ketones catalytic hydro genation has been replaced by methods based on metal hydride reducing agents The two most common reagents are sodium borohydride and lithium aluminum hydride... 

Common catalyst compositions contain oxides or ionic forms of platinum, nickel, copper, cobalt, or palladium which are often present as mixtures of more than one metal. Metal hydrides, such as lithium aluminum hydride [16853-85-3] or sodium borohydride [16940-66-2] can also be used to reduce aldehydes. Depending on additional functionahties that may be present in the aldehyde molecule, specialized reducing reagents such as trimethoxyalurninum hydride or alkylboranes (less reactive and more selective) may be used. Other less industrially significant reduction procedures such as the Clemmensen reduction or the modified Wolff-Kishner reduction exist as well. 

Preparation of the aldehyde required for the synthesis of cyclothiazide (182) starts by carbonation of the Grignard reagent obtained from the Diels-Alder adduct (186) from allyl bromide and cyclopentadiene.The resulting acid (187) is then converted to the aldehyde (189) by reduction of the corresponding diethyl amide (188) with a metal hydride. 

Pettit and coworkers—metal hydride intermediates by weak base attack over Fe carbonyl catalysts. Pettit et al.ls approached the use of metal carbonyl catalysts for the homogeneous water-gas shift reaction from the standpoint of hydroformyla-tion by the Reppe modification.7 In the typical hydroformylation reaction, an alkene is converted to the next higher aldehyde or alcohol through reaction of CO and H2 with the use of a cobalt or rhodium carbonyl catalyst. However, in the Reppe modification, the reduction is carried out with CO and H20 in lieu of H2 (Scheme 6) ... 

The effect of cryptands on the reduction of ketones and aldehydes by metal hydrides has also been studied by Loupy et al. (1976). Their results showed that, whereas cryptating the lithium cation in LiAlH4 completely inhibited the reduction of isobutyraldehyde, it merely reduced the rate of reduction of aromatic aldehydes and ketones. The authors rationalized the difference between the results obtained with aliphatic and aromatic compounds in terms of frontier orbital theory, which gave the following reactivity sequence Li+-co-ordinated aliphatic C=0 x Li+-co-ordinated aromatic C=0 > non-co-ordinated aromatic C=0 > non-co-ordinated aliphatic C=0. By increasing the reaction time, Loupy and Seyden-Penne (1978) showed that cyclohexenone [197] was reduced by LiAlH4 and LiBH4, even in the presence of [2.1.1]-cryptand, albeit much more slowly. In diethyl ether in the absence of... 

Asymmetric reduction of ketones or aldehydes to chiral alcohols has received considerable attention. Methods to accomplish this include catalytic asymmetric hydrogenation, hydrosilylation, enzymatic reduction, reductions with biomimetic model systems, and chirally modified metal hydride and alkyl metal reagents. This chapter will be concerned with chiral aluminum-containing reducing re-... 

This procedure illustrates a general method for the reduction of aldehyde and ketone functions to methylene groups under very mild conditions. Since strong acids and bases are not employed, this procedure is of particular importance for the reduction of ketones possessing an adjacent chiral center. Moreover, the use of deuterated metal hydrides permits the preparation of labelled compounds. ... 

This complex can also transfer hydride to another molecule of the carbonyl compound in a similar manner, and the process continues until all four hydrides have been delivered. Since all four hydrogens in the complex metal hydride are capable of being used in the reduction process, 1 mol of reducing agent reduces 4 mol of aldehyde or ketone. Finally, the last complex is decomposed by the addition of water as a proton source. 

There is a rather important difference between chemical reductions using complex metal hydrides and enzymic reductions involving NADH, and this relates to stereospecificity. Thus, chemical reductions of a simple aldehyde or ketone will involve hydride addition from either face of the planar carbonyl group, and if reduction creates a new chiral centre, this will normally lead to a racemic alcohol product. Naturally, the aldehyde primary alcohol conversion does not create a chiral centre. 

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