Aldehydes using hydride transfer reagents

This section covers the reduction of aldehydes and ketones, in complex molecules using hydride transfer reagents. Many of these are complex reagents designed specifically for particular reactions. LAH has been used for the reduction of cyclopropyl ketones199. Trialkyltin moieties in the cyclopropane ring cause diastereoselective reduction to occur (equation 51). 

The preparation of acyliminium ions is not restricted to aldehyde or ketone derivatives as starting materials, but can also use the more highly oxidized carboxylic acid amides as precursors, e.g. reduction of imides (66) affords (67 Scheme 33). For constitutionally unsymmetrical imides, regiocontrol can be achieved in many cases by the choice of the appropriate hydride-transfer reagent. ... 

Chiral phosphoric acids like TRYP (60a) or analogues, in association with primary amines, have already been employed as catalysts in the conjugate reduction of a,p-unsaturated aldehydes using Hantzsch esters as hydride-transfer reagents (see Scheme 3.27 in Chapter 3). However, as pointed out... 

Many other functional groups are also reactive under conditions of catalytic hydrogenation. The reduction of nitro compounds to amines, for example, usually proceeds very rapidly. Ketones, aldehydes, and esters can all be reduced to alcohols, but in most cases these reactions are slower than alkene reductions. For most synthetic applications, the hydride transfer reagents to be discussed in Section 5.2 are used for reduction of carbonyl groups. Amides and nitriles can be reduced to amines. Hydrogenation of amides requires extreme conditions and is seldom used in synthesis, but reduction of nitriles is quite useful. Scheme 5.3 gives a summary of the approximate conditions for catalytic reduction of some common functional groups. 

Recently it has been shown by Chikashita et al. that hydride transfer is possible from the benzimida-zoline (21) to an acyl chloride, giving the corresponding aldehyde and benzimidazolium salt (22 equation 1) The reaction is most effective in the presence of 1 mol equiv. of acetic acid. Although it has only been used for a few aldehydes, it is successful with aromatic and aliphatic examples (e.g. p-nit-robenzaldehyde, 82% g.c. yield cyclohexanecarbaldehyde, 80% g.c. yield) and may have substantial potential. Another new method is the treatment of aroyl chlorides with dialkylzinc reagents in the presence of catalytic palladium complexes. However, the applicability would seem to be limited by the rather low yields. 

One of the chemoselective and mild reactions for the reduction of aldehydes and ketones to primary and secondary alcohols, respectively, is the Meerwein-Ponndorf-Verley (MPV) reduction. The lifeblood reagent in this reaction is aluminum isopropoxide in isopropyl alcohol. In MPV reaction mechanism, after coordination of carbonyl oxygen to the aluminum center, the critical step is the hydride transfer from the a-position of the isopropoxide ligand to the carbonyl carbon atom through a six-mem-bered ring transition state, 37. Then in the next step, an aluminum adduct is formed by the coordination of reduced carbonyl and oxidized alcohol (supplied from the reaction solvent) to aluminum atom. The last step is the exchange of produced alcohol with solvent and detachment of oxidized alcohol which is drastically slow. This requires nearly stoichiometric quantities of aluminum alkoxide as catalyst to prevent reverse Oppenauer oxidation reaction and also to increase the time of reaction to reach complete conversion. Therefore, accelerating this reaction with the use of similar catalysts is always the subject of interest for some researchers. 

The trityl carbonium ion is well documented as a hydride-ion acceptor indeed it can be reduced by aldehyde acetals in an intramolecular hydride-transfer process. This is pivotal in a new method for the deacetaliza-tion of ketone acetals by oxidative hydride transfer trityl fluoroborate is used as reagent, and the glycol moiety is oxidized to an a-ketol, as is shown in Scheme 79. This novel procedure is successful also with hemithioacetals, but fails with thioacetals. 

Most reductions of carbonyl compounds are done with reagents that transfer a hydride from boron or aluminum. The numerous reagents of this type that are available provide a considerable degree of selectivity and stereochemical control. Sodium borohydride and lithium aluminum hydride are the most widely used of these reagents. Sodium borohydride is a mild reducing agent which reacts rapidly with aldehydes and ketones but quite slowly with esters. Lithium aluminum hydride... 

In the past, this field has been dominated by ruthenium, rhodium and iridium catalysts with extraordinary activities and furthermore superior enantioselectivities however, some investigations were carried out with iron catalysts. Early efforts were reported on the successful use of hydridocarbonyliron complexes HFcm(CO) as reducing reagent for a, P-unsaturated carbonyl compounds, dienes and C=N double bonds, albeit complexes were used in stoichiometric amounts [7]. The first catalytic approach was presented by Marko et al. on the reduction of acetone in the presence of Fe3(CO)12 or Fe(CO)5 [8]. In this reaction, the hydrogen is delivered by water under more drastic reaction conditions (100 bar, 100 °C). Addition of NEt3 as co-catalyst was necessary to obtain reasonable yields. The authors assumed a reaction of Fe(CO)5 with hydroxide ions to yield H Fe(CO)4 with liberation of carbon dioxide since basic conditions are present and exclude the formation of molecular hydrogen via the water gas shift reaction. H Fe(CO)4 is believed to be the active catalyst, which transfers the hydride to the acceptor. The catalyst presented displayed activity in the reduction of several ketones and aldehydes (Scheme 4.1) [9]. 

Note that the approach outlined in Scheme 5.10 uses piperonal as the aldehyde component and requires funetionali/alion at die h -posiiion of 14-16 after the key addition step and auxiliary removal. Kelly Rein tried a more direct approach initially, as shown in. Scheme 5.11. but reduction of the aldehyde was the major pathway 68. No addition product was found, hut the isoquinolylox-a/oline could he recovered in MY/i yield. Grignard reagents may reduce carbonyls by cither fi-hydride elimination or electron transfer. Since there are no / -hydrogens in this Grignard. SET is the only possible alternative lor die production of the observed lactone. 

Another useful reagent is the dimeric diisobutylaluminum hydride (DIBAL-H), (t-Bu2AlH)2, which can reduce esters and nitriles in a controlled manner. Thus, unlike for LAH, only one hydride is transferred to the organic substrate, so for esters the reduction stops at the aldehyde stage. 

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