Hydride Reduction of an Ester

Mechanism 21-13 Hydride Reduction of an Ester 1015 Mechanism 21-14 Reduction of an Amide to an Amine 1016 21-9 Reactions of Acid Derivatives with Organometallic Reagents 1017 Mechanism 21-15 Reaction of an Ester with Two Moles of a Grignard Reagent 1018... 

A third method of aldehyde synthesis is one that we ll mention here just briefly and then return to in Section 21.6. Certain carboxylic acid derivatives can be partially reduced to yield aldehydes. The partial reduction of an ester by dhsobutylaluminum hydride (DIBAH), for instance, is an important laboratory-scale method of aldehyde synthesis, and mechanistically related processes also occur in biological pathways. The reaction is normally carried out at —78 °C (dry-ice temperature) in toluene solution. 

If an aldehyde and an ester group occur together in the presence of a reducing agent like DIB AH (22), the aldehyde is reduced more rapidly as a consequence of Us greater electrophilicity. Selective reduction of an ester to an aldehyde is therefore possible only if product 23 of the first hydride transfer does not collapse to an aldehyde. in nonpolar solvents at low temperature the tetrahedral intermediate 23 is stable and decpolar-coordinating solvent such as THE on the other hand, the O-Al bond is weakened to such an extent by coordination of solvent with the metal atom in 24 that the aldehyde arises even before hydrolysis and is immediately reduced further to an alcohol.15... 

REDUCTION OF AN ESTER WITH LITHIUM ALUMINUM HYDRIDE. 

Similar to the case for its reaction with lithium aluminum hydride, an ester reacts with a Grignard or organolithium reagent to produce a ketone as the initial product. But because the ketone also reacts with the organometallic reagent, an alcohol is the final product. The mechanism for this reaction is shown in Figure 19.10. Note the similarities between this mechanism and that shown in Figure 19.7 for the reduction of an ester with lithium aluminum hydride. 

For example, the partial reduction of an ester by diisobutylaluminum hydride (DIBAH) is an important laboratory-scale method of aldehyde synthesis. The reaction is normally carried out at -78°C (dry-ice temperature) in toluene solution. 

The reduction of a ketone by lithium aluminium hydride to give a secondary alcohol is a very important synthetic route. A common variation is the reduction of an ester to a primary alcohol. LiAlH4 is very reactive, and hence rather unselective. In order to improve its selectivity, various... 

The dialkylboranes and dialkylaluminums are also of value when partial reduction of an ester or amide is desired. The intermediates formed by the first hydride transfer are stable under the conditions of the reduction. Subsequent hydrolysis then provides the carbonyl compound at the aldehyde reduction stage. This method using diisobutylaluminum hydride has been particularly useful for reduction of esters to... 

Reduction of an Ester by Lithium Aluminum Hydride (Section I8.10A)... 

If a DIBALH reduction of an ester is carried out at room temperature, the ester is reduced to a primary alcohol. At low temperature, the tetrahedral carbonyl addition intermediate does not eliminate alkoxide ion, and the more reactive aldehyde is not formed until after workup, when the hydride ion has been destroyed. Thus, temperature control is critical for the selective reduction of an ester to an aldehyde. 

Reduction of an Ester (Section 18.10/ Reduction of an ester by lithium aluminum hydride gives two alcohols. The mechanism involves initial nucleophilic attack by a hydride ion onto the carbonyl carbon to give a tetrahedral addition intermediate, which collapses through the loss of alkoxide to give an aldehyde, which reacts with a second hydride to give the product alcohol. 

Scheme 9.108. A cartoon representation of the reduction of an ester (L = OR ) and an N,N-disubstituted amide (L = NR2) of 2-phenylethanoic acid (2-phenylacetic acid, a-phenylacetic acid, C6H5CH2CO2H) to the corresponding aldehyde 2-phenylethanal (2-phenylacetaldehyde, a-phenylacetaldehyde, C6H5CH2CHO) with diisobutyl aluminum hydride (DIBAL-H, [(CH3)2CHCH2]2A1H) in methylbenzene [toluene (CeHsCHs)] solution at low temperatures.

This transformation involves reduction of an ester to form an alcohol. Recall that lithium aluminum hydride (LAH) can be used to accomplish this type of reaction. However, under these conditions, the ketone moiety will also be reduced. The problem above requires reduction of the ester moiety without also reducing the ketone moiety. To accomplish this, a protecting group can be used. The first step is to convert the ketone into an acetal ... 

Another important transformation, the reduction of esters to aldehydes with lithium diisobutyl-tert-butoxyaluminum hydride (LDBBA) in flow, was performed in the laboratory of Janssen Pharmaceuticals [45]. DIBAL-H applied in their previous research [44] proved to be unsuccessful in reducing ethyl benzoate (la) to benzaldehyde (2a). LDBBA appeared to be the most general and effective alternative to DIBAL-H. The selective reduction of an ester group in the presence of an aldehyde, the selective reduction of a single ester group, and the selective reduction of a primary ester in the presence of a secondary ester are achieved with the efficiency that cannot be achieved under traditional batch conditions. 

Addition to chiral, bicyclic acetals has been exploited in an approach to the synthesis of the tetrahydropyran subunit of the polyether nigerin. The particular acetal generated by the di-isobutylaluminum hydride reduction of aliphatic esters undergoes aldol addition in good yields (eq 16). ... 

An early, groundbreaking and easy to direct process was found in connection with aluminum hydride reductions of acetylenic esters 149 [54]... 

The reduction of an ester either by lithium aluminum hydride or by catalytic hydrogenation at high temperatures under a high pressure of hydrogen yields a primary alcohol. Any aldehyde intermediate that forms is much more easily reduced than the ester. Diisobutylaluminum hydride, [(CH3)2CHCH2)]2A1H, is less reactive than lithium aluminum hydride. At—78 °C in toluene, the reagent, known as DIBAL, reduces esters to aldehydes. 

The mechanism of the reduction of an ester occurs by nucleophihc attack of a one molar equivalent of a hydride ion on the carbonyl carbon atom. However, the aluminum atom is bonded to the oxygen atom and participates in the reaction. For simplicity, the structures do not show the aluminate ion. Attack by the hydride ion produces a tetrahedral intermediate whose negatively charged oxygen atom is bonded to the aluminum atom. The tetrahedral intermediate loses an alkox-ide ion, and the resulting aldehyde is even more rapidly reduced than the original ester by a second molar equivalent of hydride ion. Two molar equivalents of hydride ion or one-half molar equivalent of hthium aluminum hydride is required for the reduction. 

Reduction with sodium in alcohol was unsuccessful (54). The introduction of lithium aluminium hydride has provided an elegant method for the reduction of thiazole esters to hydroxythiazoles for example, ethyl 2-methyl-4-thiazolecarboxylate (11 with lithium aluminium hydride in diethyl ether gives 2-methyl-4-(hydroxymethyl)thiazole (12) in 66 to 69% yield (Scheme 7) (53),... 

Give the structure of an ester that will yield a mixture contain mg equimolar amounts of 1 propanol and 2 propanol on reduction with lithium aluminum hydride... 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Generally, the carboxyl group is not readily reduced. Lithium aluminum hydride is one of the few reagents that can reduce these organic acids to alcohols. The scheme involves the formation of an alkoxide, which is hydroly2ed to the alcohol. Commercially, the alternative to direct reduction involves esterification of the acid followed by the reduction of the ester. 

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

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