Aldehydes, reduction with LiAlH

In analogy to imidazolides, both triazolides and pyrazolides have been converted into aldehydes by reduction with LiAlH ... 

The bicyclization commences with the hydroformylation of an appropriate N-substituted allyl amide, producing the linear aldehyde as the main product. The compound undergoes spontaneous intramolecular cyclization. The final product of this domino reaction is formed by the reaction with the solvent (AcOH). Subsequent oxidation of the acylic keto group to the corresponding ester and reduction with LiAlH produced the targeted racemic natural compound with 33% overall yield over four steps. 

Notice in the previous reaction that the ketone carbonyl group has been reduced to an alcohol by reaction with LiAlH. The protected aldehyde group has not been reduced. Hydrolysis of the reduction product recreates the original aldehyde group in the final product. 

Amides have been converted into imidoyl chlorides and then reduced to aldimines with LiAlH(OBu ).3, as in Scheme 15. Although not claimed as a synthesis of aldehydes, the aldimines can be hydrolyzed to aldehydes quite readily. Interestingly, the authors say that an excess of the reducing agent can be used because further reduction to the amine requires 24 h, whereas the first stage to the aldimine requires only 30 min at -78 C. 

Treatment of a ketone or aldehyde with LiAlH or NaBH4 reduces the carbonyl group and yields an alcohol (Section 17.5). Although the exact details of carbonyl-group reduction are complex, LLAIH4 and NaBH act as if they were donors of hydride ion, H , and the key step is a nucleophilic addition reaction (Figure 19.7). Addition of water or aqueous acid after the hydride addition step protonates the tetrahedral alkoxide intermediate and gives the alcohol product. 

Reduction of ketoximts Ketoximes arc reduced by LiAlH< to a mixture of primary and secondary amines. In contrast, reduction with liAllU-HMPT in the molar ratio 1 10 in refluxing THF (13(f, 3 hours) results m ketones. IIMPT is believed to prevent furtbei reduction of the intine intermediate and to facilitate hydrolysis. This method is not useful for reversion of aldoximes to aldehydes because of dehydration to nitriles. 

With LiAlH[OC(CH3)3]3, a milder reducing agent, reduction stops at the aldehyde stage. 

REDUCTION TO THE CORRESPONDING ALDEHYDE Lithium triethoxyaluminum hydride [LiAlH(OEt)j] was found to readily convert pseudoephedrine carboxamides to the corresponding aldehyde with only limited erosion of the ees (Table 2.5). To do so, a solution of the pseudoephedrine carboxamide in THF is added at -78°C to a suspension of LiAlH(OEt)j (2.3 equiv) in hexanes. The reaction mixture is then warmed to 0°C before a dilute acidic aqueous solution (typically HCl 0.5 M) is added, resulting in the formation of the desired aldehyde along with the pseudoephedrine aminal 27. To avoid the formation of the byproduct, the quenching can be performed using a 1M aqueous solution of hydrochloric acid and 10 equivalents of trifluoroacetic add. 

Commercially, pure ozonides generally are not isolated or handled because of the explosive nature of lower molecular weight species. Ozonides can be hydrolyzed or reduced (eg, by Zn/CH COOH) to aldehydes and/or ketones. Hydrolysis of the cycHc bisperoxide (8) gives similar products. Catalytic (Pt/excess H2) or hydride (eg, LiAlH reduction of (7) provides alcohols. Oxidation (O2, H2O2, peracids) leads to ketones and/or carboxyUc acids. Ozonides also can be catalyticaHy converted to amines by NH and H2. Reaction with an alcohol and anhydrous HCl gives carboxyUc esters. 

Aldehyde (4) can be made by chloromethylation (P 9), the condensation with nitromethane with mild base gives an excellent yield of crystalline (3) and LiAlH can be used for the reduction. 

Aldehydes are prepared by the hydroboration-oxidation of alkynes (see Section 5.3.1) or selective oxidation of primary alcohols (see Section 5.7.9), and partial reduction of acid chlorides (see Section 5.7.21) and esters (see Section 5.7.22) or nitriles (see Section 5.7.23) with lithium tri-terr-butox-yaluminium hydride [LiAlH(0- Bu)3] and diisobutylaluminium hydride (DIBAH), respectively. 

While ether is the common solvent for LiAlH, in which it is soluble, hydroxylic solvents like water, methanol and ethanol are preferred for NaBH, It is more soluble in methanol than in ethanol, but since it reacts with the former at an appreciable rate than the latter, hence ethanol is the preferred solvent. Isopropanol, in which NaBH4 is stable, is used for kinetic studies of the reduction of aldehydes and ketones. 

The aldehyde intermediate can be isolated if a leas puwerfu] reducintt agent such as lithiu.ni trt>lerl but0xyalurniiiii3n hydride is ii. ed in place of LiAlH. This reagent, which is obtained by reaction of LiAlK with 3 cciuiv-alente of lerl-butyl alcohol, is particularly effective far carrying out the partial reduction of acid chlorides to aldehyde (Section 19.2>. 

Selective reduction of functional groups can be achieved by chemical modification of the LiALH4 for example, lithium tri(t-butoxy)aluminium hydride [LiAIH(t-OBu)3] is a more selective reagent, and reduces aldehydes and ketones, but slowly reduces esters and epoxides. Nitriles and nitro groups are not reduced by this reagent. Carboxylic acids can be converted into the aldehyde via acid chloride with lithium tri(tert-butoxy) aluminium hydride at a low temperature (—78°C). The nitro compounds are not reduced under this condition. Thus, selective reduction of 3,5-dinitrobenzoic acid (6.45) to 3,5-dinitrobenzaldehyde (6.47) can be achieved in two steps. First, 6.45 is converted into 3,5-dinitrobenzoyl chloride (6.46) and then LiAlH(t-OBu)3 reduction of 6.46 gives 6.47. 

Lithium aluminum hydride, LiAlH, is another reducing agent often used for reduction of ketones and aldehydes. A grayish powder soluble in ether and tetrahydrofuran, LiAlH4 is much more reactive than NaBH4 but also more dangerous. It reacts violently with water and decomposes explosively when heated above 120°C. 

The conjugate reduction of enones is easier than that for enal (39, 40), because aldehyde carbonyl is softer than the ketone counterpart. Alkyl substituents in the a and positions of the enones interfere with conjugate reduction (39). However, treatment of a-alkylthiocyclohexenones with NaBH4 successfully gives saturated alcohols (41). It has been proposed that intramolecular H delivery from a S-coordinated borohydride is involved. A marked increase in the 1,4-reduction of enones by LiAlH(SR)3 is observed (42) (see Table 7.1). Symbiotic softening of the reagents by the thio substituents is responsible for the reversal of the alkoxy effects. 

For example, reduction of acid chlorides (RCOCl), prepared from carboxylic acids by reaction between the acid and, for example, thionyl chloride (vide infra), with hydrogen over a barium sulfate (BaS04) poisoned palladium (Pd) catalyst (the Rosenmund reduction), can often be used to produce the corresponding aldehyde (RCHO). The same product can more easily be obtained from the same starting material by using commercially available lithium aluminum tri-r-butoxy hydride (LiAlH[OC(CH3)3]3) in an ether solvent,such as bis(2-methoxyethyl)ether [diglyme, (CH30CH2CH2)20], at -78°C (Scheme 9.106). 

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