Aldehyde reaction with LiAlH

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. 

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. 

In view of the expected instability of the mercapto aldehydes likely to be formed, the reaction mixture was extracted and the concentrated extract treated with LiAlH / acetic anhydride/pyridine. The acetates/ thioacetates isolated from this reaction mixture were analyzed with MS/NMR spectroscopy. From the results of these analyses, the reaction routes as indicated in Figure g are followed. 

Carboxylic acids, acid chlorides, acid anhydrides and esters get reduced to primary alcohols when treated with lithium aluminium hydride (LiAlH) (Fig.M). The reaction involves nucleophilic substitution by a hydride ion to give an intermediate aldehyde. This cannot be isolated since the aldehyde immediately undergoes a nucleophilic addition reaction with another hydride ion (Fig.N). The detailed mechanism is as shown in fig.O. 

With milder reducing agents such as DIBAL-H and LiAlH[OC(CH3)3]3, the process stops after reaction with one equivalent of Hr and the aldehyde is formed as product. With a stronger reducing agent like LiAlH4, two equivalents of H are added and a 1° alcohol is formed. 

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. 

These chiral alkylboronic esters are exceptionally promising intermediates for C-C bond formation reaction in the synthesis [8, 9] of a-chiral aldehydes, P Chiral alcohols, a-chiral acids, and a-chiral amines. Brown et al [10], in a real breakthrough, discovered that LiAlH readily converts these relatively inert boronic esters to a very high reactive lithium monoalkylborohydrides R BHjLi (5) of very high optical purity. The optically active monoalkylborane (R BH2) is generated, when required, by a convenient reaction with trimethylsilyl chloride [6]. Consequently, the desired B-R -9-BBN is prepared conveniently by hydroboration of 1,5-cyclooctadiene with RBHj (prepared in situ), and the desired stable 1,5-isomer is obtained by thermal isomerization. The whole sequence is illustrated in Scheme 9.1. 

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. 

Most of the methods describing the preparation of Emtricitabine (and Racivir) rely on the construction of 1,3-oxathiolane ring by reaction of glycoMdehyde or glyoxalic acid derivatives with mercaptoacetic add or mercaptoacetic aldehyde (which exists as 1,4-ditiane 154). For example, one of the first of syntheses of this type commenced from allyl alcohol which was silylated and then subjected to ozon-olysis to give glycoMdehyde derivative 155 (Schane 36) [142], Reaction of 155 with mercaptoacetic add afforded 1,3-oxathiolane 156, which was reduced with LiAlH(OtBu)3 or DIBAL and then acetylated to form 157. Finally, reaction of 157 with silylated fluorocytosine derivative 158 followed by deprotection led to the formation of racemic 8 (Racivir). 

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. 

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>. 

Lithium aluminum hydride (8) reacts with ketones and aldehydes in the same way as sodium borohydride, except that LiAlH is a more powerful reducing agent. In one experiment, reaction of heptanal (13) with LiAlH4 in diethyl ether, followed by aqueous acid workup, gave 1-heptanol (16) in 86% yield. The mechanism is identical to that of borohydride in that heptanal reacts with the negatively polarized hydrogen of the Al-H unit in 8 via the four-centered transition state 14, This leads to an alkoxyalmninate product, 15, and subsequent treatment with dilute acid... 

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). 

Treating an aldehyde or a ketone with NaBU, or LiAlH, followed by water or some other proton source, affords an alcohol. This is an addition reaction because the elanents of H2 are added across the n bond, but it is also a reduction because the product alcohol has fewer C-O bonds than the starting carbonyl compound. 

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