Carboxylic esters into aldehydes

Fig. 14.53. Mechanism of the DIBAL reduction of carboxylic esters to aldehydes and further to alcohols. In nonpolar solvents the reaction stops with the formation of the tetrahedral intermediate A. During aqueous workup, A is converted into the aldehyde via the hemiacetal. In polar solvents, however, the tetrahedral intermediate A quickly decomposes forming the aldehyde via complex B. In the latter situation the aldehyde successfully competes with unreacted ester for the remaining DIBAL. The aldehyde is reduced preferentially, since the aldehyde is the stronger electrophile, and it is converted into the alcohol.

AIH3 and alkyl derivatives are powerful Lewis acidic reducing agents that rapidly convert carboxylic esters into primary alcohols. In many cases, the reduction may be stopped at the intermediate aldehyde stage, providing that the stoichiometry and temperature are carefully controlled. However, complete reduction is experimentally easier to carry out. DIBAL-H is the most useful and widely used alane. 

The use of 2,4,6-tri-isopropylbenzenesulphonylhydrazides (in place of the tosylhydrazide) allows milder conditions to be used for the preparation of aromatic aldehydes by the McFadyen-Stevens reaction. Addition of hydrazine hydrate and traces of cupric sulphate suppresses formation of aromatic ester and alcohol by-products. Reduction of oxazolinium salts by sodium borohydride, as part of the well known sequence for the conversion of carboxylic acids into aldehydes, can lead to ring cleavage to form amino-alcohols. It is now reported that over-reduction is much less marked if potassium tri-s-butylborohydride is used as reducing agent (Scheme 2) ... 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

The conversion of primary alcohols and aldehydes into carboxylic acids is generally possible with all strong oxidants. Silver(II) oxide in THF/water is particularly useful as a neutral oxidant (E.J. Corey, 1968 A). The direct conversion of primary alcohols into carboxylic esters is achieved with MnOj in the presence of hydrogen cyanide and alcohols (E.J. Corey, 1968 A,D). The remarkably smooth oxidation of ethers to esters by ruthenium tetroxide has been employed quite often (D.G. Lee, 1973). Dibutyl ether affords butyl butanoate, and tetra-hydrofuran yields butyrolactone almost quantitatively. More complex educts also give acceptable yields (M.E. Wolff, 1963). 

When the related saccharin derived sultam (R)-29 is converted into the (Z)-boron enolate and subsequently treated with aldehydes,. vy -diastereomers 30 result almost exclusively. Thus, the diasteromeric ratios, defined as the ratio of the major product to the sum of all other stereoisomers, surpass 99 1. Hydroperoxide assisted saponification followed by esterification provides carboxylic esters 31 with recovery of sultam 32106a. 

The aerobic oxidation of alcohol under neutral or acidic conditions to produce the corresponding adds, which can avoid the neutralization of the carboxylate salts, is also an important R D issue. In Au-catalyzed alcohol oxidation in methanol, the corresponding methyl esters are obtained with high seledivity instead of carboxylic acids by using metal oxide supported Au NPs [157, 160], In this case, base is not necessary, or only a catalytic amount of base is required to promote the readion. However, in water, it was demonstrated that alcohols were not oxidized under acidic conditions [161] and only aldehydes were oxidized to carboxylic adds [162]. Even under solvent-free conditions or in organic solvents, alcohols were converted into aldehydes without base however, the alcohols were not fully oxidized to carboxylic acid under acidic conditions [163-166]. 

Successful SPS produces a final resin-bound target molecule that is released into solution by breaking a bond between the resin and a functional group in the final compound. Two examples are shown in Fig. 1.6. On the left, the basic hydrolysis of an ester bond releases a carboxylic acid into solution and simultaneously re-forms the original hydroxy PS resin. On the right, the acidic hydrolysis of an acetal function provides the starting aldehyde resin and a diol compound. 

Cleavage of alkenes to esters. 1,2-Disubstituted alkenes can be cleaved directly to carboxylic esters by ozonation in methanol containing hydrochloric acid. The reaction probably involves initial cleavage to an aldehyde and/or a methoxy hydroperoxide, which on further reaction with methanol are converted into esters. 

It has been mentioned in earlier Sections that certain electron deficient heterocyclic carboxylic acids and esters can be reduced electrochemically to aldehydes under acidic conditions, the aldehydes being protected from overreduction by geminal diol formation. This method is also applicable to the corresponding amides, allowing, for example, the conversion of amide (29) into aldehyde (30) in 93% yield. ... 

The total unsaturation from Equation (7) can be apportioned into contributions from alicyclic structural moieties such as furanose and pyra-nose rings, aromatic structural moieties such as benzene rings, and carbonyl-containing moieties such as carboxylic acids, esters, amides, aldehydes, and ketones. Olefinic moieties such as the unsaturated alkyl chains of some lipids are thought to be of only minor importance. Equation (7) can thus be rewritten as... 

Air, the cheapest oxidant, is used only rarely without irradiation and without catalysts. Examples of oxidations by air alone are the conversion of aldehydes into carboxylic acids (autoxidation) and the oxidation of acyl-oins to a-diketones. Usually, exposure to light, irradiation with ultraviolet light, or catalysts are needed. Under such circumstances, dehydrogenative coupling in benzylic positions takes place at very mild conditions [7]. In the presence of catalysts, terminal acetylenes are coupled to give diacetylenes [2], and anthracene is oxidized to anthraquinone [3]. Alcohols are converted into aldehydes or ketones with limited amounts of air [4, 5, 6, 7], Air oxidizes esters to keto esters [3], thiols to disulfides [9], and sulfoxides to sulfones [10. In the presence of mercuric bromide and under irradiation, methylene groups in allylic and benzylic positions are oxidized to carbonyls [11]. 

Sodium dichromate hydroxylates tertiary carbons [620] and oxidizes methylene groups to carbonyls [622, 623, 625, 626, 631] methyl and methylene groups, especially as side chains in aromatic compounds, to carboxylic groups [624, 632, 633, 634, 635] and benzene rings to quinones [630, 636, 637] or carboxylic acids [638]. The reagent is often used for the conversion of primary alcohols into aldehydes [629, 630, 639] or, less frequently, into carboxylic acids or their esters [640] of secondary alcohols into ketones [621, 629, 630, 641, 642, 643, 644] of phenylhydroxylamine into nitroso-benzene [645] and of alkylboranes into carbonyl compounds [646]. 

Pyridinium dichromate in dichloromethane solution converts primary alcohols into aldehydes. In dimethylformamide at 25 °C, carboxylic acids are formed. Cyclohexylmethanol thus gives cyclohexanecarboxylic acid in 84% yield [603]. Oxidations of aliphatic alcohols with ten-butyl chromate yield mixtures of acids with aldehydes and esters [677]. 

For activated esters, the problem of halting reduction at the aldehyde stage is similar to that faced in the reduction of carboxylic acids the aldehyde must be converted in situ into an electroinactive form. In one case, that of reduction of ethyl 2-thiazolecarboxylate [17], the strongly hydrated aldehyde may be obtained in about 70% yield ... 

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