Carboxylic acid derivatives to aldehydes

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

Of the several methods now available for the reduction of carboxylic acid derivatives to aldehydes, all require careful control of conditions to avoid ovorreduetion or underreduetion. The procedure described here is particularly convenient in that... 

Acylation of Hydride Donors Reduction of Carboxylic Acid Derivatives to Aldehydes... 

Complex or soluble neutral metal hydrides are usually employed for the reduction of carboxylic acid derivatives to alcohols or amines. The standard reagents for the most important transformations are shown in Table 17.6. For completeness, various reagents also are listed for the reduction of carboxylic acid derivatives to aldehydes. The latter mode of reduction was discussed in Section 6.5.2. 

There have been two major approaches towards achieving selective reduction of carboxylic acid derivatives to aldehydes (or derivatives) by hydrides. Firstly, hydride reagents themselves have been modified as, for example, sodium borohydride and sodium cyanoborohydride. Sometimes these modifications have led to finely tuned reducing agents, as with the dimethyl sulfide adduct of thexylbromoborane (see later). Secondly, the type of carboxylic acid derivative has been modified for the optimum yield of aldehyde. For example, amides have been made from an assortment of amines in efforts to maximize yields of aldehyde. Best yields of aldehydes are obtained usually by a combination of modified hydride reagent with a modified carboxylic acid derivative. 

Esters and Other Carboxylic Acid Derivatives to Aldehydes 4.4.1 Diisobutylaluminium Hydride... 

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

One of the more difficult partial reductions to accomplish is the conversion of a carboxylic acid derivative to an aldehyde without over-reduction to the alcohol. Aldehydes are inherently more reactive than acids or esters so the challenge is to stop the reduction at the aldehyde stage. Several approaches have been used to achieve this objective. One is to replace some of the hydrogens in a group III hydride with more bulky groups, thus modifying reactivity by steric factors. Lithium tr i - / - b u to x y a I u m i n u m hydride is an example of this approach.42 Sodium tri-t-butoxyaluminum hydride can also be used to reduce acyl chlorides to aldehydes without over-reduction to the alcohol.43 The excellent solubility of sodium bis(2-methoxyethoxy)aluminum hydride makes it a useful reagent for selective... 

When a nucleophile containing a heteroatom reacts at a carboxyl carbon SN, reactions occur that convert carboxylic acid derivatives into other carboxylic acid derivatives, or they convert carbonic acid derivatives into other carbonic acid derivatives. When an organometallic compound is used as the nucleophile, SN reactions at the carboxyl carbon make it possible to synthesize aldehydes (from derivatives of formic acid), ketones (from derivatives of higher carboxylic acids), or—starting from carbonic acid derivatives—carboxylic acid derivatives. Similarly, when using a hydride transfer agent as the nucleophile, SN reactions at a carboxyl carbon allow the conversion of carboxylic acid derivatives into aldehydes. 

Several related reactions involve reduction of cyclic carboxylic acid derivatives to masked aldehydes which resist further reduction but can be converted into the required aldehydes by acid hydrolysis. In a series of papers, it was established that carboxylic acids could be converted into dihydro-1,3-thiazines or dihydro-1,3-oxazines which could be reduced by NaBH4 in weakly acidic ethanol. Thus, as shown in Scheme 20, dihydro-1,3-thiazines (41) were reduced to tetrahydro-1,3-thiazines (42) in yields of 66-84%. The resulting tetrahydro compounds could be hydrolyzed to aldehydes by aqueous acid. - In a later publication, these workers showed that there was little evidence for ring opening during reduction and that other methods of reduction e.g. hydrogenation over Pt, Pd or Rh or use of dissolving metals such as Zn, Sn or Na) were totally unsuccessful. In closely similar work, reduction of 5,6-dihydro-4W-... 

Reduction of saturated carboxylic acids with the borane derivative, thexylchloro-borane, provides a direct route to aldehydes without their prior conversion to carboxylic acid derivatives. The aldehydes initially formed were isolated either as their bisulfite adducts or as their hydrazones, from which the aldehydes were regenerated. 

However, the in vivo reduction of aldehydes by this enzyme is not normally a quantitatively important reaction because aldehydes are rapidly oxidized to their corresponding carboxylic acid derivatives by aldehyde dehydrogenase. Alcohol dehydrogenase is a very important enzyme for the metabolism of ethanol. 

One equivalent of R2AIH at low temperature will add once to nitriles or many carboxylic acid derivatives to give aldehydes after an acidic aqueous workup (see Section 9.2.2). 

The direct aldol reaction of carboxylic acid derivatives and aldehydes (or ketones) is very difficult. Recently, Kobayashi and co-workers (146) extended the ketones to amides as suitable candidates successfully for the direct aldol reaction. The screening of metal sources revealed that Ba(0-tBu)2 was the better catalyst than Sr(0-iPr)2, Ca(0-iPr)2, or Mg(0-iPr)2, whereas rare earth metals (eg, La(0-iPrls) are catalytically inactive in the presence of p-methoxyphenol. In this aldol reaction, barium enolate formed in situ from barium alkoxide and acylamide and... 

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