Reduction of Acid Derivatives to Aldehydes

Lithium tri-t-butoxyaluminiim hydride LiAIH(Ot-Bu)3] (reduces an acyl chloride but not an aldehyde) 

The steric hindrance caused by the bulky tertiary butoxy groups makes this reagent much less reactive than lithium aluminum hydride. At low temperature (—78°C) it is reactive enough to attack the carbonyl carbon of an acyl chloride, but it reacts only slowly with the aldehyde product. Examples of the use of this reagent to prepare aldehydes are provided in the following equations  

Numerous other metal hydride reagents have been developed to accomplish a variety of specialized reductions. The only other one that will be discussed here is di-isobutylaluminum hydride, i-Bu2A1H or DIBALH  

This intermediate is stable at —78°C until acid is added 

Suggest methods to accomplish the following transformations. More than one step may be necessary in some cases. 

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The reduction of acid derivatives to aldehydes requires control because aldehydes are more easily reduced than the acid derivatives. The hydrogenation of acid chlorides in the presence of quinoline-5 poisoned palladium catalyst, which is a modification of the Rosenmund reduction, shows this selectivity (Eq. 6.19) [33]. 

Carbonyl Group Reduction. The flow of new methods for reduction of acid derivatives and aldehydes or ketones to alcohols continues unabated. The Report last year (4,134) featured the sodium borohydride reduction of carboxylic acid derivatives, originally thought to be 2-thiazoline-2-thiol esters (14), to give alcohols in good yields. Full details of the method have now appeared (Scheme 8), and it seems that the acid derivatives are in fact the 3-acyl thiazolidine-2-thiones (IS) dissappearance of their yellow colour is an easy way to monitor the reduction. Carboxylic acids or their chlorides can also be reduced to primary alcohols in good yields at room temperature using a titanium tetrachloride-sodium borohydride combination. ... 

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. 

Another approach to aldehydes by partial reduction of acid derivatives involves introduction of groups that stabilize the partially reduced intermediate against elimination of water. The aziridine ring has this effect because of the I-strain that is introduced if elimination occurs. The partially reduced carbinolamine intermediates are stable to further reduction, and aldehydes are formed on subsequent... 

The domain of hydrides and complex hydrides is reduction of carbonyl functions (in aldehydes, ketones, acids and acid derivatives). With the exception of boranes, which add across carbon-carbon multiple bonds and afford, after hydrolysis, hydrogenated products, isolated carbon-carbon double bonds resist reduction with hydrides and complex hydrides. However, a conjugated double bond may be reduced by some hydrides, as well as a triple bond to the double bond (p. 44). Reductions of other functions vary with the hydride reagents. Examples of applications of hydrides are shown in Procedures 14-24 (pp. 207-210). 

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... 

Trioxolanes are key intermediates in the ozonolysis of alkenes (Section 4.16.8.2). This reaction is of considerable importance in synthetic chemistry where ozonide intermediates are often reduced (to aldehydes or alcohols) or oxidized (to carboxylic acids) in situ. Advantage has been taken of the stability of certain derivatives to investigate selective chemical reactions. An example of selective reduction is shown in Scheme 47 <91TL6454> with other uses of the 1,2,4-trioxolane ring as a masked aldehyde or ester referred to in Section 4.16.5.2.1. 

Org Prep Proc Int 21 4S1 (1989) (metal hydride reduction of acids and derivatives to aldehydes)... 

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