Reduction of Acid Derivatives

The reaction tolerates ketone, chloride, internal C=C bonds, esters, nitriles, and ether functional groups. Given that the DIBAL-H reduction of acid derivatives often suffers from over-reduction to alcohols, these catalytic procedures are of synthetic value for laboratory-scale syntheses. However, it is likely that the requirement for excess (tBuCO)20 will prevent this reaction from ever being used in commercial production. 

BY REDUCTIONS OF ACID DERIVATIVES, RCOX, OR NITRILES, RfeN... 

Birch reduction of acid derivatives is even more productive if the first-formed enolate (as 66) is used as a nucleophile. Our example also links this chapter with the last as a Cope rearrangement is featured. A group of alkaloids including mesembrine have the bicyclic structure 89. Removing the structural nitrogen atom by standard disconnections (chapters 6 and 8) leaves the carbon skeleton 91 that does not immediately look a Birch reduction product. 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

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... 

Catalytic hydrogenation of nitriles gives the corresponding amine, which is another exception in the reduction of acid derivatives. Nitriles are acid derivatives because they can be hydrolyzed to the parent carboxylic acid (see Chapter 20, Section 20.13). Conversion of the C=N unit to a CH2NH2 unit requires two molar equivalents of hydrogen gas. In principle, it is possible to add one molar equivalent of hydrogen to convert the CsN unit to an imine (-CH=NH), but imines are very difficult to isolate under these conditions. (For further information about imines, see Chapter 18, Section 18.7.1.) For that reason, an excess of hydrogen is typically used to ensure conversion of the nitrile to the amine. Indeed, this is an important preparation of amines. 

Carboxylic acids, their esters, and amides are usually resistant to sodium borohydride reduction, whereas carboxylic acid chlorides may be reduced in inert solvents to give alcohols. Where this proves unsatisfactory a new alternative procedure for acid chloride reduction in ether solution involves sodium borohydride adsorbed on alumina. Other recently published borohydride reductions of acid derivatives to primary alcohols include those of the 1-succinimidyl esters (8)" and the N-nitroso-amides (9). 2-Methoxyethoxymethyl (MEM) esters have the possibility of co-ordinating the metal cation of complex hydrides at the MEM group, and hence of activating the carbonyl group towards reduction by intramolecular hydride delivery. The selective reduction of the less hindered ester group in the bis-MEM ester (10) to give (11) illustrates this idea. 

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 intermediate oxidation state of carbon in which there are two bonds to electronegative atoms is attained by reduction of acid derivatives or oxidation of alcohols and hydrocarbons. Interconversions at the same oxidation level such as hydration of alkynes and hydrolysis of vinyl halides are also valuable. 

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]. 

FIGURE 15.38 Reduction of acid derivatives by boroiaydride reagents. 

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