Aldehydes reductive amidation

Reductive Amidation of Aldehydes. The reductive amidation of aldehydes using an organosilane as the reducing agent has been realized. Benzaldehyde reacts over a 74-hour period with triethylsilane and acetonitrile in 75% aqueous sulfuric acid at room temperature to produce an 80% isolated yield of N-benzylacetamide (Eq. 169).313 Octanal fails to react under the same conditions.313 Reductive amidation of aldehydes also occurs with the reagent combination Et3SiH/TFA/primary amide (Eq. 170).326... 

Aldehydes and ketones are readily reduced back to primary and secondary alcohols, respectively. In the case of ketones, although the reduction is reversible, ketoreductase utilizes NADPH, the concentration of which is higher than NADP+, and this drives the reaction toward the secondary alcohol. A good example is warfarin as shown in Figure 5.3 (19). However, aldehydes are further oxidized to carboxylic acids and carboxylic acids are not reduced back to aldehydes thus eliminating the aldehyde. Reductive metabolism of esters and amides also does not generally occur. 

While the reduction of amides to aldehydes competes successfully with other synthetic routes leading to aldehydes, reduction of amides to alcohols is only exceptionally used for preparative purposes. One such example is the conversion of trifluoroacetamide to trifluoroethanol in 76.5% yield by catalytic hydrogenation over platinum oxide at 90° and 105 atm [7770]. 

In the amide reduction scheme on p. 618, the step framed in green gives an iminium ion. Stopping the reaction here would therefore provide a way of making aldehydes from amides. Because these tetrahedral intermediates are rather more stable than those from ester reduction, this can often be achieved simply by carrying out the amide reduction, and quenching, at 0°C (-70 °C is usually needed to stop esters overreducing to alcohols). 

Although amides are the least reactive of the common acid derivatives under most circumstances, they are involved in several reductive syntheses of aldehydes. As described below the conversion can be accomplished by one-electron reducing agents (though relatively powerful ones), and there are specific types of amide which can be caused to decompose to aldehydes. Moreover, amides are precursors of imi-doyl chlorides, Vilsmeier complexes and thioamides, which can also be reduced to aldehydes as discussed in later sections. 

Borane reduction of carbonyl compounds such as aldehydes, ketones, amides, and carboxylic acids was established in 1960s [10,31]. 

NN MULLER Aldehyde synthesis amides or ketoximes, by reduction of imino chlondes. 

Esters are reduced more slowly than ketones and aldehydes. Conjugate carbonyls give mostly 1,2-reduction. Amides, nitriles are reduced to aldehydes. 

Aldehydes from amides. Aromatic tertiary amides (1) can be converted into aryl aldehydes (3) by formation of the Vilsmeier complex (2) followed by reduction with zinc dust (equation I). ... 

Imines are reduced by triethylsilane to their amines when the proper Ir orNi catalysts areemployed. Non-metal-mediated reductions of C=N groups by EtsSiH are also possible. Among these, the trifluorosulfonic acid promoted reductive amidation of aliphatic and aromatic aldehydes with EtsSiH is an excellent way to mono (V-alkylate aliphatic and aromatic amides, thioamides, carbamates, and ureas (eq 26). It is also worth noting that trifluorosulfonic acid/EtsSiH reduces acyl- and tosylhydrazones to hydrazines and 2-aminopyrimidines to 2-amino-dihydro-or 2-aminotetrahydropyrimidines (eq 27). ... 

The dialkylboranes and dialkylaluminums are also of value when partial reduction of an ester or amide is desired. The intermediates formed by the first hydride transfer are stable under the conditions of the reduction. Subsequent hydrolysis then provides the carbonyl compound at the aldehyde reduction stage. This method using diisobutylaluminum hydride has been particularly useful for reduction of esters to... 

Foreign compounds may be metabolized by non-microsomal enzyme systems. These reactions include deamination of amines, oxidation of alcohols and aldehydes, reduction of aldehydes and ketones, hydrolysis of some esters and amides and may occur in the mitochondria, or the cell supernatant fraction, or in the circulating plasma. A thorough discussion of these non-microsomal mechanisms has been presented by Parke [20], These reactions are confined to Phase I oxidations, reductions, and hydrolyses (see Fig. 1). 

The imides, primaiy and secondary nitro compounds, oximes and sulphon amides of Solubility Group III are weakly acidic nitrogen compounds they cannot be titrated satisfactorily with a standard alkaU nor do they exhibit the reactions characteristic of phenols. The neutral nitrogen compounds of Solubility Group VII include tertiary nitro compounds amides (simple and substituted) derivatives of aldehydes and ketones (hydrazones, semlcarb-azones, ete.) nitriles nitroso, azo, hydrazo and other Intermediate reduction products of aromatic nitro compounds. All the above nitrogen compounds, and also the sulphonamides of Solubility Group VII, respond, with few exceptions, to the same classification reactions (reduction and hydrolysis) and hence will be considered together. 

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