Amides reduction with LiAlH

So far, we have considered protocols that result in chiral centres in the C and position (actnally always with the same substiment). Let us now turn to satnrated carbenes that have only one chiral centre in the backbone. Figure 5.15 shows a procedure that utilises a chiral diamine derived from proline, a naturally occurring a-amino acid. Reaction with aniline to the corresponding amide and reduction with LiAlH yields the diamine used [60]. The actual synthesis of the chiral carbene then calls for reaction of the proUne derived diamine with thiophosgene and subsequent S/Cl exchange with oxalyl chloride [50]. The... 

Another method of alkylating an amine is to acylate the amine to peld an amide and then carry out a reduction with LiAlH. Although two steps are involved, there is no risk of overalkylafion since acylation can only occur once. 

Final reduction of the amide moiety with LiAlH produces crispine A, a potent antitumor agent. Harmicine and its analogs were synthesized in a similar manner. 

The bicyclization commences with the hydroformylation of an appropriate N-substituted allyl amide, producing the linear aldehyde as the main product. The compound undergoes spontaneous intramolecular cyclization. The final product of this domino reaction is formed by the reaction with the solvent (AcOH). Subsequent oxidation of the acylic keto group to the corresponding ester and reduction with LiAlH produced the targeted racemic natural compound with 33% overall yield over four steps. 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

Fig. 17.66. Amide -> amine reduction (top) and lactam -> cycloamine reduction (bottom) with LiAlH..

Amides have been converted into imidoyl chlorides and then reduced to aldimines with LiAlH(OBu ).3, as in Scheme 15. Although not claimed as a synthesis of aldehydes, the aldimines can be hydrolyzed to aldehydes quite readily. Interestingly, the authors say that an excess of the reducing agent can be used because further reduction to the amine requires 24 h, whereas the first stage to the aldimine requires only 30 min at -78 C. 

Prepare methyl ester (a) by Fischer esterification of phenylacetic acid with methanol. Then treat this ester with ammonia to prepare amide (b). Alternatively, treat phenylacetic acid with thionyl chloride (Section 17.8) to give an acid chloride. Then treat this acid chloride with ammonia to give amide (b). Reduction of the amide (b) by LiAlH gives the primary amine (c). Similar reduction of either phenylacetic acid or ester (a) gives alcohol (d). 

A number of organic species, including amides, oximes, and nitriles, undergo reductive amination, a variety of reduction reactions that produce cimines. In general, these processes involve imines, R=N-R, or related species. Reduction processes include hydrogenation using Raney nickel as the catalyst (for nitriles), the reaction with sodium/EtOH (for oximes), and the use of lithium aluminum hydride, LiAlH (for amides or nitriles). Figure 13-16 illustrates the preparation of amphetamine by reductive amination. 

---