Lithium aluminum hydride reduction of amide

Lithium aluminum hydride reduction of amides is one of the best methods for the preparation of amines, including arylamines. 

By the lithium aluminum hydride reduction of amides, amino alcohols (and their derivatives) can be obtained, which have a different arrangement of amino and hydroxy groups to those derived from amino acids. Thus, (5)-2-amino-l-phenylethanol is obtained by reduction of (S)-mandelic acid amide1. 

The introduction of iV-substituents in aminoborneols is also possible by lithium aluminum hydride reduction of amides formed with activated carboxylic acids44, e.g., (S)-iV-(benzyloxy-carbony])proline. Compounds of this type 39-41 have been used as catalysts in the enantiose-lective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.). 

Lithium aluminum hydride reduction of amides can be used to prepare 1°, 2°, or 3° amines, depending on the degree of substitution of fhe amide. 

Amines of the formula n 2n+ be prepared by the lithium aluminum hydride reduction of the corresponding amide, hydrogenolysis... 

Excellent procedures are available for the preparation of primary, secondary, and tertiary amines by the reduction of a variety of nitrogen compounds. Primary amines can be obtained by hydrogenation or by lithium aluminum hydride reduction of nitro compounds, azides, oximes, imines, nitriles, or unsubstituted amides [all possible with H2 over a metal catalyst (Pt or Ni) or with LiAlH4] ... 

Secondary and tertiary amines, particularly those with different R groups, are prepared easily by lithium aluminum hydride reduction of substituted amides (Section 18-7C). 

Enantiomerically pure a-amino aldehydes containing nonpolar side chains such as Boc-Ala-H, Boc-Leu-H, and Boc-Phe-H are synthesized by lithium aluminum hydride reduction of the corresponding Weinreb amides, Boc-Ala-N(Me)OMe, Boc-Leu-N(Me)OMe, and Boc-Phe-N(Me)OMe, respectively (Table 4). The lithium aluminum hydride does not affect the Boc group due to the low temperature and short 15-minute reaction time. Successful synthesis of side-chain Bzl-protected Boc-Thr(Bzl)-H gives a 95% yield of crude product, however, reduction of N-protected aspartyl and glutamyl aldehydes from their corresponding A-methoxy-A-methylamides leads to overreduction and unreacted hydroxamateJ1920 ... 

Table 4 Synthesis of a-Amino Aldehydes by Lithium Aluminum Hydride Reduction of Weinreb Amides 20-32 ...

Lithium Aluminum Hydride Reduction of an Amide See section 4.3.1 for a description of lithium aluminum hydride (LAH). 

As a result of their potent pharmacological activity, 4-aryl-1,2,3,4- tetrahydroisoquinolines have attracted numerous synthetic efforts. Treatment of ( S)-1 with acetone under acid catalysis generates ( S)-( + )-2,2-dimethyl-5-phenyl-l,3-dioxolan-4-one (55) in 80% yield. Reaction of 55 with methylamine followed by lithium aluminum hydride reduction of the resultant amide provides ( S)-(+ )-A-methylamino-l-phenylethanol [(5)-( + )-halostachine] (56). N-... 

Triol 767 originates from lithium aluminum hydride reduction of alkylated malate 225a. Acetal formation with benzaldehyde furnishes 768 [86], which is further transformed into amide 771 via the nitrile 770. Hydrogenolysis of the acetal leads to a diol that is lactonized... 

Whitesell observed that alkylation at the a-carbon of an amide of a C2-symmetric amine, in which the amine acts as a chiral auxiliary, should result in effective symmetric induction [166]. The C2-symmetric aziridines 519 and 520 are readily accessible from 503 and 514, respectively. Ring opening of either epoxide with sodium azide, mesyl activation of the free hy oxy group, and lithium aluminum hydride reduction of the azide with concomitant ring... 

The asymmetric solvent ( S, S)-(-h)-l,4-bis(dimethylamino)-2,3-dimethoxybutane (593) can be easily prepared in 88% yield from 592a by lithium aluminum hydride reduction of both amides. Interestingly, 592a is prepared from 591 by bis-alkylation with dimethyl sulfate under phase-transfer conditions [191]. 

Lithium aluminum hydride reduction of 7V-formylcorydamine afforded the tertiary base 5, and sodium formate-formic acid formylation of corydamine produced material identical with A -formylcorydamine, thus completing the structural elucidation of this amidic alkaloid (Scheme 22.2). ... 

Pridefine (80) is a somewhat structurally related antidepressant. It is a centrally active neurotransmitter blocking agent. It blocks norepinephrine in the hypothalamus but does not affect dopamine or 5-hydroxytryptamine. Its synthesis be-(jins by lithium amide-promoted condensation of diethyl succinate and benzophenone followed by saponification to 78. Heating in the presence of ethylamine gives N-ethylsuccinimide 79. Lithium aluminum hydride reduction completes the synthesis of pridefine (80)... 

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. 

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