Lithium aluminum hydride amide reduction

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

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)... 

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 ...

The lithium aluminum hydride reduction of225 afforded two products, namely 227 and 228. Emde reduction, however, gave only 227. By contrast, lithium aluminum hydride gave a single product from 224, but lithium in liquid ammonia produced multiple products. Thus either method may be selective, depending on the nature of X. The Emde method has also been applied to 9-cyanoindolizidines with the formation of medium-ring amides.267... 

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

In 1973 Koda el al. 122) exposed pilocarpine to aminolysis and lithium aluminum hydride reduction, and then obtained several analogs. Treatment with ammonia or with aqueous methylamine or isopropylamine at room temperature gave the hydroxy amides 64-66. Reaction of pilocarpine with ammonia at 200-210°C yielded a lactam, the pilocarpine analog 67. Similarly, the /V-methyllactam 68 was prepared by reaction with liquid methylamine at 225°C. Reduction of pilocarpine with lithium aluminum hydride (LAH) in tetrahydrofuran yielded the tetrahydrofuran analog 69. Preliminary pharmacological studies indicated interesting cholinergic activity. 

Lithium aluminum hydride reduction in equally effective with both acyclic aitd i ctic amides, i r lactams. The reduction of a lactam is a good method for preparing a cyclic amine. 

An even more facile synthesis of XX was achieved by Mondon (10) using the amide derived from 3,4-dimethoxyphenyIethylamine (XXVI) and 2-ketocyclohexaneacetic acid (XXVII). The amide XXVIII is prepared simply by heating the ethylene ketal of XXVII with XXVI it cyclizes on warming in phosphoric acid to a lactam (XXIX) isomeric with Belleau s. Lithium aluminum hydride reduction gives the same racemic base (XX). The intermediate lactam XXX can be prepared in... 

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

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.). 

This postulate was confirmed by synthesis. Reaction of 2-ethyIindole with oxalyl chloride gave 262, which reacted with 3-ethylpiperidine to afford the amide 263. Lithium aluminum hydride reduction gave the amine 260, identical with the natural material. The correct name for this compound, based on secodine nomenclature (117), is 16-decarbomethoxy-14,15,16,17-tetrahydrosecodine. 

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]. 

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