Lithium Aluminum Hydride Reduction of an Amide

2RCNR 2 + LiAlH4 diethyl ether 2RCH2NR 2 Amide Amine 

Step 1 Hydride is transferred from aluminum to the carbonyl carbon of the amide to give a tetrahedral intermediate. The carbonyl oxygen becomes bound to aluminum. 

Step 2 The tetrahedral intermediate undergoes elimination to form an iminium ion. 

Step 3 The iminium ion undergoes addition of a second hydride. For simplicity, the source of hydride shown in the next equation is the [LiOAlHj] species formed in step 2, but it can be any species present in the reaction mixture that retains an Al—bond. Thus, the overall stoichiometry corresponds to reduction of two moles of amide per mole of LiAlHt and the final inorganic product is LiA102. 

Because amides are so easy to prepare, this is a versatile method for preparing amines. 

Lithium Aluminum Hydride Reduction of an Amide THE OVERALL REACTION  

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

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... 

Mechanism of the reduction of an amide to an amine by lithium aluminum hydride. 

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... 

Reduction of an amide is the last step in a useful procedure for monoalkylation of an amine. The process begins with acylation of the amine using an acyl chloride or acid anhydride then the amide is reduced with lithium aluminum hydride. For example,... 

Reduction of an Amide by Lithium Aluminum Hydride (Section I8.10B)... 

LAH 2) H2O Lithium aluminum hydride is a powerful hydride reducing agent. It will reduce ketone, aldehydes, esters and carboxylic acids to give alcohols. Reduction of esters and carboxylic acids requires the use of excess LAH. Reduction of an amide (with LAH) gives an amine. 

Reduction of an azide a nitrile or a nitro compound furnishes a primary amine A method that provides access to primary secondary or tertiary amines is reduction of the carbonyl group of an amide by lithium aluminum hydride... 

Reduction of amides (Section 22.9) Lithium aluminum hydride reduces the carbonyl group of an amide to a methylene group. Primary, secondary, or tertiary amines may be prepared by proper choice of the starting amide. R and R may be either alkyl or aryl. 

Vinylogous amides undergo reduction with lithium aluminum hydride, by Michael addition of hydride and formation of an enolate, which can resist further reduction. Thus -aminoketones are usually produced (309, 563,564). However, the alternative selective reduction of the carbonyl group has also been claimed (555). 

A thio-substituted, quaternary ammonium salt can be synthesized by the Michael addition of an alkyl thiol to acrylamide in the presence of benzyl trimethyl ammonium hydroxide as a catalyst [793-795]. The reaction leads to the crystallization of the adducts in essentially quantitative yield. Reduction of the amides by lithium aluminum hydride in tetrahydrofuran solution produces the desired amines, which are converted to desired halide by reaction of the methyl iodide with the amines. The inhibitor is useful in controlling corrosion such as that caused by CO2 and H2S. 

The stoichiometry determines the ratios of lithium aluminum hydride to other compounds to be reduced. Esters or tertiary amides treated with one hydride equivalent (one fourth of a molecule) of lithium aluminum hydride are reduced to the stage of aldehydes (or their nitrogen analogs). In order to reduce an ester to the corresponding alcohol, two hydride equivalents, i.e. 0.5 mol of lithium aluminum hydride, is needed since, after the reduction of the carbonyl, hydrogenolysis requires one more hydride equivalent. 

Free acids require still an additional hydride equivalent because their acidic hydrogens combine with one hydride ion of lithium aluminum hydride forming acyloxy trihydroaluminate ion. Complete reduction of free carboxylic acids to alcohols requires 0.75 mol of lithium aluminum hydride. The same amount is needed for reduction of monosubstituted amides to secondary amines. Unsubstituted amides require one full mole of lithium aluminum hydride since one half reacts with two acidic hydrogens while the second half achieves the reduction. 

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