An efficient, general procedure for reductive monoalkylation of amines and amine derivatives with aldehydes is reported. Treatment of aldehydes with primary amines, secondary amines, Otrimethylsilylhydroxylamine, and N,N-dimethylhydrazine in lithium perchlorate/diethyl ether and trimethylsilyl chloride, followed by BH 3 •NEt 3 reduction, and straightforward workup afforded secondary amines, tertiary amines, N-substituted hydroxylamines, and hydrazines, respectively. Reductive alkylation of a-amino esters with aldehydes afforded the corresponding N-monoalkylated aamino esters selectively.

Abstract:The sodium tungstate-catalyzed (10 mol %) oxidation of primary amines with a urea-hydrogen peroxide complex (UHP) gives the corresponding N-monoalkylhydroxylamines, which are important biologically active compounds, in good to excellent yields. The method is applicable for a wide range of primary amines, including chiral benzylic amines, a-1,2-hydroxylamine and a-amino esters.Keywords: homogeneous catalysis; hydroxylamines; tungsten; urea-hydrogen peroxide complex a-Hydroxylamino acids and hydroxamic acids have important biological activities. The synthesis of their precursors, N-monoalkylhydroxylamines, has been a topic of considerable research interest.[1] Our investigations have revealed only few examples of the synthesis of Nmonoalkylhydroxylamines from primary amines. These involve the oxidation of the amine with an appropriate oxidation reagent such as benzoyl peroxide (this method requires treatment of an intermediate O-benzylated hydroxylamine with base in order to obtain the free hydroxylamine), [2] hydrogen peroxide or m-chloroperbenzoic acid (this often leads to overoxidation products such as nitroso and nitro compounds and is generally ineffective), [3] or the reduction of the corresponding nitroso and/or nitro compound, or oxime (this method is not applicable to the synthesis of optically active N-alkylhydroxylamines).[4] Other reported methods include the oxidation of a primary amine with dimethyldioxirane (this protocol is applicable to only a limited range of substrates), [5] and the indirect oxidation of primary amines, involving imine formation, oxidation, and oxaziridine hydrolysis [6] (this method is amenable to the synthesis of optically active hydroxylamines, although the acid-labile Schiff base is one of its disadvantages). The direct microwave-induced oxidation of primary amines with oxone over silica gel or alumina, [7] the three-step procedure involving cyanomethylation of primary amines, nitrone formation, and hydroxylaminolysis of the nitrones, [8] the asymmetric hydrogenation of nitrones with an iridium catalyst system, [9] the oxidation of primary amines to nitrones followed by hydrolysis under acidic conditions, or treatment with hydroxylamine to afford the desired N-alkylhydroxylamine (this protocol is applicable only to a limited substrates), [10] and finally the alkylation of amines with a-haloacetonitrile followed oxidation to give the convertible nitrone [11] should also be mentioned.In connection with our interest in one-pot, three-component coupling reactions involving 1,3-asymmetric induction of aldehydes, hydroxylamines and nucleophiles in a 5.0 M solution of lithium perchlorate in diethyl ether, [12] we required access to various optically active N-alkylhydroxylamines. In the course of these studies we encountered difficulties in the oxidation of primary amines to the corresponding hydroxylamines. We investigated a series of reagents for this transformation and discovered that using sodium tungstate (Na 2 WO 4 ) in the presence of the hydrogen peroxide/urea comple...

Condensation of N,N-dimethylhydrazine, an aldehyde in lithium perchlorate/diethylether solution (5.0 M) gave N,N-dimethylhydrazone, which were treated with trimethylsilyl-cyanide to afford α-C-cyanohydrazine. These compounds are important precursors of nitrogen-substituted reagents.

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A General One-Pot, Three-Component Mono N-Alkylation of Amines and Amine Derivatives in Lithium Perchlorate/Diethyl Ether Solution. -An efficient, general procedure for the reductive monoalkylation of amines and amine derivatives with aldehydes is presented. -(HEYDARI*, A.; TAVAKOL, H.; ASLANZADEH, S.; AZARNIA, J.; AHMADI, N.; Synthesis 2005, 4, 627-633; Dep. Chem., Univ. Tarbiat Modarres, Tehran, Iran; Eng.) -D. Singer 32-061