Complex intermediates in the NO insertion reactions into lithium amides

Abstract

Nitric oxide (NO) is known to produce the carcinogenetic nitrosamines but it has also been recently reported, both as a regulator of many important physiological functions and as a possible pharmaceutical delivery system. The present paper describes the NO insertion into N-Li bond of lithium amides, to afford very good to almost quantitative yields of N-nitrosamines. A study of the reaction intermediate suggested a further advantage of this synthetic methodology, widening its scope to its use in tandem reactions. Thus, in situ addition of an organolithium reagent into the N --O bond leads to an almost quantitative conversion into the corresponding hydrazone. This compound could further add a second equivalent of the same (or another) organolithium affording substituted hydrazines. The hydrazines thus prepared have a potential chiral carbon, by running the reaction in the presence of a chiral auxiliary, enantiomeric excess could be obtained. By reducing the compound with Raney Ni, the scope of this methology could be enlarged for the potential preparation of chiral primary amines, project that is currently under progress. RESULTS AND DISCUSSION Reaction of lithium amides with NOThis reaction constitutes a very convenient methodology for the synthesis of alkyl N-nitrosamines, 3, from JOURNAL OF PHYSICAL ORGANIC CHEMISTRY

Addition Reactions: Polar Addition

“…These results show the complexity of solvation effects and the specificity of the substrate-reagent-ligand-solvent interactions. 222 Organolithium reagents undergo highly regio-and diastereo-selective 1,4-addition to α.β-unsaturated amides (172) derived from (S,S)-(+)-pseudoephedrine, furnishing the de corresponding β-alkyl-substituted adducts in excellent yields and diastereoselectivities. Furthermore, the intermediate lithium enolates, generated in the conjugate addition step, undergo a highly diastereoselective alkylation reaction to afford α,β-dialkylsubstituted amides (173) Mixed aggregates of chiral lithium amide and lithium ester enolate have been employed in the enantioselective conjugate addition on α,β-unsaturated esters.…”

Carbanions and Electrophilic Aliphatic Substitution

“…As an extension of the above study, in situ addition of an organolithium reagent into the N=O bond leads to an almost quantitative conversion into the corresponding hydrazone. 79 Intramolecular hydroamination of cyclohexa-2,5-dienes has afforded the corresponding bicyclic allylic amines with high selectivity (Scheme 13). 80 The reaction does not proceed through a direct hydroamination of one of the diastereotopic alkenes but more likely involves a diastereoselective protonation of a pentadienyl anion, followed by addition of a lithium amide across the double bond of the resulting 1,3-diene and a highly regioselective protonation of the final allylic anion.…”