Reaction of Tosylamide Monosodium Salt with Bis(halomethyl) Compounds: An Easy Entry to Symmetrical N-Tosyl Aza Macrocycles

Article abstract of DOI:10.1021/jo00250a020

A one-step, general procedure for a variety of N-tosyl aza macrocycles (including aza-crown ethers, pyridino- and bipyridino-aza-crown analogues, and azacyclophanes), by reaction of appropriate bis(halomethyl) precursors with tosylamide monosodium salt (TsNHNa) in N,N-dimethylformamide, is described.In polymethyl-substituted 2,11-diaza<3.3>cyclophane systems, the methyl substituents play an important role in inducing stereospecific ring closures.Thus, coupling of 1,4-bis(chloromethyl)-2,5-dimethylbenzene (15b) with TsNHNa produced only one of the two possible diastereomeric dimers, to which chiral structure 16db was assigned by means of the chiral Eu(dcm)3 shift reagent.This stereochemical assignment was confirmed by a single-crystal X-ray study on 16d.Detosylation of N-tosyl aza macrocycles to the free polyamino macrocycles by reductive (Na-NH3) or hydrolytic (90percent H2SO4) methods, followed by N-methylation (CH2O-HCO2H), was also accomplished in excellent yield.The 1H NMR spectra of 2,11-diaza<3.3>cyclophanes and 2,11-diaza<3.3>(2,6)pyridinophanes are discussed in terms of conformation and conformational mobility.