Improved synthesis of symmetrically & asymmetrically N-substituted pyridinophane derivatives.

The N,N'-di(toluenesulfonyl)-2,11-diaza[3,3](2,6)pyridinophane (N4) precursor was sought after as a starting point for the preparation of various symmetric and asymmetric pyridinophane-derived ligands. Various procedures to synthesize N4 had been published, but the crucial problem had been the purification of N4 from the larger 18- and 24-membered azamacrocycles. Most commonly, column chromatography or other laborious methods have been utilized for this separation, yet we have found an alternate selective dissolution method upon protonation which allows for multi-gram scale output of N4·HCl. This optimized synthesis of N4 also led to the development of symmetric N4 derivatives as well as the asymmetric derivative N-(tosyl)-2,11-diaza[3,3](2,6)pyridinophane (N4). Using this N4 precursor, different N-substituents can be added to create a library of asymmetric N4 macrocyclic ligands. These asymmetric N4 derivatives expand the utility of the N4 framework in coordination chemistry and the ability to study the electronic, steric, and denticity effects of these pyridinophane ligands on the metal center.