Synthetic pathways towards tetra-aza-18-crown-6-ether

​Crown ethers have gained a lot of attention since their discovery due to their wide range of applications. Aza-crown ethers, in particular, contain soft nitrogen donors that allow substitution on the nitrogen and can effectively bind a wide range of cations. In particular, 1,4,10,13-tetra-aza-18-crown-6 ether has been shown to have potential for application in for example targeted radionuclide therapy.

​The conventional [2+2] cyclisation method for synthesising tetra-aza-18-crown-6 ether only affords a low yield of the desired product. Therefore, the primary aim of this thesis is to develop a convenient, scalable, and robust synthetic pathway for tetra-aza-18-crown-6 ether with improved yield compared to existing methods.

​The first part of the thesis investigates two stepwise synthetic pathways towards tetra-aza-18-crown-6 ether exploring different protecting groups such as o-nosyl, p-nosyl, tosyl, and benzyl.

​The first approach utilises ethylenediamine and 2,2’-dichlorodiethylether as building blocks. The tosyl or nosyl protected ethylenediamines could be prepared by reaction of ethylenediamine with the corresponding arylsulfonyl chloride. The bisbenzyl protected ethylenediamine is commercially available. Subsequently, the protected diamines were reacted with two dichloride molecules to obtain the desired intermediate. Finally, the ring closure was attempted using a second protected ethylenediamine molecule. Attempts were made to synthesise the macrocycle either with four identical protecting groups or with two-by-two different protecting groups. For those structures which were successfully synthesised, deprotection was performed trying to afford the final compound. Successful ring closure could be obtained by using a combination of tosyl and o-nosyl or benzyl and o-nosyl containing compounds. Interestingly, closing the ring containing four tosyls resulted in a significantly higher yield compared to literature. Attempts to simultaneously deprotect both the o-nosyl and tosyl groups did not yield the desired product. Conversely, the deprotection of the ring with four tosyls was carried out with an improved yield compared to literature. As a result, the stepwise method incorporating tosyl protecting groups turned out to be successful. Tetra-aza-18-crown-6 ether was prepared with increased yield compared to reported methods.

​The second approach employs 2,2'-oxydiethanamine and dichloroethane as building blocks. Due to time constraints, this method was only tested with o-nosyl groups. The substitution of the protected diamine molecule with two dichloroethane molecules resulted in a significantly higher yield of the intermediate compared to the first method, demonstrating its potential. However, the ring closing step did not yield the desired product due to degradation of the o-nosyl compounds.

​Additionally, an alternative synthetic pathway via lactamisation was explored briefly by combining two existing methods. Via the first method a benzyl-protected tetralactam derivative of tetra-aza-18-crown-6 ether was successfully synthesised without reducing it, while via the second method the reduction was achieved but the synthesis process was lengthy. Despite its theoretical promise, this approach faced challenges in obtaining the tetralactam ring and was not investigated further due to time constraints.