Improved synthetic methods to mixed-donor thiacrown ethers

A series of azathia- and azaoxathiacrown ether macrocycles have been prepared in good yields via the use of N-boc-bis(2-chloroethyl)amine as a precursor, which minimises undesirable side reactions and facilitates subsequent deprotection to the free cyclic amine. The mono-aza macrocycles, [12]aneNS3, [12]aneNOS2, [15]aneNS4, [15]aneNO2S2 and [16]aneNS4 have been prepared via this route. The single-crystal X-ray structure of [12]aneNS3 · HBr · 2H2O confirms the macrocycle to be distorted quadrangular with the S-centres lying along the edges and six out of 12 torsion angles less than 90°. The synthesis of di-aza macrocycles utilising the diamide precursors, N,N′-bis(chloroacetyl)-1,2-diaminoethane and N,N′-bis(chloroacetyl)-1,3-diaminopropane, affords the free macrocycles [12]aneN2S2, [15]aneN2S3, [15]aneN2OS2, [16]aneN2S3 and [19]aneN2S4 after reduction of the intermediate cyclic amides. Reaction of 3,6-dioxa-1,8-octanediamine with the dimethyl ester of thiadiglycolic acid followed by reduction affords [15]aneN2O2S, while the hydroxy-substituted macrocycles [20]aneS6(OH)2, [13]aneS4(OH), and [26]aneS8(OH)2 have been prepared by reaction of 1,3-dichloro-2-hydroxypropane with the appropriate dithiol. The crystal structure of [20]aneS6(OH)2 shows two endo- and four exo-dentate S-centres as observed in the parent [18]aneS6. The N-aryl substituted macrocycles N-4-NO2Ph-[12]aneNS3 (N-4-nitrophenyl-7-aza-1,4,10-trithiacyclododecane) and N-4-NH2COPh-[12]aneNS3 (N-4-benzamido-7-aza-1,4,10-trithiacyclododecane) have been prepared by reaction of 4-substituted bis-tosylated N,N-bis(2-hydroxyethyl)aniline with 3-thia-1,5-pentanedithiol.

Graphical abstractA series of azathia- and azaoxathiacrown ether macrocycles have been prepared in good yields via the use of N-boc-bis(2-chloroethyl)amine as a precursor; this route minimises undesirable side reactions and facilitates subsequent deprotection to the free cyclic amine.Figure optionsDownload full-size imageDownload as PowerPoint slide