Collect. Czech. Chem. Commun. 2006, 71, 337-367

Selective Protection of 1,4,8,11-Tetraazacyclotetradecane (Cyclam) in Position 1,4 with the Phosphonothioyl Group and Synthesis of a Cyclam-1,4-bis(methylphosphonic Acid). Crystal Structures of Several Cyclic Phosphonothioamides

Tomáš Vitha, Jan Kotek, Jakub Rudovský, Vojtěch Kubíček, Ivana Císařová, Petr Hermann* and Ivan Lukeš

Department of Inorganic Chemistry, Charles University, Hlavova 2030, 128 40 Prague 2, Czech Republic


A new cyclam-based ligand, 1,4,8,11-tetraazacyclotetradecane-1,4-bis(methylphosphonic acid) (1,4-H4te2p), was synthesized. Cyclam was protected by the reaction with PhP(S)Cl2 to form exclusively five-membered cyclic phenylphosphonothioic diamide 2 in a moderate yield. The solid-state structures of 2 and several by-products were determined. Compound 2 was isolated as two stable conformers differing in a mutual position of benzene ring and sulfur atom with respect to the cyclam ring. Compound 2 was used for the synthesis of 1,4-dibenzylcyclam. However, the deprotection of the thiophosphoryl-protected bis(methylphosphonate diester) with aqueous HCl under non-optimized conditions led to a mixture of cyclam derivatives differently substituted with methylphosphonic acid groups. The crystal structures of the target product, 1,4-H4te2p, and also 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrakis(methylphosphonic acid) (H8tetp) were determined. A similar reaction with cyclen (1,4,7,10-tetraazacyclododecane) led only to hardly purifiable mixtures.

Keywords: Aminophosphonic acids; Azacycle; Azacrown; Cyclam cis-protection; Cyclam; Cyclen; Macrocyclic ligands; Phosphonate ligands; Crystal structure determination; TETP; Thiophosphonic amides; Radiopharmaceuticals.

References: 61 live references.