Pergamon 0040-4020(94)00990-2 Tetrahedron Vol. 51, No. 4, pp. 1197-1208, 1995 Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0040-4020/95 $9.50+0.00 First Unequivocal Synthesis of 1 or 8-N-Monosubstituted 1,4,8,12-Tetraazacyciopentadecane Colin Granier and Roger Guilard* Laboratoire d'IngEnierie Mol6culaire pour la S6paration et l'Application des Gaz Associ6au CNRS (LIMSAG) IYMR 9953 Facult6des Sciences"Gabriel" 6, Boulevard Gabriel 21100 Dijon France Abstract: A novel method derived from Kaden's modification I of the Richman and Atkins's cyclization 2 using tosylated synthons allows the unequivocal synthesis of 1 and 8-monofunctionalized 1,4,8,12-tetraazacyclo-pentadecane. Both syntheses are described. Despite the ever growing interest in the coordinating properties of macrocycles such as crown-ethers, cryptands or cyclophanes 3'4 most studies involving N-monosubstituted derivatives of tetraazamacrocycles have been made either on cyclam or isocyclam. The N-monofunctionalization of the former was achieved by reacting five equivalents of the parent "free-base" with one equivalent (to avoid polysubstitution) of halogenated derivative 5. Still, removing the excess of cyclam from the final product remains time consuming and therefore, prior to the substitution, it can be interesting to protect three of the nitrogens as recently described 6'7. On the other hand, the synthesis of N-monosubstituted derivatives of isocyclam involves the condensation of symmetrical synthons 8'9. We report here the results of our research on the synthesis of N- monosubstituted tetraazamacrocycles by reaction of an unsymmetrical synthon with a symmetrical one. The method is partially derived from that used by Kaden and al.1 involving a macrocycle in which one nitrogen is discriminated. Condensation of N-cyanoethylbenzylamine 1 with chloroacetonitrile 10 yielded after careful distillation the N-cyanomethyI-N-cyanoethyl-benzylamine 2 (52%) (Scheme 1). Hydrogenation ll of 2 gave 4-benzyl- 1,4,8-triazaoctane 3 in a quantitative yield. Tosylation of 3 was performed by dropwise addition over a period of 5 hours of tosyl chloride in an etheral solution on a stirred solution of 3 in presence of two equivalents of sodium hydroxyde leading to the first synthon 4 in a quantitative yield. 1197