An organic template approach for the synthesis of selectively functionalised tetraazacycloalkanes Frédéric Boschetti, Franck Denat, Enrique Espinosa and Roger Guilard* Laboratoire d’Ingénierie Moléculaire pour la Séparation et les Applications des Gaz, LIMSAG UMR 5633, Faculté des Sciences Gabriel, 6 Bd Gabriel 21100. Dijon, France. E-mail: limsag@u-bourgogne.fr Received (in Cambridge, UK) 12th September 2001, Accepted 6th December 2001 First published as an Advance Article on the web 18th January 2002 Selectively functionalised tetraazacycloalkanes are obtained from the open-chain tetraamine by using a bisaminal moiety acting both as a template agent and as a N-protecting group. Cyclic tetraamines have received considerable attention owing to their coordination properties towards various metal cations. 1 The increasing need of finely tuned macrocycles requires the development of new synthetic tools for the preparation of such ligands. The research in this field has been focused on the synthesis of bifunctional chelating agents (BFCs or BCAs) based on a cyclic amine containing two kinds of functional groups, one for the coordination of the guest, another one for the anchoring of the macrocycle onto a solid support or an antibody. 2 In a recent review, we have described the different strategies for the regioselective functionalisation of tetra- azacycloalkanes. 3 Besides some typical procedures developed for the synthesis of some target molecules, mono-N-functional- isation of cyclic tetraamines usually involves the use of a large excess of macrocycle relative to the electrophile agent, typically five equivalents in the cyclam series. Although the excess of the ligand might be recovered and re-used in most cases, such an approach is macrocycle consuming and the formation of small amounts of polysubstituted macrocycles may not be completely avoided. Another method consists of protecting three nitrogen atoms with Boc groups prior to the functionalisation of the remaining secondary amine. 4 This procedure has been success- fully used for the synthesis of many different ligands but its main drawback is the chromatographic work-up necessary to separate the triprotected macrocycle from the reaction mixture. Finally, the above methods involve the use of a high cost macrocycle, i.e. cyclam or cyclen, as starting material and they cannot be utilized in the case of unsymmetrical macrocycles such as 1,4,7,10-tetraazacyclotridecane for which two different mono- or tri-N-functionalised compounds may be formed. Substituting the hydrogen atom of one secondary amine of a cyclic tetraamine by a benzyl group is also a convenient method for synthesis of trifunctionalised cyclams, since the benzylic C– N bond is easily hydrogenolysed. The mild conditions used to remove the protecting group allow the survival of many different functionalities. Conveniently substituted benzene rings, such as nitrobenzene, may allow a further functionalisa- tion of the arm to graft, for example, the macrocycle on an antibody. Moreover, such benzylated tetraazacycloalkanes, and especially bismacrocycles containing two cyclam units linked together through a xylyl spacer, are highly potent anti-HIV compounds. 5 In this paper, we wish to report a convenient and general synthesis of mono-N-benzylated tetraazacycloalkanes starting from the suitable open-chain tetraamine. The reaction proceeds as depicted in Scheme 1. The first step involves the reaction of the linear tetraamine with pyruvic aldehyde to form the bisaminal derivative 1. Cyclisation occurs in a second step, by condensation of the bisaminal compound with the convenient biselectrophile, leading to 2a and 2b in good yields. The addition of benzyl bromide to 2a and 2b gives the mono- benzylated bisaminal protected tetraazamacrocycles as quater- nary salts 3a and 3b. These compounds are easily deprotected in very mild conditions to yield the desired monobenzylated 1,4,7,10-tetraazacyclotridecane 4a and cyclam 4b. These de- protection conditions might slightly differ depending on the nature of the macrocycle. Thus, while refluxing NaOH solution is necessary to remove the bisaminal bridge from 3a, the benzylcyclam 4b is already released at rt, proving that the quaternary ammonium salt 3a is more stable than 3b. The yields for each step are nearly identical in both series and the monobenzylated macrocycles, 4a and 4b, can be readily obtained from the linear tetraamine in overall yields close to 30%. The structures of compounds 1 and 3b have been confirmed by single crystal X-ray analyses (Fig. 1). The compound 1 is obtained as the sole product and no trace of the other seven possible isomers has been detected in the NMR spectra. An interesting characteristic of compound 3b is the exceptional length of the bond between the ammonium nitrogen atom and the aminal-type carbon atom (N1–C41 = 1.582 (4) Å) when compared to similar ammonium salts (1.547 (6) Å in the glyoxal adduct). 6 Scheme 1 Fig. 1 ORTEP 13 views of (a) cis-9a-methyloctahydro-1H,4H,7H-1,3a,6a,9- tetraazaphenalene (1) and (b) the cis-3a-benzyl-10b-methyldecahydro- 1H,6H-5a,8a,10a-triaza-3a-azoniapyrene cation of (3b), showing thermal ellipsoids at the 50% probability level. Selected bond distances: N1–C41 = 1.455 (2) and 1.582 (4) Å, N2–C21 = 1.478 (2) and 1.480 (4) Å, N3–C21 = 1.463 (2) and 1.460 (4) Å, N4–C41 = 1.491 (2) and 1.482 (5) Å, C21– C41 = 1.544 (2) and 1.561 (5) Å, for (a) and (b), respectively. H-atoms omitted for clarity.† This journal is © The Royal Society of Chemistry 2002 312 CHEM. COMMUN. , 2002, 312–313 DOI: 10.1039/b108244b