exo-Diastereoisomer of 10-aryl-1,4,7-triazabicyclo[5.2.1]decane as intermediary in specific derivatisation of triazacyclononane M  elissa Roger, V  eronique Patinec * , Martine Bourgeois, Rapha € el Tripier, Smail Triki, Henri Handel Laboratoire de Chimie, Electrochimie Mol eculaires et Chimie Analytique, Universit e de Bretagne Occidentale, UMR C NRS 6521, 6 Avenue Le Gorgeu, 29200 Brest, France article info Article history: Received 17 February 2012 Received in revised form 6 April 2012 Accepted 13 April 2012 Available online 27 April 2012 Keywords: Triazacyclonane Aminal protecting group Specific derivatisation Ditopic ligand cyclam derivative abstract Reaction of triazacyclononane (tacn) and aromatic aldehydes leads to aminal adducts, which exhibit only the exo configuration. In these aminal compounds, secondary amine function possesses a higher re- activity towards electrophilic reactants than the two nitrogen atoms linked to aminal carbon, giving rise to the specific derivatisation of tacn by different functionalised groups. Study of this behaviour also permits the access to a ditopic tacnecyclam bicyclic polyamine. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction The various applications of triazacyclononane (tacn) and de- rivatives generally imply their remarkable coordinating proper- ties. 1 Protein orientation at interfaces, 2 metalloenzyme biosite models, 3 diagnostical or therapeutical metal carriers, 4 magnet molecule clusters, 5 sensors 6 . constitute examples of domains in which the potentialities of these small azamacrocycles are in- volved. Combination of tacn potentialities with different abilities of other chelators could extend the applications fields. A possible approach consists in synthesising polytopic ligands containing different workable characteristic sites. Such an association exists in ditopic cyclic-cyclic or cyclic-linear bispolyamines that have been investigated for biological or medicinal applications. 4,7 In the previous different examples, the use of modified tacn, bearing one, two or three arms with- or without- coordinating atoms is usually required. The introduction on the triazamacrocycle of identical or different substituents necessitates to discriminate the amine functions of the macrocycle. The classical method con- sists in the introduction of the functional group before the cycli- sation step leading to N-alkylated derivatives at the end of the synthetic process, which has, obviously, to be reconsidered when a new product is needed. 8 Recently, this way was used to synthesise tacn-containing cationic lipids with good buffering capacity, which is an important behaviour for non-viral gene delivery reagents. 9 Statistic N-functionalisation also constitutes a synthetic strategy by reacting tacn and alkylating agent in a 1:1 or 1:2 ratio, but generally requires purification steps to separate non-reacted tacn and mono- or/and poly-substituted derivatives. 10 Reaction of tacn with BOC-ON in a 1:2 ratio has given rise to the diprotected 1,4- diBOCetacn synthesis, which permitted for instance to obtain fur- ther Cu(II) complexes of tacn derivatives with alkyl- or xylyl-linked guanidinium groups studied as models compounds for cleaving the phosphonate ester backbone of DNA. 11 Protection of one or two nitrogen atoms of tacn has also been employed by tosylation, 12 carbamation 13 or pH controlled sulfomethylation, 14 including fur- ther purification and/or deprotection steps. Finally, a method based on an intermediate orthoamide has also been described and per- mits to graft independently one, two or three substituents on the tacn macrocycle by playing with the orthoamide hydrolysis. 15 Dipicolyl-tacn derivative studied in low spinehigh spin iron mo- lecular switching, 16 N-aminoalkyl-tacn derivatives suitable for functionalisation of carboxy terminated supports as self-assembled monolayers SAM 17 are examples of compounds issued from the orthoamide protection method. These different routes are complementary methods and it is still important to develop such ways for grafting arms to cyclic poly- amines in order to make it possible in various conditions offering more choice in the nature of substituents. Reaction of tacn with anhydrous paraformaldehyde and dia- lkyloxyphosphine to give trimethylenephosphinate ester derivative was studied by D. Parker et al. 18 It was found to give a bicyclic aminal monophosphinate ester as a secondary product together with the expected trimethylenephosphinate ester. Acidic hydrolysis * Corresponding author. Tel.: þ33 298 017 127; fax: þ33 298 017 001; e-mail address: veronique.patinec@univ-brest.fr (V. Patinec). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2012.04.057 Tetrahedron 68 (2012) 5637e5643