Reduced number of steps for the synthesis of dense and highly functionalized dendrimers Paul Servin, a Cyrille Rebout, a Re ´gis Laurent, a Maurizio Peruzzini, b Anne-Marie Caminade a, * and Jean-Pierre Majoral a, * ,  a Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France b ICCOM CNR, Istituto di Chimica dei Composti Organo Metallici, Via Madonna del Piano, 10 Polo Scientifico di Sesto Fiorentino 50019 Sesto Fiorentino, Italy Received 28 September 2006; revised 16 November 2006; accepted 20 November 2006 Available online 11 December 2006 Abstract—A series of densely functionalized dendrimers is synthesized using two branched monomers of type AB 2 and CD 2 , in which the A function (NH 2 ) reacts with D (CHO) and the B function (Cl) reacts with C (OH). The reaction has been carried out up to the fourth generation possessing 96 end groups and has been obtained in only four steps. Ó 2006 Elsevier Ltd. All rights reserved. The hyperbranched, perfectly defined structure of den- drimers, 1 and the easy functionalization of their end groups have induced a dramatic expansion of their potential application in various fields of nanosciences including materials 2 and biology. 3 However, the achievement of dendrimers with numerous end groups after only a small number of synthetic steps is not trivial. A few methods have been already proposed to diminish the number of steps, in particular the ‘double stage method’ 4 and the ‘double exponential growth’, 5 but these methods does not really decrease the number of steps when considering the whole synthetic process used. In fact, the most powerful strategy to date is the ‘ortho- gonal coupling strategy’, 6 which consists in using two types of branched units (AB n and CD n 0 monomers, where n and n 0 are generally equal to 2). This method gives at each step a new generation of layered dendri- mers, but it has been mainly used with a set of com- pletely independent classes of protecting groups. To avoid the inconvenience of using protection/deprotec- tion strategies, we have previously proposed for the first time AB n and CD n 0 monomers (n, n 0 = 2 and/or 5) bear- ing two pairs of complementary functions able to react quantitatively and spontaneously without any activating agent. 7 In all cases, the A and D functions were phos- phines and azides reacting by Staudinger reactions and creating P@N linkages, whereas the B and C functions were hydrazines and aldehydes reacting by condensation reactions and creating CH@NN linkages. These meth- ods are particularly powerful, but imply the use of easily oxidable phosphines, which must be manipulated under a controlled atmosphere excluding oxygen. On the other hand, our main method of synthesis consists in the repetition of condensation reactions and nucleophilic substitutions; 8 it does not necessitate any drastic condi- tions, and allowed us to synthesize and characterize the highest generation 9 ever described for any type of den- drimer, but is relatively tedious since the number of end groups is multiplied twice only after two synthetic steps. We report in this paper a substantial improvement of this method, which allows multiplying by two the number of end groups at each step. The method of synthesis we generally use requires a branched building block of type AB 2 (H 2 NNMeP(S)Cl 2 , with A = NH 2 and B = Cl) and a linear one of type CD (4-hydroxybenzaldehyde, with C = OH and D = CHO). In order to densify more rapidly the number of end groups, this linear building-block should be replaced by a branched one, but having the same type of func- tions. This is the reason as to why we have considered 5-hydroxyisophthaldehyde 1, prepared from 5-hydroxy- diethylisophthalate 10 in this study. The first step to build the dendrimer consists in grafting 6 equiv of the sodium salt of 1 to N 3 P 3 Cl 6 (Scheme 1). The reaction 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.11.112 Keywords: Dendrimer; Density; Aldehyde; Hydrazone; Phosphorus. * Corresponding authors. Fax: +335 6155 3003 (A.-M.C.); e-mail addresses: caminade@lcc-toulouse.fr; majoral@lcc-toulouse.fr   Fax: +335 6155 3003. Tetrahedron Letters 48 (2007) 579–583