FULL PAPER DOI: 10.1002/ejoc.200900779 An Efficient (2-Aminoarenethiolato)copper(I) Complex for the Copper-Catalysed Huisgen Reaction (CuAAC) Pierangelo Fabbrizzi,* [a] Stefano Cicchi,* [a] Alberto Brandi, [a] Elena Sperotto, [b][‡] and Gerard van Koten [b] Keywords: Azides / Alkynes / Click chemistry / Cycloaddition / Dendrimers / N ligands A (2-aminoarenethiolato)copper(I) complex has been used as an efficient catalyst (1 mol-%) for the copper-catalysed Huisgen reaction (CuAAC) of azides and terminal alkynes in an organic solvent. The reaction was also extremely effective Introduction The Huisgen reaction, the 1,3-dipolar cycloaddition of azides to terminal alkynes, has probably become one of the most frequently used reactions in organic chemistry, espe- cially after the development by Sharpless and Fokin of a copper-catalysed version (CuAAC). [1] This reaction was the first of a restricted group of reactions generally known by the term “click chemistry”. [2] The efficiency of this reaction is demonstrated by the huge number of applications in sup- ramolecular chemistry, [3] peptidomimetics, [4] dendrimer synthesis, [5] bioconjugation, polymer and materials synthe- sis [6,7] and many other fields. [8] Such a wide variety of applications requires the reaction to be performed under many different conditions, for exam- ple, organic and aqueous solvents, and heterogeneous con- ditions. Despite this variety of reaction conditions a very limited set of catalysts are available. The use of Cu II salts with a sacrificial reducing agent such as sodium ascorbate is the most common procedure: sodium ascorbate provides the Cu I ions that are needed for the catalytic reaction. [1,9] However, even a copper wire can afford the required Cu I ions by comproportionation of Cu II and Cu 0 . Simple Cu I salts have also been used, but the thermodynamic instability of Cu I can lead to oxidation to catalytically inactive Cu II . The use of ligands such as tris(1-benzyltriazol-4-ylmethyl)- amine (TBTA) [10] or sulfonated bathophenanthroline [11] im- [a] Dipartimento di Chimica Organica “Ugo Schiff”, Università degli Studi di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy Fax: +39-055-4573531 E-mail: pfabbrizzi@gmail.com [b] Chemical Biology & Organic Chemistry, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands [‡] Present address: Physikalische Chemie, Universität Siegen, Adolf-Reichwein-Str. 2, 57076 Siegen, Germany Eur. J. Org. Chem. 2009, 5423–5430 © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5423 in CH 2 Cl 2 allowing the complete decoration of dendrimeric scaffolds. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) proves the rate and efficiency of more delicate reactions. The limited solubility of cuprous salts in organic solvents restricts the choice to soluble preformed coordination com- plexes of Cu I , for example, under these circumstances [Cu(PPh 3 ) 3 ]Br [12] and (EtO) 3 PCuI [13] are the catalysts of choice. The availability of new Cu I complexes, which have been shown to be active in other reactions, allows the effi- ciency of these compounds to be tested in another useful reaction. In this work we report the results obtained by using the (aminoarenethiolato)copper(I) complex 1 [14] (Figure 1) as a catalyst in the 1,3-dipolar cycloaddition of azides to ter- minal alkynes. In (aminoarenethiolato)copper(I) complexes, the copper(I) cation is bonded to a monoanionic, poten- tially S,N-bidentate-coordinating 2-aminoarenethiolate li- gand. These complexes show excellent solubility in a range of useful solvents. They exist, both in the solid state and in solution, as aggregate species, for example, as dimers, tri- mers, tetramers or nonamers, [15] and exhibit good thermal stability. In addition, electronic and physical properties can easily be fine-tuned by introducing substituents onto the arene ring or the amino functionality. These (aminoarene- thiolato)copper(I) complexes have already been tested as catalysts in allylic substitution, [16] 1,4- [17] and 1,6-addition [18] reactions and aromatic N-arylation reactions [19] and have shown good catalytic properties. Figure 1. {[2-(Dimethylamino)methyl]thiophenolato}copper(I) (1).