FULL PAPER DOI: 10.1002/ejoc.201000046 Aromatic Nitrogen Donors for Efficient Copper(I)–NHC CuAAC under Reductant-Free Conditions Marie-Laure Teyssot, [a] Lionel Nauton, [a,b] Jean-Louis Canet, [b,c] Federico Cisnetti, [a,b] Aurélien Chevry, [a] and Arnaud Gautier* [a,b] Keywords: Click chemistry / CuAAC / Heterocycles / Carbenes / Copper Copper(I)-catalysed azide–alkyne cycloaddition (CuAAC) has been successfully conducted under reductant-free condi- tions. The catalytic system consisted of a combination of a Introduction The emergence of “click chemistry” as a new way of cate- gorizing organic reactions involving simple, selective, modu- lar, high-yielding and easily workable transformations has facilitated an extraordinary expansion in the number of mo- lecules available for medicinal chemistry, biology and mate- rials science. [1] Among these synthetic “click” tools, cop- per(I)-catalysed azide–alkyne cycloaddition (CuAAC) has received unrivalled attention. [2] The CuAAC procedure classically requires the presence of a sacrificial reducing agent such as ascorbic acid or TCEP [tris(2-carboxyethyl)- phosphane] to form the copper(I) species from a copper(II) source. The discovery of ligand-accelerating effects in CuAAC, despite increasing the reaction rate, has allowed both copper catalyst and reducing agent loadings to be dra- matically reduced. The ligands (Figure 1) are usually aro- matic N-donors, for example, triazole [1, TBTA: tris(benz- yltriazolylmethyl)amine], benzimidazole [2, (BimC 4 A) 3 ] and phenanthroline (3, bathophenanthrolinedisulfonic acid disodium salt). [3] Nevertheless, few homogeneous catalytic systems giving rapid and efficient catalysis without the aid of a reducing reagent are available (Figure 2). This is important because ascorbic acid, dehydroascorbate and other byproducts have been reported to interact with azo amides, lysine and guan- idine. [4] Also, in the case of lanthanide probes, ascorbic acid is known to act as a luminescence quencher. [5] In this con- text, the highly crowded [Cu(C18 6 tren)]Br (4) introduced by [a] Clermont Université, Université Blaise Pascal, Laboratoire SEESIB, B. P. 10448, 63000 Clermont Ferrand, France Fax: +33-4-73407717 E-mail: arnaud.gautier@univ-bpclermont.fr [b] CNRS, UMR 6504, SEESIB, 63177 Aubiere, France [c] Clermont Université, ENSCCF, Laboratoire SEESIB, B. P. 10448, 63000 Clermont Ferrand, France Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201000046. Eur. J. Org. Chem. 2010, 3507–3515 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3507 copper(I)–N-heterocyclic carbene complex and aromatic N- donors. The catalyst is stable and can be stored, thus render- ing the reaction valuable for routine use. Figure 1. N-donor ligands that accelerate CuAAC. Vincent and co-workers exhibits very good stability towards oxygen, thereby allowing a catalyst loading as low as 10 –3 mol-% with an impressive turnover number. [6] On the other hand, this high catalytic efficiency is achieved at the expense of the high temperature needed for the reactions. Pericàs and co-workers recently reported a contracted ver- sion of the tripodal ligand 1. [7] The stable complex 5 (0.5 mol-%) can be used in neat or “on water” conditions. (Aminoarenethiolato)copper(I) 6, which exhibits excellent thermal stability, is also able to promote CuAAC at low loading (1 mol-%). [8] Unfortunately, the reactions cannot be conducted in water, and organic solvents such as dichloro- methane are preferred. Finally, the seminal work of Nolan Figure 2. Oxygen-stable catalysts 4–9.