Copper Catalysis DOI: 10.1002/ange.200902236 Copper-Catalyzed Cross-Couplings with Part-per-Million Catalyst Loadings** Per-Fredrik Larsson, Arkaitz Correa, Monica Carril, Per-Ola Norrby,* and Carsten Bolm* Due to the importance of functionalized arenes as scaffolds in applied organic materials and biologically relevant molecules, metal-catalyzed cross-couplings have gained significant atten- tion in recent years. [1, 2] Among them Ullmann type C ÀX bond formations are particularly attractive because they often allow the use of low-cost starting materials in combination with readily available copper salts. [2] Whereas the initial protocols [3] required high temperatures and over-stoichiomet- ric quantities of metal, recent approaches involving well- chosen and optimized metal–ligand combinations allow for milder reaction conditions and catalytic turnover. [4] Despite these significant advances it has to be noted that commonly in these catalytic Ullmann type reactions both TONs (turnover numbers) as well as TOFs (turnover frequencies) remain rather limited resulting in the requirement of metal salt amounts in the range of 5 to 10 mol %. [5] Lowering the catalyst loading leads to extended reaction times and decreased product yields. Here, we report on Ullmann type reactions with “homeopathic amounts” of copper salts. [6] During investigations of iron-catalyzed cross-coupling reactions [7, 8] it was noted that for some substrate combina- tions the catalyst activity depended on the metal salt source and its purity. [9] Those observations suggested a closer look into the effects of metal traces under the applied reaction conditions. [10] Taking into account the results by Taillefer and others on Fe/Cu co-catalyses, [11] copper became the prime metal of choice. To our surprise we found that even with catalyst loadings in the 0.01 mol % range of copper(II) salts N-, O-, and S-arylations were possible to provide the corresponding products in yields > 90 %. As a representative example, the coupling between pyrazole (1) and phenyliodide (2, 1.5 equiv) to provide N-arylated product 3 [Eq. (1)] was studied in detail. Further reaction components were N,N’- dimethylethylenediamine (DMEDA) as (potential) ligand (20 mol %), K 3 PO 4 ·H 2 O as base (2 equiv) [12] and toluene as solvent. The reaction mixture was kept under inert atmos- phere at 135 8C in a sealed microwave tube for 24 h. Figure 1 shows the dependence of the yield of 3 on the amount of copper(II) chloride applied under the conditions described above (as determined by GC using dodecane as internal standard). Catalyst loadings in the range of 0– 0.64 mol % were tested, and as the graph reveals even 0.01 mol % of the copper salt led to 88 % yield of coupled product 3. The presence of 0.08 mol% of CuCl 2 proved optimal, affording 3 in essentially quantitative (GC) yield. In the absence of both metal and ligand the target arylation did not take place. [13] Similar profiles were obtained when sub-mol % amounts of CuCl 2 were applied in reactions of phenyliodide (1) with benzamide (4) or indole (6) to give N-arylated products 5 and Figure 1. Yield of 3 versus catalyst loading (expressed in mol % of CuCl 2 ); reaction conditions as depicted in Equation (1). [*] P.-F. Larsson, Prof. Dr. P.-O. Norrby University of Gothenburg, Department of Chemistry Kemigården 4, 41296 Göteborg (Sweden) Fax: (+ 46) 31-772-3840 E-mail: pon@chem.gu.se Dr. A. Correa, Dr. M. Carril, Prof.Dr. C. Bolm Institute for Organic Chemistry, RWTH Aachen University Landoltweg 1, 52056 Aachen (Germany) Fax: (+ 49) 241-8092-391 E-mail: carsten.bolm@oc.rwth-aachen.de [**] We are grateful to the Fonds der Chemischen Industrie, the Swedish Research Council, and AstraZeneca for financial support and we acknowledge the EU for financing a Short Term Scientific Mission within the COST D40 program of P.-F.L. We thank Prof. Dr. S. L. Buchwald for kindly sharing unpublished data and for alerting us to his findings of the cross-coupling activity of ppm amounts of Cu 2 O. We also thank Prof. Dr. R. Dronskowski and L. Stork (Institute for Inorganic Chemistry, RWTH Aachen University) for substrate analyses by atom absorption spectroscopy and Dr. E. Zuidema, I. ThomØ, J. Bonnamour and A. Beyer for stimulating discussions and performing various control experiments. Angewandte Chemie 5801 Angew. Chem. 2009, 121, 5801 –5803  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim