Copper‐Catalyzed Cross‐Couplings with Part‐per‐Million Catalyst Loadings

Abstract

Due to the importance of functionalized arenes as scaffolds in applied organic materials and biologically relevant molecules, metal-catalyzed cross-couplings have gained significant attention in recent years. [1,2] Among them Ullmann type CÀX 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-stoichiometric quantities of metal, recent approaches involving wellchosen 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 combinations 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 atmosphere 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

Commentary on “A New, Efficient and Recyclable Lanthanum(III) Oxide‐Catalyzed CN Cross‐Coupling” by S. Narayana Murthy, B. Madhav, V. Prakash Reddy, and Y. V. D. Nageswar, Adv. Synth. Catal. 2010, 352, 3241–3245

“…Although Nageswar and co-workers state that > 99.9% La 2 O 3 is utilized in these reactions, Bolm and Buchwald have shown that the presence of only ppm levels of copper can effectively catalyze these reactions. [7,12] Further, several of the observations made in this paper are consistent with the hypothesis that the active catalyst is copper-based. [5] First, the best ligand for the reported transformation (DMEDA) is also the best ligand for these reactions using a copper-based system.…”

Ligand-free copper(i) oxide nanoparticle-catalysed amination of aryl halides in ionic liquids

“…In contrast to ref. 17, we could not show activity for Cu 2+ species in our reaction sequence. All used Cu(II) salts (Cu(NO 3 ) 2 , CuSO 4 , CuCl 2 , Cu(OAc) 2 and CuF 2 ) failed completely in catalysing the amination of iodobenzene with ammonia under the same conditions.…”

“…[12][13][14] Homogeneously driven copper(I) catalysed C-N bond formation sometimes requires only homeopathic catalyst loadings, but the use of ligands, base or other additives as well as inert conditions are usually necessary. [15][16][17] Heterogeneous C-N cross coupling catalysed by copper(I) requires rather harsh reaction conditions but does not need ligands and shows a good reaction workup. 18,19 However, up to now nanoscale copper(I) catalysed cross coupling reactions, especially C-N bond formation, have rarely been reported in scientific literature 13,[20][21][22] or show drawbacks in versatility and catalyst loadings.…”

Room Temperature N-Arylation of 1,2,4-Triazoles under Ligand-Free Condition

“…However, current methods have some potential limitations because these transformations often use expensive transition-metal catalyst as palladium [9], rhodium [10], nickel [11], and cobalt [12] complexes. Thus, screening out inexpensive and environmentally benign metal catalysts for the N-arylation of azoles still remains a great challenge [13]. Inexpensive copper catalysts bearing various ligands provided a highly economical and efficient method for N-arylation of nitrogen-containing heterocycles with aryl halides.…”