The mechanism of the iron‐catalyzed cross‐coupling of aryl electrophiles with alkyl Grignard reagents is studied by a combination of GC monitoring, Hammett competition experiments, and DFT calculations. The reaction follows a pathway where an FeI complex, formed in situ, reacts in a rate‐limiting oxidative addition with the aryl electrophile. A rapid thermoneutral transmetalation from a Grignard reagent occurs either before or after the oxidative addition, with little to differentiate between the two pathways. A reductive elimination of the resulting alkyl aryl FeIII complex closes the catalytic cycle. Iron in lower oxidation states can act as a competent precatalyst by oxidation into the FeI–FeIII cycle. FeII complexes can give FeI catalysts through reductive elimination of a bimetallic complex. Added ligands, dilution, and powerful aryl electrophiles all serve to increase the stability of the active catalyst, presumably by counteracting oligomerization of low‐valent iron.

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

Unique ligand acceleration: A kinetic investigation of the copper‐catalyzed CN cross‐coupling in the sub‐mol % range reveals an exceptional ligand dependence. Dimethylethylenediamine (DMEDA) is unique in promoting this reaction, and even at a ratio of >2000:1 relative to the catalyst, the reaction order is still positive in DMEDA. This discovery allowed the development of milder reaction conditions. The reaction order in copper becomes zero at very low concentration.

Abstract:The title reaction has been studied under low temperature conditions. Coupling with active substrates can be done even at dry ice temperature. Initial rate studies at À25 8C indicate that high concentrations of any reagent can lead to either complete or partial catalyst deactivation. Under strongly reducing conditions, iron seems to form less active complexes that only slowly re-enter the catalytic cycle, possibly through bimolecular coupling of iron(II) complexes. Computational studies support the experimental observations, and indicate that oxidation states below + I cannot be reached by reductive elimination.

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