On the Role of Metal Contaminants in Catalyses with FeCl₃

Abstract

Metal catalysis has a dominant role in modern organic chemistry. In particular, crosscoupling reactions allow bond formations, which have previously been impossible to perform. [1] Precious metal catalysts dominate the field, but alternative systems based on nickel and copper salts have also, historically, been important. In particular, recent systems based on these metals have been described that provide products in a highly efficient manner. [2] In this context, one of us (C.B.) reported iron-catalyzed cross-couplings leading to arylated amides, phenols, thiols and alkynes. [3,4] Commonly, 10 mol % of an iron salt in combination with 20 mol % of a ligand (a diamine or a diketone) in a solvent such as toluene at 135 °C (using closed vials) was used. It was noticed by chemists at RWTH and MIT (past and present) that the catalyst activity depended on the metal salt purity and even more so on its commercial source. [5] Also, a parallel between the results with the iron systems and some of those realized with copper catalysts by S.L.B.'s group and that of Song was recognized. For example, as in the case of much of the chemistry from S.L.B.'s group, N,N'-dimethyl-1,2-diamines were superior ligands, and the best results were realized in conversions of aryl iodides.These observations prompted us to collaborate to investigate whether it was possible that trace amounts of copper impurities were influencing these reactions. Thus, different sources of FeCl 3 (from >98-99.99% metal purity) were examined in the couplings of pyrazole, phenyl amide, phenol and thiophenol with aryl iodides. The literature data and the new results (obtained by B. Fors and R. Martin in the S.L.B. group) are shown below (Tables 1-4).In all cases when >99.99% FeCl 3 was employed lower yields were obtained than when the reactions were run using >98% FeCl 3 . [6,7] Furthermore, when different sources of >98% FeCl 3 were used different results were observed. These findings suggest that both the purity and the source of the FeCl 3 play a crucial role in the success of these transformations.In order to further investigate the cause of these findings, small amounts of Cu 2 O were added to the reactions using >99.99% FeCl 3 . With only 10 ppm of Cu 2 O a significant increase in yield was observed in all cases. [8,9] Moreover, in two cases examined, essentially (Tables 1 and 2, last entries).Although questions remain, we conclude that the outcome of the reported reactions with FeCl 3 may in certain cases be significantly affected by trace quantities of other metals, particularly copper. Considering that metal contaminants have also been found relevant in other processes involving metals (such as the chromium-mediated Nozaki-Hiyama-Kishi reaction, [10] olefinations and Simmons-Smith reactions with organozinc reagents, [11] and "metal-free" Suzuki- [12] and Sonogashira-coupling [13] ), we suspect that the presence of trace metal impurities may play a more important role than is generally assumed.

Synthesis of 2‐Aminobenzothiazoles via Copper(I)‐Catalyzed Cross‐Coupling with Part‐Per‐Million Catalyst Loadings

“…For example, only 5 ppm of Cu 2 O catalyst could effectively catalyze the N-arylation reaction of pyrrazole or phenylamide, affording the corresponding product in good yield (77% and 97%, respectively). [6] Larsson et al [7] also found a similar effect and reported on Ullmann-type coupling reactions in the presence of "homeopathic amounts" of copper salts. Moreover, the scope of Ullmann-type reactions could be extended to N-, O-, and S-arylations with submol% amounts of copper.…”

Iron‐Catalyzed ortho Monoarylation of Benzamide Derivatives

“…Reducing the catalyst loading to 10 mol % ( Table 1, entry 5) resulted in a significant decrease in the yield of product. The use of FeA C H T U N G T R E N N U N G (acac) 3 of lower purity (> 94 %) gave a slightly lower yield (67 %), and the reactions with Cu 2 O or PdA C H T U N G T R E N N U N G (OAc) 2 , which are usual contaminant suspects in iron catalysis, [14] did not proceed at all under these conditions. The presence of a bipyridyl-type ligand to stabilize the catalytic iron species was essential (Table 1, entry 6), and dtbpy performed slightly better than 2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen, Table 1, entries 7 and 8, respectively).…”

Base‐Mediated Direct Arylation of Pyrrole Derivatives

“…[16] It is known that impurities present in commercially available metal salts can catalyze various reactions. [17] Taking into consideration that trace amounts of transition metals, which are known to catalyze direct arylation, can be present in t-BuOLi, some additional experiments were done to examine this issue. No difference in yield was noted in experiments when t-BuOLi from different sources was used.…”