Remarkably high reactivity of Pd(OAc)2/pyridine catalysts: nondirected C-H oxygenation of arenes.

Over the past eight years there has been tremendous progress in the development of Pd-catalyzed ligand-directed C H oxidation reactions to form C O, C N, C S, C halogen, and C C bonds. In marked contrast, analogous C H oxidation reactions of substrates that do not contain directing groups remain challenging. The lack of a directing group typically renders these transformations (as exemplified by C H oxygenation) kinetically slow, particularly with electron-deficient arene substrates. The palladium-catalyzed C H oxygenation of simple arenes is also plagued by low turnover numbers and competing biaryl formation, which often leads to catalyst decomposition through precipitation of palladium black. Furthermore, with substituted aromatic substrates, the site selectivity is typically low and difficult to control. As part of a program aimed at developing efficient, selective, and robust catalysts for nondirected C H functionalization reactions, we sought to identify supporting ligands that would address these limitations and promote the Pdcatalyzed C H acetoxylation of arenes. The vast majority of palladium-catalyzed arene C H oxygenations utilize simple palladium salts (e.g., Pd(OAc)2 or PdCl2), [3–5] and literature studies have provided conflicting data about the influence of added ligands on these reactions. Several reports have shown that most common ligands (e.g., 2,2’-bipyridine, 1,10-phenanthroline, pyridine, triphenylphosphine oxide, etc.) inhibit the palladium-catalyzed C H acetoxylation of arenes. In contrast, in a few related systems bidentate sp N-donor ligands (e.g., 2,2’-bipyridine and/or 1,10-phenanthroline) were shown to provide modest enhancement of catalytic activity. However, these latter reactions exhibited low turnover numbers (typically < 10); furthermore, the origin of the observed effects was not explored in detail. Herein we describe the use of careful mechanistic analysis to identify new, efficient, and general palladium catalysts for the C H acetoxylation of benzene derivatives. Remarkably, these catalysts can be formed in situ from Pd(OAc)2 and the simple ligand pyridine (pyr). Furthermore, their catalytic activities and site selectivities can be dramatically modulated through variation of the palladium/ pyridine ratio. Inspired by recent reports of Pd-catalyzed C H functionalizations, our initial explorations focused on pyridine as a ligand for the Pd-catalyzed C H acetoxylation of benzene with [PhI(OAc)2]. As shown in Figure 1, the Pd(OAc)2-catalyzed transformation proceeded to completion after 24 hours at 100 8C. However, in marked contrast, [(pyr)2Pd(OAc)2] (generated in situ from 1 equiv of Pd(OAc)2 and 2 equiv of pyr) performed very poorly, providing less than 20% yield under the same reaction conditions (Figure 1).