Synergistic palladium-catalyzed C(sp3)-H activation/C(sp3)-O bond formation: a direct, step-economical route to benzolactones.

In the last decade, C H bond-activation protocols have profoundly changed the landscape of organic synthesis through unconventional bond-disconnection strategies for the assembly of complex organic molecules. Ideally, directing groups that are commonly employed in C H activation processes should have a dual role by assisting chelation and subsequently promoting further functionalization. The use of benzoic acids holds great promise in this regard, as illustrated by the recent work of Yu and co-workers, and other research groups. Despite the available background knowledge, the development of catalytic methods for activating C(sp) H bonds is still in its infancy. Indeed, it is highly desirable to design new synthetic pathways based on C(sp) H activation in order to dramatically increase molecular complexity while avoiding tedious functional group manipulation. Benzolactones are a prominent structural motif of many bioactive natural products and pharmaceutically important compounds. Classical methods for the synthesis of benzolactones include the cyclization of hydroxy acids or halolactonization processes (Scheme 1, path b). Unfortunately, these methods require prefunctionalization steps, which limit the applicability because of the need for additional synthetic steps (Scheme 1, path a). The most attractive route toward benzolactones 2 would imply a direct catalytic conversion of benzoic acids 1, thus drastically reducing the overall number of synthetic steps (Scheme 1, path c). Despite encouraging precedents, particularly the pioneering and elegant work reported by Sames and co-workers when using Pt catalysts, this seemingly routine transformation is not yet efficient because of the low functional group tolerance, the high price of Pt, and the limited substitution patterns that can be accessed, thus enforcing a change in strategy. As part of our ongoing interest in the synthesis of benzoic acids by Pdcatalyzed CO2 activation, [11] it was anticipated that 1 might undergo a Pd-catalyzed activation of a proximal C(sp) H bond, followed by a virtually unexplored reductive elimination of a Pd intermediate to form a C(sp) O bond (Scheme 1, path c). This step would be rather challenging because of the large energy gap between the highest occupied molecular orbital (HOMO) of the Pd O bond and the lowest unoccupied molecular orbital (LUMO) of the Pd C bond, and the substantial ionic character of the Pd O bond. Overall, path c (Scheme 1) would constitute a direct, stepeconomical approach toward benzolactones 2. We hypothesized that the judicious choice of a supporting ligand and its appropriate fine-tuning might play an important, if not critical, role in the synthesis of 2. Herein, we demonstrate that these two mechanistically distinct Pd-catalyzed processes can be drastically accelerated by the employment of an Nprotected amino acid as the supporting ligand in the synthesis of highly functionalized benzolactones with a diverse set of substitution patterns that are beyond reach otherwise. We began our study with 1a as the model substrate. After considerable optimization, we found that the use of Pd(OAc)2, K2HPO4, and Ag2CO3 as the oxidant in chlorobenzene as the solvent afforded a remarkable level of activity (Table 1). As expected from our previous work in inert-bond activation, a minor modification in the ligand backbone had a detrimental impact on the reaction outcome. Among the ligands examined, we noticed that the use of L2 and L3 was highly beneficial (Table 1, entries 2–3). Subsequently, we found that commercially available N-protected amino acids L4–L9 could be successfully employed as ligands (Table 1, entries 4–10). The beneficial effect of using Nprotected amino acids for the activation of various C(sp) H bonds has already been demonstrated by the pioneering work of Yu and co-workers; however, the use of N-protected amino acids for the functionalization of C(sp) H bonds has received much less attention. To the best of our knowledge, N-protected amino acids have not been employed as ligands in Pd-catalyzed C(sp) O bond-forming reactions. Ligand L7 was particularly active; its use drastically reduced the yield of 3a while the yield of 2a was increased up to 95% (Table 1, Scheme 1. Synthetic approaches to benzolactones.