Palladium‐Catalyzed meta‐Selective C‐H Alkenylation and Acetoxylation of Arylacetic Acid Using a Pyrimidine Template

Abstract

Palladium‐catalyzed remote meta‐selective C‐H functionalization of arylacetic acid has been developed using a pyrimidine template. This transformation is not only tolerated to a diverse range of arylacetic acid and alkene substrates but also applicable to the synthesis of pharmaceutically active ibuprofen derivatives. Moreover, the pyrimidine template was readily removable and recyclable under mild conditions.

Two Directing Groups Used for Metal Catalysed Meta‐C−H Functionalisation Only Effect Ortho Electrophilic C−H Borylation

“…Compound 5 was selected as ester/BBr 3 combinations do not affect directed ortho borylation [12b] (in contrast to the more basic amide analogues), this will preclude ortho borylation without having to install alkyl blocking groups onto the template. Furthermore, an extremely similar ester linked template has been used successfully in palladium catalysed meta C−H deuteration, [10c] and alkenyl‐/acetoxylation [17] . However, the combination of excess BCl 3 or BBr 3 with compound 5 led to no C−H borylation ( ortho or meta ) under a range of conditions, with complex mixtures formed from which the only boron containing species that can be assigned with confidence being due to pyridyl→BX 3 adducts (for X=Cl δ 11B =8.3, for X=Br δ 11B =−7.4).…”

Palladium-catalyzed remote para-C–H activation of arenes assisted by a recyclable pyridine-based template

“… 13 Therefore, phenylpropionic acid was selected as the model substrate for our investigation of para -C–H activation of arenes. Based on our recent work on meta -C–H activation of phenylpropionic acid 14 and inspired by recent research on meta -C–H activation assisted by pyridine-based DTs, 12 we designed a series of potential pyridine-based para -DTs with different substitutions to attach with phenylpropionic acid, leading to the amide substrates ( Table 1 , see ESI † for more DTs evaluated), where the nitrogen atom of pyridine could coordinate to the transition metal to induce site-selective C–H activation. The design of the structure of the template was also inspired by previous reported nitrile-based biphenyl containing para -directing template.…”

Recent Developments in Remote Meta‐C−H Bond Functionalizations

“…Prompted by the broad substrate scope of templates and alkenylation of C−H bonds activation, [31,108,112,113] in another report, Zhou's group has revealed the selective meta‐ functionalization of phenylacetic acid as this vital scaffold is found in several medicines namely, analgesic, ibuprofen, antipyretic drugs and so forth. In this study, the pyrimidine‐based template was employed under operationally simple reaction conditions in the presence of Pd(OAc) 2 [114] . This ideal approach not only turns out to be a great methodology for the synthesis of ibuprofen derivatives but also a variety of phenylacetic acid derivatives has been assembled using this wonderful strategy (Scheme 13).…”

“…In this study, the pyrimidine-based template was employed under operationally simple reaction conditions in the presence of Pd(OAc) 2 . [114] This ideal approach not only turns out to be a great methodology for the synthesis of ibuprofen derivatives but also a variety of phenylacetic acid derivatives has been assembled using this wonderful strategy (Scheme 13). More importantly, this strategy not only shows a broad substrate scope and tolerates diverse functional groups but also the pyrimidine template was easily removable as well as recyclable under mild reaction conditions.…”