2-Amino-5,6-difluorophenyl-1H-pyrazole-Directed Pd^II Catalysis: Arylation of Unactivated β-C(sp³)–H Bonds

Abstract

Palladium-catalyzed arylation of unactivated β-C­(sp3)–H bonds in carboxylic acid derivatives with aryl iodides is described for the first time using 2-amino-5,6-difluorophenyl-1H-pyrazole as an efficient and readily removable directing group. Two fluoro groups are installed at the 5- and 6-position of the anilino moiety in 2-aminophenyl-1H-pyrazole, clearly enhancing the directing ability of the auxiliary. In addition, the protocol employs Cu­(OAc)2/Ag3PO4 (1.2/0.3) as additives, evidently reducing the stoichiometric amount of expensive silver salts. Furthermore, this process exhibits high β-site selectivity, compatibility with diverse substrates containing α-hydrogen atoms, and excellent functional group tolerance.

Tuning Reactivity in Pd‐catalysed C(sp3)‐H Arylations via Directing Group Modifications and Solvent Selection

“…Building upon pioneering work on the use of stoichiometric quantities of palladium(II) salts to mediate selective reactions of CÀ H bonds in sp 3 -rich scaffolds, [3] catalytic reactions employing a directing group to coordinate to the palladium(II) catalyst to control the site of reaction have proved to be especially effective. [4][5] In most cases, the directing group incorporates one or more heteroatoms which can act as ligands for the palladium and deliver it to an adjacent CÀ H bond. Nitrogen-rich scaffolds are of particular importance in a wide range of chemistry-related fields, so nitrogen-linked directing groups have been the focus of considerable attention.…”

“…Nitrogen-rich scaffolds are of particular importance in a wide range of chemistry-related fields, so nitrogen-linked directing groups have been the focus of considerable attention. [5] In 2005 Daugulis introduced the 8-aminoquinoline and picolinamide directing groups, [5a] and since then a number of nitrogen-linked directing groups for CÀ H activation have been reported (Figure 1). [5] Typically, these directing groups deliver the palladium catalyst to a nearby CÀ H bond via the formation of a 5-or 6membered palladacycle, though transannular functionalisation reactions have been observed in some cases.…”

“…[5] In 2005 Daugulis introduced the 8-aminoquinoline and picolinamide directing groups, [5a] and since then a number of nitrogen-linked directing groups for CÀ H activation have been reported (Figure 1). [5] Typically, these directing groups deliver the palladium catalyst to a nearby CÀ H bond via the formation of a 5-or 6membered palladacycle, though transannular functionalisation reactions have been observed in some cases. [5d] Two major drawbacks of many of these reactions are the requirement for excess silver salt in the CÀ H activation reaction, as well as difficulty in removing the directing group from the product molecule to recover a free amine for use in further synthetic manipulation.…”