General Chemoselective Suzuki–Miyaura Coupling of Polyhalogenated Aryl Triflates Enabled by an Alkyl-Heteroaryl-Based Phosphine Ligand

Abstract

This study describes a general chemoselective Suzuki–Miyaura coupling of polyhalogenated aryl triflates with the reactivity order of C–Cl > C–OTf using a Pd/L33 catalyst. The methine hydrogen and the steric hindrance offered by the alkyl bottom ring of L33 were found to be key factors in reactivity and chemoselectivity. With the Pd/L33 catalyst, a wide range of polyhalogenated (hetero)­aryl triflates, which were independent of the substrates and of the relative positioning of the competing reaction sites, coupled well with (hetero)­aryl, alkenyl, and alkylboronic acids to obtain the corresponding products with good chemoselectivity and yields. The chemoselective reaction could easily be scaled up to the gram scale, and the use of parts per million levels of Pd catalyst (as low as 10 ppm Pd) was achieved.

Palladium-catalyzed chemoselective direct α-arylation of carbonyl compounds with chloroaryl triflates at the C–Cl site

“…, –Cl > –OTf) is an incredibly attractive strategy and would significantly broaden the choice of synthetic routes in actual applications. 7 However, only a few reports demonstrating Suzuki coupling and a single example of the Stille reaction have demonstrated the possibility of inverting the conventional reactivity order in cross-coupling reactions, which is still highly difficult to achieve ( Scheme 1B ). 7 …”

“… 7 However, only a few reports demonstrating Suzuki coupling and a single example of the Stille reaction have demonstrated the possibility of inverting the conventional reactivity order in cross-coupling reactions, which is still highly difficult to achieve ( Scheme 1B ). 7 …”

“… 14 In fact, the fundamental phosphine ligands, such as PCy 3 and P t -Bu 3 , have been commonly employed in the study of the oxidative addition step to account for –Cl/–OTf chemoselectivity. 7 As such, the factors of ligand design with mechanistic insights for handling a chemoselective reaction involving the potential reductive elimination-demanding step remain unexplored. Second, the catalytic system must offer excellent chemoselectivity toward the Ar–Cl bond and leave the Ar–OTf bond intact to prevent the occurrence of multiple arylation reactions from generating non-separable reaction mixtures.…”

Palladium‐Catalyzed Chemoselective Borylation of (Poly)halogenated Aryl Triflates and Their Application in Consecutive Reactions

“…Only Fu's, [10b] Neufeldt's, [10f] and our research group [10g] have reported this inversion of the common reactivity order of C−Cl>C−OTf in the Suzuki‐Miyaura reaction, with one example in the Stille coupling reaction [11] . In our recent study, we designed and synthesized a novel type of heteroaryl‐based phosphine ligand, in which the preagostic interaction and the steric hindrance offered by the C2‐alkyl group enabled palladium‐catalyzed chemoselectivity in C−Cl for the Suzuki‐Miyaura reaction involving polyhalogenated aryl triflates with aryl boronic acids [10g] . Herein, we report our efforts in the first palladium‐catalyzed chemoselective C−Cl (over C−OTf) borylation reaction (Scheme 1C).…”

An indole-amide-based phosphine ligand enabling a general palladium-catalyzed sterically hindered Suzuki–Miyaura cross-coupling reaction

“…14 a – d In our design, we chose indole as the skeleton because the electronic-biased heterocyclic core and its bicyclic structure may have a different electronic and steric influence on the reaction. 15 In addition, this ligand offers the following advantages in modular synthetic processes: (1) versatile ligand precursors can be prepared from readily available indoles as well as indole carboxylic acids; (2) the substituents of the N atom and the aromatic ring provide additional electronic tunability; (3) the acidic hydrogen at the C2-position provides a facial installation of the amide group through direct deprotonation; and (4) the installation of phosphine motifs to the electron-donating C3-position could increase the electron density of the phosphine motifs and facilitate the oxidative process (Scheme 2). Starting with commercially available N -substituted indoles or indole-2-carboxylic acids, a series of phosphine ligands with an indole-amide-based backbone was prepared and tested in palladium-catalyzed cross-coupling reactions (Scheme 2).…”