Recent Developments in Palladium-Catalysed Non-Directed C–H Bond Activation in Arenes

Kancherla, Sindhu; Jørgensen, Kåre B.; Fernández-Ibáñez, M. Á́ngeles

doi:10.1055/s-0037-1610852

Cited by 48 publications

(4 citation statements)

References 90 publications

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“…Advances in transition-metal-catalyzed C–H functionalization have been accompanied by the development of new ligands. − In particular, in nondirected Pd(II)-catalyzed C–H functionalization, the assistance of external ligands is essential for addressing the intrinsically insufficient electronic and steric biases of arenes in the absence of directing groups . Further, in addition to their role in the C–H cleavage step, the ligands affect subsequent steps, including the formation of C–C and C–heteroatom bonds and the oxidation of Pd species .…”

Section: Introductionmentioning

confidence: 99%

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

et al. 2023

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The development of ligands and the elucidation of their roles in the catalytic cycle are key to achieving high efficiency and selectivity in nondirected transition-metal-catalyzed C–H functionalization. In particular, careful ligand design can enable the functionalization of previously inaccessible substrate positions, which can lead to regiodivergent transformations of common reactants. In this study, a series of pyrazolopyridone (PzPyOH) ligands that can be easily prepared in a single step was developed for the Pd-catalyzed perdeuteration and meta-selective alkenylation of arenes. In this system, the 2-pyridone moiety was incorporated to function as an internal base, facilitating C–H cleavage and rendering C–H activation reversible, even at challenging sp2 C–H bonds, thus enabling perdeuteration. In addition, the reversible activation of the C–H bonds implies that site selectivity is determined during the migratory insertion step in the alkenylation reaction, thereby preferentially functionalizing the meta-positions rather than the typically more reactive ortho- and para-positions of anisole derivatives. Further, the electronic and structural properties of the pyrazole moiety provide flexibility in the ligand binding to Pd, enabling the facile coordination of an alkene coupling partner during alkenylation. In this process, the hydrogen bonding between pyridone and acetate ligands was crucial to stabilize intermediates, allowing for different types of binding modes, including L,L- and L,X-type bidentate and monodentate binding. Kinetic and computational studies support the proposed mechanisms for perdeuteration and alkenylation, and the findings reveal crucial factors in the design of ligands for Pd-catalyzed C–H functionalization, which will be useful for further development of pyrazole- and pyridone-containing ligands in transition metal catalysis.

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Section: Introductionmentioning

confidence: 99%

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

et al. 2023

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“…4 From the background, direct carbonylation by C–H bond activation has attracted much attention in recent years. 5,6 However, the development of direct/catalytic carbonylation of aromatic compounds is almost unprecedented. In the 1990s, pioneering studies for palladium-promoted direct carbonylation of aromatics were reported; in the systems, an excess amount of furan or thiophene was required under CO, resulting in the corresponding carboxylic acids in trace yields (Scheme 1a).…”

Section: Introductionmentioning

confidence: 99%

Palladium-catalyzed direct carbonylation of thiophenes and furans under CO/CO₂-binary conditions leading to carboxylic acids

Yamamoto,

Kurata,

Ogawa

2023

Catal. Sci. Technol.

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“…Despite the DG being beneficial in achieving regioselective functionalizations, its very use strains the practicality of the transformation due to added steps and the requirement of engineered DGs or functionalities to tether a DG. Nondirected C–H activation is a “one-shot” solution that could herald the present phase of C–H activation in restructuring the drug development and diversification processes without compromising the regioselectivity …”

Section: Introductionmentioning

confidence: 99%

Nondirected C–H/C–F Coupling for the Synthesis of α-Fluoro Olefinated Arenes

Porey,

Bairagi,

Guin

et al. 2023

ACS Catal.

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The fluorinated entities are considered a privileged structure class in the field of medicinal chemistry because of the amplified bioactivity they exhibit. In this regard, developments in C–H fluorination and trifluoromethylation have been mostly targeted. The α-fluoro olefins also show potential applications as bioisosteres of amides and are also prevalent in drug candidates, but their synthetic accessibility by a C–H activation strategy remains an elusive domain. The assistance of the directing group (DG) does enable the fluoroalkenylation but also constrains the scope in terms of expansion of chemical space for drug development programs. The nondirected strategy is a “one-shot” solution to the existing issues on the use of DGs. With this perspective, we herein report the nondirected protocol on Pd-catalyzed C–H/C–F coupling for accessing α-fluoro olefins in a regioselective fashion. The transformation is governed by the dual control of a pyridine and amino acid-based ligand, which dictate the complementary selectivity achieved. The protocol allows for the late-stage derivatization of drugs and natural products and also enables the conjugation of the drug with the natural product by means of a fluoro-olefin bridge. The incorporation of these fluorinated moieties can potentially modulate the parent bioactivity of drugs. Mechanistic investigations and DFT calculations suggest the vital role of monoprotected amino acid ligand in the C–H activation step through concerted metalation deprotonation, which is the overall turnover frequency-determining state of the catalytic cycle.

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Recent Developments in Palladium-Catalysed Non-Directed C–H Bond Activation in Arenes

Cited by 48 publications

References 90 publications

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

Palladium-catalyzed direct carbonylation of thiophenes and furans under CO/CO₂-binary conditions leading to carboxylic acids

Nondirected C–H/C–F Coupling for the Synthesis of α-Fluoro Olefinated Arenes

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Recent Developments in Palladium-Catalysed Non-Directed C–H Bond Activation in Arenes

Cited by 48 publications

References 90 publications

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

Palladium-catalyzed direct carbonylation of thiophenes and furans under CO/CO2-binary conditions leading to carboxylic acids

Nondirected C–H/C–F Coupling for the Synthesis of α-Fluoro Olefinated Arenes

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Palladium-catalyzed direct carbonylation of thiophenes and furans under CO/CO₂-binary conditions leading to carboxylic acids