Site-Selective and Late-Stage Deuteration of (Hetero)arenes with Supported Iridium Nanoparticles

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 2822 - 2826

Published: Jan. 31, 2025

Deuterated compounds have emerged as critical tools across diverse research areas, including pharmaceuticals, where deuterium incorporation can modulate the absorption, distribution, metabolism, and excretion (ADME) properties of drugs. In this study, we report development a new hydrogen/deuterium (H/D) exchange catalyst based on supported iridium nanoparticles that enables selective deuteration arenes heteroarenes under mild conditions. Using C6D6 source, our catalytic system achieves high chemo- regioselectivity, avoiding common side reactions such hydrogenation dehalogenation observed with traditional heterogeneous catalysts. Notably, occurs selectively at para- meta-C(sp2)–H bonds, leaving ortho-C(sp2)–H C(sp3)–H bonds intact, exhibits broad functional group tolerance, ketones, amides, alkenes, aryl ethers, acidic protons. The nature was confirmed via filtration mercury drop tests. This work presents for regioselective complex molecules, offering complementary site selectivity to existing homogeneous methods possibility being used in late-stage pharmaceuticals.

Language: Английский

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Silylarylation of Alkenes via meta-Selective C–H Activation of Arenes under Ruthenium/Iron Cooperative Catalysis: Mechanistic Insights from Combined Experimental and Computational Studies

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(7), P. 4510 - 4522

Published: March 12, 2024

Organosilicons are privileged skeletons in the domains of pharmaceutical chemistry, organic synthesis, and materials science. Hence, investigating catalytic techniques for synthesis organosilicon compounds has received a great deal emphasis. Carbosilylation alkenes is an efficient technique to introduce diverse molecular architectures containing silicon into chemical space. However, organohalides pseudohalides prerequisites most existing carbosilylation protocols. On other hand, utilization C–H activation been sowing seeds successful development intricate scaffolds. In this regard, synthetic accessibility complexed derivatives by through meta-C–H approach remained intangible. Herein, we present three-component strategy arylsilylation olefins with (het)arenes silanes integrating iron-catalyzed silyl radical generation, coupled intrinsic reactivity alkene, ruthenium-catalyzed functionalization (het)arene, leading targeted cross-coupled carbosilylated product. addition, theoretical investigations state-of-the-art dispersion corrected density functional theory at B3PW91-D3/Def2TZVP/CPCM(PhCF3) shed intriguing insights on selectivity probable mechanistic pathway underexplored cooperative 3d/4d transition metal catalysis, such as formation its addition alkene catalyzed iron, followed meta-selective ruthenium bound arene, furnishing C4 substituted (het)arene functionalized compounds.

Language: Английский

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Deuteration and Tritiation of Pharmaceuticals by Non‐Directed Palladium‐Catalyzed C–H Activation in Heavy and Super‐Heavy Water

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(48)

Published: Aug. 7, 2024

Abstract Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction using non‐directed homogeneous Pd‐catalysis. Aromatic C−H activation is achieved by commercially available pyridine ligand. Using the most convenient cheapest deuterium source, D 2 O, as only solvent 39 pharmaceuticals were labelled with clean profiles high uptakes. Additionally, describe first application Pd‐catalysis H/T on three different T O isotopic demonstrating applicability to synthesis radiotracers.

Language: Английский

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Palladium(II)‐Catalyzed Nondirected Late‐Stage C(sp²)−H Deuteration of Heteroarenes Enabled Through a Multi‐Substrate Screening Approach

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(27)

Published: March 21, 2024

The importance of deuterium labelling in a variety applications, ranging from mechanistic studies to drug-discovery, has spurred immense interest the development new methods for its efficient incorporation organic, and especially bioactive molecules. five-membered heteroarenes at center this work are ubiquitous motifs molecules these compounds therefore highly desirable. However, profound differences chemical properties encountered between different hamper single set broadly applicable reaction conditions, often necessitating separate optimization campaign given type heteroarene. In study we describe use multi-substrate screening approach identify optimal conditions classes minimal number reactions. Using approach, four sets complementary derived our dual ligand-based palladium catalysts nondirected C(sp

Language: Английский

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Site‐Selective Ortho/Ipso C−H Difunctionalizations of Arenes using Thianthrene as a Leaving Group

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(30)

Published: May 7, 2024

Abstract Site‐selective ortho/ipso C−H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4‐tetrasubstituted ones (62 examples, up 97 % yields). To ensure the excellent regioselectivity process while keeping high efficiency, an original strategy based on a “C−H thianthenation/Catellani‐type reaction” sequence was developed starting from simple arenes. Non‐prefunctionalized first regioselectively converted into corresponding thianthrenium salts. Then, palladium‐catalyzed, norbornene (NBE)‐mediated allowed synthesis ipso ‐olefinated/ ortho ‐alkylated using thianthrene as leaving group (revisited Catellani reaction). Pleasingly, commercially available (NBE) and unique catalytic system, synthetic challenges known for reaction with aryl iodides smoothly successfully tackled “thianthrenium” approach. The protocol robust (gram‐scale reaction) widely applied two‐fold functionalization various bio‐active compounds. Moreover, panel olefins alkyl halides coupling partners suitable. further incorporation other groups at (CN/alkyl/H, aryl) (alkyl, aryl, amine, thiol) positions, showcasing generality process.

Language: Английский

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Late‐Stage C−H Activation of Drug (Derivative) Molecules with Pd(ll) Catalysis

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(71)

Published: Oct. 17, 2023

Abstract This review comprehensively analyses representative examples of Pd(II)‐catalyzed late‐stage C−H activation reactions and demonstrates their efficacy in converting bonds at multiple positions within drug (derivative) molecules into diverse functional groups. These transformative hold immense potential medicinal chemistry, enabling the efficient selective functionalization specific sites molecules, thereby enhancing pharmacological activity expanding scope candidates. Although notable articles have focused on drug‐like using transition‐metal catalysts, reviews specifically focusing Pd(II) catalysts are required owing to prominence as most widely utilized metal for ability introduce a myriad groups bonds. The utilization Pd‐catalyzed methodologies impressive success introducing various groups, such cyano (CN), fluorine (F), chlorine (Cl), aromatic rings, olefin, alkyl, alkyne, hydroxyl with high regioselectivity functional‐group tolerance. breakthroughs serve invaluable tools discovery development, offering strategic options optimize candidates drive exploration innovative therapeutic solutions.

Language: Английский

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Late-Stage C–H Deuteration of (Hetero)Arenes via Deuterium-Bonding Enhanced Rhenium Catalysis

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 4711 - 4718

Published: March 6, 2025

Language: Английский

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Merging directed sp³ and nondirected sp² C–H functionalization for Pd-catalyzed polydeuteration of (hetero)arenes

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A ligand-enabled strategy achieves deuteration with high deuterium enrichment through both directed sp 3 and nondirected 2 C–H deuteration.

Language: Английский

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Late-Stage C–H Deuteration of Organic Compounds via Ligand-Enabled Palladium-Catalyzed Hydrogen Isotope Exchange

Synlett, Journal Year: 2024, Volume and Issue: 35(19), P. 2191 - 2200

Published: March 22, 2024

Abstract Over the past years our lab has established a research program towards late-stage introduction of deuterium into organic molecules using Pd-catalyzed reversible C–H activation as means to affect hydrogen isotope exchange. Through catalyst design, including novel ligand scaffolds, well use strategically chosen optimization and screening approaches, e.g., exploiting microscopic reversibility by first optimizing de-deuteration processes or multi-substrate approach, studies have resulted in number synthetically useful labelling protocols are described herein from personal perspective. 1 Introduction 2 β-C(sp3)–H Deuteration Free Carboxylic Acids 3 Nondirected Arenes 4 Heteroarenes 5 Conclusion

Language: Английский

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Ligand-Controlled Nondirected meta- or para-C–H Olefination of Silyl-Protected Phenols

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(17), P. 12806 - 12813

Published: Aug. 9, 2024

Recent advances in ligand design have enabled Pd(II)-catalyzed nondirected C–H functionalization using arenes as the limiting reagent, but achieving catalyst control over site selectivity these transformations remains a significant challenge. Instead, is typically governed by inherent steric and electronic properties of arene substrates or directing effects. Consequently, it can be difficult to selectively functionalize para-position electron-deficient meta-positions electron-rich arenes, respectively. In this report, we demonstrate that choice olefination switch between activated para- deactivated meta-C–H bonds silyl-protected phenols, thereby highly enabling site-selective either position with broad substrate scopes. Specifically, monodentate 2-pyridone ligands enable high-yielding conventional para-selectivity largely intrinsic bias substrate, whereas dual-ligand system consisting bidentate pyridine–pyridone pyridine reversed site-selectivity favor relatively meta-position. Mechanistic studies indicate renders para-C–H palladation reversible not palladation, favoring arenes.

Language: Английский

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