Broadening of horizons in the synthesis of CD<sub>3</sub>-labeled molecules

Sun, Qiao; Soulé, Jean‐François

doi:10.1039/d1cs00544h

Cited by 56 publications

(20 citation statements)

References 118 publications

(128 reference statements)

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“…Because of all these applications, development of methodologies for the synthesis of deuterated and tritiated compounds continued to receive an impressive attention over the years. General reviews, ,− as well as more specific ones dedicated to subareas in the field of deuteration such as hydrogen isotope exchange (HIE), visible-light photocatalytic deuteration reactions, nanocatalyzed HIE, trideuteromethyl incorporation, , reductive deuteration, base metal-catalyzed HIE, HIE catalysis in alkanes, iridium-catalyzed HIE, specific labeling of the α position of heteroatoms, of the C(sp 2 )-H, as well as of the C(sp 3 )–H positions have been published in recent years . Similarly, the number of scientific publications dealing with hydrogen isotopes is constantly increasing.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

et al. 2022

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Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017−2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.

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Section: Introductionmentioning

confidence: 99%

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

et al. 2022

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“…The development of a robust C sp 2 –C sp 3 cross-coupling process amenable to late-stage functionalization attracted our attention since it could help to meet the growing demand for molecular editing to access molecules with a higher fraction of sp 3 (Fsp 3 ) centers. − The so-called “magic methyl” effect has been recognized by medicinal chemists as one approach to enhancing the pharmacological properties of a molecule that includes modulating the potency and/or metabolic stability of drug molecules; hence, our interest in developing a robust methylative cross-coupling methodology. − Only two metallaphotoredox methylation processes have been reported in the literature, both of which are Ni-catalyzed cross-coupling methods that employ an iridium-based photoredox catalyst. , …”

Section: Introductionmentioning

confidence: 99%

Photo-Initiated Nickel Catalysis (PiNiC): Unmasking Dimethylnickel with Light

et al. 2022

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Nickel catalysis has garnered interest in mainstream organic synthesis for constructing chemical bonds and has been merged with photoredox catalysis and electrocatalysis. Despite its success and increasing adoption by academia and industry, the mechanism by which Ni catalyzes C−C cross-coupling reactions and how the precatalyst is activated remains unclear. An exploration of stabilized dimethylNi II complexes, [(dtbbpy)Ni-(Me) 2 ] (dtbbpy = 4,4′-di-tert-butyl-2,2′-bipyridine, 1) and [(bpy)-Ni(Me) 2 ] (bpy = 2,2′-bipyridine, 2), as Ni-precatalysts for promoting C sp 2 −C sp 3 cross-coupling revealed that they readily undergo photo-induced Ni−C bond homolysis upon exposure to visible light and are a source of Ni 0 species. Photo-initiation of dimethylNi II complexes 1 and 2 produced active Ni 0 and reactive methyl radicals, which were harnessed to promote methylative and other C sp 2 −C sp 3 cross-coupling reactions.The mechanistic studies conducted to illuminate aspects of the process include a competition reaction, Ni II ArBr-complex synthesis, light-on and lightoff studies, density functional theory (DFT) calculations of the bond dissociation free energies (BDFE), as well as control experiments with a Ni 0 -precursor. We further demonstrated the robustness and utility of dimethylNi II as a Ni 0 -precursor in the latestage installation of methyl, CD 3 , alkyl, and benzyl groups on aryl bromides that have potential value in drug design and optimization. This work sheds light on the activation mechanism of Ni-catalyzed cross-coupling of aryl halides with organozinc reagents when a Ni II -precatalyst is employed and the critical role that visible light plays in the process.

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“…[4] Alternatively, reactions that rely on the intervention of the CH 3 + synthon (CH 3 I and related reagents), such as electrophile cross-coupling [5] or some CÀ H activation reactions [6] are also limited by the use of substrates that must not exhibit strongly nucleophilic functions. Notwithstanding these potential polarity mismatches, a series of reagents have been recently developed for the introduction of a CH 3 /CD 3 group, [7][8][9] but their use cannot be extended to other more costly isotopic analogs, as they are generally used in large excess or even as solvents. It is therefore not surprising that pathways involving the neutral CH 3 * synthon corresponding to the methyl radical have recently appeared as alternatives and witnessed intense developments.…”

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confidence: 99%

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

et al. 2023

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The introduction of a methyl group and its 13C and 2H labeled analogs on Csp2‐centers remains a challenging issue in synthetic chemistry. While the photoredox/Ni dual catalysis has proven to constitute a valuable methodology for the forging of Csp2−Csp3 bonds, the high difficulty to generate the methyl radical and to control its reactivity has severely limited the development of reliable processes. Herein, we introduce the easily prepared and bench‐stable Martin methylsilicates bearing two C,O‐bidentate hexafluorocumyl alcohol ligands as a class of radical precursors for dual catalysis enabling the chemoselective methylation of (hetero)aryl halides and acyl chlorides as well as the access to the corresponding CD3, CD2H, CHD2 and 13CH3 analogs in good yields.

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Broadening of horizons in the synthesis of CD₃-labeled molecules

Abstract: This review highlights the different approaches for the preparation of CD3-labeling molecules.

Cited by 56 publications

References 118 publications

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Photo-Initiated Nickel Catalysis (PiNiC): Unmasking Dimethylnickel with Light

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

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Broadening of horizons in the synthesis of CD3-labeled molecules

Abstract: This review highlights the different approaches for the preparation of CD3-labeling molecules.

Cited by 56 publications

References 118 publications

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Photo-Initiated Nickel Catalysis (PiNiC): Unmasking Dimethylnickel with Light

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH3, CH2D, CD2H, CD3and13CH3Groups onto (Hetero)Arenes

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Broadening of horizons in the synthesis of CD₃-labeled molecules

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes