Emergence of Pyrimidine-Based meta-Directing Group: Journey from Weak to Strong Coordination in Diversifying meta-C–H Functionalization

Accounts of Chemical Research, Journal Year: 2022, Volume and Issue: 55(3), P. 354 - 372

Published: Jan. 12, 2022

C-H activation has emerged as a powerful transformative synthetic tool to construct complex molecular frameworks, which are ubiquitous in natural products, medicines, dyes, polymers, and many more. However, reactivity selectivity, arising from the inertness of bonds their overabundance organic molecules, two major fundamental challenges developing various carbon-carbon (C-C) carbon-heteroatom (C-X) bond formation reactions via technique. Functional groups with coordinating capacity transition metal catalysts, profoundly known directing (DGs), have shown great promise exerting selective activation, often called site-selective or regioselective transformation target molecule. Advent group (DG)-assisted strategies not only resolved selectivity issues but also offers unique solution rapid synthesis molecules convenient predictable manner. Our laboratory, this regard, is fascinated by prospect DG-assisted distal functionalization arenes, remotely located existing group. Notably, opposition proximal ortho-C-H proceeded an energetically favorable five- seven-membered metallacycle, remained formidable challenge it required large macrocyclic metallacycle. Therefore, designing suitable template that would maintain distance geometric relationship between appended auxiliary order ensure prolific delivery catalyst closest proximity targeted was key success. In Yu devised elegant "U-shaped" for first time execute meta-C-H recruiting cyano-based initial effort diversify scope using led us realize "cyano-based DGs" intrinsically limited weak ability, competitive binding mode (end-on vs side-on), incompatibility acidic basic reaction conditions. search robust auxiliary, we were intrigued possibility strongly ability pyrimidine quinoline-based DGs.In Account, describe our journey weakly DG pyrimidine-based achieve diverse electronically sterically unbiased arenes. While some functionalizations achieved finding conditions, others mechanistic understanding. development realm constrained short linkers, attached arene interest through 2-4 atoms. later studies, demonstrated can be attained even though 10-atoms away arene. More importantly, transient successfully utilized deliver olefination arenes situ imine formation, provided step-economic route activation.We hope Account will stimulate further design provide guiding platform future functionalization.

Language: Английский

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Pd-catalysed C–H functionalisation of free carboxylic acids

Chemical Science, Journal Year: 2022, Volume and Issue: 13(9), P. 2551 - 2573

Published: Jan. 1, 2022

Pd-catalysed C–H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to predominance acid moieties in pharmaceuticals and agrochemicals.

Language: Английский

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Empirical Guidelines for the Development of Remote Directing Templates through Quantitative and Experimental Analyses

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(6), P. 2793 - 2803

Published: Feb. 2, 2022

The ability to differentiate and selectively activate remote C-H bonds represents a perennial challenge in the field of activation. Since its first report 2012, now-established "directing template" (DT) approach remains demonstrably effective for functionalization bonds. As selectivity is hypothesized be principally determined by optimal positioning reactive catalyst target bond, DT's spatial factors are particularly important toward achieving high selectivity, though systematic study on requisite remain unelucidated. Through an in-depth analysis 119 structurally unique published DTs, this summarizes key that central at defined aryl positions, which experimentally corroborated through development new aliphatic meta para-selective DTs electronically unbiased arenes. These empirical rules, summarize distance geometric factors, expected useful tools future site-selective arene activation as well other reactions rely covalent/noncovalent DT-mediated regioselection.

Language: Английский

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Controlling Reactivity and Selectivity in the Nondirected C–H Activation of Arenes with Palladium

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(18), P. 2459 - 2472

Published: Aug. 24, 2023

ConspectusAromatic structures are widespread motifs throughout organic chemistry, and C-H activation has been recognized as a major tool for enabling their sustainable efficient functionalization. Through activation, arenes can be modified without the need prefunctionalization, leading to inherent atom- step-economic advantages over traditional methods. However, development of synthetically useful methods, several hurdles have overcome. The strength bonds necessitates sufficiently reactive catalysts, while presence multiple within substrate poses challenges in terms site-selectivity. Traditionally these addressed by control. By attaching different directing groups (DGs), reactivity respective arene was significantly enhanced DG guided metal close proximity specific bonds, resulting high introduction removal add additional steps synthetic sequence, scope reaction is limited class. complementary nondirected methods that applied broad range necessity carry functional group coordinates Pd (referred simple arenes) therefore highly desirable. intrinsically lower such substrates absence selectivity-determining pose significant solved only catalysts. Consequently, field especially with respect Pd-catalyzed remained comparatively underdeveloped when we initiated our research program 2017. At time, state-of-the-art required used large excess, precluding its use late-stage Since organopalladium species among most versatile intermediates, realized developing system, which effectively selectively activate limiting reagent, would powerful chemistry. This account summarizes groups' toward application catalytic systems offering this desired focuses explicitly on functionalization reactions arenes, where employed reagent. After an state before 2017 associated challenges, experimental mechanistic details about first arene-limited, palladium will discussed. enabled identification combination two ligands, N-heterocycle amino acid-derived ligand. Afterward discuss expansion dual-ligand approach further arene-limited transformations. Finally, describe methodologies originated from observations made during studies, namely, deuteration selective olefination method uses noncovalent interactions induce meta selectivity.

Language: Английский

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Directing group assisted rhodium catalyzed meta-C–H alkynylation of arenes

Chemical Science, Journal Year: 2022, Volume and Issue: 13(19), P. 5616 - 5621

Published: Jan. 1, 2022

An unprecedented report on Rh-catalyzed meta -C–H alkynylation of arenes, aided by a weakly coordinating cyano-based directing template, was developed using bromoalkynes as the coupling partner.

Language: Английский

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Pd(ii)-catalyzed meta-C–H bromination and chlorination of aniline and benzoic acid derivatives

Chemical Science, Journal Year: 2022, Volume and Issue: 13(29), P. 8686 - 8692

Published: Jan. 1, 2022

The classic electrophilic bromination leads to

Language: Английский

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Harnessing the “Methyl Effect” in the Development of Novel meta-Directing Template for C–H Cyanation

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(4), P. 2216 - 2228

Published: Jan. 29, 2024

The significance of chelation-assisted C–H functionalization stands upon the superior site-selectivity, easy synthesis, and diverse product utility. In this work, we design a meta-directing scaffold by tuning side chain pyrimidine-based template to attain unconventional site-selectivity in anilines. A simple methyl substitution at enhances directing group (DG) efficacy significantly, leading an almost exclusive meta-selectivity. current DG further enables meta-selective cyanation aniline its higher homologues irrespective substrate electronic bias. synthetic impact methodology is highlighted with late-stage functionalizations two very popular local anesthetics butamben benzocaine. thorough experimental silico study unfolds importance effect attaining role silver carbonate mechanistic cycle.

Language: Английский

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Asymmetric Remote meta-C–H Activation Controlled by a Chiral Ligand

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(21), P. 13435 - 13445

Published: Oct. 19, 2022

The use of a chiral ligand for stereocontrol has assisted the development number asymmetric functionalization proximal C–H bonds. Herein, we report ligand-controlled, remote meta-C–H activation arenes, leading to olefination and arylation hydrocinnamic acid derivatives through desymmetrization with Ac-L-Phe-OH as using Pd(II) catalyst. origins enantioselectivity were explained density functional theory calculations. larger distortion energy substrate part in bond transition structure S-TS1 is major controlling factor that disfavors formation S-enantiomer product.

Language: Английский

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Palladium‐Catalyzed Enantioselective Isodesmic C−H Iodination of Phenylacetic Weinreb Amides

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(20)

Published: March 10, 2023

Isodesmic reactions represent mild alternatives to other chemical transformations that require harsh oxidizing agents or highly reactive intermediates. However, enantioselective isodesmic C-H functionalization is unknown and direct iodination of inert bond very rare. Rapid synthesis chiral aromatic iodides significant importance for synthetic chemistry. Herein, we report an unprecedented access iodinated phenylacetic Weinreb amides via desymmetrization kinetic resolution with PdII catalysis. Importantly, further the enantioenriched products are readily available at amide position, paving way related studies medicinal chemists.

Language: Английский

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Sterically controlled isodesmic late-stage C–H iodination of arenes

Chemical Science, Journal Year: 2023, Volume and Issue: 14(16), P. 4357 - 4362

Published: Jan. 1, 2023

Aryl iodides are key motifs in organic chemistry due to their versatility as linchpins metal-mediated cross-coupling reactions for synthesis and drug discovery. These scaffolds typically prepared indirectly from prefunctionalized starting materials or via electrophilic aromatic iodination protocols. methods limited specific regioisomers by inherent selectivities and/or the availability of required materials. Herein, we describe sterically controlled arenes through an isodesmic C-H/C-I bond metathesis approach enabled our dual ligand-based catalysts arene-limited nondirected C-H activation. The protocol gives direct access a complementary product spectrum with respect traditional methods. Its synthetic utility is demonstrated broad scope suitability late-stage modification.

Language: Английский

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