Achieving Site-Selectivity for C–H Activation Processes Based on Distance and Geometry: A Carpenter’s Approach

Journal of the American Chemical Society, Journal Year: 2020, Volume and Issue: 142(24), P. 10571 - 10591

Published: May 21, 2020

The ability to differentiate between highly similar C–H bonds in a given molecule remains fundamental challenge organic chemistry. In particular, the lack of sufficient steric and electronic differences located distal functional groups has prevented development site-selective catalysts with broad scope. An emerging approach circumvent this obstacle is utilize distance target bond coordinating group, along geometry cyclic transition state directed activation, as core molecular recognition parameters multiple bonds. Perspective, we discuss advent recent advances concept. We cover wide range transition-metal-catalyzed, template-directed remote activation reactions alcohols, carboxylic acids, sulfonates, phosphonates, amines. Additionally, review eminent examples which take advantage non-covalent interactions achieve regiocontrol. Continued advancement distance- geometry-based differentiation for regioselective functionalization may lead ultimate realization editing: freedom modify molecules at any site, order.

Language: Английский

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HFIP in Organic Synthesis

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(15), P. 12544 - 12747

Published: July 17, 2022

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability stabilize ionic species, transfer protons, and engage range of other intermolecular interactions. The use this exponentially increased the past decade become choice some areas, such as C–H functionalization chemistry. In review, following brief history HFIP an overview physical properties, literature examples reactions using or additive are presented, emphasizing effect each reaction.

Language: Английский

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Strategic evolution in transition metal-catalyzed directed C–H bond activation and future directions

Coordination Chemistry Reviews, Journal Year: 2020, Volume and Issue: 431, P. 213683 - 213683

Published: Dec. 9, 2020

Language: Английский

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Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C–H activation

Chemical Science, Journal Year: 2021, Volume and Issue: 12(11), P. 3857 - 3870

Published: Jan. 1, 2021

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years.

Language: Английский

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Chiral Transient Directing Groups in Transition-Metal-Catalyzed Enantioselective C–H Bond Functionalization

ACS Catalysis, Journal Year: 2020, Volume and Issue: 10(21), P. 12898 - 12919

Published: Oct. 21, 2020

Transition-metal-catalyzed C–H bond functionalization has known a rapid evolution in the last years, offering modern strategies for reaching high molecular complexity step- and atom-economical way. Despite indisputable advances, selectivity issues still remain, given ubiquity of bonds on molecules; thus, several approaches have been developed to tackle this challenge. Among them, use transient directing group emerged as an effective tool, circumventing need extra synthetic steps install then cleave molecule. More recently, strategy successfully applied even more challenging transition-metal-catalyzed enantioselective functionalization. This review will highlight discuss main advances made chiral C(sp2)–H C(sp3)–H by transition-metal catalysis.

Language: Английский

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Decoding Directing Groups and Their Pivotal Role in C−H Activation

Chemistry - A European Journal, Journal Year: 2021, Volume and Issue: 27(49), P. 12453 - 12508

Published: May 26, 2021

Synthetic organic chemistry has witnessed a plethora of functionalization and defunctionalization strategies. In this regard, C-H been at the forefront due to multifarious applications in development simple complex molecular architectures holds brilliant prospect drug discovery. Despite explored tremendously by chemists, strategy still enjoys employment novel metal catalysts as well metal-free ligands. Moreover, switch photo- electrochemistry widened our understanding alternative pathways via which reaction can proceed these strategies have garnered prominence when applied activation. chemists foraging for new directing groups templates selective activation bonds from myriad carbon-hydrogen aromatic aliphatic systems. As matter fact, varying groups, scientists found answer challenge distal bond remained an obstacle very long time. These frequently harnessed selectively activating natural products, drugs, macromolecules decorated with multiple bonds. This itself was before commencement field site other than targeted could modify hamper biological activity pharmacophore. Total synthesis pharmacophore often faces difficulty superfluous steps towards functionalization. solved late-stage simply harnessing green conditions seen light past few decades rising concern about environmental issues. Therefore, or usage non-toxic metals recently showcased number elegant works. Also, research across world are developing rational group free non-directed protocols that just guided review encapsulates works pertinent discusses science devoted it fundamental level. gives readers broad how work, execution various catalysts, groups. not only helps budding scientist his/her but also matured mind searching out A detailed picture its progress time portrayed lucid scientific language motive inculcate educate minds beautiful overview most relevant significant era. The unique trait is description classification their utility over wide substrate scope. allows experimental chemist understand applicability domain employ any substrate.

Language: Английский

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Traceless directing groups: a novel strategy in regiodivergent C–H functionalization

Chemical Communications, Journal Year: 2020, Volume and Issue: 56(83), P. 12479 - 12521

Published: Jan. 1, 2020

The use of functional groups as internal ligands for assisting C-H functionalization, termed the chelation assisted strategy, is emerging one most powerful tools construction C-C and C-X bonds from inert bonds. However, there are various directing which cannot be either removed after functionalization or require some additional steps reagents their removal, thereby limiting scope structural diversity products, step atom economy system. These limitations overcome by traceless group (TDG) strategy wherein substrate removal can carried out in a pot fashion. Traceless serve ideal with high degree reactivity selectivity without any requirement removal. present review overviews such carboxylic acids, aldehydes, N-oxides, nitrones, N-nitroso amines, amides, sulfoxonium ylides silicon tethered transition metal catalyzed reactions last decade.

Language: Английский

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The emergence of the C–H functionalization strategy in medicinal chemistry and drug discovery

Chemical Communications, Journal Year: 2021, Volume and Issue: 57(83), P. 10842 - 10866

Published: Jan. 1, 2021

Owing to the market competitiveness and urgent societal need, an optimum speed of drug discovery is important criterion for successful implementation. Despite rapid ascent artificial intelligence computational bioanalytical techniques accelerate in big pharma, organic synthesis privileged scaffolds predicted silico vitro vivo studies still considered as rate-limiting step. C-H activation latest technology added into chemist's toolbox construction late-stage modification functional molecules achieve desired chemical physical properties. Particularly, elimination prefunctionalization steps, exceptional group tolerance, complexity-to-diversity oriented synthesis, functionalization medicinal expand space. It has immense potential a library molecules, structural required pharmacological properties such absorption, distribution, metabolism, excretion, toxicology (ADMET) attachment reporters proteome profiling, metabolite etc. preclinical studies. Although heterocycle modification, 18F labelling, methylation, via have been reviewed from synthetic standpoint, general overview these protocols aspects not reviewed. In this feature article, we will discuss recent trends methodologies through activation/annulation cascade; arylation sp2-sp2 sp2-sp3 cross-coupling; borylation/silylation introduce linchpin further manipulation; amination N-heterocycles hydrogen bond acceptors; fluorination/fluoroalkylation tune polarity lipophilicity; methylation: methyl magic discovery; peptide macrocyclization therapeutics biologics; fluorescent labelling radiolabelling bioimaging; bioconjugation biology studies; drug-metabolite biodistribution excretion diversification drug-molecules increase efficacy safety; cutting-edge DNA encoded improved chemistry discovery.

Language: Английский

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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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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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