Late-Stage C–H Functionalization of Azines

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7655 - 7691

Published: May 3, 2023

Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite physiochemical properties that match key criteria in drug design is tunable by varying their substituents. Developments synthetic chemistry, therefore, directly impact these efforts, methods can install various groups azine C–H bonds particularly valuable. Furthermore, there growing interest late-stage functionalization (LSF) reactions focus on advanced candidate compounds often complex structures with multiple heterocycles, functional groups, reactive sites. Because factors electron-deficient nature the effects Lewis basic N atom, distinct arene counterparts, application LSF contexts difficult. However, have been many significant advances reactions, this review will describe progress, much which has occurred over past decade. It possible to categorize radical addition processes, metal-catalyzed activation transformations occurring via dearomatized intermediates. Substantial variation reaction within each category indicates both rich reactivity heterocycles creativity approaches involved.

Language: Английский

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Radical and ionic meta -C–H functionalization of pyridines, quinolines, and isoquinolines

Science, Journal Year: 2022, Volume and Issue: 378(6621), P. 779 - 785

Published: Nov. 17, 2022

Carbon-hydrogen (C−H) functionalization of pyridines is a powerful tool for the rapid construction and derivatization many agrochemicals, pharmaceuticals, materials. Because inherent electronic properties pyridines, selective meta -C−H challenging. Here, we present protocol highly regioselective trifluoromethylation, perfluoroalkylation, chlorination, bromination, iodination, nitration, sulfanylation, selenylation through redox-neutral dearomatization-rearomatization process. The introduced dearomative activation mode provides diversification platform meta-selective reactions on other azaarenes radical as well ionic pathways. broad scope high selectivity these catalyst-free render processes applicable late-stage drugs.

Language: Английский

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Skeletal editing of pyridines through atom-pair swap from CN to CC

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(5), P. 741 - 748

Published: Jan. 18, 2024

Abstract Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures complex molecules; it enables quick diversification compounds that not possible by applying peripheral strategies. Previously reported skeletal common arenes mainly relies on carbene- nitrene-type insertion reactions rearrangements. Although powerful, efficient and applicable to late-stage heteroarene structure modification, these strategies cannot be used pyridines. Here we report the direct pyridines through atom-pair swap from CN CC generate benzenes naphthalenes modular fashion. Specifically, use sequential dearomatization, cycloaddition rearomatizing retrocycloaddition one-pot sequence transform parent into bearing diversified substituents at specific sites, as defined reaction components. Applications pyridine cores several drugs are demonstrated.

Language: Английский

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meta‐Selective C−H Functionalization of Pyridines

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(42)

Published: April 4, 2023

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization C-H bonds in pyridines straightforward approach to access valuable substituted pyridines. Compared the direct ortho- para-functionalization, meta-selective far more challenging due inherent electronic properties entity. This review summarizes currently available methods meta-C-H using directing group, non-directed metalation, temporary dearomatization strategies. Recent advances ligand control are highlighted. We analyze advantages as well limitations current techniques hope inspire further developments this area.

Language: Английский

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C3-Selective Trifluoromethylthiolation and Difluoromethylthiolation of Pyridines and Pyridine Drugs via Dihydropyridine Intermediates

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(32), P. 14463 - 14470

Published: Aug. 1, 2022

Herein, we report a method for C3-selective C–H tri- and difluoromethylthiolation of pyridines. The relies on borane-catalyzed pyridine hydroboration generation nucleophilic dihydropyridines; these intermediates react with trifluoromethylthio difluoromethylthio electrophiles to form functionalized dihydropyridines, which then undergo oxidative aromatization. can be used late-stage functionalization drugs the new drug candidates.

Language: Английский

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Asymmetric C3-Allylation of Pyridines

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: unknown

Published: May 17, 2023

Asymmetric intermolecular C–H functionalization of pyridines at C3 is unprecedented. Herein, we report the first examples such transformations: specifically, C3-allylation via tandem borane and iridium catalysis. First, borane-catalyzed pyridine hydroboration generates nucleophilic dihydropyridines; then, dihydropyridine undergoes enantioselective iridium-catalyzed allylation; finally, oxidative aromatization with air as oxidant gives C3-allylated pyridine. This protocol provides direct access to excellent enantioselectivity (up >99% ee) suitable for late-stage pyridine-containing drugs.

Language: Английский

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C–H functionalization of pyridines

Organic & Biomolecular Chemistry, Journal Year: 2023, Volume and Issue: 21(28), P. 5671 - 5690

Published: Jan. 1, 2023

This review discusses known approaches for selective pyridine C–H editing, focusing on recent discoveries uniquely suited to pyridines.

Language: Английский

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Late‐Stage Functionalisation of Pyridine‐Containing Bioactive Molecules: Recent Strategies and Perspectives

European Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 26(16)

Published: Feb. 21, 2023

Abstract Late‐Stage Functionalisation (LSF) is an innovative technique that has been successfully applied to the C−H diversification of pharmaceuticals. However, LSF pyridine ring in drug‐like molecules often unselective. As a result, mixture structurally related products obtained, thus making purification tedious and time‐consuming. This review shines light on recent strategies addressing selectivity issue complex natural or drugs containing moiety. Specifically, we have reviewed efforts reported both academia industries with hope providing guide for elaborated pyridines.

Language: Английский

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Enantioselective C3‐Allylation of Pyridines via Tandem Borane and Palladium Catalysis

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(34)

Published: July 3, 2023

Abstract Herein, we report a one‐pot method for enantioselective C−H allylation of pyridines at C3 via tandem borane and palladium catalysis. This involves borane‐catalyzed pyridine hydroboration to generate dihydropyridines, then palladium‐catalyzed the dihydropyridines with allylic esters, finally air oxidation allylated afford products. enables introduction an group excellent regio‐ enantioselectivities.

Language: Английский

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Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 15, 2024

Abstract Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C−H-difluoromethylation of represents a highly efficient economic way to access these azines. However, the meta-difluoromethylation has remained elusive methods for site-switchable regioselective meta- para-difluoromethylation are unknown. Here, we demonstrate meta-C−H-difluoromethylation through radical process by using oxazino pyridine intermediates, which easily accessed from pyridines. selectivity can be readily switched para situ transformation pyridinium salts upon acid treatment. preparation various para-difluoromethylated this approach is presented. mild conditions used also allow late-stage or containing drugs. Sequential double functionalization presented, further underlines value work.

Language: Английский

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