Synthetic Advantages of Defluorinative C−F Bond Functionalization

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(49)

Опубликована: Авг. 22, 2023

Abstract Much progress has been made in the development of methods to both create compounds that contain C−F bonds and functionalize bonds. As such, are becoming common versatile synthetic functional handles. This review summarizes advantages defluorinative functionalization reactions for small molecule synthesis. The coverage is organized by type carbon framework fluorine attached mono‐ polyfluorinated motifs. main challenges, opportunities advances discussed each class organofluorine. Most text focuses on case studies illustrate how defluorofunctionalization can improve routes targets or properties enable unique mechanisms reactions. broader goal showcase incorporating exploiting design routes, improvement specific advent new methods.

Язык: Английский

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Highlights on U.S. FDA-approved fluorinated drugs over the past five years (2018–2022)

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 256, С. 115476 - 115476

Опубликована: Май 15, 2023

Язык: Английский

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C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Янв. 10, 2024

Abstract Bioisosteric design has become an essential approach in the development of drug molecules. Recent advancements synthetic methodologies have enabled rapid adoption this strategy into discovery programs. Consequently, conceptionally innovative practices would be appreciated by medicinal chemistry community. Here we report expeditous method for synthesizing aryl difluoromethyl bicyclopentane (ADB) as a bioisostere benzophenone core. This involves merger light-driven C−F bond activation and strain-release under catalysis newly designed N -anionic-based organic photocatalyst. defluorinative coupling methodology enables direct conversion wide variety commercially available trifluoromethylaromatic bonds (more than 70 examples) corresponding bicyclo[1.1.1]pentanes (BCP) arenes/difluoromethyl BCP boronates single step. The can also applied to [3.1.1]and [4.1.1]propellane systems, providing access analogues with different geometries. Moreover, successfully used protocol rapidly prepare ADB-substituted bioactive molecule Adiporon. Biological testing shown that ADB scaffold potential enhance pharmacological properties benzophenone-type candidates.

Язык: Английский

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BrCF2CN for photocatalytic cyanodifluoromethylation

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 7, 2025

Considering the unique electronic properties of CF2 and CN groups, CF2CN group has significant potential in drug agrochemical development, as well material sciences. However, incorporating a remains considerable challenge. In this work, we disclose use bromodifluoroacetonitrile (BrCF2CN), cost-effective readily available reagent, radical source for cyanodifluoromethylation alkyl alkenes, aryl alkynes, (hetero)arenes under photocatalytic conditions. This protocol demonstrates an exceptionally broad substrate scope remarkable tolerance to various functional groups. Notably, alkynes predominantly provides sterically hindered thermodynamically unfavorable outcome, (hetero)arene C-H bonds are directly amenable without pre-functionalization. Here, authors report (BrCF2CN)

Язык: Английский

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Defluorinative functionalization approach led by difluoromethyl anion chemistry

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 7, 2025

Язык: Английский

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Organoboron Reagent‐Controlled Selective (Deutero)Hydrodefluorination

Angewandte Chemie International Edition, Год журнала: 2022, Номер 62(7)

Опубликована: Дек. 16, 2022

(Deuterium-labeled) CF2 H- and CFH2 -moieties are of high interest in drug discovery. The demand for the incorporation these fluoroalkyl moieties into molecular structures has witnessed significant synthetic progress, particularly (deutero)hydrodefluorination CF3 -containing compounds. However, controllable replacement fluorine atoms while maintaining chemoselectivity remains challenging. Herein, we describe development a selective reaction via electrolysis. exhibits remarkable control, which is enabled by addition different organoboron sources. procedure operationally simple scalable, provides access one step to high-value building blocks application medicinal chemistry. Furthermore, density functional theory (DFT) calculations have been carried out investigate mechanism rationalize observed.

Язык: Английский

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Construction of C–X (X = S, O, Se) Bonds via Lewis Acid-Promoted Functionalization of Trifluoromethylarenes

ACS Catalysis, Год журнала: 2023, Номер 13(11), С. 7339 - 7346

Опубликована: Май 16, 2023

The conversion of easily available trifluoromethylarenes through C–F bond activation provides an attractive pathway for rapid access to difluorobenzylic substructures in producing pharmaceuticals and agrochemicals. However, recent advances this area have been confined C–C(H) construction, thus limiting the diversity accessible motifs. In contrast, selective formation a carbon–heteroatom via functionalization, which enable fast convenient diverse fluorine-containing motifs with high chemical diversity, remains formidable synthetic challenge. Herein, we disclosed Lewis acid promoted photoredox-catalyzed strategy construction C–X (X = S, O or Se) bonds by single C(sp3)–F trifluoromethylarenes, direct synthesis medicinally interesting aryldifluoromethyl ether [ArCF2X– O, Se)] scaffolds. This method relies on readily reagents can tolerate range thiol, phenol, selenol nucleophiles. Its utility was exemplified late-stage modifications several pharmaceutical ingredients. Preliminary studies suggest two parallel pathways: photocatalytic electron-transfer (SET), electron donor–acceptor (EDA) process.

Язык: Английский

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Defluoroalkylation of Trifluoromethylarenes with Hydrazones: Rapid Access to Benzylic Difluoroarylethylamines

Organic Letters, Год журнала: 2023, Номер 25(9), С. 1397 - 1402

Опубликована: Фев. 27, 2023

Here, we report an efficient and modular approach toward the formation of difluorinated arylethylamines from simple aldehyde-derived N,N-dialkylhydrazones trifluoromethylarenes (CF3-arenes). This method relies on selective C-F bond cleavage via reduction CF3-arene. We show that a diverse set CF3-arenes CF3-heteroarenes react smoothly with range aryl alkyl hydrazones. The β-difluorobenzylic hydrazine product can be selectively cleaved to form corresponding benzylic difluoroarylethylamines.

Язык: Английский

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Photoinduced copper-catalyzed C–N coupling with trifluoromethylated arenes

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 14, 2023

Selective defluorinative functionalization of trifluoromethyl group (-CF3) is an attractive synthetic route to the pharmaceutically privileged fluorine-containing moiety. Herein, we report a strategy based on photoexcited copper catalysis activate C-F bond di- or trifluoromethylated arenes for divergent radical C-N coupling with carbazoles and aromatic amines. The use different ligands can tune reaction products diversity. A range substituted, structurally diverse α,α-difluoromethylamines be obtained from via carbazoles, while interesting double ready difluoromethylated arenes. Based this success, carbazole-centered PNP ligand designed optimal ligand, enabling copper-catalyzed construction imidoyl fluorides amines through functionalization. Interestingly, 1,2-difluoroalkylamination styrenes also developed, delivering γ,γ-difluoroalkylamines, bioisostere β-aminoketones, in synthetically useful yields. DFT studies reveal inner-sphere electron transfer mechanism Cu-catalyzed selective activation C(sp3)-F bonds.

Язык: Английский

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α‐Difluoroalkylation of Benzyl Amines with Trifluoromethylarenes

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(40)

Опубликована: Авг. 19, 2023

Abstract An α‐difluoroalkylation of benzyl amines with trifluoromethylarenes is disclosed herein. This protocol characterized by its operational simplicity, excellent chemoselectivity and broad scope—even advanced synthetic intermediates—, thus offering a new entry point to medicinally‐relevant α‐difluoroalkylated from simple, yet readily accessible, precursors.

Язык: Английский

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