Synthesis of 1-(Halo)alkyl-3-heteroaryl Bicyclo[1.1.1]pentanes Enabled by a Photocatalytic Minisci-type Multicomponent Reaction

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(8), P. 6247 - 6258

Published: April 10, 2024

Aryl-substituted bicyclo[1.1.1]pentane (BCP-aryl) derivatives represent the most important bioisosteres of biaryl scaffolds and widely exist in numerous complex pharmaceutical molecules. The current synthetic method limitations using only tertiary radical precursors, prefunctionalized heteroarenes, toxic transition metals, expensive photocatalysts make it urgent to develop a more simple practical protocol. To confront enrich Minisci-type chemistry, herein, we disclose photocatalytic multicomponent reaction for synthesis various (halo)alkyl BCP-aryls [1.1.1]propellane, alkyl halides, unfunctionalized heteroarenes as starting materials. Diverse kinds radicals (primary, secondary, carbons) derived from chlorides, bromides, fluoroalkyl iodides are very compatible this transformation. practicability is additionally boosted by product derivatizations late-stage functionalization pharmaceutically relevant mechanistic studies demonstrate that relay mechanism initiated consecutive photoinduced electron transfer (ConPET) process operation. We anticipate methodology would act useful tool biaryl-type drug derivatives, ultimately resulting great utility discovery program.

Language: Английский

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

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

Published: Jan. 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.

Language: Английский

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Strain-release transformations of bicyclo[1.1.0]butanes and [1.1.1]propellanes

Tetrahedron Chem, Journal Year: 2024, Volume and Issue: 9, P. 100070 - 100070

Published: Feb. 28, 2024

Bicyclo[1.1.0]butanes (BCBs) and [1.1.1]propellanes (tricyclo[1.1.1.01,3]pentanes, TCPs) are structurally unique compounds with different chemical properties. Strain-release driven reactions have emerged as an atom- step-economic strategy for the organic synthesis. Using this strategy, a variety of functional ring molecules been efficiently synthesized, including various cyclobutane molecules, bicyclo[2.1.1]hexanes, bicyclo[1.1.1]pentanes, others. More specifically, these strain release-driven include aspects nucleophilic addition, radical electrophilic or transition metal catalysis. This review will discuss recent developments in strain-release transformations bicyclo[1.1.0]butanes [1.1.1]propellanes.

Language: Английский

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Overcoming a Radical Polarity Mismatch in Strain‐Release Pentafluorosulfanylation of [1.1.0]Bicyclobutanes: An Entryway to Sulfone‐ and Carbonyl‐Containing SF₅‐Cyclobutanes

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(19)

Published: Jan. 18, 2024

The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF

Language: Английский

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Tetrafluoro(aryl)sulfanylated Bicyclopentane Crystals That Self-Destruct upon Cooling

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(2), P. 1463 - 1473

Published: Jan. 6, 2025

Whereas single crystals of organic compounds that respond to heat or light have been reported and studied in detail, studies on crystalline elicit an extreme mechanical response upon cooling very low temperatures are relatively rare the chemical literature. A tetrafluoro(aryl)sulfanylated bicyclopentane synthesized our laboratory was discovered exhibit such behavior; i.e., jumped forcefully disintegrated below ∼193 K. Accordingly, origin this low-temperature thermosalient effect investigated through NMR, SC-XRD, PXRD, microscopy, DSC, Raman, Brillouin experiments. To surprise, DSC experiments suggest phenomenon can neither be attributed solely a transformation nor phase transition entire material. Rather, XRD, provide evidence built-up strain released from crystal self-destruction may associated with microstructure occurs another material (i.e., impurity) crystal. This study demonstrates molecular structural changes impurity phases (which not necessarily visible by X-ray diffraction) significant impact behavior bulk Thus, role considered more heavily future mechanistic mechanically responsive crystals.

Language: Английский

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Multicomponent Synthesis of Alkyl BCP-Heteroaryls via Electron Donor–Acceptor Complex Photoactivation under Mild Conditions

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: 90(4), P. 1683 - 1696

Published: Jan. 17, 2025

In the vanguard of sustainable chemistry, pursuit efficient pathways for synthesis alkyl bicyclo[1.1.1]pentane-heteroaryls has captured attention scientific vanguard. We herein report a groundbreaking and eco-conscious multicomponent coupling reaction that paves way alkylation heteroarylation [1.1.1]propellane, process uniquely enabled by photochemical prowess an electron donor–acceptor (EDA) complex. This method is distinguished its minimalist yet powerful approach: devoid transition metals, additives, photosensitizers. Its universality further exemplified seamless compatibility broad spectrum halides heteroarenes under standardized conditions, heralding new era synthetic versatility. The method's practicality underscored capacity late-stage modification pharmaceuticals, offering transformative tool enhancement existing drug molecules. Moreover, facile derivatization synthesized products underscores adaptability potential diverse applications. Our mechanistic studies have elucidated underlying radical-relay pathway, pinpointing pivotal role EDA complex in initiating transformation. discovery not only enriches our fundamental understanding but also opens avenues strategic optimization.

Language: Английский

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Rapid and Scalable Halosulfonylation of Strain‐Release Reagents**

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(3)

Published: Oct. 13, 2022

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non-classical arene bioisosteres, which could improve physicochemical properties drug agrochemical candidates, limited. Here we report a solution to this challenge: one-pot halosulfonylation [1.1.1]propellane, [3.1.1]propellane bicyclo[1.1.0]butanes that proceeds under practical, scalable mild conditions. The sulfonyl halides used chemistry feature aryl, heteroaryl alkyl substituents, conveniently generated situ from readily available sulfinate salts halogen atom sources. This methodology enables an array pharmaceutically agrochemically relevant halogen/sulfonyl-substituted bioisosteres cyclobutanes, on up multidecagram scale.

Language: Английский

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Strain‐Release Pentafluorosulfanylation and Tetrafluoro(aryl)sulfanylation of [1.1.1]Propellane: Reactivity and Structural Insight**

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(48)

Published: Sept. 22, 2022

We leveraged the recent increase in synthetic accessibility of SF

Language: Английский

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Regio‐ and Stereoselective Hydroelementation of SF₅‐Alkynes and Further Functionalizations.

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(19)

Published: March 9, 2023

Herein is described a fully regio- and stereoselective hydroelementation reaction of SF5 -alkynes with N, O S-nucleophiles further functionalization the corresponding Z-(hetero)vinyl-SF5 intermediates, suitable platform to access α-SF5 ketones esters, β-SF5 amines alcohols under mild conditions. Experimental computational comparative studies between - CF3 have been performed highlight explain difference reactivity selectivity observed these two fluorinated motifs.

Language: Английский

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A General Organophotoredox Strategy to Difluoroalkyl Bicycloalkane (CF2‐BCA) Hybrid Bioisosteres**

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(31)

Published: June 1, 2023

Here, we report a general approach to the synthesis of difluoroalkyl bicycloalkanes (CF2 -BCAs), as structural surrogates aryl ketones and ethers. The chemistry is driven by dihydrobenzoacridine photocatalyst, that engages in catalytic electron-donor acceptor (EDA) complex, or directly reduces fluorinated substrate. These two convergent manifolds lead generation R-CF2 radical, reacts with [1.1.1]- [3.1.1.]-propellane. method extremely general, extendable complex bioactive molecules (30 examples, up 87 % yield). features CF2 -BCP hybrid bioisostere were investigated single crystal X-ray. Finally, synthesised analogue Leukotriene A4 hydrolase inhibitor, replacing original ether motif. In silico docking studies indicated this new maintains same arrangement within enzyme pocket, profiling use -BCA medicinal settings.

Language: Английский

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