Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp³)–C(sp³) Cross-Coupling via Radical Sorting

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(14), P. 6185 - 6192

Published: March 30, 2022

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, resulting open-shell intermediates can subsequently participate transition metal catalysis. In this report, we describe C(sp3)–C(sp3) cross-coupling of alcohols through dual combination N-heterocyclic carbene (NHC)-mediated deoxygenation hypervalent iodine-mediated decarboxylation. This mild practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array alkyl–alkyl cross-coupled products, including highly congested quaternary carbon centers from corresponding tertiary or acids. We demonstrate applications methodology alcohol C1-alkylation formal homologation, as well late-stage functionalization drugs, natural biomolecules.

Language: Английский

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Boryl Radical Activation of Benzylic C–OH Bond: Cross-Electrophile Coupling of Free Alcohols and CO₂ via Photoredox Catalysis

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(19), P. 8551 - 8559

Published: April 4, 2022

A new strategy for the direct cleavage of C(sp3)-OH bond has been developed via activation free alcohols with neutral diphenyl boryl radical generated from sodium tetraphenylborate under mild visible light photoredox conditions. This verified by cross-electrophile coupling and carbon dioxide synthesis carboxylic acids. Direct transformation a range primary, secondary, tertiary benzyl to acids achieved. Control experiments computational studies indicate that undergoes homolysis bond, generating alkyl radicals. After reducing into anion conditions, following carboxylation CO2 affords product.

Language: Английский

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Rapid and Modular Access to Quaternary Carbons from Tertiary Alcohols via Bimolecular Homolytic Substitution

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(30), P. 16330 - 16336

Published: July 20, 2023

Quaternary carbons are ubiquitous in bioactive molecules; however, synthetic methods for the construction of this motif remain underdeveloped. Here, we report synthesis quaternary from tertiary alcohols, a class structurally diverse, bench-stable feedstocks, via merger photoredox catalysis and iron-mediated SH2 bond formation. This alcohol-bromide cross-coupling is enabled by novel halogen-atom transfer (XAT) reagent, which first reductively activated XAT reagent to be reported. A wide variety sterically congested products can accessed through mild practical protocol including derived both alkylation benzylation fragments. We further demonstrate utility method expedited liver receptor agonist two-step conversion ketones esters products, enables modular control up three four substituents on center.

Language: Английский

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Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(8), P. 5067 - 5073

Published: Feb. 16, 2024

The replacement of a functional group with its corresponding bioisostere is widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties candidates while maintaining potency. However, incorporation bioisosteres typically requires lengthy de novo resynthesis potential candidates, which represents bottleneck in their broader evaluation. An alternative would be directly convert into at late stage. Herein, we report realization this approach through conversion aliphatic alcohols difluoromethylated analogues via merger benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)–CF2H bond formation. utility method showcased variety complex compounds.

Language: Английский

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Boryl radical-mediated halogen-atom transfer enables arylation of alkyl halides with electrophilic and nucleophilic coupling partners

Nature Synthesis, Journal Year: 2024, Volume and Issue: 3(10), P. 1221 - 1230

Published: July 1, 2024

Language: Английский

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Electrosynthetic C−O Bond Activation in Alcohols and Alcohol Derivatives

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(4)

Published: Oct. 24, 2022

Alcohols and their derivatives are ubiquitous versatile motifs in organic synthesis. Deoxygenative transformations of these compounds often challenging due to the thermodynamic penalty associated with cleavage C-O bond. However, electrochemically driven redox events have been shown facilitate bond alcohols either through direct electron transfer or use mediators electroactive catalysts. Herein, a comprehensive overview preparative mediated protocols for activation functionalization is detailed, including indirect electrosynthetic methods, as well photoelectrochemical strategies.

Language: Английский

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Radical Deoxyfunctionalisation Strategies**

European Journal of Organic Chemistry, Journal Year: 2022, Volume and Issue: 2022(26)

Published: May 10, 2022

Abstract Due to their abundance and readily available synthesis, alcohols provide ideal handles for the selective derivatisation of organic molecules. Radical chemistry offers versatile strategies conversion Csp 3 −O bonds into a wide range −C, −H, or −heteroatom bonds. In these reactions, are derivatised with an activator group which can undergo facile mesolysis generate primary, secondary, tertiary open‐shell species that engage in further transformations. These particularly effective at overcoming steric limitations associated nucleophilic substitution pathways. Despite potential, use radical deoxyfunctionalisation reactions as general strategy synthesis useful complex molecules remains underutilised. this Review, we highlight recent advancements exciting field photocatalysis, transition metal catalysis electrochemistry used initiate processes.

Language: Английский

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Aryl Radical Enabled, Copper-Catalyzed Sonogashira-Type Cross-Coupling of Alkynes with Alkyl Iodides

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(4), P. 2761 - 2770

Published: Feb. 8, 2023

Despite the success of Sonogashira coupling for synthesis arylalkynes and conjugated enynes, engagement unactivated alkyl halides in such reactions remains historically challenging. We report herein a strategy that merges Cu-catalyzed alkyne transfer with aryl radical activation carbon-halide bonds to enable general approach iodides terminal alkynes. This unprecedented Sonogashira-type cross-coupling reaction tolerates broad range functional groups has been applied late-stage densely functionalized pharmaceutical agents as well positron emission tomography tracers.

Language: Английский

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Alcohols as Alkyl Synthons Enabled by Photoredox-Catalyzed Deoxygenative Activation

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(17), P. 13451 - 13496

Published: Aug. 26, 2024

Alcohols are abundant with versatile structural variety and have ample use as pivotal functional groups in numerous organic processes. Because of their frequent occurrence enumerable natural products, bioactive molecules, medicinal components, alcohol functionalities provide a promising scope research to advance the operational diversity for improving clinical success. Recent years witnessed design modern C–C C–heteroatom bond-forming approaches easily accessible commercially available unactivated aliphatic alcohols native adaptive sp3 handles, hence offering groundbreaking transformative pathways functionalization complex molecular architectures. The judicial application appropriate activating generate alkyl radical from through C–O bond fragmentation employ it potential alkylating agent unfolds unique synthetic strategies, thereby replacing obvious requirement halides. This review elaborately discusses recent trends regarding using C(sp3)-centered various chemical transformations by exploiting different activation modes disrupter under photoredox catalysis. presentation is organized nature scaffolds, kind formation, progress achieved this domain since original discovery providing illustrative examples mechanistic details, focus on difficulties future prospects.

Language: Английский

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Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(52), P. 27070 - 27077

Published: Oct. 15, 2021

Abstract The engagement of unactivated alkyl halides in copper‐catalyzed cross‐coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition copper(I) catalysts. In this work, we report a novel strategy that leverages halogen abstraction ability aryl radicals, thereby engaging diverse range iodides Negishi‐type at room temperature. Specifically, radicals generated via copper catalysis efficiently initiate cleavage carbon–iodide bonds iodides. thus enter catalytic cycles couple with difluoromethyl zinc reagent, furnishing difluoromethane products. This unprecedented difluoromethylation approach applied late‐stage modification densely functionalized pharmaceutical agents natural

Language: Английский

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