Modular synthesis of α-arylated carboxylic acids, esters and amides <i>via</i> photocatalyzed triple C–F bond cleavage of methyltrifluorides

Li, Sifan; Davies, Paul W.; Shu, Wei

doi:10.1039/d2sc01905a

Cited by 9 publications

(3 citation statements)

References 54 publications

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“…As shown in Scheme 5a , treatment of mono-γ,γ-difluoroallylated 1,3-benzodioxole 3a with pyrrolidine (10 equiv) in MeCN at room temperature afforded amide 6 in 85% yield without any other additives. 18 The oxygen of the carbonyl group might have come from the trace amount of water in the solvent. The catechol protecting group of 5a can be readily removed in 0.5 mL of 90% v/v aqueous trifluoroacetic acid (TFA) solution at room temperature.…”

Section: Resultsmentioning

confidence: 99%

Photoredox radical/polar crossover enables C–H gem-difunctionalization of 1,3-benzodioxoles for the synthesis of monofluorocyclohexenes

Tian

Zhou

2023

Chem. Sci.

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Section: Resultsmentioning

confidence: 99%

Photoredox radical/polar crossover enables C–H gem-difunctionalization of 1,3-benzodioxoles for the synthesis of monofluorocyclohexenes

Tian

Zhou

2023

Chem. Sci.

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“…Aryl carboxylic acids and their derivatives represent an example of a highly abundant structural motif in numerous bioactive structures. 6 Classical approaches for accessing their isotopically labelled variants include the carboxylation of preformed but reactive organometallic reagents or nitrile substitutions followed by hydrolysis (Fig. 1a).…”

Section: Introductionmentioning

confidence: 99%

Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

Skrydstrup,

Batista,

Ebenbauer

et al. 2024

Preprint

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Carbon isotope labelling of bioactive molecules is a critical step for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs commonly found in many pharmaceutically active molecules and are ideal target structures for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalytic systems. Herein, we report the development of a practical and affordable electrochemical CRC setup based on palladium catalysis. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. Further studies provide more details in the mechanistic understanding of this process, allowing CRC to be performed in solvents alternative to DMF. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.

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“…Aryl carboxylic acids and their derivatives represent an example of a highly abundant structural motif in numerous bioactive structures 6 . Classical approaches for accessing their isotopically labelled variants include the carboxylation of preformed but reactive organometallic reagents or nitrile substitutions followed by hydrolysis (Fig.…”

mentioning

confidence: 99%

Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

Batista,

Ebenbauer,

Day

et al. 2024

Nat Commun

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Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.

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Modular synthesis of α-arylated carboxylic acids, esters and amides via photocatalyzed triple C–F bond cleavage of methyltrifluorides

Abstract: α-Arylated carboxylic acids and amides are widespread motifs in bioactive molecules and important building blocks in chemical synthesis. Thus, straightforward and rapid access to such structures is highly desirable. Here...

Cited by 9 publications

References 54 publications

Photoredox radical/polar crossover enables C–H gem-difunctionalization of 1,3-benzodioxoles for the synthesis of monofluorocyclohexenes

Photoredox radical/polar crossover enables C–H gem-difunctionalization of 1,3-benzodioxoles for the synthesis of monofluorocyclohexenes

Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

Efficient palladium-catalyzed electrocarboxylation enables late-stage carbon isotope labelling

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