Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis

Eric W. Webb; John B. Park; Erin L. Cole; David J. Donnelly; Samuel J. Bonacorsi; William R. Ewing; Abigail G. Doyle

doi:10.1021/jacs.0c03125

Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis

Eric W. Webb, John B. Park, Erin L. Cole, David J. Donnelly, Samuel J. Bonacorsi, William R. Ewing, Abigail G. Doyle

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

Abstract

We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [¹⁸F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral S_N1 substitutions under mild conditions.

Original language	English (US)
Pages (from-to)	9493-9500
Number of pages	8
Journal	Journal of the American Chemical Society
Volume	142
Issue number	20
DOIs	https://doi.org/10.1021/jacs.0c03125
State	Published - May 20 2020

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry
Catalysis
Colloid and Surface Chemistry

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10.1021/jacs.0c03125

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title = "Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis",

abstract = "We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [18F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral SN1 substitutions under mild conditions.",

author = "Webb, {Eric W.} and Park, {John B.} and Cole, {Erin L.} and Donnelly, {David J.} and Bonacorsi, {Samuel J.} and Ewing, {William R.} and Doyle, {Abigail G.}",

note = "Funding Information: Financial support was generously provided by NSF (CHE-1565983) and Bristol-Myers Squibb. We thank Dhar Murali (BMS) for helpful suggestions, Erin E. Gomes (BMS) for radiochemical and analytical expertise, and Daniel Batella (BMS) for construction of the apparatus to allow radiochemical irradiation. Istv{\'a}n Pelzer, Kenneth Conover, and John Eng are acknowledged for analytical aid. We thank Laura K. G. Ackermann, Meredith A. Borden, and Talia J. Steiman for helpful discussions. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = may,

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doi = "10.1021/jacs.0c03125",

language = "English (US)",

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T1 - Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis

AU - Webb, Eric W.

AU - Park, John B.

AU - Cole, Erin L.

AU - Donnelly, David J.

AU - Bonacorsi, Samuel J.

AU - Ewing, William R.

AU - Doyle, Abigail G.

N1 - Funding Information: Financial support was generously provided by NSF (CHE-1565983) and Bristol-Myers Squibb. We thank Dhar Murali (BMS) for helpful suggestions, Erin E. Gomes (BMS) for radiochemical and analytical expertise, and Daniel Batella (BMS) for construction of the apparatus to allow radiochemical irradiation. István Pelzer, Kenneth Conover, and John Eng are acknowledged for analytical aid. We thank Laura K. G. Ackermann, Meredith A. Borden, and Talia J. Steiman for helpful discussions. Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/5/20

Y1 - 2020/5/20

N2 - We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [18F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral SN1 substitutions under mild conditions.

AB - We report a redox-neutral method for nucleophilic fluorination of N-hydroxyphthalimide esters using an Ir photocatalyst under visible light irradiation. The method provides access to a broad range of aliphatic fluorides, including primary, secondary, and tertiary benzylic fluorides as well as unactivated tertiary fluorides, that are typically inaccessible by nucleophilic fluorination due to competing elimination. In addition, we show that the decarboxylative fluorination conditions are readily adapted to radiofluorination with [18F]KF. We propose that the reactions proceed by two electron transfers between the Ir catalyst and redox-active ester substrate to afford a carbocation intermediate that undergoes subsequent trapping by fluoride. Examples of trapping with O- and C-centered nucleophiles and deoxyfluorination via N-hydroxyphthalimidoyl oxalates are also presented, suggesting that this approach may offer a general blueprint for affecting redox-neutral SN1 substitutions under mild conditions.

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Nucleophilic (Radio)Fluorination of Redox-Active Esters via Radical-Polar Crossover Enabled by Photoredox Catalysis

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