[3+2]-Cycloaddition reactions of gem-difluorocyclopropenes with azomethine ylides – access to novel fluorinated scaffolds

Kian Donnelly; Amritpal Singh; Tell Tuttle; Marcus Baumann

doi:10.1002/chem.202301861

[3+2]-Cycloaddition reactions of gem-difluorocyclopropenes with azomethine ylides – access to novel fluorinated scaffolds

Kian Donnelly, Amritpal Singh, Tell Tuttle, Marcus Baumann

Pure And Applied Chemistry

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

4 Citations (Scopus)

53 Downloads (Pure)

Abstract

The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.

Original language	English
Article number	e202301861
Number of pages	8
Journal	Chemistry - A European Journal
Volume	29
Issue number	54
Early online date	18 Aug 2023
DOIs	https://doi.org/10.1002/chem.202301861
Publication status	Published - 26 Sept 2023

Funding

We are grateful to the School of Chemistry at University College Dublin for the provision of a Sir Walter Hartley PhD Scholarship (to KD), and to Dr. Yannick Ortin and Dr. Jimmy Muldoon for assistance with NMR and MS data analysis. Dr Dmitry Yufit (Durham University, UK) is acknowledged for solving the X-ray single crystal structure reported in this manuscript. Computational results were obtained using the EPSRC-funded ARCHIE-WeSt High-Performance Computer (www.archie-west.ac.uk; EPSRC grant no: EP/K000586/1). This publication has emanated from research supported in part by a grant from Science Foundation Ireland under Grant number [20/FFP−P/8712, 12/RC2275_P2 and 18/RI/5702]. For the purpose of Open Access, the author has applied for a CC BY public copyright license. Open Access funding provided by IReL. We are grateful to the School of Chemistry at University College Dublin for the provision of a Sir Walter Hartley PhD Scholarship (to KD), and to Dr. Yannick Ortin and Dr. Jimmy Muldoon for assistance with NMR and MS data analysis. Dr Dmitry Yufit (Durham University, UK) is acknowledged for solving the X‐ray single crystal structure reported in this manuscript. Computational results were obtained using the EPSRC‐funded ARCHIE‐WeSt High‐Performance Computer (www.archie‐west.ac.uk; EPSRC grant no: EP/K000586/1). This publication has emanated from research supported in part by a grant from Science Foundation Ireland under Grant number [20/FFP−P/8712, 12/RC2275_P2 and 18/RI/5702]. For the purpose of Open Access, the author has applied for a CC BY public copyright license. Open Access funding provided by IReL.

Keywords

Ar−H⋅⋅⋅F bonding
difluorocyclopropene
dipolar cycloaddition
fluorinated heterocycle
reaction mechanism

Access to Document

10.1002/chem.202301861Licence: CC BY 4.0

Donnelly-etal-CAEJ-2023-Cycloaddition-reactions-of-gem-difluorocyclopropenes-with-azomethine-ylidesFinal published version, 5.91 MBLicence: CC BY 4.0

ARCHIE-WeSt (UOSHPC)
Martin, R. (Manager)
University Of Strathclyde
Facility/equipment: Facility

Cite this

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title = "[3+2]-Cycloaddition reactions of gem-difluorocyclopropenes with azomethine ylides – access to novel fluorinated scaffolds",

abstract = "The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.",

keywords = "Ar−H⋅⋅⋅F bonding, difluorocyclopropene, dipolar cycloaddition, fluorinated heterocycle, reaction mechanism",

author = "Kian Donnelly and Amritpal Singh and Tell Tuttle and Marcus Baumann",

year = "2023",

month = sep,

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doi = "10.1002/chem.202301861",

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AU - Donnelly, Kian

AU - Singh, Amritpal

AU - Tuttle, Tell

AU - Baumann, Marcus

PY - 2023/9/26

Y1 - 2023/9/26

N2 - The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.

AB - The introduction of fluorinated moieties into drugs as well as the increase of their overall three-dimensionality have become key strategies amongst medicinal chemists to generate sets of compounds with favorable drug-like properties. However, the introduction of fluorinated cyclopropane ring systems which combines both strategies is not widely exploited to date. This paper reports synthetic strategies exploiting the reactivity of gem-difluorocyclopropenes in dipolar cycloaddition reactions with azomethine ylides to afford sets of new fluorine-containing 3-azabicyclo[3.1.0]hexanes. In addition, the unexpected formation of complex trifluorinated scaffolds arising from proline esters and gem-difluorocyclopropenes is highlighted along with computational studies to elucidate the underlying mechanism. This study presents new avenues towards pharmaceutically relevant fluorinated 3-azabicyclo[3.1.0]hexanes that are accessible via robust and short synthetic sequences.

KW - Ar−H⋅⋅⋅F bonding

KW - difluorocyclopropene

KW - dipolar cycloaddition

KW - fluorinated heterocycle

KW - reaction mechanism

U2 - 10.1002/chem.202301861

DO - 10.1002/chem.202301861

M3 - Article

SN - 0947-6539

VL - 29

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

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M1 - e202301861

ER -

[3+2]-Cycloaddition reactions of gem-difluorocyclopropenes with azomethine ylides – access to novel fluorinated scaffolds

Abstract

Funding

Keywords

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