PhenoFluor: Practical Synthesis, New Formulation, and Deoxyfluorination of Heteroaromatics

Fujimoto, Teppei; Becker, Fabian; Ritter, Tobias

doi:10.1021/op500121w

Cited by 65 publications

(41 citation statements)

References 41 publications

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“…6 We show here that the deoxyfluorination reaction of phenols with the reagent PhenoFluor (Fig. 2b) reported by our group 7,8 proceeds via a concerted pathway with electron-rich as well as electron-poor substrates, and how a detailed mechanistic analysis enabled us to design a deoxyfluorination reaction of phenols with 18 F. A concerted reaction with activation energies between 20 and 25 kcal/mol is observed because the concerted pathway is favored rather than because the classic two-step mechanism is disfavored, which sets our reaction apart from previous transformations that proceed with substantially higher activation barriers. 1,3,6,9 Gas phase nucleophilic aromatic substitutions can take place by concerted nucleophile attack and loss of the leaving group but only isolated cases of intermolecular CS N Ar reactions in solution or ionic melt have been reported.…”

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confidence: 66%

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Concerted nucleophilic aromatic substitution with 19F− and 18F−

Neumann

Hooker

Ritter

2016

Nature

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254

170

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Nucleophilic aromatic substitution (S N Ar) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain a 18 F for use in PET imaging. 1 A wide range of nucleophiles exhibit S N Ar reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. 2 During S N Ar, attack of a nucleophile at a carbon atom bearing a 'leaving group' leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of S N Ar reactions: the most common S N Ar substrates contain strong π-acceptors in the ortho and/or para position(s). 3 In this manuscript, we present an unusual concerted nucleophilic aromatic substitution reaction (CS N Ar) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CS N Ar is favored over a stepwise displacement. Mechanistic insights enabled us to develop a functional grouptolerant 18 F-deoxyfluorination reaction of phenols, which can be used to synthesize 18 F-PET probes. Selective 18 F introduction, without the need for the common, but cumbersome, azeotropic drying of 18 F, can now be accomplished from phenols as starting materials, and provides access to 18 F-labeled compounds not accessible through conventional chemistry.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsReprints and permissions information is available at www.nature.com/reprints.Correspondence and requests for materials should be addressed to T.R. (ritter@mpi-muelheim.mpg.de). Supplementary Information is available in the online version of the paper. Readers are welcome to comment on the online version of the paper. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptNucleophilic aromatic substitution reactions generally take place via either an additionelimination or elimination-addition mechanism. Both two-step mechanisms display a highenergy intermediate, either an aryne species (elimination-addition) or a Meisenheimer complex (addition-elimination). 2,4 A concerted displacement of the leaving group by an incoming nucleophile could avoid the formation of high-energy intermediates and thus broaden the scope of suitable electrophiles. Displacements at primary aliphatic centers, where charge build-up in a hypothetical S N 1 mechanism is unfavorable, commonly take place via a concerted mechanism involving the σ * (C alkyl -LG) orbital (S N 2 mechanism). For aromatic substrates a direct substitution pathway involving the σ * orbital of the areneleaving group bond (σ ...

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confidence: 66%

“…1c). The PhenoFluor-mediated deoxyfluorination reaction allows the interconversion of 4-hydroxyanisole to 4-fluoroanisole at only 110 °C 7,8 – far below the temperature commonly observed for aromatic substitutions on unactivated arenes. 3,6,9 …”

mentioning

confidence: 94%

Concerted nucleophilic aromatic substitution with 19F− and 18F−

Neumann

Hooker

Ritter

2016

Nature

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254

170

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“…Ritter's studies [53][54][55][56] on the deoxyfluorination of phenols. [58] This methodology was compatible with electron-donating and electron-withdrawing substituents on the methoxyarene.…”

Section: Scheme 19mentioning

confidence: 99%

Concerted Nucleophilic Aromatic Substitution Reactions

et al. 2019

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Recent developments in experimental and computational chemistry have identified a rapidly growing class of nucleophilic aromatic substitutions that proceed by concerted (cSNAr) rather than classical, two‐step, SNAr mechanisms. Whereas traditional SNAr reactions require substantial activation of the aromatic ring by electron‐withdrawing substituents, such activating groups are not mandatory in the concerted pathways.

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“…Fluorid spielte eine Hauptrolle in den wichtigen Studien [53][54][55][56] [53][54][55][56] der Deoxyfluorierung von Phenolen.…”

Section: Fluordeoxygenierung Von Phenolen Und Derivatenunclassified

Konzertierte nukleophile aromatische Substitutionen

Rohrbach¹,

Sutherland-Smith²,

Pang

et al. 2019

Angewandte Chemie

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Jüngste Entwicklungen in der experimentellen und theoretischen Chemie haben zur Identifizierung einer schnell wachsenden Klasse von nukleophilen aromatischen Substitutionsreaktionen geführt, die einem konzertierten Mechanismus (cSNAr) folgen, und nicht dem klassischen, zweistufigen SNAr‐Mechanismus. Während klassische SNAr‐Reaktionen auf die substantielle Aktivierung des aromatischen Ringes durch elektronenziehende Substituenten angewiesen sind, ist eine solche Aktivierung für den konzertierten Reaktionsverlauf nicht zwingend nötig.

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PhenoFluor: Practical Synthesis, New Formulation, and Deoxyfluorination of Heteroaromatics

Cited by 65 publications

References 41 publications

Concerted nucleophilic aromatic substitution with 19F− and 18F−

Concerted nucleophilic aromatic substitution with 19F− and 18F−

Concerted Nucleophilic Aromatic Substitution Reactions

Konzertierte nukleophile aromatische Substitutionen

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