Ultrafast Click Chemistry with Fluorosydnones

Abstract

We report the synthesis and reactivity of 4-fluorosydnones, a unique class of mesoionic dipoles displaying exquisite reactivity towards both copper-catalyzed and strain-promoted cycloaddition reactions with alkynes. Synthetic access to these new mesoionic compounds was granted by electrophilic fluorination of σ-sydnone Pd(II) precursors in the presence of Selectfluor. Their reactions with terminal and cyclic alkynes were found to proceed very rapidly and selectively, affording 5-fluoro-1,4-pyrazoles with bimolecular rate constants up to 10(4) m(-1) s(-1) , surpassing those documented in the literature with cycloalkynes. Kinetic studies were carried out to unravel the mechanism of the reaction, and the value of 4-fluorosydnones was further highlighted by successful radiolabeling with [(18) F]Selectfluor.

A practical and catalyst-free trifluoroethylation reaction of amines using trifluoroacetic acid

“…However, the use of fluorine in this field is currently limited to a small number of chemotypes with aryl fluorides being dominant56789. Given the beneficial properties of fluorine, practical new methods that allow access to a more diverse range of medicinally relevant fluorinated building blocks are of particular importance1011121314151617181920212223242526. For example, β -fluoroalkylamines are less basic than their hydrocarbon counterparts (p K a H 10.7 versus 5.7 for ethylamine and trifluoroethylamine respectively)27 and often exhibit decreased acute toxicity and increased metabolic stability rendering them very attractive in pharmaceutical contexts (for examples, see Fig.…”

Synthesis of [18F]Fluoroarenes by Nucleophilic Radiofluorination of N‐Arylsydnones

“…[19b] Our application of [ 18 F]sydnones as bioorthogonal prosthetic groups for the production of 18 F radiotracers is related to Taran and coworkers’ recent Pd(II)-mediated formation of 4-[ 18 F]fluoro- N -( p -tolyl)-sydnone, which is also an efficient cycloaddition partner. [29] Indeed, our method compares advantageously as it uses simple reagents for one-step, direct radiofluorination without transition metals, gives improved RCY and is fully automatable.…”

Bioorthogonal Ligations and Cleavages in Chemical Biology

“…The reactions showed very fast reaction rate (rate constant up to 10 4 M À 1 s À 1 ) and high selectivity giving 5-fluoro-1,4-pyrazoles ( Figure 21d). [103] Very recently, Yu and co-workers developed the photoclickable strain-promoted cycloaddition of diarylsydnones with alkynes, which showed the robust selectivity for in vitro and in vivo protein labelling. [104] Furthermore, the method has been successful for the fluorescent molecular imaging [105] and metabolic labeling of sialoconjugates.…”