4-Halogeno-sydnones for fast strain promoted cycloaddition with bicyclo-[6.1.0]-nonyne

Abstract

New sydnone derivatives have been synthesized and screened for their capacity to undergo fast copper-free cycloaddition reaction with bicyclo-[6.1.0]-nonyne. The influences of substitution in positions N-3 and C-4 of sydnones have been particularly studied leading to the identification of highly reactive partners for bio-orthogonal ligation reactions.

Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and Organic Azides

“…Similarly, both our laboratory [27] and Sanders et al [47] reported the reaction of cyclooctynes with nitrile oxides (SPANOC) leading to isoxazoles, which is a factor *10 faster than SPAAC and SPANC. Finally, strain-promoted cycloaddition with diazo-compounds is also known [47] as well as reaction of BCN with sydnone [42,61]. Interestingly, in the field of (4 ?…”

Ultrafast Click Chemistry with Fluorosydnones

“…[2] Nitrones, [3] tetrazines, [4] and diazo groups [5] are also suitable dipole partners for strained cycloalkynes,but with the exception of tetrazines (k values up to 10 3 m À1 s À1 ), [6] strain-promoted cycloadditions involving cycloalkyne partners display lower second-order rate constants,which typically range from 10 À2 to 30 m À1 s À1 .Recently, our group has identified sydnones as anew class of dipoles for Cu-catalyzed cycloaddition with terminal alkynes,l eading to 1,4-pyrazoles with complete control over regioselectivity;the reaction was coined CuSAC( copper-catalyzed sydnonealkyne cycloaddition). [9] In their work, sydnones were found to react more slowly than azides with cyclic alkynes, thereby limiting applicability as ab ioorthogonal ligation substrate.Atthe same time,wereported [10] that the presence of ah alogen in the 4-position has ab eneficial impact on the rate of the reaction, with the order of reactivity correlating with halogen electronegativity (Cl > Br > I). [9] In their work, sydnones were found to react more slowly than azides with cyclic alkynes, thereby limiting applicability as ab ioorthogonal ligation substrate.Atthe same time,wereported [10] that the presence of ah alogen in the 4-position has ab eneficial impact on the rate of the reaction, with the order of reactivity correlating with halogen electronegativity (Cl > Br > I).…”

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

“…[17] Subsequent N -nitrosation and cyclodehydration of the resulting nitrosamines affords the mesoionic compounds in good yields.…”

“…[17b, 25] Previously, we disclosed the bioorthogonal reaction of phenyl sydnones with dibenzocyclooctyne derivatives DIBAC and BARAC to undergo [3+2] cycloaddition for applications in fluorescence protein labeling. [25c] Encouraged by these results, we sought to utilize this ligation to rapidly incorporate [ 18 F]fluorine into peptides and other biomolecules for applications in PET molecular imaging.…”