Access to N-Carbonyl Derivatives of Iminosydnones by Carbonylimidazolium Activation

Abstract

A new methodology for N-exocyclic functionalization of iminosydnones was developed involving the addition of a large variety of nucleophiles on carbonyl-imidazolium-activated iminosydnones. This practical and highly versatile method provided access to new classes of iminosydnones and opened a straightforward synthetic route to prepare iminosydnone-based prodrugs.

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

“…A convenient methodology for the selective N 6 -exocyclic functionalization of sydnone imines involving the addition of a large variety of nucleophiles on carbonyl-imidazolium-activated iminosydnones 15 was developed [ 40 ]. Initial imidazolium derivatives 15 can be easily obtained in two steps from the corresponding sydnone imines on a multigram scale.…”

“…Initial imidazolium derivatives 15 can be easily obtained in two steps from the corresponding sydnone imines on a multigram scale. Compounds 15 are bench-stable for several weeks at room temperature and react efficiently with diverse heteroatom nucleophiles to afford a library of functionalized sydnone imines 16 ( Scheme 9 ) [ 40 ]. This method has a broad substrate scope and tolerates sensitive functional groups.…”

“…A [3+2]-cycloaddition of N 6 -derived iminosydnones with several strained alkynes resulted in the formation of pyrazoles and isocyanates ( Scheme 20 ). This method is based on a general concept of bioorthogonal click-and-release reactions [ 36 , 38 , 39 , 40 , 52 , 53 ] due to the ability of sydnone imines to remove the mesoionic fragment through cycloaddition with alkyne triggers. It was shown that electron-withdrawing substituents at N 3 -aryl iminosydnones and a urea moiety connected to the exocyclic nitrogen atom of the iminosydnone core had a strong beneficial impact on the reaction kinetics.…”

Click and Bio-Orthogonal Reactions with Mesoionic Compounds

“…Those key intermediates can be further functionalized in the presence of a large variety of nucleophiles. 74,75 The other possibilities to further derivatize iminosydnones are relatively similar to those used for sydnones, since the C 4 position is nucleophilic and acidic, as well. However, lithiated iminosydnones are less stable and less nucleophilic than their sydnone counterparts.…”

Phosphine-Mediated Bioconjugation of the 3′-End of RNA

“…Phosphine 2j containing a sydnone substituent, recently reported as a suitable partner for click and release experiments for bioconjugation, , was synthesized according to the synthetic route described in Scheme . Iminosydnone 7 was prepared following standard procedures and activated using a two-step strategy to afford the corresponding carbonyl-imidazolium salt 8 in 75% yield. The sydnone compound 8 was then treated in the presence of DIPEA and unprotected phosphine 2i in DCM to lead to the phosphine 2j in 54% yield.…”