Cu-free 1,3-dipolar cycloaddition click reactions to form isoxazole linkers in chelating ligands for fac -[MI(CO)3]+ centers (M = Re, 99mTc)

Abstract

Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to CuI-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the fac-[MI(CO)3]+ (M = Re, 99mTc) core for use as a noncoordinating linker strategy between covalently linked molecules. Two click assembly methods (click, then chelate and chelate, then click) were examined to determine the feasibility of isoxazole ring formation with either alkyne-functionalized tridentate chelates or their respective fac-[MI(CO)3]+ complexes with a model nitrile oxide generator. Macroscale experiments, alkyne-functionalized chelates, or Re complexes indicate facile formation of the isoxazole ring. 99mTc experiments demonstrate efficient radiolabeling with click, then chelate; however, the chelate, then click approach led to faster product formation, but lower yields compared to the Re analogues. © 2014 American Chemical Society.