Synthesis of cyclooctyne-sulfamates by the Nicholas cyclisation

Here, we present the Nicholas cyclisation as an alternative, simple synthetic method for producing cyclooctyne-sulfamates as promising SPAAC reagents. Co₂(CO)₆-complexes of both monocyclic and benzene-fused cyclooctyne-sulfamates were prepared using the Nicholas cyclisation. After cobalt deprotection, the non-fused cyclooctyne-sulfamate SNO-Me2 remained stable and underwent SPAAC with benzyl azide (<i>k</i> = 0.0163 M^-1 s^-1) readily. In contrast, the benzene-fused cyclooctyne-sulfamates B-SNO and B-SNO-Me2 were found to be kinetically unstable. The reactivity and stability of monocyclic and benzene-fused cyclooctyne-sulfamates were predicted and compared using DFT calculations. The crucial influence of benzene-fusion and propargylic methyl groups on geometry, electronic structure, stability and reactivity was demonstrated.