Computational and experimental investigations of oxadiazinone reactivity with cyclooctynes and other dienophiles

Tetrazines are heterocycles famous in bioorthogonal chemistry for their fast rates of cycloadditions with strained alkenes and alkynes. Oxadiazinones are lactone analogues of tetrazines that show potential for but have not yet been exploited in bioorthogonal use. We present computational assessment and analysis of cycloadditions of oxadiazinones to several complementary bioorthogonal alkene and alkyne handles: cyclooctyne, bicyclononyne, and trans-cyclooctene gave low transition state barriers, while the similar 8-cycle dibenzocyclooctyne did not, due to greater geometric distortion; 3- and 4-membered cycloalkenes gave intermediate values. Secondary alkyne additions to oxadiazinones and analogues following retro-Diels–Alder eliminations of N 2 from adducts of initial alkyne additions are explored, as the possible reversal of electron demand from first to second addition makes them interesting tools for selective dual-addition schemes. We also show experimental rate constants up to 0.028 mol L −1 s −1 for additions of bicyclononyne to a series of oxadiazinones.