The Cyclization of Allenyl-Substituted Hydroxylamines to 1,2-Oxazines: an Experimental and Computational Study

Abstract

To gain a deeper understanding of the formation of the synthetically important 3,6-dihydro-2H-1,2-oxazines, the 6-endo-trig cyclization of allenyl-substituted hydroxylamines was experimentally investigated in detail employing a model compound. The solvent effect was moderate with respect to the rate, but crucial to suppress side-product formation. Surprisingly, acids or bases had no big influence on the cyclization rate. With O-deuterated allenyl hydroxylamine a high primary isotope effect was found, indicating that the proton transfer is crucial in the rate-determining step. DFT calculations evidence that the allenyl-substituted hydroxylamine is converted into an energetically similar zwitterionic intermediate with an allyl cation subunit. It cyclizes to the 1,2-oxazine as the most stable species. Alternative pathways starting from the zwitterion were computationally investigated. Interestingly, it can also undergo a fragmentation to give a pentadiene derivative and a nitroso compound. The hetero Diels–Alder reaction of these components may also deliver the 1,2-oxazine. To evaluate an alternative mechanistic scenario, calculations of the protonated allenyl-substituted hydroxylamine were also performed.