A Molecular Electron Density Theory Study of the Domino [4+2]/[3+2] Cycloaddition Leading to a Tricyclic 1,2-Oxazine Nitrones

The reaction of 2,5-dimethylfuran (DMF) with two equivalents of α-nitrosostyrene (NS) leading to a tricyclic 1,2-oxazine nitrone (TON) has been examined theoretically at the ωB97X-D/6-311G(d,p) computational level. In this case, the domino process should be considered: (i) a [4+2] cycloaddition (42CA) between DMF and NS yielding a bicyclic 1,2-oxazine (BO); and (ii) a second formal [3+2] cycloaddition (32CA) reaction between BO and NS yielding the final TON. Analysis of the reactivity indices shows that DMF and BO generated along the first 42CA reaction are strong nucleophiles, while NS is a strong electrophile. The first 42CA reaction takes place according to a one-step mechanism. In turn, the second 32CA proceeds according to a two-step mechanism through the zwitterionic intermediate ZW. It is worth noting that the activation enthalpy of the significant point (TS-1mn) of the 42CA is very low, 2.17 kcal·mol−1, the reaction being strongly exothermic by −37.71 kcal·mol−1. This cycloaddition reaction is completely meta regioselective and endo stereoselective. The first step of the formal 32CA reaction has an activation enthalpy of 8.48 kcal·mol−1 (TS-21), the overall domino process being strongly exothermic by −40.34 kcal·mol−1. Both TS-1mn and TS-21 are associated with highly asynchronous single bond processes. The high global electron density transfer (GEDT) found at both TSs, higher than 0.32e, points out the high polar character of these cycloaddition reactions, classified as reverse electron density flux (REDF). Electron Localization Function (ELF) analysis of TS-1mn and TS-21 shows that the C2-C3 and C3-N5 bonds are not formed at the same time, while in the intermediate ZW we observed the creation of one of them.