Regioselectivity in iron-catalyzed [2+2+1] cycloadditions: a DFT investigation of substituent effects in 1,4-diazabutadienes

The transition-metal-catalyzed 2+2+1] cycloaddition reaction of 1,4-diazabutadienes, in which the imine-carbon atoms are part of an oxazine ring system, with ethylene and carbon monoxide leads to the regioselective formation of pyrrolidinone derivatives. To explain this regioselectivity, the transition states and intermediates of the rate-determining step of the catalysis are determined by high-level DFT calculations. The experimentally observed regioselectivity is consistent with the lower activation energy of the addition of ethylene towards the carbon atom next to the oxazine oxygen atom. Furthermore, the activation barrier of a conceivable back reaction is higher for the intermediates with the experimentally observed regioselectivity. These thermodynamic and kinetic arguments at first sight appear to be confirmed by the calculated NPA charges in the transition states, which reveal that the differences in these charges are greatest for those transition states that lead to the formation of the energetically favored transition structures. Nevertheless, calculations of analogous transition structures and reaction products starting from 1,4-diazabutadienes with a 2-fluoro, 2-hydroxo or 2-amino substituent revealed that the regioselectivity is not determined by the electronegativity of the heteroatom and thus by the differences in the NPA charges or the resulting Coulombic interactions in the transition structures. The main reason for the observed regioselectivities is the pi-donor ability of the substituent to contribute to a delocalized pi system incorporating the adjacent imine moiety. The increasing pi-donor capability results in decreased reactivity of this moiety and increases the (relative) reactivity of the second imine group. This effect can even overcompensate for strong intramolecular Coulombic attractions in the transition structures.