Regioselectivity in Iron‐Catalyzed [2+2+1] Cycloadditions: A DFT Investigation of Substituent Effects in 1,4‐Diazabutadienes

Abstract

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.

Recent advances in the iron-catalyzed cycloaddition reactions

“…The reaction of an imine instead of a 1,4-diazabutadiene under the same conditions only proceeded with lower selectivity. This result revealed that the ketimine functionality acted as a bidentate ligand and subtle substituent effects were responsible Scheme 24 for the regioselectivity, as also suggested by the theoretical studies [53].…”

Iron Catalysis in Organic Synthesis

“…A catalytic version has only been reported by Imhof et al for the hetero-Pauson–Khand cycloaddition of cyclic imidates, carbon monoxide, and ethylene catalyzed by nonacarbonyldiiron (Scheme ). − A second imine moiety was required in proximity to the reacting imidate, suggesting that the substrate acts as a bidentate ligand for the iron. Computational results revealed that the ethylene will always attack the less stable imine group with less efficient delocalization of π-electron density.…”

Iron-Catalyzed Direct Suzuki–Miyaura Reaction: Theoretical and Experimental Studies on the Mechanism and the Regioselectivity

“…Previous investigations indicated that the B3LYP method can give reasonable structures and energies for iron-containing reactions. − All the stationary points on the potential energy surface (PES) were optimized on the quartet and sextet spin states first using the hybrid density functional B3LYP − method with the 6-31+G(d) basis set. , Meanwhile, the test of stability of the density functional theory (DFT) wave function was passed. If an instability is found, the wave function is reoptimized, and the stability tests and reoptimizations are repeated until a stable wave function is found.…”