The High Selectivity of the Cp2ZrHCl Reducing Agent for Imides: A Combined Experimental and Theoretical Study on γ-Lactam and Isoxazolidinone Derivatives

Selective reductions of semicyclic imides either to hemiaminals (endo carbonyl reduction) or to aldehydes and amines(exo carbonyl reduction) in high yields by Schwartz’s reagent (Cp2ZrHCl) are reported. Mechanistic aspects of these reactionshave been investigated at the DFT ab initio level withconsideration of implicit solvent effects and thermal and pressure corrections to 298 K/1 atm. The reactions proceed from the reagents to very stable final Zr-oxo intermediates through the formation of σ complexes and subsequent four-centertransition state structures (1,2-migratory insertion).The energetic barriers for the insertion steps depend strongly on the natures of the ancillary groups at the reducing carbonyl groups. N-Carbamoyl groups are reduced to hemiaminals whereas N-acyl groups react at the exo carbonyl groups.The absence of the second carbonyl group in the simple Nmethyl-2-pyrrolidone (less oxidized system) strongly reduces the thermodynamic drive for the formation of the metallocene oxo-intermediate and allows an explanation of the remarkablechemoselectivity of the hydrozirconation. The zirconocene-oxo intermediates hydrolyze quickly throughoutan ionic mechanism in which water molecules strongly assist the process by stabilizing ion pair separation. The computationalresults are consistent with a large set of experimentaldata on reduction of γ-lactam and isoxazolidinone derivatives under mild conditions. They provide a way to explain and predict the relative importance of the two competitive endo/exo reduction channels of semicyclic imides by considering the electronic and steric features of substituents.