Cascade [1,3]-Sigmatropic Rearrangements of Ketene <i>O</i>,<i>O</i>-Acetals: Kinetic and DFT Level Mechanistic Studies

The regioisomeric α-cyano ketene-O,O-dialkyl acetals 2a−e and 4a−e, sequential intermediates in the diazomethane induced conversion of indole α-cyano-γ-lactones 1a−e to 2-indolyl cyanomalonates 5a−e, were isolated and characterized. Formation of the steady-state intermediate cycloprop[b]indoles 3a−e was evidenced by means of NMR and confirmed by the X-ray structure of 3c, demonstrating that the formation of 5a−e from 2a−e proceeds through two consecutive and one parallel unimolecular steps, with intermediates 3a−e formed in reversible processes. Evidence that the reversible reactions proceed via [1,3]-rearrangements is presented. The steady-state kinetic approach applied to intermediate 3 allowed a minimal two consecutive step 2 → 4→ 5 kinetic model, in which the steric bulkiness of the alkyl substituent affects strongly the associated rate constants, k1 and k2, inverting the rate-determining step. The solvation effects enhanced the feasibility of these skeletal rearrangements as they stabilized the transition states to a great extent. The experimental determined thermodynamic parameters and DFT calculations suggest that these cascade rearrangements occur through [1,3]-sigmatropic mechanisms, in which asynchronous bond reorganization processes via four membered pseudopericyclic transition states are highly favorable.