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Synthesis of α-Ketoester- and α-Hydroxyester-Substituted Isoindazoles via the Thermodynamic Coarctate Cyclization of Ester-Terminated Azo-Ene-Yne Systems

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journal contribution
posted on 04.09.2009, 00:00 by Sean P. McClintock, Nathan Forster, Rainer Herges, Michael M. Haley
The synthesis of isoindazoles bearing α-ketoester and α-hydroxyester groups via the coarctate cyclization of ester-terminated azo-ene-yne precursors is described. Whereas previous studies on isoindazole formation have shown the reaction to proceed through a kinetic coarctate pathway, functionalization of the terminal acetylene with a methyl ester sufficiently stabilizes the carbene intermediate to make the coarctate cyclization the thermodynamic pathway. Density functional theory (DFT) computations reveal ca. 8−9 kcal mol−1 lower energy transition states for the coarctate pathway compared to the parent system.