3-Methyleneisoindolin-1-one Assembly via Base- and CuI/l-Proline-Catalyzed Domino Reaction: Mechanism of Regioselective Anionic Cyclization.

Anionic cyclization of o-alkynylbenzamides is proposed as a crucial step in many heterocycle syntheses. The cyclization can produce three products: Z-3-methylenisoindolin-1-one (Z-5-exo), E-3-methylenisoindolin-1-one (E-5-exo), and isoquinolinone (6-endo). Under base catalysis, the selectivity is generally poor. However, a copper-involved domino reaction of coupling and cyclization gives surprising selectivity for the thermodynamically disfavored Z-5-exo product (Org. Lett. 2009, 11, 1309-1312). We study the selectivity of anionic cyclization in the presence of K2CO3 and copper-l-proline, using surveys of the experimental literature and density functional theory (DFT) calculations. The o-alkynylbenzamide is predicted to be readily deprotonated by many bases, with subsequent cyclization via nucleophilic attack of the amide N- to alkynyl. In the absence of copper, endo-exo selectivity is predicted to arise from substituent effects, while Z/E selectivity is a sensitive function of the tautomerization rate of an alkenyl anion intermediate. Most importantly, we predict that the remarkable selectivity of the copper-involved reaction occurs because copper-l-proline "locks" the alkene anion intermediates into the initially formed Z-5-exo configuration. Calculations on other metals suggest that soft Lewis acid additives provide a potential route to improved regiocontrol of other anionic cyclizations.