Regioselective synthesis of spirocyclic pyrrolines via a palladium-catalyzed Narasaka-Heck/C-H activation/[4 + 2] annulation cascade reaction

Abstract

A novel palladium-catalyzed spirocyclization through sequential Narasaka-Heck cyclization, C-H activation and [4 + 2] annulation has been developed. In this reaction, cheap and readily available 2-chlorobenzoic acid or ethyl phenylpropiolate was employed as the C2 insertion unit to react with γ,δ-unsaturated oxime ester. The key step in this transformation is the regioselective insertion of the C2 synthon into the spiro-palladacycle intermediate that is formed by the δ-C-H activation process, thereby efficiently assembling a series of spirocyclic pyrrolines with high regiocontrol. Furthermore, density functional theory (DFT) calculations and control experiments were performed to gain some insights into the reaction mechanism.

Scheme 1. (a) Our previous study; (b) this study.

Fig. 1. Free energy profile for the migratory insertion step with ethyl phenylpropiolate 4a and the direct reductive elimination of spiropalladacycle C (L = PPh₃). The relative free energies are presented in kcal mol⁻¹.

Scheme 2. Control experiments, (a) kinetic isotope effect experiment of 1a and 1a-D₅ with 2a; (b) kinetic isotope effect experiment of 1a and 1a-D₅ with 4a.

Scheme 3. Proposed mechanism.