Palladium-Catalyzed Heteroannulation Route to 4-Alkylidene-4H-3,1-benzoxazines

Significance

Reported here is the regio- and ­stereoselective synthesis of 4-alkylidene-4H-3,1-benzoxazines 2 via a 6-endo-dig-type cyclization of o-alkynyl-N-carboxanilides 1. After screening palladium catalysts to control the regioselectivity of the reaction (6-endo-dig vs 5-exo-dig mode), Pd(OAc)₂ was found to be the most effective one. It was also established that the addition of AcOH (1 equiv) accelerates considerably the reaction rate and affords exclusively benzoxazines 2 without the formation of by-product 3. A variety of substituents (R^¹, R^² = Alk, Ar) were tested for this transformation. The reaction affords poor or no yields with terminal alkynes (e.g. 25% yield for R^¹ = H, R^² = 4-O₂NC₆H₄). A plausible mechanism was proposed involving α-complex 4, which is supported by the formation of Michael adduct 5 in the presence of methyl acrylate.