Synthesis of Oxazinoindoles and Pyrrolooxazines by Sc(III) Catalysis

Significance

Reported is a methodology involving the scandium-catalyzed sequential oxirane ring opening and Friedel–Crafts intramolecular alkylation of indol-1-yl 1 and pyrroles 3 to give functionalized [1,4]oxazino[4,3-a]indoles 2 and 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazines 4 in good to excellent yields. The substrate scopes of 1 and 3 were explored for EDG and EWG groups (R¹, R², and R³) and it was found that 1 with EDGs afford the products 2 in excellent yields under the optimized conditions, but with EWGs, higher temperatures and higher catalyst loadings are required. The pyrrolooxiranes 3 also produced the products 4 in excellent yields at higher temperature and higher catalyst loading. With a blocked 2-position of the indole (1b), 6 was obtained.

Comment

Oxazinoindoles 2 and pyrrolooxazines 4 are important classes of compounds, well known for their biological and pharmaceutical properties. Although methods of their syntheses are known (G. Abbiati, V. Canevari, S. Caimi, E. Rossi Tetrahedron Lett. 2005, 46, 7117), the reported method involves an easy, atom-economic, and mild one-step route. The reaction was optimized with respect to solvent, temperature, and time. The conversion of 1a into compounds 2a and 5 was also reported. Structure 2a (R¹ = H, R² = 4-BrC₆H₄, R³ = Me) was confirmed by X-ray crystal structural analysis, and this structure has confirmed the oxirane C–C bond cleavage (structure 7). Further application of this chemistry is encouraged.