Palladium-Catalyzed [4+2] Cycloaddition of Vinyl Benzoxazinanones with 1,3-Indanedione: Approach to Spiro-Tetrahydroquinoline Scaffolds

A palladium catalyzed decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with 2-arylidene indan-1,3-dione has been established, which afford a series of bioactive spiro-tetrahydroquinolines (27 examples) in moderate to good yield (up to 87 %) with high diastereoselectivities. The synthetic utility of this reaction was demonstrated by gram-scale synthesis. Compounds synthesized by this method potently inhibited proliferation in a panel of cancer cell lines. Particularly, the most potent compounds 3 ae, 3 ah, 3 aj and 3 fa displayed selective inhibition of MDA-MB-231 breast carcinoma cells with IC50 values of 1.292, 0.6118, 0.6558, 1.656 and 2.215 & mu;M, respectively. A palladium catalyzed decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with 1,3-indanedione was developed, affording a series of biologically potential spiro-tetrahydroquinolines. Gram-scale synthesis and product elaboration demonstrated the utility of this method. The product demonstrated exhibited potency in inhibiting MDA-MB-231 cell line.+image