Abstract:

As important natural and pharmaceutical motifs, the catalytic construction of structurally diverse 3,3-disubstituted oxindoles often requires elaborate synthetic efforts on optimizations. Herein, we developed a simple and divergent approach for constructing reverse-prenylated and prenylated oxindoles launched by Ni catalysis with bulk chemical isoprene. Using C3-unsubstituted oxindoles as starting materials, mono reverse-prenylation was demonstrated in high chemo- and regioselectivities facilitated by the combination of Ni(0) and monodentate phosphine ligand. Using the obtained reverse-prenylated oxindoles as versatile synthon, substitutions at the pseudobenzylic position with various electrophiles created vicinal quaternary centers in a concise way. With the help of additives (PPh₃ and NaH), air could be directly used as green oxidant to construct prenylated and reverse-prenylated α-hydroxy-oxindoles divergently from the same substrates. In situ esterification of prenylated α-hydroxy-oxindoles allowed subsequent Friedel-Crafts substitutions with diverse nucleophiles to deliver prenyl substituted dimeric or spiro-oxindoles. This protocol provides a divergent synthetic approach for the construction of highly functionalized 3,3-disubstituted oxindoles, which have been otherwise difficult to access in a unified approach.

Key words: Nickel catalysis, Unified construction, Isoprene, (Reverse-)prenylation, Oxindole