Tuned C-H functionalization to construct aza-podophyllotoxin/aza-conidendrin derivatives by means of domino cyclization.

An efficient domino cyclization method for the construction of aza-podophyllotoxin/aza-conidendrin derivatives has been established. Reactions of different dienes with aryl halides in the presence of a palladium catalytic system produced different kinds of podophyllotoxin derivatives through a highly regioselective C-H functionalization. Treatment of dienes with aryl halides that have electron-withdrawing substituents on the phenyl ring created aza-podophyllotoxin derivatives by means of the functionalization of the C-H bonds ortho to the C-halide bonds of the incoming aryl halides. The reaction of dienes with 1-iodobenzene or aryl halides that incorporate electron-donating groups produced aza-conidendrin derivatives by means of the functionalization of both sp(3) C-H and sp(2) C-H bonds. The regioselective C-H functionalization for the formation of different pseudo-podophyllotoxin/-conidendrin derivatives is proven by analyses of the (1)H NMR spectra of the products and selective X-ray analyses of the structures of the products. Thus, the palladium-catalyzed domino cyclization of 1,6-dienes for the preparation of aza-podophyllotoxin/aza-conidendrin derivatives can be controlled by selectively controlling the C-H functionalization.