Comparative Study of the Kumada, Negishi, Stille, and Suzuki−Miyaura Reactions in the Synthesis of the Indole Alkaloids Hippadine and Pratosine

The total synthesis of hippadine by a tandem metalation/cross-coupling/lactamization strategy was investigated starting from either 7-bromoindole or a 6-halogenated methyl piperonate. The Kumada and Negishi cross-coupling reactions failed to provide any of the desired product. However, the Stille and Suzuki reactions furnished hippadine in low yields starting from the electron-deficient methyl 6-iodo- and 6-bromopiperonate, respectively. Starting from the metalated indole, only the Suzuki reaction occurred, affording hippadine in 67−74% and pratosine in 62% isolated yield.