Three-Step Access to the Tricyclic Benzo[a]quinolizine Ring System

Access to the tricyclic benzo[ a ]quinolizine ring system, which forms the characteristic framework of alkaloids of the berberine and emetine type, is readily obtained by a three-step reaction sequence. This sequence includes the formation of a Schiff base, derived from a 2-bromo-substituted phenylethylamine, and its tandem Mannich/conjugate addition reaction with an electron-rich silyloxy diene forming an intermediate enaminone, which subsequently undergoes a Heck-type cyclization. Highest yields of the tandem Mannich/conjugate addition for aromatic Schiff bases and formaldehyde imines are observed in the presence of ZnCl 2 in THF, whereas aromatic imines give the best results in the presence of EtAlCl 2 in CH 2 Cl 2 . The best results for the Heck-type cyclizations are obtained either under heterogeneous conditions in the presence of K 2 CO 3 /NEt 4 Cl at 120 °C in DMF or in refluxing toluene or under homogeneous conditions at 100 °C in DMF in the presence of NEt( i -Pr) 2 . Depending on the substitution pattern of the diene and the steric demand of the base employed in the Heck cyclization, benzo[ a ]quinolizines carrying a double bond in the 11b,1- or 3,4-position or in an exocyclic position are obtained with fair to good results. A mechanistic rationale for this behavior is proposed. If chiral amines, e.g., derived from an amino acid ester, are employed in the three-step reaction sequence, chiral tricyclic benzo[ a ]quinolizines become accessible in a straightforward manner.