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Abstract

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 ZnCl2 in THF, whereas aromatic imines give the best results in the presence of EtAlCl2 in CH2Cl2. The best results for the Heck-type cyclizations are obtained either under heterogeneous conditions in the presence of K2CO3/NEt4Cl at 120 degrees C in DMF or in refluxing toluene or under homogeneous conditions at 100 degrees 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.