Synthesis of 1,4-Disubstituted and 1-Substituted β-Carbolines via 3-Substituted 2-Acylindoles

Abstract

β-Carbolines represent a large class of bioactive natural products, whereby most of these alkaloids bear residues at C1, and occasionally at C3, and only limited examples of 1,4-disubstituted β-carbolines are known. In this project we worked out a novel approach to 1,4-disubstituted β-carbolines and performed a comprehensive analysis of the scope and limitations of this methodology. The 1,4-disubstituted β-carbolines were synthesized via 3-substituted 2-acylindoles, for which effective synthesis procedures were developed. Our studies revealed that a broad range of target compounds with electron-withdrawing substituents at C4 are accessible. Limitations of this method arose from competing CH and NH acidities of precursors. Nevertheless, the work described herein provides a unique approach to highly substituted β-carbolines. In addition, intermediates from this route opened a novel approach to 1-substituted β-carbolines utilizing a chemoselective Mo(CO)6-catalyzed amide reduction with tetramethyldisiloxane.