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

Abstract

Abstractβ‐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.