Related Experiment Video
Updated: Jun 7, 2025

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species
Published on: August 16, 2018
C1 Functionalization of β-Carboline via Knochel-Hauser Base-Directed Metalation and Negishi Coupling
Jin Tan1, Kyle Clagg1, Haiming Zhang1
1Department of Synthetic Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Abstract:
The synthesis of C1-functionalized β-carbolines from N-Boc norharman is described. Substitution is realized by employing the Knochel-Hauser base (TMPMgCl·LiCl) followed by transmetalation with ZnCl2 and subsequent Negishi cross-coupling of the resulting organozinc species. A variety of aryl or heteroaryl bromides participated in this one-pot reaction sequence, allowing for rapid diversification of the β-carboline scaffold in moderate to excellent yields. The reaction protocol has been applied to the synthesis of natural alkaloids nitramarine, nitraridine, eudistomin U, and perlolyrine.
Related Concept Videos
Conjugate Addition to α,β-Unsaturated Carbonyl Compounds
Conjugate Addition (1,4-Addition) vs Direct Addition (1,2-Addition)
Conjugate addition results in a thermodynamically stable product. The reaction retains the stronger C=O bond at the expense of the weaker C=C π bond. The process is slow as the β carbon is less electrophilic than the carbonyl carbon.
Direct addition products are...
Conjugate Addition of Enolates: Michael Addition
α-Alkylation of Ketones via Enolate Ions
Reactions of α-Halocarbonyl Compounds: Nucleophilic Substitution
Aldol Condensation with β-Diesters: Knoevenagel Condensation

