Synthesis of Medium-Ring N-Heterocycles

  • Author: Angewandte Chemie International Edition
  • Published Date: 16 August 2016
  • Source / Publisher: Angewandte Chemie International Edition/Wiley-VCH
  • Copyright: Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
thumbnail image: Synthesis of Medium-Ring N-Heterocycles

More than 80 % of approved drug molecules contain a nitrogen heterocycle within their structure. Almost all of these are easy-to-make 5–7 membered rings. Although medium-ring nitrogen heterocycles (containing 8–12 members) are present in biologically active natural products, they are absent from medicinally important structures. This is principally due to the difficulties associated with their synthesis. Common cyclization methods are notoriously inefficient and the most common methods employ expensive metal catalysts, thus limiting their industrial use.

Jonathan Clayden, University of Bristol, UK, and colleagues have developed a simple and efficient method for the construction of medium-ring benzo-fused nitrogen heterocycles by using a migratory ring expansion. Benzylic urea derivatives of benzo-fused nitrogen heterocycles undergo this expansion after deprotonation with lithium diisopropylamide (LDA) in the presence of N,N'-dimethylpropylideneurea (DMPU). The reaction allows the synthesis of an array of medium-ring structures in moderate to excellent yields (49–90 %), with excellent enantio- and diastereoselectivity.

This method can be scaled up to synthetically useful levels and allows rapid access to some complex molecular architectures. The ability to make medium rings simply and efficiently could facilitate the investigation of medicinal chemistry of this unexplored region of chemical space.


Article Views: 3938

Sign in Area

Please sign in below

Additional Sign In options

Please note that to comment on an article you must be registered and logged in.
Registration is for free, you may already be registered to receive, e.g., the newsletter. When you register on this website, please ensure you view our terms and conditions. All comments are subject to moderation.

Article Comments - To add a comment please sign in

If you would like to reuse any content, in print or online, from, please contact us first for permission and consult our permission guidance prior to making your request

Follow on Facebook Follow on Twitter Follow on YouTube Follow on LinkedIn Follow on Instagram RSS Sign up for newsletters

Magazine of Chemistry Europe (16 European Chemical Societies) published by Wiley-VCH