Strain‐Release‐Driven Friedel‐Crafts Spirocyclization of Azabicyclo[1.1.0]butanes

Jasper L. Tyler, Adam Noble, Varinder Kumar Aggarwal*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

11 Citations (Scopus)
111 Downloads (Pure)

Abstract

The identification of spiro N-heterocycles as scaffolds that display structural novelty, three-dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain-release-driven Friedel-Crafts spirocyclization of azabicyclo[1.1.0]butane-tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro-tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.
Original languageEnglish
Article numbere202114235
Number of pages7
JournalAngewandte Chemie - International Edition
Volume61
Issue number3
Early online date15 Nov 2021
DOIs
Publication statusPublished - 17 Jan 2022

Bibliographical note

Funding Information:
J.T. thanks the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. We thank Natalie E. Pridmore for X‐ray analysis.

Publisher Copyright:
© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH

Structured keywords

  • BCS and TECS CDTs

Keywords

  • azabicylo[1.1.0]butanes
  • azetidines
  • dearomatization
  • spiro compounds
  • strained molecules

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