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Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
Strain-Release-Driven Friedel-Crafts Spirocyclization of Azabicyclo[1.1.0]butanes
Jasper L Tyler1, Adam Noble1, Varinder K Aggarwal1
1School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK.
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.
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