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

• Published in: Angewandte Chemie International Edition 2022-01, Vol.61 (3), p.e202114235-n/a
• Main Authors: Tyler, Jasper L., Noble, Adam, Aggarwal, Varinder K.
• Format: Article
• Language: English
• Subjects: azabicylo[1.1.0]butanes; azetidines; dearomatization; spiro compounds; strained molecules
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202114235

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. The exploitation of the inherent strain energy of azabicyclo[1.1.0]butane for the Friedel–Crafts inspired synthesis of a unique library of azetidine‐containing spirocycles is described. The observed dearomatized intermediate of this reaction can be converted to the Friedel–Crafts product upon electrophilic activation or trapped as the Diels–Alder adduct to generate complex sp3‐rich architectures.