Access to spirocyclic vinyl sulfones via radical cyclization and functional group migration

Abstract

Spirocyclic vinyl sulfones, which incorporate the three-dimensional structure inherent to spiro compounds and the Michael acceptor reactivity associated with vinyl sulfones, hold promise for novel biological activities. The lack of efficient synthetic methods, however, hinders their extensive investigations in drug discovery and development. In this work, we describe a practical and versatile approach for the synthesis of multi-functionalized spirocyclic vinyl sulfones from easily available materials. The reaction proceeds efficiently through a cascade of radical cyclization followed by (hetero)aryl migration. The protocol features mild photocatalytic conditions and provides access to a diverse range of products, enabling the construction of complex scaffolds, including medium-sized ring-fused spirocyclic vinyl sulfones.

Scheme 1. Importance and practical synthesis of spirocyclic vinyl sulfones.

Scheme 2. Demonstration of broad functional group compatibility. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Na₂HPO₄ (0.2 mmol), and fac-Ir(ppy)₃ (3 mol%) in DCM/H₂O (v/v 2 mL/0.2 mL), irradiated with 12 W blue LEDs at room temperature under N₂. Yields of isolated products are given.

Scheme 3. Construction of complex ring-fused spirocyclic vinyl sulfones. Reaction conditions: 4 (0.2 mmol), 2 (0.3 mmol), Na₂HPO₄ (0.2 mmol), and fac-Ir(ppy)₃ (3 mol%) in DCM/H₂O (v/v 2 mL/0.2 mL), irradiated with 12 W blue LEDs at room temperature under N₂. Yields of isolated products are given.

Scheme 4. Gram-scale preparation, mechanistic studies and proposed mechanism.