Scalable Synthesis of (R,R)-N,N-Dibenzyl-2-fluorocyclohexan-1-amine with CsF under Hydrogen Bonding Phase-Transfer Catalysis

Abstract

Hydrogen bonding phase-transfer catalysis offers a convenient solution to activate safe and economical metal alkali fluorides for enantioselective nucleophilic fluorination. Herein, we demonstrate the scalability of this protocol with the fluorination of 200 g of racemic trans-N,N-dibenzyl-2-bromocyclohexan-1-amine in a mechanically stirred 1 L glass reactor using 0.5 mol % of a bis-urea organocatalyst. In these experiments, full conversions were obtained for high mixing intensities (impeller average shear rate >10 000 s–1; maximum energy dissipation per unit of mass >300 W/kg). The thermal safety of the reaction was assessed by differential scanning calorimetry and reaction calorimetry, assigning the reaction to Stoessel’s critical class 3.