PICTET-SPENGLER REACTION FOR THE SYNTHESIS OF TETRAHYDROISOQUINOLINES AND RELATED HETEROCYCLIC COMPOUNDS

PURPOSE: A commercial scale process for the production of tetrahydroisoquinolines and related heterocyclics by reaction, in mildly acidic conditions, of aryl N-sulfonylethylamines in the presence of suitable Lewis acid, and a compound capable of in situ generation of formaldehyde is provided. CONSTITUTION: A process creates a compound of the formula(I), wherein R1 and R2 are each independently C1-3 alkyl or R1 and R2 together form C2-7 alkylene, n is an integar from 0-2, R3 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, -CF3, -OCF3 and -OH, and Ts is para-toluenesulfonyl, by reacting under alkaline conditions a compound of the formula(II) with a suitable Lewis acid in a formaldehyde generating solvent. The process is characterized by formaldehyde being generated by the reaction of the Lewis acid upon the formaldehyde generating agent, instead of being present as an initial reactant. These process further avoids the presence of initial water which destroys the Lewis acid before it can act upon the formaldehyde generating agent.