One-Pot Synthesis of Tetrahydroisoquinolines via Benzene Ring Annulation

Abstract

While most of the classical ways for the preparation of tetrahydroisoquinolines have involved heteroannulation approaches (e.g. Pictet-Spengler reaction, see first Review), the present work reports an unusual one-pot three-component strategy involving benzene ring annulation to afford polyfunctionalized tetrahydroisoquinolines 4. The three-component, one-pot reaction of commercially available piperidin-4-ones 1 as heterocyclic precursor, malononitrile (2), β-nitrostyr­enes 3, and morpholine as base were found to be the optimal conditions to obtain products 4 in 60-78% yields. The reaction is believed to proceed through a domino mechanism, bringing into play three named reactions: 1) Knoevenagel reaction between 1 and 2; 2) Michael addition to 3; 3) Thorpe-Ziegler cyclization-tautomerization followed by aromatization under air atmosphere. The structure of 4 was confirmed by single crystal X-ray crystallographic analysis. This reaction was applied to the synthesis of carbocycles 6 in high yields starting from cyclic ketones 5.