The Mannich reaction of tetrahydroisoquinolines (IVa, b) with 36% formalin in acetic acid gave respectively protoberberines (Va, b) and each compounds were converted to tetramethoxyprotoberberines (Ic, d). Ic was identified by the infrared and nuclear magnetic resonance spectral comparisons with caseadine methyl ether derived from natural caseamine or caseadine. Hydrochloric acid catalyzed condensation of 7, 8-disubstituted tetrahydroisoquinoline (VIII) with 36% formalin gave the same compound (Ic).