The Application of the Titanium-Catalyzed Hydroamination of Alkynes toward the Synthesis of Benzylisoquinoline Derivatives

Abstract

The enantioselective synthesis of (+)-(S)-laudanosine (101) and (–)-(S)-xylopinine (102) were achieved successfully in 7 steps from commercially available homoveratylamine (86) in 62% and 51% yield, respectively. The key intermediate aminoalkyne 123 was accessed easily by coupling aryl iodide 115 and alkyne 121 using a Sonogashira reaction. Dihydroisoquinoline 124 was obtained by intramolecular hydroamination of the aminoalkyne 123. Employing Noyori´s reduction protocol, the absolute configuration at C-1 of the benzylisoquinoline was introduced with 93% ee. Finally, methylation of norlaudanosine (146) by a reductive amination protocol afforded (+)-(S)-laudanosine (101). Alternatively, formation of the berberin-bridge using a Pictet-Spengler reaction afforded (–)-(S)-xylopinine (102). The strategy was also applied to synthesize benzylisoquinolines with electron-deficient A-rings. 5-Trifluoromethyl-benzylisoquinoline (174) was successfully synthesized in 8 steps from commercially available 4-bromo-trifluorotoluene (162) in 20% yield. Both Sonogashira reaction and hydroamination gave the desired products in excellent yields. Moreover, 6,7-difluoro-benzylisoquinoline (182), was synthesized following a similar route from commercially available o-bromo-benzoic acid (175) in 19% yield for the seven steps.