Modified Pomeranz–Fritsch Reaction for the Synthesis of 1,2-Dihydroisoquinolines

Significance

The 1,2-dihydroisoquinoline heterocyclic system is an important scaffold in natural products and is present in intermediates for the synthesis of therapeutic agents such as anti-HIV agents, anticancer agents, and topoisomerase I inhibitors. Modern methods for preparing this skeleton include a transition-metal-catalyzed 6-endo-dig cyclization of alkynylarylimines (Urvashi, G. K. Rastogi, S. K. Ginotra, A. Agarwal, V. Tandon Org. Biomol. Chem. 2015, 13, 1000). The present work reports an expansion of the classical Pomeranz–Fritsch reaction that tolerates acid-sensitive substrates and heterocyclic derivatives such as 2a and 2b. Furthermore, the synthetic utility of this protocol was demonstrated by the syntheses of (±)-salsolidine and nigelimine.

Comment

Reported is a synthesis of 1,2-dihydroisoquinolines 2 by the cyclization of benzyl­amino acetals 1 in the presence of silyl triflate and a sterically hindered amine base. Carbamate 3 was formed when triflate was substituted for a more Lewis basic group, such as Boc or Cbz. The reaction scope follows the trend of electrophilic aromatic substitution, as evidenced by the fact that substrates 1 with EDGs on the benzylamine group furnished the corresponding products in good yields. Furthermore, heterocyclic analogues such as thiophene and indole derivatives were prepared efficiently. C1-substituted products 2 were also prepared, although it was necessary to replace the bulky aliphatic amine with a nonreducing amine base, such as 2,6-lutidine. Reductive and oxidative transformations of products 2 as intermediates afforded isoquinoline and tetrahydroisoquinoline scaffolds.