The isoquinoline ring is a widely abundant motif present both in Nature and in a large number of pharmaceutical drugs. Tetrahydroisoquinoline alkaloids form a very broad group of important biologically active compounds containing the common isoquinoline ring moiety, and are traditionally accessed through Pictet-Spengler or Bischler-Napieralski reactions. Due to the common electrophillic aromatic substitution step, the synthesis of these is largely limited to activated analogues, bearing electron-donating groups on the ring. Fast and efficient intramolecular acid catalysed cyclisation of 2-alkenylarylethylamines allows accessing tetrahydroisoquinoline derivatives via generation of benzylic carbenium ion from a double bond or a departing �OH group, followed by ring closure in a 5-endo-trig hydroamination reaction in good to excellent yields. The scope of the reaction was probed and the chemistry was applied to synthesis of various tetrahydroisoquinoline alkaloids, natural products, as well as aporphine and berberine skeleton, and serves as an alternative and potentially more flexible strategy to the classical Pictet-Spengler reaction utilised for syntheses of such heterocycles.

Acid catalysed hydroaminations in the synthesis of tetrahydroisoquinoline, aporphine, and berberine skeletons

248th National Meeting (2014)

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