Synthesis of Tetrahydroisoquinoline Alkaloids via Anodic Cyanation as the Key Step

Abstract

We report a new route to tetrahydroisoquinoline (THIQ) alkaloids involving the alkylation of alpha-aminonitrile 2 as a key step. The latter compound was prepared by anodic cyanation of the corresponding tertiary amine 1. Reductive decyanation of alpha-aminonitriles 6a-c proceeded diastereoselectively (up to 95% de) to deliver the C1-substituted alkaloids precursors 9a-c. The syntheses of (+/-)-carnegine, (+/-)-norlaudanosine, and (+/-)-O,O-dimethylcoclaurine have been achieved.

Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance

“…Hurvois and co-workers prepared a series of tetrahydroisoquinoline alkaloids through the electrochemical cyanation of tetrahydroisoquinoline derivatives (e.g., crispine A, Figure 11C). 172,173 The reaction was shown to proceed with good stereoselectivity in the presence of a chiral auxiliary. The same group capitalized on similar transformations to synthesize pumiliotoxin C. 174 Kam showcased that kopsine, kopsidine, kopsinitrarine, and bisindole derivatives can be obtained through the anodic Shono-type oxidation of aspidofractinine-type alkaloids (Figure 11D).…”

Controlling One- or Two-Electron Oxidation for Selective Amine Functionalization by Alternating Current Frequency

“…Under DC electrolysis, formation of cyanation product was predominantly observed in good yield 36-63% because the benzylic position is prone to overoxidation to form iminium cation. [28][29][30] Under AC electrolysis, arylation product formation significantly improved to good/moderate yields of 26-51%. However, the cyanation product yields were comparable to the DC electrolysis results, even though the CV data in Figures S27-34 predicts that the two-electron oxidation of N-aryl tetrahydroisoquinolines should be largely reduced at fexp, like the N-aryl pyrrolidine oxidation.…”

“…We have also identified the tertiary amine-containing heteroaromatic rings as a suitable class of substrates (28)(29)(30)(31). Various N-benzyl/alkyl thienopyridines containing susceptible functional groups such as ester and allyl were tested.…”

DDQ-Promoted Mild and Efficient Metal-Free Oxidative α-Cyanation of N-Acyl/Sulfonyl 1,2,3,4-Tetrahydroisoquinolines

“…In recent years, several methods for the direct α-cyanation of N -protected THIQs have been developed. Most notable methods involve using a transition metal or metal-free oxidants for the α-cyanation of N -aryl THIQs via the direct C(sp 3 )-H functionalization (Scheme 1, Equation (1)) [16,17,18,19,20,21,22,23,24,25]. However, the removal of aryl-protecting groups from the nitrogen in the presence of other functional groups proves to be problematic, which limits the synthetic utility of these approaches.…”

“…For instance, the removal of a phenyl group from amines required conditions that are only tolerated by a small set of organic compounds (100 equivalent of Li/NH 3 /THF/−40 °C) [26,27,28]. An electrochemical method [16,21] or visible-light photoredox catalysis [18,19,20,23,25] was also developed (Scheme 1, Equation (2)). However, these methods also need specific instrumentation or a catalytic system that is not readily available for general synthetic organic chemistry.…”