Tropylium-Promoted Oxidative Functionalization of Tetrahydroisoquinolines

Abstract

Structural modification of the tetrahydroisoquinoline (THIQ) framework is of significant interest to organic chemists due to its central role in heterocyclic and medicinal chemistry. Here we demonstrate an efficient metal-free method for the oxidative functionalization of THIQs at the C1 position, which is amenable to a diverse range of C-C coupling reactions. These reactions proceed through a hydride abstraction involving the tropylium ion followed by quenching the generated iminium intermediates with nucleophiles to afford THIQ derivatives with excellent efficiencies and interesting selectivities.

Toward Rational Understandings of α-C–H Functionalization: Energetic Studies of Representative Tertiary Amines

“…This also explains the need of a longer reaction time (2h) reported for N-Cbz-THIQ (Yan et al, 2015) and the loss of its reactivity with a weaker oxidant, tropylium (T + ,-DH H -A = 85 kcal mol À1 ) (Oss et al, 2018). It was also found that only the more reactive N-alkyl-THIQs (DH H -D : 72-76 kcal mol À1 ) could be oxidized by T + (Oss et al, 2018). These examples demonstrated that the energetic data here derived can actually well rationalize the previously observed reactivity trend in the oxidation of various THIQs by different oxidants as represented in Scheme 2A and 2B.…”

“…Indeed, strong oxidants with -DH H -A values greater than 100 kcal mol À1 (e.g., DDQ, Ph 3 C + , AcNH-TEMPO + ) were experimentally observed to be capable of splitting the a-C-H bonds of all N-alkyl/aryl-THIQs in a few minutes at room temperature (de Costa et al, 1992;Tsang et al, 2017). This also explains the need of a longer reaction time (2h) reported for N-Cbz-THIQ (Yan et al, 2015) and the loss of its reactivity with a weaker oxidant, tropylium (T + ,-DH H -A = 85 kcal mol À1 ) (Oss et al, 2018). It was also found that only the more reactive N-alkyl-THIQs (DH H -D : 72-76 kcal mol À1 ) could be oxidized by T + (Oss et al, 2018).…”

“…Moreover, Scheme 2C shows an example of a varying mechanism for two similar Cu-catalyzed CDCs, that is, an electron-hydrogen transfer (ET-HT) is followed with the CuCl 2 /O 2 pair, whereas a hydrogen-electron transfer (HT-ET) is favored with a CuBr/tBuOOH pair. Although the relevance of a-C-H bond cleavage in affecting the reaction pattern and outcomes was well demonstrated (Oss et al, 2018;Zhang et al, 2012), till now, no practical guideline could be found in literature for reasonably elucidating these puzzling observations exemplified. This actually points out a keen demand for a rational understanding of the diversified CDC reactivity and mechanisms.…”

Transition-Metal-Free Strategies for the Synthesis of C-1 Aryl-Substituted Tetrahydroisoquinolines

“…Template for SYNTHESIS © Thieme Stuttgart • New York 2020-12-09 page 4 of 14 Another effective methodology for oxidative functionalization of THIQs on the C-1 position under metal-free conditions was explored by Nguyen and co-workers. 30 This method presented the use of tropylium-ion as an oxidant for the coupling of THIQs with Grignard reagents and organozinc species as nucleophiles (Scheme 7). However, for arylation, the reactions with aryl Grignard reagents were attempted only in acetonitrile at reflux for 3 h to afford the corresponding products in moderate to good yield.…”

“…Another effective methodology for the oxidative functionalization of THIQs at the C-1 position under metal-free conditions was explored by Nguyen and co-workers. 30 This method presented the use of a tropylium ion as an oxidant for the coupling of THIQs with Grignard reagents or Scheme 5 Substrate scope of THIQs under oxidative conditions with Grignard reagents…”