Gold Catalyzed Photoredox C1‐Alkynylation of N‐Alkyl‐1,2,3,4‐tetrahydroisoquinolines by 1‐Bromoalkynes with UVA LED Light

Abstract

A synthetic method that combines [Au 2 (m-dppm) 2 ]Cl 2 (dppm = bis(diphenylphosphanyl)methane) and UVA LED (LED = light emitting diode) light (365 nm) to catalyze the regioselective C1-alkynylation of N-alkyl-1,2,3,4-tetrahydroisoquinolines (THIQs) with alkynyl bromides is described. The reaction mechanism was delineated to involve a reductive quench pathway to generate the two posited radical species of the nitrogen-containing heterocycle and organic halide. In contrast, radical formation via an oxidative quench pathway was suggested to be operative in analogous control experiments with a 1-iodoalkyne. The usefulness of this carbon-carbon bond forming strategy was also exemplified by its application to the formal synthesis of the opioid analgesic drug methopholine and synthesis of a protoberberine alkaloid derivative.

Recent Advances in Gold(III) Chemistry: Structure, Bonding, Reactivity, and Role in Homogeneous Catalysis

“…453 This contrasts with the coupling of tetrahydroisoquinolines and 1-bromoalkynes in the presence of [Au 2 (μdppm) 2 ]Cl 2 under UVA LED light irradiation, for which a lowoxidation state radical quench pathway was proposed. 454 The gold catalyzed Heck-coupling reactions of arenediazonium o-benzenedisulfonimides was described in 2018 by Barbero and Dughera. 455 Although originally conceived as photochemically assisted catalysis with [Ru(bipy) 3 ] 2+ as photosensitizer, it became evident that these reactions proceeded very well in the dark, without sensitizers, using Ph 3 PAuCl in a variety of solvents of different polarity (toluene, THF, and MeCN).…”

“…The oxidative addition of 1-bromoalkynes has been used to couple alkynes with allenoates for the synthesis of β-alkynyl-γ-butenolides (Scheme ), most probably via Au­(III) alkynyl intermediates 268 followed by reductive C­(sp)-C­(sp) coupling . This contrasts with the coupling of tetrahydroisoquinolines and 1-bromoalkynes in the presence of [Au 2 (μ-dppm) 2 ]­Cl 2 under UVA LED light irradiation, for which a low-oxidation state radical quench pathway was proposed …”

Alkynylation of radicals: spotlight on the “Third Way” to transfer triple bonds

“…Finally, radical coupling (eqn (2)) between the α-amino radical (long lifetime) and the alkynyl radical (short lifetime) is envisioned. In 2019, Chan and coworkers reported the alkynylation of THQs derivatives using alkynylbromides and the same gold catalyst as reported by Hashmi 59…”

Light in Gold Catalysis

“…The group of Chan developed the regioselective C1-alkynylation of N -alkyl-1,2,3,4-tetrahydroisoquinolines (THIQs, 328 ) by bromoalkynes ( 329 ) by employing the dinuclear gold­(I) complex and UV-light irradiation (Scheme ). A series of alkynylated THIQs 330 were obtained in a good functional group tolerance, with yields ranging from 19 to 89%. In general, electron-rich substitutions on both alkyne and THIQs were significantly more compatible than electron-poor.…”