Electrocatalytic C(sp3)–H/C(sp)–H cross-coupling in continuous flow through TEMPO/copper relay catalysis

Electrocatalytic dehydrogenative C(sp3)–H/C(sp)–H cross-coupling of tetrahydroisoquinolines with terminal alkynes has been achieved in a continuous-flow microreactor through 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)/copper relay catalysis. The reaction is easily scalable and requires low concentration of supporting electrolyte and no external chemical oxidants or ligands, providing straightforward and sustainable access to 2-functionalized tetrahydroisoquinolines.


Introduction
The dehydrogenative cross-coupling of two C-H bonds represents an ideal strategy for the construction of C-C bonds [1,2]. In this context, few methods have been developed for the dehydrogenative cross-coupling of tetrahydroisoquinolines with terminal alkynes because of the prevalence of the tetrahydroisoquinoline moiety in natural products and bioactive molecules [3][4][5][6][7][8][9][10]. These methods proceed through the oxidation of the tetrahydroisoquinoline to an iminium intermediate with various chemical oxidants such as peroxides and DDQ followed by reaction with the copper acetylide species to deliver the 2-substituted tetrahydroisoquinoline product (Scheme 1A). These methods usually require elevated temperatures [3][4][5], prompting the development of mild conditions by merging photoredox catalysis with copper catalysis (Scheme 1B) [8,9]. Notwithstanding of these outstanding achievements, noble metal-based catalysts and chemical oxidants are employed under these photochemical conditions.
The continuous-flow electrosynthesis is easily scaled up by passing more material through the reactor [43,49]. Hence, repeating the reaction under flow conditions, with a solution containing 0.98 g of tetrahydroisoquinoline 1a and 1.11 g of alkyne 22 afforded 1.05 g (61%) of product 14 in 13 h (Scheme 3). The productivity could be increased if multiple reactors were employed in parallel [43].
A mechanism for the electrochemical synthesis was proposed based on reported studies (Scheme 4) [3,10]. Anodic oxidation of TEMPO generates the oxoammonium salt TEMPO + [50,51], which reacts with tetrahydroisoquinoline 23 to generate TEMPOH and iminium ion 24 [52], TEMPOH is oxidized back to TEMPO + on the anode. On the other hand, 24 is converted to the final product 25 through reaction with copper acetylide 26, which is generated from Cu I and the alkyne 27 with the assistance of CF 3 CH 2 O − . The added Cu II precatalyst is likely reduced at the cathode to produce the requisite Cu I . The base CF 3 CH 2 O − is produced through cathodic reduction of TFE. The addition of TFE to the reactions helps cathodic H 2 evolution and may also stabilize the iminium ion through reversible reaction with this cationic species.

Conclusion
In summary, we have achieved the electrochemical dehydrogenation cross-coupling of tetrahydroisoquinolines with terminal alkynes in continuous flow through Cu/TEMPO relay catalysis. This work demonstrates that continuous-flow electrochemical microreactors can be a viable tool for developing efficient transition-metal electrocatalysis.

Supporting Information
Supporting Information File 1 General procedure, characterization data for electrolysis products and NMR spectra.

Funding
Financial support of this research from NSFC (21971213) and the Fundamental Research Funds for the Central Universities is acknowledged.