*2.1. C-H Functionalization*

Asymmetric C–H functionalization of α-positions in carbonyl compounds through enamine intermediates is a well-explored topic in organocatalysis, often employing proline-derived catalysts [26]. In an electrochemical setting, Jang and co-workers reported on α-oxyamination of aldehydes in the presence of the prolinol derivative (S)-<sup>α</sup>,<sup>α</sup>-diphenyl-2-pyrrolidine methanol trimethylsilyl ether in catalytic amounts using platinum electrodes under constant current in an undivided cell (Scheme 1a) [27]. Supported by control experiments and CV, the authors suggested that the reaction proceeds via single-electron oxidation of the intermediate enamine, formed by dehydrative condensation between the substrate and pyrrolidine catalyst. The resulting cation radicals were trapped by TEMPO to form the oxyaminated products in 60–70% *ee*, in accordance with the design principle in Figure 2a. As such, this study was the first to demonstrate that anodic oxidation could be used to promote

enamine-mediated organocatalytic reactions via cationic radical enamine intermediates. A similar strategy was used by the same group for α-alkylation of aldehydes with xanthene using chiral pyrrolidine catalysts in an undivided cell with platinum electrodes under constant current conditions (Scheme 1b) [28]. Supported by CV analysis and control experiments, the mechanism was proposed to proceed via single-electron oxidation of both the enamine and the xanthene, followed by radical coupling to a fford the product in up to 74% yield and 70% *ee* (Figure 2a). However, as homocoupled products were not observed, a mechanism in accordance with the design principle of Figure 2b proceeding via enamine attack of an electrochemically formed xanthene cation could not be excluded. This alternative activation mode was proposed by Jørgensen and co-workers for α-arylation of aldehydes with N-tosyl *p*-anisidine to form enantioenriched alcohols with *ee*'s up to 96% using (S)- <sup>α</sup>,<sup>α</sup>-diphenyl-2-pyrrolidine methanol trimethylsilyl ether as catalyst (10 mol%) in an undivided cell with carbon anode and platinum cathode under constant current conditions (Scheme 1c) [29]. The authors suggested that electrochemical oxidation of the phenolic compound results in an electrophilic intermediate that is attacked by the chiral enamine, formed from the catalyst and the aldehyde substrate. Following the mechanistic rationale of traditional enamine catalysis, the resulting iminium ion is hydrolyzed to release the catalyst, which enters a new cycle, whereas the product would rearomatize and eventually cyclize to the corresponding dihydrobenzofuran.

Building on this initial work [27–29], Luo and co-workers utilized the enamine strategy for electrooxidative coupling of tertiary amines with ketones using a chiral diamine catalyst to obtain enantioenriched alkylated tetrahydroisoquinolines, using a graphite anode and Pt cathode in an undivided cell at constant potential (Scheme 2) [30]. No reaction was observed in the absence of either catalyst or current, and under optimized conditions the reaction proceeded with good to excellent enantioselectivities (up to 95% *ee*) and good yields for several N-arylated tetrahydroisoquinolines and ketones. The transformation was proposed to proceed via anodic oxidation of the benzylic position in the N-aryl tetrahydroisoquinoline substrate to form an intermediate iminium ion (Scheme 2), in accordance with the design principle in Figure 2b. Subsequent attack by the chiral enamine, formed by dehydrative condensation of the catalyst and ketone substrate, results in the enantioenriched product in high yields and *ee*'s after hydrolysis with release of the catalyst. The presence of a protonic additive (CF3CH2OH) was found to facilitate the C–C bond formation, supposedly by capturing the iminium ion as a more stable hemiaminal intermediate. The proposed mechanism was supported by control experiments, where pre-oxidation of the tetrahydroisoquinoline substrate to the corresponding iminium ion and subsequent addition of catalyst/TfOH and ketone gave close to identical results compared to standard conditions. Furthermore, electroanalytic studies confirmed that preferential oxidation of the tetrahydroisoquinoline occurred in the reaction mixture.

The use of TEMPO and analogous N-oxide compounds as redox mediators in electrochemical oxidation of organic substrates is well-established. In several examples, chiral N-oxide derivatives were developed and a fforded asymmetric electrochemical transformations such as the oxidative kinetic resolution of secondary alcohols and amines [31–39]. Similarly, asymmetric Cu-catalysis under electrooxidative conditions has been reported for kinetic resolution of 1, 2 diols, aminoalcohols and aminoaldehydes [40]. Mei and co-workers reported on a co-catalytic Cu/TEMPO system for oxidative substitution of N-aryl and N-carbamate tetrahydroisoquinolines with terminal alkynes [41]. The use of TEMPO as redox mediator (20 mol%) and a CuII-species (10 mol%) with a chiral bisoxazoline ligand enabled good yields and up to 98% *ee* of the C1-alkynylated products under constant current conditions in an undivided cell using Pt electrodes (Scheme 3). The broad substrate scope demonstrated good functional group tolerance of the process and control experiments indicated that each reaction component was necessary for converting starting material into product. Based on CV measurements, the authors proposed that TEMPO acts as a redox mediator for Shono oxidation [42] of the tetrahydroisoquinoline to form the corresponding iminium species in benzylic position. Addition of the chiral copper acetylide, supposedly formed in situ from the Cu<sup>I</sup> catalyst and the alkyne in the presence of base, results in the enantioenriched product. As such, the authors propose a mechanism

following the general principles of Figures 1b and 2b, although alternative cooperative mechanisms involving both Cu and TEMPO were not ruled out. The active Cu<sup>I</sup> was suggested to form by interaction of CuII with the reduced TEMPO mediator (TEMPO-H) or by cathodic reduction. A kinetic isotope effect study for the benzylic α-hydrogens of the tetrahydroisoquinoline indicated C–H cleavage is not rate-determining in the process.

**Scheme 1.** (**a**) electrochemical organocatalytic α-oxyamination of aldehydes; (**b**) electrochemical organocatalytic α-alkylation of aldehydes; (**c**) electrochemical organocatalytic α-arylation of aldehydes.

**Figure 2.** Two design principles for α-functionalization of carbonyl compounds in electrooxidative enamine catalysis: (**a**) electrogenerated SOMOphile; (**b**) electrogenerated electrophile.

**Scheme 2.** Enantioselective organocatalytic coupling of tetrahydroisoquinolines and ketones under electrooxidative conditions.

**Scheme 3.** CuII/TEMPO-catalyzed enantioselective electrooxidative alkynylation of tetrahydroisoquinolines.

Guan, He and co-workers reported on the proline-catalyzed enantioselective synthesis of C2-quaternary indolin-3-ones from 2-arylindoles and ketones under electrochemical conditions (Scheme 4) [43]. The transformation was carried out in an undivided cell at constant current with Pt electrodes and resulted in moderate to good yields and excellent diastereo-and enantioselectivities (up to 99% *ee*) of 2,2-disubstituted indol-3-one products bearing a quaternary stereocenter, an interesting compound class found in naturally occurring biologically active substances. The procedure was mostly found to be efficient on cyclic ketones, but two acyclic examples were also reported and could afford high *ee*'s. Similar to the findings of Luo and co-workers [30], no reaction occurred in the absence of proline or electric current. In addition, no reaction was observed when starting from N-methyl-substituted indole. The reaction was proposed to proceed in accordance with the design principle in Figure 1b via indirect oxidation of the indole to the corresponding radical cation, using TEMPO as redox mediator. Upon loss of a proton, the resulting indole radical was proposed to react with atmospheric oxygen after a hydrogen atom transfer (HAT). Subsequent attack of the imine carbon by the enamine, formed by the proline catalyst and the ketone substrate, results in the product after hydrolysis. Control experiments using isolated imine in the presence of the proline catalyst and ketone substrate under non-electrochemical conditions resulted in excellent yields and enantioselectivity and provided support for the proposed mechanism. Furthermore, the addition of BHT to standard conditions resulted in lower yields of the product as well as in the formation of a BHT adduct of the indole, detected by HRMS, thus indicating that a radical mechanism is operating. The use of 18O-labelled O2 and H2O indicated that the former was indeed the source of the incorporated oxygen, a hypothesis that was further strengthened by the greatly reduced yields observed when the reaction was performed under an Ar atmosphere. Benzoic acid was used as weakly acidic additive, which aided to increase the yield by facilitating enamine formation, an effect reported in various examples of asymmetric enamine catalysis [44]. The reaction was found to proceed in the absence of TEMPO with the same enantioselectivity but reaching lower yields. Based on CV analysis, the authors proposed that direct oxidation of the indole at the anode is occurring in the absence of TEMPO.

**Scheme 4.** Enantioselective proline-catalyzed electrosynthesis of C2-quaternary indolin-3-ones.

Luo and co-workers reported on the first asymmetric enamine-benzyne coupling (Scheme 5) [45]. Using a chiral diamine catalyst in an undivided cell with Pt electrodes and constant current conditions, α-arylation of cyclic α-ketocarbonyls with anodically formed benzyne occurred to form products with quaternary carbon stereocenters in good yields and with *ee*'s up to 99%. Under the electrochemical conditions, 1-aminobenzotriazole could be used as benzyne precursor in the absence of the toxic oxidant Pb(OAc)4, typically required under non-electrochemical conditions [46–50]. In addition, the strategy was extended to the generation and use of cyclohexyne via the corresponding triazole precursor. Trapping experiments with tetraphenylcyclopentadienone under standard conditions resulted in good yields of the benzyne and cyclohexyne adducts but only trace amounts of the benchmark products, thus confirming the existence of the elusive intermediates. The substrate scope was limited to cyclic ketoesters and products were in some cases obtained as regioisomers, however all with high *ee*'s and in moderate to good yields. No reaction was observed in the absence of the aminocatalyst, whereas results in the absence of electric current was not explicitly discussed. Experimentally, it was found that Co(OAc)2·4H2O was beneficial as an additive (20 mol%) with a major e ffect on yield (71% vs. 28%) and a minor e ffect on *ee* (94% *ee* vs. 88% *ee*) of the product. With the use of CV, the authors found that the redox potentials of the Co salt and 1-aminobenzotriazole were comparable (Eox = 0.83 vs. 0.84 V), hence suggesting that the Co salt was likely not functioning as a redox mediator for oxidative benzyne generation. However, control experiments with benzyne quenching reagents in the absence of α-ketocarbonyl substrates resulted in rapid decomposition of the benzotriazole but only trace amounts of quenching adducts in the absence of the Co salt, whereas considerably higher yields were obtained in the presence of Co. Based on these findings, the authors proposed that the Co salt stabilizes the intermediate arynes by binding to the triple bond, thereby enhancing the propensity for enamine coupling. This hypothesis was supported by DTF calculations, indicating that coordination to Co acetate stabilizes benzyne by 18.6 kcal/mol.

**Scheme 5.** Asymmetric catalytic α-arylation of cyclic α-ketocarbonyls with anodically formed benzyne or cyclohexyne.

Meggers and co-workers described an oxidative metal-catalyzed asymmetric C–H functionalization of the α-position of 2-acyl imidazoles in an undivided cell equipped with a C anode and Pt cathode under constant current conditions (Scheme 6) [51]. Using a chiral Lewis acidic Rh complex, 2-acyl imidazoles and silyl enol ethers were coupled to provide enantioenriched 1,4-dicarbonyls in up to 91% yield and >99% *ee*, including >10 examples of the formation of all-carbon quaternary stereocenters as well as two examples of complex natural product derivatization. Considerably lower yields were observed in the absence of a base, whereas only homocoupling of the silyl enol ether was obtained in the absence of the Rh catalyst. Mechanistically, the reaction was proposed to proceed via initial coordination of the 2-acyl imidazole substrate to the metal catalyst, followed by deprotonation by the external base (2,6-lutidine). The resulting Rh-coordinated enolate was envisioned to undergo anodic oxidation to a fford a C-centered radical in α-position that would undergo stereocontrolled C–C

bond formation with the silyl enol ether and form a TMS-protected ketyl radical. A second anodic oxidation, followed by subsequent desilylation would close the catalytic cycle (Scheme 6). As presented, the anodic oxidations of the catalyst-bound substrate were envisioned as direct electrolysis events in accordance with the general principle in Figure 1a. The mechanistic proposal was supported by CV analysis, indicating that the Rh-bound 2-acyl imidazole has a considerably lower oxidation potential compared to the silyl enol ether and the unbound 2-acyl imidazole. Furthermore, control experiments using TEMPO as a radical quenching agen<sup>t</sup> resulted in high yields of TEMPO-functionalized 2-acyl imidazole in α-position, thus indicating that this carbon indeed hosts an intermediate radical.

Similar to the work of Meggers, Guo and co-workers reported the use of a Lewis acidic chiral Ni catalyst for enantioselective α-benzylation of 2-acyl imidazoles with substituted hydroxytoluenes (Scheme 7) [52]. In an undivided cell at 0 ◦C using C electrodes at constant potential, electrochemical benzylation was carried out with good yields and excellent enantioselectivities (up to 97% *ee*) in the presence of Ni(OAc)2, a chiral diamine ligand and base (quinuclidine). No product formed in the absence of either Ni, diamine ligand or current, whereas the absence of base resulted in reduced yields but similar *ee*. Trapping experiments afforded 11% of the TEMPO adduct in α-position to the 2-acyl imidazole, suggesting that a radical can form at this carbon. Furthermore, dimerization of the 1,4,6-trimethylphenol under different conditions indicated that an intermediate benzylic radical may also form. Based on the combined results from these studies as well as CV and electron paramagnetic resonance (EPR) spectroscopy, the authors proposed the mechanism found in Scheme 7. Initial coordination of the 2-acyl imidazole to the chiral Ni catalyst followed by deprotonation by the base affords the Ni-bound enolate. Anodic oxidation of this species affords the C-centered radical in α-position to the coordinated carbonyl, which undergoes coupling with a benzylic radical, formed via anodic oxidation via a separate route. As such, a mechanism similar to that of electrogenerated SOMOphiles in enamine catalysis (Figure 2a) was proposed. The possibility of direct interaction between the benzylic radical and the Ni center that could result in product formation after reductive elimination was not discussed by the authors. While quinuclidine is a known HAT catalyst in photoredox catalysis [53–58], additional mechanistic roles of this base, e.g., assistance in the formation of the postulated benzylic radical coupling partner, were not proposed.

**Scheme 7.** Lewis acid-catalyzed electrooxidative enantioselective α-benzylation of 2-acyl imidazoles.

Along the same lines, the same group developed an enantioselective bifunctional squaramidecatalyzed detrifluoroacetylative alkylation reaction using substituted hydroxytoluenes under electrochemical conditions [59]. Using carbon electrodes under constant current conditions at 70 ◦C, fluorine-containing compounds bearing stereocenters at the C-F bond were formed in good yields and *ee*'s up to 95%. As suggested by the authors, the trifluoromethyl α-fluorinated β-keto *gem*-diol substrate is activated by the squaramide catalyst and reacts with the electrochemically formed *p*-quinone methide (Scheme 8), as such resembling the principles of Figure 2b with anodic electrophile formation. Base-induced detrifluoroacetylation followed by stereoselective proton transfer generates the product as the final step in the absence of electricity.

**Scheme 8.** Squaramide-catalyzed electrooxidative enantioselective α-benzylation/detrifluoroacetylation of trifluoromethyl α-fluorinated β-keto *gem*-diols.

Ackermann and co-workers demonstrated the first asymmetric electrooxidative C–H activation process using Pd-catalysis and L-*tert*-leucine as transient directing group to provide access to axially chiral biaryls (Scheme 9) [60]. In an undivided cell with graphite felt anode and Pt plate cathode and constant current at 60 ◦C, various aldehyde-substituted biaryls were alkenylated to form axially chiral products in good yields with excellent *ee*'s (up to 99%) and high position- and diastereocontrol. The substrate scope also included examples of N–C axially chiral N-aryl pyrroles and the use of perfluorinated alkenes. Furthermore, it was demonstrated how the axially chiral products could be converted into enantioenriched [5]-and [6]-helicenes, dicarboxylic acids and BINOL derivatives in high yields and optical purity. Control experiments revealed that no reaction occurred in the absence of either Pd catalyst or L-*tert*-leucine, whereas the absence of current resulted in considerably lower yield of the benchmark substrate (25% vs. 71%). Labelling experiments indicated that C–H activation is the rate-limiting step and that no H/D scrambling occurs between the substrate and the acetic acid solvent. Furthermore, a non-linear-effect (NLE) was not observed, indicating that the reaction proceeds with a metal to ligand ratio of 1:1 in the enantiodetermining step.

With the aid of DFT calculations, the authors proposed a PdII-mechanism where initial imine formation between the leucine ligand and the aldehyde substrate results in a transient directing group that facilitates the asymmetric Pd-catalyzed C(sp2)–H activation. The nature of the transition state for this step was not discussed by the authors. Based on the presented geometry-optimized structures of intermediates, it does however appear as if the C–H bond breakage is envisioned to occur with the aid of an acetate base. The resulting PdII species coordinates an alkene reactant, followed by its insertion into the Pd–C bond. Although not explicitly mentioned, it can be envisioned that β-hydride elimination followed by hydrolysis of the transient imine releases the product. The role of the electricity was not specifically discussed by the authors. However, as the control reaction without current resulted in a product yield corresponding to more than two catalyst turnovers, it appears as if electricity is accelerating product formation rather than enabling it.

**Scheme 9.** Palladium-catalyzed C–H activationwith a transientdirecting groupunder electrochemical conditions.
