*3.2. Cross-Electrophile Couplings*

Reductive dehalogenation is a classic transformation in electrosynthesis [113] that includes stereoselective examples using cobalt catalysis [99,100]. The principle is relevant for transition metal-catalyzed reductive cross-electrophile couplings [114–116], and an enantioselective coupling of alkenyl and benzyl halides using a chiral Ni catalyst was demonstrated by Reisman and co-workers under electrochemical conditions [117]. Electrochemical catalyst activation and turnover granted C(sp2)–C(sp3) bond formation without the need for sensitive organometallic reagents or metal powder reductants, and products bearing allyl stereocenters were obtained under mild conditions. NiCl2 dme (10 mol%) was employed as catalyst precursor together with an indanyl-substituted bisoxazoline ligand (20 mol%) in the presence of NaI in an undivided cell with a reticulated vitreous carbon (RVC) cathode and a Zn sacrificial anode at 0 ◦C, furnishing the products in good yields and high *ee*'s (up to 95%) (Scheme 15). Control experiments confirmed that all components (Ni, ligand, current, additive) were essential for the reaction outcome. Although not specifically discussed in the paper, the cross-coupling has been considered to follow a sequential reduction mechanism [118,119] taking into account results that proved inconsistent with a radical chain mechanism for the non-electrochemically-driven variant of the reaction [120]. In the sequential reduction pathway, a Ni<sup>0</sup> complex would be generated from electroreduction of the NiII precursor, and the C(sp2) coupling partner (the alkenyl bromide) would undergo oxidative addition with this Ni<sup>0</sup> species. The resulting NiII intermediate is reduced at the cathode to a Ni<sup>I</sup> intermediate with concomitant loss of halide, while the following oxidative addition (of the racemic benzyl chloride) was defined as the stereoconvergent step. Upon reductive elimination, the NiIII complex is envisioned to liberate the enantioenriched product and forms a NiI-Cl species, which is again reduced to Ni<sup>0</sup> to allow for catalyst turnover.

Another asymmetric cross-electrophile coupling was reported by Mei and co-workers to afford enantioselective electrochemical homocoupling of aryl bromides to axially chiral biaryls [121]. By the use of 10 mol% NiCl2·glyme with chiral pyridine-oxazoline ligands in presence of NaI and 4A molecular sieves in an undivided cell equipped with a Ni cathode and a sacrificial Fe anode at 0 ◦C, yields up to 91% and stereoselectivities up to 96% *ee* were obtained (Scheme 16). Control experiments showed that the reaction does not occur in absence of Ni or current, while Mn<sup>0</sup> or Zn<sup>0</sup> as alternative reductants afforded lower yields and slightly lower *ee*'s. CV analysis indicated that the Ni catalyst is preferentially reduced

over the substrate, and that the latter can undergo oxidative addition to Ni0. The authors suggested a reductive coupling mechanism analogous to that suggested for Reisman's work (Scheme 15), in which cathodic reduction of the initial complex to Ni0, followed by oxidative addition of the aryl bromide, results in a NiII complex. Subsequent cathodic reduction to Ni<sup>I</sup> and oxidative addition of another molecule of the aryl bromide substrate generates a NiIII intermediate. Reductive elimination releases the biaryl product, while the Ni<sup>I</sup> species undergoes further electrochemical reduction to close the catalytic cycle. However, the authors state that other pathways could not be ruled out at this stage.

**Scheme 15.** Electrochemically driven cross-electrophile coupling with Ni-catalysis.

**Scheme 16.** Reductive cross-electrophile coupling for the formation of axially chiral biaryls using Ni-catalysis under electrochemical conditions.

#### **4. Conclusions and Outlook**

Asymmetric catalysis under electrosynthetic conditions is a rapidly expanding research field that has equipped the organic chemist toolbox with new methods for enantioselective synthesis of organic molecules in the last few years, not the least for electrochemically driven metal catalysis. In comparison with the use of pre-functionalized chiral electrodes, chiral electrolytes or solvents or pre-modified substrates with chiral auxiliaries, homogeneous catalysis for the conversion of prochiral substrates appears as an economical, user-friendly and modular approach for asymmetric electrosynthesis [3–6]. It can be noted that the use of electricity to promote enantioselective oxidative processes is currently considerably more explored compared to its use in reductive transformations. As such, further developments on the latter topic can be anticipated.

Electrosynthesis o ffers the possibility to bypass the use of (super)stoichiometric and commonly hazardous and toxic chemical redox reagents, which results in increased safety and atom e fficiency of the processes. On the other hand, large amounts of electrolyte are typically required to provide su fficient conductivity to the organic medium, which clearly hampers atom e fficiency. Development of easily recyclable electrolytes, economic ionic liquids or microfluidic systems that make electrolytes superfluous due to the small distance between cathode and anode are interesting possibilities to address this problem that may promote the transition from academic research to industrial processes for the synthesis of fine chemicals [122,123]. Up until now, however, such approaches have not been applied for asymmetric catalysis. Furthermore, the energy e fficiency of electrosynthetic processes is not necessarily optimized as more current is typically required to transform starting material into product compared to what theory would suggest. This Faradaic loss may be partly addressed by the use of redox mediators for indirect electrolysis. As redox mediators can allow for redox events to occur at lower potentials (in absolute numbers), this may also enable higher selectivities and functional group tolerance [15]. There is plenty of room for innovation in this field, not the least for reductive transformations, and inspiration for electrosynthetic applications is likely to be found in photoredox catalysis, as well as the proceedings of the organic battery community [124].

It can be noted that chiral amines and derivatives thereof play a key role for asymmetric catalysis in an electrosynthetic setting, either as organocatalysts or as ligands in metal-catalyzed systems. In this light, future development of other chiral inductors will be interesting. For example, chiral hypervalent iodine reagents were recently demonstrated to induce optical activity in organic molecules under electrosynthetic conditions [125]. As electrochemical synthesis of hypervalent halogen compounds has been demonstrated viable [126–129] and the use of halides and halogen compounds as electrochemical redox mediators is already known [40,69,70,130], future developments in this area are anticipated.

**Author Contributions:** Conceptualization, C.M. and H.L.; writing—original draft preparation, C.M. and H.L.; writing—review and editing, C.M. and H.L.; supervision, H.L.; project administration, H.L.; funding acquisition, H.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by The Swedish Research Council, gran<sup>t</sup> number 2015-06466, and Stiftelsen Olle Engkvist Byggmästare. Magnus Bergvalls stiftelse C.F. Lundströms stiftelse (The Royal Swedish Academy of Agriculture and Forestry) Stiftelsen Lars Hiertas minne.

**Acknowledgments:** We gratefully acknowledge Piret Villo for valuable feedback on the manuscript.

**Conflicts of Interest:** The authors declare no conflict of interest.
