4.6. Nickel-Catalyzed Cross-Couplings

The synthetic utility of nickel-catalyzed cross-couplings has recently grown alongside the advances in understanding the radical-based mechanisms of odd-electron Ni species. When combined with the radical-forming pathways associated with photoredox catalysis and electrochemistry, Ni catalysis enables the discovery of new reaction platforms complementary to palladium-catalyzed methods.⁵⁶⁴ Three examples — C(sp²)–N, C(sp²)–S, and reductive C(sp²)–C(sp³) cross-couplings — are presented.

The Buchwald-Hartwig amination is the gold standard for arene C–N cross couplings, with applications ranging from medicinal chemistry to materials research.⁵⁶⁵ However, because of the high costs associated with Pd and the specialized ligands involved, there is a demand for alternative, low-cost methods. One important solution is the development of Ni-catalyzed methods that use photoredox and electrochemical strategies to overcome redox barriers. A tandem photoredox- and nickel-catalyzed method (termed Ni metallaphotoredox hereafter) was reported by MacMillan, Buchwald and co-workers, in which an Ir^III photocatalyst and Ni^II pre-catalyst were used to couple secondary and primary amines to aryl bromides and iodides in good to excellent yields under ambient conditions (Schemes 30 and ​and3131).⁵⁶⁶ No specialized ligand was used in this transformation as the presumed ligands on the nickel center are the halide and amine nucleophile with the latter existing in equilibrium speciation states.⁵⁶⁷ This transformation was subjected to high-throughput screening by collaborators at Merck & Co., Inc., Kenilworth, NJ, USA. C–N cross-coupling with piperidine was observed for 78% of complex, drug-like aryl halides studied, highlighting its utility for high-throughput experimentation (HTE). The putative mechanism proceeds by oxidative addition of the aryl halide into a Ni⁰ species to form Ni^II oxidative addition complex 30.1 that undergoes ligand exchange with an amine to form a Ni^II aryl imido complex (30.2) (Scheme 30A). This intermediate is then oxidized to Ni^III species 30.3 by photoinduced electron transfer to excited state heteroleptic Ir^III photocatalyst Ir[dF(CF)₃ppy]₂(dtbbpy)PF₆ (11.6). This Ni^III species then undergoes facile reductive elimination to yield the desired aryl amination product. The two catalytic cycles converge with electron transfer from the reduced Ir^II photocatalyst to the Ni^I intermediate. Buchwald and co-workers then adapted this method to a flow system with Ru(bpy)₃(PF₆)₂ replacing Ir[dF(CF)₃ppy]₂(dtbbpy)PF₆ as the photocatalyst.⁵⁶⁸ Gram-scale C–N cross-couplings with (hetero)arenes were demonstrated, with 2.21 g of commercial anesthetic tetracaine synthesized in 84% yield with a 10-minute residence time. Johannes and Oderinde reported a similar transformation, albeit with dtbbpy as a supporting ligand on Ni and is limited to aniline, sulfonamide, and benzylamine nucleophiles (Scheme 30B).⁵⁶⁹ An alternative mechanism is proposed, in which reductive quenching of photoexcited Ir[dF(CF)₃ppy]₂(dtbbpy)PF₆ by aniline generates an aniline cation radical that is deprotonated to form an anilinyl radical (30.4). Trapping this open shell species at a Ni^I center forms a Ni^II imido intermediate (30.5) that is reduced to Ni^I by Ir^II before undergoing oxidative addition with the aryl halide. Facile reductive elimination from the Ni^III aryl imido complex 30.6 yields the desired arylamine. Further investigation of this mechanism by Miyake and co-workers suggest that either direct UV photoexcitation of NiIIBr₂-tris(amino) species⁵⁷⁰ or Förster-type energy transfer from Ru(bpy)₃Cl₂⁵⁶⁷ can facilitate the same transformation. More recently, MacMillan and co-workers present a revised mechanism in which aryl C–N cross-coupling proceeds via a Ni^(I/III) dark cycle and photoreduction of off-cycle Ni^II species initiates and sustains the catalytic Ni pathway (Scheme 30C).⁵⁷¹ Stern-Volmer and transient absorption spectroscopy studies show that DABCO is the primary quencher of photoexcited Ir^III, which generates a Ir^II reductant. Reduction of resting-state Ni^II species 30.7 by Ir^II initiates the Ni^I/Ni^(/III) cycle responsible for C–N coupling, as suggested by stoichiometric reductive elimination and quantum yield studies. Because Ni^II reduction is the rate-determining step, photocatalyst ligand modifications to obtain greater reductive overpotentials led to 37-fold and 10-fold increases in initial rate and quantum yield of product formation respectively. Nocera and co-worker independently provide evidence for the Ni^I/Ni^III cycle, as C–N cross-coupling is observed when a catalytic amount of Zn reductant is used in place of a photoredox catalyst, albeit for a limited substrate scope.⁵⁷² Taken together, these results suggest a complex mechanistic landscape in which modifications to catalyst, reagent and irradiation wavelength result in C–N coupling operating by different mechanisms and that a dark catalytic cycle (thermally sustained cycle, free of requiring light) may be operational with light serving to drive photoredox chemistry to bring off-cycle Ni species onto the catalytic cycle.

(A) The original mechanism proposed for nickel metallaphotoredox-catalyzed C–N cross coupling. (B) An alternate C–N cross coupling mechanism for aniline substrates proposed by Oderinde. (C) Current revised mechanism for nickel metallaphotoredox-catalyzed C–N cross coupling. Note: blue SET boxes represent a specific coupled electron transfer even between Ir^III* and organometallic intermediate 30.2.

Representative examples of electrocatalysis and photoredox catalysis for nickel-catalyzed C–N cross coupling.

The electrochemical approach to Ni-catalyzed arene C–N cross coupling was developed by Baran and co-workers using catalytic NiBr₂-dtbbpy in an undivided, galvanostatic cell.⁵⁷³ This method enables the coupling of hetero(aryl) bromides with 1°, 2°, and 3° amines in yields comparable to photoredox and palladium catalysis. This method was also scalable, with the coupled product of 4-bromobenzotrifluoride and N-Boc piperazine obtained in 66% yield. Further mechanistic investigation was carried out by Baran, Minteer, Neurock, and co-workers in which UV-Vis spectroscopy, cyclic and square wave voltammetry, and DFT computations were used to probe the elementary steps for the transformation (Scheme 31).⁵⁷⁴ A Ni^I/Ni^III pathway was found to be operative, with a Ni^I-halide species 32.1 formed via cathodic reduction from Ni^II undergoing oxidative addition with the aryl halide to form a Ni^III intermediate (32.2). This complex can substitute a halide for an amine nucleophile, setting up the Ni^III aryl imido complex (32.3) for reductive elimination to yield the desired product. However, this ligand exchange step is the minor pathway in this transformation, as 32.2 forms stable Ni^II intermediate 32.4 via facile comproportionation with 32.1 or through cathodic reduction. Ligand exchange at 32.4 is the rate-determining step and is dependent on base loading; the resultant Ni^II aryl imido complex 32.5 can then be oxidized to the key reductive elimination adduct 32.3 Thus, the overarching role of electrical current is to regenerate catalytically-active Ni^I/Ni^III intermediates. With a better understanding of mechanism, Baran, Minteer and Neurock were able to expand the nucleophile scope to amino acid esters, nucleoside analogs, and oligopeptides and the arene scope to aryl chlorides. Additionally, they demonstrate the use of flow chemistry to synthesize a precursor to the FDA-approved antidepressant vilazodone, obtaining the aminated product in 64% yield on a 100 g scale.

The cross-coupling of aryl halides and thiols has historically been a challenge for transition metal catalysis as catalysis deactivation via the strong coordination of thiolates necessitates the use of specialized ligands, high catalyst loadings and/or high reaction temperatures for successful C–S bond formation.⁵⁷⁵ As a result, redox strategies using nickel catalysis have been developed to overcome some of these issues (Scheme 33). Oderinde, Johannes and co-workers circumvent this problem by using oxidative photoredox catalysis to generate thiyl radicals that participate in a Ni^I/Ni^III catalytic cycle to provide aryl sulfides from aryl iodides.⁵⁷⁶ Benzylthiols, thiophenols, alkyl thiols and cysteine derivatives were competent nucleophiles, with the only low-yielding substrate being the sterically-hindered tertiary thiol. The electrochemical counterpart to this method was reported by the Wang⁵⁷⁷ and Mei⁵⁷⁸ groups independently, in which cathodic reduction generates active Ni⁰ and thiolate from thiol with concomitant hydrogen evolution, while diametrical anodic oxidation provides the active thiyl radicals from the thiolate. Both undivided cell systems use LiBr, amide solvents, and nickel foam as the electrolyte, solvent, and cathode respectively, however they diverge in choice of anode and electrochemical set-up. Wang uses graphite felt (anode) under potentiostatic electrolysis, whereas Mei uses a sacrificial magnesium (anode) under a constant current. A notable side reaction pathway observed in the electrochemical set-ups is the formation of disulfides, which presumably forms via thiyl dimerization. This side product is not appreciably observed under photoredox conditions because thiyl radicals are catalytically formed.

Electrochemical and photoredox approaches to activating nickel-catalyzed aryl thiolation.

The facile and general construction of alkyl-aryl bonds via transition metal catalysis is a longstanding challenge of organic synthesis and the development of redox-centered pathways have provided important contributions towards solving this problem and streamlined its use for drug discovery.⁵⁷⁹ In particular, we highlight photoredox and electrochemical strategies involving the coupling of aryl halides with either (1) alkyl trifluoroborates (Schemes 34 and ​and35)35) or (2) alkyl halides (Schemes 36 and ​and3737).

Representative examples of Ni-metallaphotoredox catalyzed cross-coupling of alkyl trifluoroborates and aryl halides, with respective putative mechanisms depicted.

Representative examples of electrochemically-mediated nickel-catalyzed cross-coupling of alkyl trifluoroborates and aryl halides alongside its putative mechanism.

Representative examples of nickel-metallaphotoredox catalyzed cross-electrophile coupling of alkyl and aryl halides, with respective putative mechanisms depicted.

Representative examples of electrochemical methods for nickel-catalyzed cross-electrophile coupling of alkyl and aryl halides, with respective putative mechanisms depicted.

Palladium-catalyzed cross-couplings between aryl halides and alkyl boron nucleophiles is a classical strategy for accessing C(sp²)–C(sp³) bonds^580,581,582, with recent methods developed for enantiospecific couplings.^583,584 Despite its successes, Pd-catalyzed reactions generally require high temperatures or additives to accelerate the slow alkyl transmetalation step, which is potentially problematic for secondary alkyl boron nucleophiles due to the potential for β-hydride elimination at the palladium center. One way to alleviate this problem is to use analogous tetravalent organotrifluoroborates, which undergo cleaner transmetalation and are less susceptible to degradative oxidation relative to trivalent boron nucleophiles.^585,586 However, a more general solution is single electron transmetalation, where an alkyl radical generated via single electron oxidation of the parent alkyl trifluoroborate can add to a transition metal center to generate an odd-electron organometallic species.^587,588 Molander and coworkers report a Ni-metallaphotoredox method for generating stabilized benzyl radicals from single electron oxidation of a corresponding alkyl BF₃K species and coupling it with aryl bromides.⁵⁸⁹ A wide range of benzylic BF₃K species and aryl bromides with differing electronic properties are tolerated in this transformation, with the products obtained in moderate to excellent yield. Follow-up work by Molander and coworkers expanded the scope to include secondary alkyl trifluoroborates^590,591 — a key limitation of previously described Pd-catalyzed methods — as well as α-alkoxy-,^592,593,594 α-amino,⁵⁹⁵ α-hydroxyalkyl-,⁵⁹⁶ and α-trifluoromethyltrifluoroborates.⁵⁹⁷ Notably, the use of alkyltrifluoroborates enables selective C(sp²)–C(sp³) cross-couplings even for aryl halides containing boronic acids, boronic esters or MIDA boronates.⁵⁹⁸ The putative mechanism is as follows: The photoredox-generated open shell alkyl radical 34.5 readily enters the catalytic cycle by adding to a Ni^II-arene oxidative addition complex 34.6 to form a Ni^III intermediate 34.7 that readily undergoes reductive elimination to provide the desired C(sp²)–C(sp³) coupling product 34.8. Concomitant reduction of the resultant Ni^I complex 34.9 to Ni⁰ by an Ir^II species closes the two catalytic cycles. However, follow-up computational studies by Kozlowski and Molander reveal that an alternate mechanism may exists, where a Ni⁰-tbbpy species 34.15 intercepts an alkyl radical 34.16 to form a Ni^I species 34.17, which then participates in haloarene oxidative addition and subsequent reductive elimination to furnish the C(sp²)–C(sp³) coupled product.⁵⁹⁹ This revision likens the mechanism to aryl-alkyl Ni-catalyzed Negishi^600,601 and Kumada^602,603 couplings, where the participation of alkyl radicals is shown. This study also proposes that asymmetry at the C(sp³) center can be induced by using a sterically biased chiral bisoxazoline ligand; reversible alkyl radical fragmentation from the Ni^III intermediate leads to enantioconvergent dynamic kinetic resolution and the formation of the desired chiral species. In order to activate tertiary alkyl trifluoroborates to aryl halides, Molander and Primer switched from neutral bipyridine scaffold on Ni to the anionic 2,2,6,6-tetramethyl-3,5-heptanedionate (TMHD).⁶⁰⁴ This change enables the coupling of several tertiary alkyltrifluoroborates with electron-deficient bromoarenes; however, electron-rich bromoarenes and N-heteroaryl bromides were inefficient coupling partners. The effectiveness of this ligand switch was detailed by Gutierrez, Molander and coworkers, in which computational studies suggest that in the anionic TMHD-Ni system, aryl-alkyl coupling occurs via an outer-sphere reductive elimination (34.24), whereas inner-sphere reductive elimination is operative when the neutral tbbpy-Ni system is used.⁶⁰⁵ This distinction arises from the steric congestion at the aryl-alkyl-halo- Ni^III intermediate, where the cross-coupling barrier is at least 10 kcal•mol⁻¹ higher for acyclic tertiary alkyls. Taken together, these studies add to the growing field of work incorporating alkyl radicals into transition metal catalysis.^428,606

Electrochemical methods for the coupling of alkyltrifluoroborates and aryl halides have been relatively underdeveloped due to the difficulties in minimizing undesirable Ni-associated homocoupling side reactions, but a recent report by Liu and coworkers using convergent paired electrolysis to effect the coupling of benzyltrifluoroborates and aryl halides suggests that this strategy can mimic redox-neutral photoredox catalysis.⁶⁰⁷ Using galvanostatic electrolysis, C(sp²)–C(sp³) coupled products are obtained from electronically distinct aryl bromides and benzyltrifluoroborates in moderate to excellent yields, with the compatibility of aryl chlorides and vinyl bromides as coupling partners displayed. Notably, one advantage of this electrochemical method is its scalability, as the coupling of benzyltrifluoroborate and methyl 4-bromobenzoate can be scaled (up to 3.0 g) with minimal yield drop (93% to 86%). A key distinction of this transformation is that mechanistic studies of cathodic reduction suggest that only Ni^II/Ni^I reduction is operative, which rules out the involvement of a Ni⁰ species as proposed by the Kozlowski and Molander mechanism. Thus, the putative mechanism involves a Ni^I/Ni^III cycle, where cathodic reduction of a Ni^II-tbbpy intermediate 35.7 forms a Ni^I species 35.8 that readily undergoes oxidative addition with an aryl halide to form an aryl-bishalo Ni intermediate 35.9. Further cathodic reduction of 35.9 and halide extrusion leads to formation of the corresponding Ni^II complex 35.10, which intercepts the benzyl radical — generated from anodic oxidation of the benzyl trifluoroborate — to form the aryl-alkyl-halo Ni^III intermediate 35.11. Reductive elimination furnishes the desired C(sp²)–C(sp³) coupled product and completes the catalytic cycle. Despite their success with benzyl trifluoroborates, Liu and coworkers were unable to use other alkyl trifluoroborates, which is a current limitation, but future developments in this field should enable greater generality of both coupling partners.

Transition-metal catalyzed cross-electrophile couplings (XECs) between aryl and alkyl halides typically involves the use of stoichiometric metal reductants (e.g. Zn, Mn), with odd-electron organometallic species and radical intermediates implicated in the transformation.⁶⁰⁸ Thus, replacing these chemical reductants with photoredox- or electrochemical- generated electrons offer new XEC strategies (Schemes 36 and ​and37).37). Lei, Lu, and co-workers report a metallaphotoredox XEC between aryl and alkyl bromides using triethylamine as the terminal reductant, and obtained moderate to good yields for the desired products, albeit with limited substrate generality.⁶⁰⁹ The mechanism proposed is similar to the seminal XEC report by Weix and co-workers⁶¹⁰ with Ir^III photocatalyst 11.5 facilitating Ni^I/Ni⁰ reduction via the Ir^III/Ir^II cycle. A more general metallaphotoredox approach was reported by MacMillan and co-workers in which Ir^III photocatalyst 11.6 and NiCl₂•dtbbpy are used to effect C(sp²)–C(sp³) XEC between alkyl and aryl bromides in good to excellent yields.⁶¹¹ The putative mechanism operates by a Ni⁰ complex 36.10 that undergoes oxidative addition with the aryl halide to form Ni^II species 36.11, which then intercepts an alkyl radical formed in situ to yield the Ni^III complex 36.12. This alkyl radical is formed via halogen abstraction by a silyl radical 36.13 originating from tris(trimethylsilyl)silane (TTMSS); bromine radical generated from the bromide oxidation by photoexcited 11.6 participates in H-atom abstraction from TTMSS to form 36.13. Reductive elimination from 36.12 yields the desired C(sp²)–C(sp³) XEC product, and a Ni^I intermediate that closes the nickel and photoredox cycles by oxidizing Ir^II. Notably, five-membered heterocycles are compatible electrophiles, which have historically been difficult for palladium-catalyzed cross-coupling reactions. This strategy was also applicable to activated alkyl halides such as α-chloro carbonyls⁶¹² and bromodifluoromethane.⁶¹³ More recently, MacMillan and co-workers reported the XEC of aryl chlorides and alkyl chlorides through photoredox-mediated generation of a polarity-matched aza-silyl radical 36.18 to mediate effective chlorine atom abstraction from unactivated alkyl chlorides.⁶¹⁴ The scope of alkyl chlorides and aryl chlorides is broad, and good functional group tolerance is observed. Additionally, the late-stage functionalization of several pharmaceuticals is shown, with desired C(sp²)– C(sp³) coupling obtained in the presence of triazoles, amides, sulfones, and carbamates — functional groups common in medicinal chemistry settings.

The electrochemical approach to XEC⁶¹⁵ was first detailed by Périchon and co-workers, which couples activated alkyl halides (e.g. α-chloro carbonyls) and aryl bromides/iodides) using superstoichiometric Ni(bpy)₂Br₂ under constant current electrolysis in an undivided cell.⁶¹⁶ Two-electron reduction of Ni^II to Ni⁰ is observed and this species participates in oxidative addition with the aryl halide to an aryl-Ni^II intermediate that can intercept an α-carbonyl radical originating from cathodic reduction of the parent α-chloro carbonyl. This Ni^III species rapidly undergoes reductive elimination to furnish the desired C(sp²)–C(sp³) coupled product. Slow addition of the alkyl halide was necessary for circumventing unproductive alkyl halide homocoupling. The racemization of chiral methyl 2-chloropropionate suggests a radical pathway for the formation of the α-carbonyl radical and using a substrate with chiral auxiliary enables the diastereo- and enantioselective C(sp²)–C(sp³) couplings.⁶¹⁷ Hansen and co-workers extended the method to include unactivated alkyl halides, with the main modifications being the use of 4,4′-dimethoxy-2–2′-bipyridine (dmbpy) as the supporting ligand on Ni, higher constant current (10 mA; 2.0 F•mol⁻¹), and higher temperatures (65 °C) (Scheme 37A).⁶¹⁸ This XEC method is scalable up to 6.5 mmol, with a constant current of 2.0 F•mol⁻¹ and 10 mol% of NiCl₂•dmbpy. The reaction is sensitive to the rate of Ni^II reduction, as the use of high currents leads to low yield, poor selectivity, and low mass balance. Pyridine-amidine and 2,6-bis(amidine)pyridine (37.10) ligands were also used as they enabled higher yields for certain substrate classes (e.g. heteroaryl bromides) relative to dmbpy. Sevov and co-workers improved further on this system by introducing a redox shuttle to mitigate unproductive overcharge electron transfer that leads to catalyst degradation and undesirable protodehalogenated and homocoupling arene byproducts (Scheme 37B).⁶¹⁹ The reaction was performed under constant current conditions (3 mA; 2.5 F•mol⁻¹) in an undivided cell, with a tridentate bis-(pyridylamino)isoindoline[(BPyI), 37.12]-Ni species and a Ni(BPyI)₂ redox mediator found to be the most effective co-catalyst system. The overcharge protection afforded by Ni(BPyI)₂ enables XEC for redox sensitive groups such as sulfones and nitriles and challenging secondary alkyl halides at ambient temperatures and in good yields; without the redox mediator, yields are typically < 20%. Furthermore, the redox mediator enabled this transformation to be scaled in batch (75 mmol) with a high 400 mA current, providing the XEC product in 85% yield after 12 h. However, a potential downside may be a decrease in charge efficiency, as degenerate shuttling requires approximately an additional 0.5 equivalents of e (2.5 F•mol⁻¹).

The methods discussed thus far require sacrificial anodes that produce stochiometric metal waste, leading to reproducibility issues that limit its application on larger scales. Hansen, Weix and co-workers offer a workaround by using diisopropylamine as the terminal reductant, albeit in a divided cell run at a constant current (25 mA; 2.0 F•mol⁻¹), with substrates and catalyst segregated in the cathodic chamber and the reductant isolated in the anodic chamber.⁶²⁰ A dual ligand system — terpyridine (tpy) and bipyridine (bpy) — were used for Ni in this method, with varying ratios of each species influencing product yield. Qualitative analysis suggests that substrates with fast alkyl halide activation benefit from a lower tpy:bpy loading whereas high levels of aryl homocoupling can be circumvented using a higher tpy:bpy ratio.

Reisman and co-workers demonstrated C(sp²)–C(sp³) XEC can be rendered enantioselective, albeit through Ni-catalyzed reductive alkenylation between benzyl halides and vinyl bromides.⁶²¹ A chiral indanyl- substituted bis(oxazoline) (37.13) catalyst enables moderate to excellent yields with good to excellent ee under constant current electrolysis (10 mA; 2.0 F•mol⁻¹) in an undivided cell. This transformation could be scaled up on a gram scale by increasing the current to 100 mA with only minor losses in yield and enantioselectivity for a XEC between (E)-1-(2-bromovinyl)-4-methoxybenzene and (1-chloroethyl)benzene (83% yield, 91% ee). While the electrochemical and photoredox XECs may appear similar, the mechanisms are distinct because of the net electron flow involved in each respective transformation. In the electrochemical mechanism, a minimum input of 2 electrons via cathodic reduction is necessary to reduce a Ni^II pre-catalyst to generate a catalytically-active Ni species whereas in photoredox catalysis, a one-electron mechanism is invoked for generating Ni⁰ from Ni^I, with net neutral electron flow. More recently, Li and coworkers report a dehydroxylative method for alkyl-aryl XEC that proceeds through an anodic Appel reaction to yield an alkyl bromide intermediate that readily engages in the electrochemically-mediated Ni-catalyzed XEC with aryl bromides in accordance with the previously-discussed mechanism.⁶²²

C(sp³)–P^V and C(sp²)–P^V bonds are important synthetic motifs that are found in pharmaceuticals^{623,624,625,626}, agrochemicals, organic materials⁶²⁷, ligands for asymmetric synthesis,⁶²⁸ and as organocatalysts^{629,630,631,632,633}. Precursors to the synthesis of these functional motifs via redox pathways involve the single electron oxidation of diaryl and dialkyl phosphine oxides, as well as organophosphites to generate phosphinoyl radicals after deprotonation. The formation of phosphinoyl radicals via photochemical pathways have been previously studied⁶³⁴ and their generation via photoredox or electrochemical methods opens up new reactivity pathways for these reactive intermediates. For this review, we will specifically highlight nickel-catalyzed phosphorylation of aryl halides via redox strategies (Schemes 38 and ​and39),39), but readers should consult the following reviews for convergent and divergent phosphorylation methods between photoredox catalysis^635,636 and electrochemistry⁶³⁷.

Photoredox and electrochemical arene C–P cross-coupling methods.

Proposed mechanism for photochemical and electrochemical arene C–P cross-couplings.

In 2015, Lu, Xiao and co-workers report a metallaphotoredox method using Ni(cod)₂ and Ru(bpy)₃Cl₂ to couple aryl iodides with H-diarylphosphine oxides.⁶³⁸ The arene scope is tolerant of electronic changes and compatible with heterocycles such as 5-methoxyindole and 2-iodopyridine. The putative mechanism is as follows (Scheme 39A): Ru(bpy)₃²⁺ photoexcitation and subsequent oxidation of a trivalent phosphinic acid 39.1 (the preferred tautomer relative to the alternative pentavalent H-diarylphosphine oxide 39.2) forms a phosphine centered cation radical that yields a phosphinoyl radical 39.3 upon deprotonation. Concomitant oxidative addition of the aryl iodide with Ni⁰ leads to an nickelarene intermediate 39.4 that intercepts the phosphinoyl radical to form a Ni^III complex 39.5, which then undergoes reductive elimination to yield the desired triarylphosphine oxide. Regeneration of active Ni⁰ from Ni^I via oxidation of a Ru^I species back to ground state Ru^II closes the catalytic cycles. The main limitation of this work is its reliance on H-diarylphosphine oxides, as H-dicyclohexylphosphine oxide and ethyl H-phenylphosphinate were incompatible coupling partners. This is rationalized by the preference of electron-rich secondary phosphine oxides to exist in its pentavalent form, which negates the possibility of single electron oxidation by photoexcited Ru(bpy)₃²⁺.⁶³⁹ Yu and co-workers improve on this precedent by extending the method to aryl and vinyl pseudohalides, as well as expanding the nucleophile scope to include H-diaryl and H-dialkyl phosphonates.⁶⁴⁰ The reaction scope is broad for alkenyl tosylates with moderate to excellent yields observed; however, the range of compatible aryl tosylates is rather limited but examples of C–P bond formation with an aryl mesylate and an aryl sulfamate are shown. The mechanism of this transformation is similar to the one described by Lu, Xiao and coworkers, however, Yu notes that a side pathway in which the phosphinoyl radical adds to Ni⁰ before arene oxidative addition with a Ni^I intermediate 39.6 cannot be discounted (Scheme 39B).

The electrochemical counterpart to this transformation was first reported by Léonel and co-workers, in which the nickel-catalyzed coupling of aryl bromides with H-dialkylphosphites is accomplished under galvanostatic conditions (i = 200 mA).⁶⁴¹ This strategy enables the use of a Ni^II catalyst, which is reduced to Ni⁰ to facilitate oxidative addition with the aryl halide. A wide range of aryl bromides are compatible with this transformation, and good tolerance is observed for arene electronics, albeit with reduced yields observed when ortho-substitution or carbonyl functional groups are present. A smaller scope of compatible H-dialkylphosphites is presented, but high yields are observed, except when a loss in conversion is observed with bulky isopropyl groups. Léonel and co-workers follow up on this work by demonstrating the synthesis of aryl and vinyl phosphinates when using alkyl H-phenylphosphinates as the coupling partner.⁶⁴² Cui, Xiang and co-workers report a similar transformation coupling aryl bromides with H-dialkyl phosphites, except that non-sacrificial RVC electrodes are used with a ten-fold reduction in current (i = 10 mA).⁶⁴³ This change enables cleaner reactions with previously problematic electron-rich substrates and eliminates the need of a sacrificial anode. Additionally, the synthesis of alkyl-diarylphosphinates and triarylphosphine oxides from alkyl H-arylphosphinate and H-diarylphosphine oxides is shown respectively. The putative mechanisms proposed by Xiang and Léonel diverge on active oxidation states of nickel and on the formation of the phosphinoyl radical. In Léonel’s example, a Ni^I species 39.7 —formed via cathodic reduction of an arylnickel^II intermediate 39.8 — intercepts the trivalent H-dimethylphosphite before undergoing deprotonation to arrive at an aryl-nickel-dimethylphosphonate ate complex 39.9 (Scheme 39C). Anodic oxidation, followed by reductive elimination, yields the product and closes the catalytic cycle; thus, the possibility of a phosphinoyl radical is not considered. By contrast, Cui, Xiang and coworkers propose a mechanism identical to aforementioned photoredox conditions, wherein the active catalytic cycle is a Ni⁰/Ni^II/Ni^III system, with 1 and 2 e reduction of respective Ni^I (39.10) and Ni^II (39.11) intermediates regenerating active Ni⁰ (Scheme 39D). Additionally, two-step anodic oxidation and deprotonation purportedly generates active phosphinoyl radical that joins the catalytic cycle through addition to either a Ni^II or Ni⁰ intermediate. More recently, Rueping and coworkers provide a route to unsymmetrical triarylphosphines via sequential paired electrolysis.⁶⁴⁴ Their method couples aryl halides and H-diphenylphosphine oxide in moderate to excellent yields, with H-dialkylphosphites also viable phosphorus partners.