Iron‐Electrocatalyzed C−H Arylations: Mechanistic Insights into Oxidation‐Induced Reductive Elimination for Ferraelectrocatalysis

Abstract Despite major advances, organometallic C−H transformations are dominated by precious 5d and 4d transition metals, such as iridium, palladium and rhodium. In contrast, the unique potential of less toxic Earth‐abundant 3d metals has been underexplored. While iron is the most naturally abundant transition metal, its use in oxidative, organometallic C−H activation has faced major limitations due to the need for superstoichiometric amounts of corrosive, cost‐intensive DCIB as the sacrificial oxidant. To fully address these restrictions, we describe herein the unprecedented merger of electrosynthesis with iron‐catalyzed C−H activation through oxidation‐induced reductive elimination. Thus, ferra‐ and manganaelectro‐catalyzed C−H arylations were accomplished at mild reaction temperatures with ample scope by the action of sustainable iron catalysts, employing electricity as a benign oxidant.

Abstract: Despite major advances, organometallic CÀH transformations are dominated by precious 5d and4dt ransition metals,s uch as iridium,p alladium and rhodium. In contrast, the unique potentialo fl ess toxic Earth-abundant 3d metals has been underexplored. While iron is the mostn aturally abundant transition metal, its use in oxidative, organometallic CÀHa ctivationh as faced major limitations due to the need for superstoichiometric amountso fc orrosive, cost-intensiveD CIB as the sacrificial oxidant. To fully address these restrictions, we describe herein the unprecedented merger of electrosynthesis with iron-catalyzed CÀHa ctivation through oxidation-inducedr eductive elimination. Thus, ferra-and manganaelectro-catalyzed CÀHa rylations werea ccomplished at mild reaction temperatures with ample scope by the action of sustainable iron catalysts, employing electricity as ab enign oxidant.
CÀHa ctivation has surfaced as an increasingly powerful tool for molecular engineering, [1] with transformative applications throughout the materials ciences, [2] natural product syntheses, [3] late-stage diversification, [4] and have also been used on pharmaceutical industrials cales. [5] In particular, arylationso f otherwisei nert CÀHb onds have proven instrumental as a step-economical alternative to the Nobel Prize winning palladium-catalyzed cross-couplings, [6] avoiding lengthyp refunctionalizationp rotocols and therebyp reventing undesired waste formation. [7] While theseC ÀHa ctivationsh ave thus far been dominated by rare and toxic 4d transitionm etals (Figure 1a), considerable recent impetus was gainedb yi dentifying viable catalysts based on Earth-abundant [8] 3d base metals. [9] In particular,i nexpensive iron catalysis has gained considerable recent momentum due to its non-toxic nature (Figure 1b), [10] with major potentialf or translationala pplications on scale, particularly when considering trace metal impurities. Despite these major advances,a ll documented iron-catalyzed CÀHa rylations continue to be strongly limited by the need for superstoichiometricq uantities of dichloroisobutane (DCIB)a st he sacrificial oxidant,w hile simplev icinal dihalides or other chemical oxidants are generally not effective in iron-catalyzed CÀHa ctivations. [10c] Unfortunately,D CIB [11] is elusive on commercial scale, features considerables afety hazards, generates overstoichiometrica mounts of corrosive by-products,w hich overall signifi- cantly deteriorates the environmental footprint of oxidative iron catalysis. Importantly,D CIB is characterized by costs that are comparable to those of the typical noble transition metal catalystP d(OAc) 2 (Figure 1c), hence jeopardizing the inherent sustainable nature of the iron-catalyzed CÀHa ctivation approach.Asas ignificantly more sustainable alternative, we have now devised as trategy for the unprecedented DCIB-free, ironcatalyzed CÀHa rylation through the action of user-friendly electricity [12] as environmentally benign oxidant. Salient features of our findings include (a) first electrochemical iron-catalyzed CÀHa ctivation, (b) electrolysis devoid of toxic chemical oxidants, and (c) versatility by iron-or manganese-electrocatalysis, which were guided by (d) detailed experimental and computational mechanistic insights into an as of yet elusive electrooxidative iron(II/III/I) regime, (d) spin-crossover for iron-electrocatalysis, and (e) manganese electrocatalysis ford irect arylations ( Figure 1d). Thus, the presents tudy provides ap roof-ofconcept for illustrating that cost-intensive chemical halide oxidants can be replacedb yu ser-friendlye lectricityi na"lowvalent" metal catalysis, highlighting iron-catalyzed [10n] CÀHa rylations ( Figure 1e). In terms of cost of goods, viable trace metal impurities in biorelevantd rugs and inherent metal toxicities, [13] iron as the most Earth-abundant transition metal compares favourably with all other previously exploredt ransition metals for electrocatalytic strong bond activation, including cobalt, [14] copper, [15] manganese, [16] and nickel. [17] At the outseto fo ur studies we exploredt he oxidation potentialo ft he putative iron(II/III) manifold by means of computation ( Figure 2a and the Supporting Information). [18] Our findings were indicative of an iron(II) active catalyst, being supported by Mçssbauer spectroscopy studies, [19] revealing a viable redox event at E 1/2 = 0.01 Vv ersus Fc 0/ + . [18] The latter could be rationalized by the oxidationo fb imetallic magnesium-iron complex, S-3'',g enerated through transmetalation followed by single-electron-transfer.W ith these computational insights in hand, we set out to identify viable reactionconditions for the elusive electrooxidative iron-catalyzed CÀHa rylation of TAM-benzamide 1 bearing ap eptide-isosteric click-triazole [20] in au ser-friendly undivided cell setup ( Figure 2b). After considerable preliminarye xperimentation, we observed that the desired electrochemical CÀHa rylation product 3 was obtained at an exceedingly mild reactiont emperature of 40 8C, when using aRVC anode,along with aplatinum cathode.Notably,the electrochemical CÀHa ctivation was even operative at room temperature, reflecting the outstanding performanceo ft he electrocatalysis manifold. Among ar epresentative set of iron sources, Fe(acac) 3 was found to be optimal. [18] Control experiments confirmed the essential role of the electricity,t he iron catalyst and the additive.The iron-catalyzed electrooxidative CÀHarylation provedl ikewise viable in the biomass-derived [21] solvent 2-MeTHF, [18] further substantiating the sustainable natureo fo ur electrocatalysis. The ferraelectrocatalysis was also conveniently conducted with commercially available equipment,m irroring its user-friendly nature.
With the optimized reaction conditions for the electrooxidative iron-catalyzed CÀHa rylationb eing identified, we next probedi ts robustness with ar epresentative set of benzamides 1 (Scheme 1a). Differently N-substituted triazoles 1 were selectively converted into the desired products. Likewise, the robust electrocatalysis enabled the efficient CÀHa rylation on amides with para-o rmeta-substitutionp atterns. Notably,v aluable electrophilicc hloro groups as well as oxidation-sensitive sulfides were fully tolerated (8,and 10), which shouldprove invaluablef or further post-synthetic late-stage diversification. Moreover,h eteroarene thiophene and ferrocene delivered the desired arylated products 16 and 17 with high catalytic efficacy.T he electrochemical CÀHa ctivation approach was not limited to TAM-benzamides. Indeed, the synthetically usefulp yridine PIP-derivative [22] 18 and 19 proved to be amenable to the CÀHa ctivation likewise. In sharp contrast,m ono-dentate pyridine, imine and amide fell thus far short in providing effective electrocatalysis (3-I-3-III). Thereafter,w et ested the viable arylation motifsi nt he iron-catalyzed electrochemical CÀHa rylation (Scheme1b). Here, ad iversity of aromatic scaffolds could be introducedi naprogrammable fashion,a sw ell as heteroaromatic motifs with excellentl evels of chemo-and site-selectivity.
Given the unique features of the DCIB-free electrochemical CÀHa ctivation, we next compared the performance of the heterogeneous ferraelectrocatalysis regime with the optimized homogenous DCIB-mediated [10n] transformation.T hus, the performance of the electrocatalysis outperformed the chemical oxidanti nt erms of the isolated yields (Scheme 2a)a nd the kinetic profile (Scheme 2b), both of whichw ere found to be considerably improved by the iron-electrocatalysis manifold.
Intrigued by the outstanding efficacy of the electrochemical CÀHa rylation,w ebecamea ttracted to unravellingi ts mode of action. To this end, intermolecularc ompetition experiments revealed electron-rich substrates to feature an inherenth igher reactivity (Scheme 3a). This finding is not in agreement with an CÀHo xidative addition or ac oncerted-metalation-deprotonation (CMD)p athway. [23] Instead, it can be explained in terms of al igand-to-ligand hydrogen transfer (LLHT) [24] pathway or base-assisted internal electrophilic-type substitution (BIES) [25] workingm ode (vide supra).
Detailed mechanistic studies by cyclic voltammetry have been conducted to delineate the catalyst's mode of action (Scheme 4). First, the electrochemistry of the chemical oxidant DCIB was probed, featuring an irreversible onset potential at E p = À1.80 Vv s. Fc 0/ + (Scheme4a). Second, the addition of the diphosphine ligand dppe shifts the redox-potential of Fe(acac) 3 at E 1/2 = À1.3 Vv s. Fc 0/ + by 171 mV towards more positive potential (Scheme 4b). This observation renders ac oordination of the phosphine ligand likely to be operative. Third, in the presence of ZnCl 2 ·TMEDA the reversibler edox event becomes quasi-reversible by shifting the oxidation potential to E p = À0.46 Vv s. Fc 0/ + (Scheme 4c,b lue). Fourth, it is especially noteworthy that the addition of the Grignard reagent leads to the disappearance of the reversible oxidation of Fe(acac) 3 .I n Scheme1.Robustness of the electrochemicalC ÀHa rylation of amides 1. contrast, two new reversible redox eventse merge, which can be assigned to the corresponding iron(I)/iron(II) and iron(II)/iron(III) redox events at E 1/2 = À0.6 Vand at E 1/2 = À0.1 V vs. Fc 0/ + ,r espectively (Scheme4c, green). Our observationsa re in good agreement with cyclic voltammetric studies by Jutand [26] on iron-catalyzed Kumada-Corriu-type cross-coupling reactions, as wella so ur previous Mçssbauers pectroscopic studies [19] and current computational findings (vide infra) on iron(II/III/I) catalysis. Our cyclic voltammetrystudies on iron-cat- While we thus rationalized the anodic oxidation elementary steps, we next interrogated the nature of the cathodic event.
Here, detailed analyses of the electrode material by means of scanningelectron microscopy energy-dispersive X-ray spectroscopy (SEM-EDS), which clearly highlightedt he crucial role of the zinc additive at the surfaceo ft he electrode (Scheme 5a). Thus, the zinc additive serves multiple roles, including the adjustment of the conductivity.B ased on these mechanistic studies, ap roposed catalytic cycle for the iron-electrocatalytic CÀH functionalization commencesb yafacile organometallic CÀH cleavage ( Figure S9 in the Supporting Information). [18] Thereafter,t he key anodic single-electron-transfer (SET) oxidation and subsequent transmetalation occur to furnish af ive-membered ferra(III)cycle S-4, which subsequently undergoes reductive elimination, delivering the desired product 3 and the key iron(I) intermediate S-6. The catalytically active iron(II) intermediate S-1 is regenerated by anodic oxidation.
Finally,t he robustness of our strategy for electrochemical DCIB-free CÀHa rylationsw as furtheri llustrated by the gramscale synthesis of product 3 with comparable levels of efficacy (Scheme 5b).
In order to shape our understanding of the iron-electrocatalyzed CÀHa rylation, we probedi ts mode of action by DFT calculationa tt he PW6B95-D3(BJ)/def2-TZVP + SMD(THF)//TPSS-D3(BJ)/def2-SVP level of theory. [27] Our findings are hence indicative of af acile CÀHa ctivation step, which proceeds through al igand-to-ligand hydrogen transfer transition-state structure TS(1-2), by means of spin-crossover with an activation barrier of 21.8 kcal mol À1 .I no rder to access the electrooxidative step severalp athways were explored. First, we considered an oxida-tion through SET from intermediate S-2, [28] along with transmetalation to give intermediate S-4 ( Figure 3). This route has an endergonic activation barrier with an oxidationp otential (Table S4)n ot comparable to the one that was experimentally observed by CV.T he subsequentr eductivee limination is very facile. These results indicate the electrooxidation as the rate  Subsequently,w ee xplored ap ossible transmetalation prior to the SET (Figure 4), whichl eads to ac onsiderable decrease of the energy barrier associated with this process. The oxidation potential associated to theiron(II)/iron(III) was found to be comparably low (Table S4). Next, we assessed the influence of the Lewis acidic speciesi ns olution on this oxidation-induced reductivee limination ( Figure 5), which significantly lowered the transmetalation activation energy by the formation of ab imetallici ron(II) complex (S-3''). This bimetallic intermediate is in good agreement with our recent findings on stoichiometric transformations. [19a] This bimetallic intermediate S-3'' leads via anodic oxidation to the aryl-iron(III) complex (S-4). The calculated half-wave oxidation potential associated with this process is of 0.01 Vvs. ferrocene, which is in excellent agreement with the experimentally observed one (vide supra).  Finally,t he generality of the metallaelectrocatalysis strategy was reflected by the merger of electrosynthesis with environmentally benignm anganese catalysis. Indeed, unprecedented electrochemical manganese-catalyzed CÀHa ctivation was realized, indicating the broad nature of our strategy beyond iron catalysis, featuring cost-effective, non-toxic MnCl 2 as the catalyst (Scheme 6). It is particularly noteworthy that the manganese-catalyzed electrochemical CÀHa rylation did not require any zinc additives. These findings clearly show that this approach is not limited to cathodic zinc reduction manifolds.
In summary,t oxic and cost-intensive dihalide oxidants were for the first time replaced by electrocatalysis, allowing for versatile iron-catalyzed CÀHa ctivations. The unprecedented ferraelectrocatalytic CÀHa rylation enabledd irect arylations with ample scope, even efficiently occurring at room temperature. Our strategy set the stage for avoiding chemicalo xidants in low-valent metal-catalyzed CÀHa ctivation, featuringn on-toxic, Earth-abundant iron Fe(acac) 3 and user-friendly MnCl 2 catalysts. Detailed analyses by experiment,s pectroscopy and computation unravelled key insights into the role of additives within an iron(II/III/I) manifold, which should prove invaluable for the future design of iron-and manganese-catalyzed electrochemical strong bond activations. Detailed mechanistic studies on 3d metallaelectro-catalyzed CÀHa ctivation are currently ongoing in our laboratories and will be reported in due course.