C−H Oxygenation Reactions Enabled by Dual Catalysis with Electrogenerated Hypervalent Iodine Species and Ruthenium Complexes

Abstract The catalytic generation of hypervalent iodine(III) reagents by anodic electrooxidation was orchestrated towards an unprecedented electrocatalytic C−H oxygenation of weakly coordinating aromatic amides and ketones. Thus, catalytic quantities of iodoarenes in concert with catalytic amounts of ruthenium(II) complexes set the stage for versatile C−H activations with ample scope and high functional group tolerance. Detailed mechanistic studies by experiment and computation substantiate the role of the iodoarene as the electrochemically relevant species towards C−H oxygenations with electricity as a sustainable oxidant and molecular hydrogen as the sole by‐product. para‐Selective C−H oxygenations likewise proved viable in the absence of directing groups.

Abstract: The catalytic generation of hypervalent iodine(III) reagents by anodic electrooxidation was orchestrated towards an unprecedented electrocatalytic C À Hoxygenation of weakly coordinating aromatic amides and ketones.T hus,c atalytic quantities of iodoarenes in concert with catalytic amounts of ruthenium(II) complexes set the stage for versatile CÀH activations with ample scope and high functional group tolerance.D etailed mechanistic studies by experiment and computation substantiate the role of the iodoarene as the electrochemically relevant species towards C À Ho xygenations with electricity as as ustainable oxidant and molecular hydrogen as the sole by-product. para-Selective C À Ho xygenations likewise proved viable in the absence of directing groups.
Organic electrochemistry has emerged as an increasingly viable tool for molecular synthesis. [1] In addition to the unique potential of electrosynthesis,itisattractive also because of its storability and sustainable properties. [2] Thus,t he effective conversion of renewable electricity into value-added chemical products holds major prospect for as ustainable energy economy. [1h] In this scenario,t he merger of electrosynthesis and metal-catalyzed C À Ha ctivation [3] has recently been identified as ap articularly powerful approach for the resource-economic transformation of ubiquitous,b ut otherwise inert CÀHbonds. [4] Despite indisputable advances by the groups of Mei, Sanford, and Ackermann, [5] electrochemical CÀHo xygenations [6] of challenging arenes by weak coordination [7] have thus far proven elusive.T he reported metalcatalyzed C À Ho xygenations largely require cost-intensive palladium complexes and were inherently limited to strongly coordinating N-directing groups,s uch as oximes and pyr-idines. [5] In sharp contrast, CÀHoxygenations by synthetically useful weak O-coordination have not been realized in terms of sustainable electrocatalysis.Instead, highly reactive hypervalent iodine(III) reagents, [8,9] such as (diacetoxyiodo)benzene and [bis(trifluoroacetoxy)iodo]benzene,a re required in overstoichiometric quantities,which calls for strong chemical oxidants for their synthesis and leads to equimolar amounts of undesired halogenated waste products during the CÀH functionalization process.C ontrarily,w eh erein present am echanistically distinct strategy to address this molecular challenge,w hich orchestrates the catalytic electro-regeneration [10] of hypervalent iodine(III) reagents with ruthenium-(II)-catalyzed [11,12] CÀHf unctionalizations ( Figure 1). Salient features of our findings include a) the first electrocatalyzed CÀHoxygenations by weak coordination, b) the user-friendly electrochemical generation of hypervalent iodine reagents, c) ioda/ruthena-electrocatalyzedC À Hfunctionalizations that combine the advantages of ruthenium-catalyzed C À Hactivation with electrocatalytic hypervalent iodine chemistry,a nd d) mechanistic studies by experiment, computation, cyclic voltammetry,a nd in operando NMR spectroscopy.
We began our studies by exploring various reaction conditions for the envisioned electrochemical orchestrated C À Hoxygenation of substrate 1a in auser-friendly undivided cell (Table 1; see also Table S1 in the Supporting Information). [13] Preliminary experimentation indicated that the reaction could indeed be accomplished in the presence of catalytic amounts of iodobenzene and ruthenium(II) carboxylate (entry 1). Thei deal current density was found to be 2.67 mA cm À2 (entries 2a nd 3), and the C À Ha ctivation proceeded equally well under constant potential conditions at a2 .0 Vw orking potential (entry 4). Interestingly,ap latinum plate as the anode was found to be beneficial in comparison to areticulated vitreous carbon (RVC) anode (entries 5and 6). Here,d etailed IR-spectroscopic analysis of the RVCa node indicated its electrochemical modification. [13] Control experiments confirmed the essential role of electricity,t he ruthenium catalyst, and the iodoarene (entries 7-9). Furthermore, iodobenzene was found to be the only co-catalyst that enabled the desired C À Hoxygenation, while benzoquinone (entry 10) as well as chlorine,b romine,o rc halcogenide redox catalysis [14] fell short in converting substrate 1a (entries 11 and 12). [12] Notably,t he replacement of electricity by the typical chemical oxidants mCPBAorOxone resulted in considerably inferior efficacy (entries 13 and 14).
With optimized reaction conditions in hand, we probed the versatility of the co-catalytic [15] electrochemical C À H oxygenation system with ar epresentative set of weakly O-coordinating amides 1 (Scheme 1). Differently decorated amides bearing para and meta substituents were efficiently transformed into products 2a-k.U seful electrophilic functional groups,s uch as chloro,b romo,o re ven iodo substituents,aswell as sensitive benzyl chlorides were fully tolerated, an invaluable asset in terms of future late-stage modifications (2l-p). It is noteworthy that the reaction was not limited to Weinreb amides 1.Indeed, differently substituted amides 1qw were efficiently converted into the corresponding oxygenated arenes 2 with excellent efficiency (Scheme 2).
Theoutstanding robustness of the iodine(III)/ruthenium-(II)-catalyzed C À Ho xygenation process was further highlighted by its ability to also transform weakly coordinating ketones 4 (Scheme 3). [7] Theversatility of the electrocatalysis was hence reflected by the successful use of differently decorated ketones 4.T hereby,v arious substitution patterns were well tolerated to deliver products 5e-j.T he inherent selectivity features were probed by intramolecular competition experiments with diaryl ketones 4k and 4l,w hich were both functionalized with excellent mono-and chemoselectivity.T he regioselectivity of the C À Ht ransformation of the unsymmetrically substituted substrate 4l further illustrates the inherent preference for electron-rich arenes (see below). PhBr or PhCl instead of PhI -12 PhS-SPh or PhSe-SePhinstead of PhI -13 mCPBA instead of electricity 15 14 Oxone instead of electricity 32 [a] Undivided cell, 1a (0.50 mmol), iodobenzene (20 mol %), 3 Scheme 1. Electro-catalyzed CÀHa ctivation of Weinreb amides 1.
It is noteworthy that the ruthena-electrocatalyzed C À H functionalization was not limited to chelation-assisted ortho oxygenation. Indeed, directing-group-free [6f] functionalization in the challenging remote position was likewise sequentially accomplished with excellent levels of site selectivity, while the ruthenium catalyst was found to be essential (Scheme 5).
Thes calability of the orchestrated electrochemical C À H oxygenation was demonstrated by the gram-scale synthesis of product 2a without loss of efficiency( Scheme 6).
Given the efficiencyo ft he unprecedented electrochemical C À Ho xygenation system, we became interested in delineating its mode of action. First, the use of ad euterated solvent in the catalytic reaction revealed the reversibility of the CÀHa ctivation step (Scheme 7a). This finding contrasts with CÀHo xygenations enabled by the chemical oxidant PIFA, for which H/D scrambling was not observed. [6g] Second, kinetic studies provided strong support for af ast and reversible C À Hm etalation with am inor kinetic isotope effect (KIE) of only k H /k D % 1.6. [13] These observations overall suggest that not the CÀHactivation, but rather the oxidation of the cyclometalated species is the rate-determining step. These experimental data are again in contrast with the use of chemical oxidants,f or which the CÀHa ctivation was proposed to be the rate-limiting step with aKIE of k H /k D % 3.0. [6f] Third, competition experiments,u sing either the Weinreb amides 1b and 1d or the difunctionalized ketone 4m, highlighted that electron-rich substrates are preferentially functionalized (see above;S cheme 7b), which can be rationalized in terms of ab ase-assisted internal electrophilic-type substitution (BIES) being operative for the C À Hm etalation. [16] Forth, an intramolecular competition experiment with substrate 1x revealed the Weinreb amide as am ore powerful coordinating group for the iodine/ruthenium-cocatalyzed CÀHtransformation (Scheme 7c). Fifth, we probed the possibility of p-cymene dissociation. [17] Detailed GC analysis did not provide evidence for free p-cymene in the reaction mixture at any point during the reaction. [12] Next, we studied the reaction profile of the direct anodic generation of the hypervalent iodine reagents by in operando NMR spectroscopy (Figure 2a). [12] This combination of electrochemistry and in situ spectroscopy enabled us to study the generation of otherwise unstable electrochemically generated

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Communications 3186 www.angewandte.org iodine(III) reagents.I nitially,t he anodic oxidation of iodobenzene in trifluoroethanol (TFE) was monitored and showed almost full conversion of the aryl halide after 2.5 h at 10 mA (Figure 2a,i). [10a] Subsequently,t he anodic generation of hypervalent iodine 11 b from TFAa nd iodobenzene was completed with only slightly prolonged reaction times within 3h (Figure 2a,ii).T hereafter,w ee xamined the electrochemical CÀHo xygenation by means of cyclic voltammetry ( Figure 2b). [12] To this end, the oxidation of different aryl halides was recorded. [13] In trifluoroacetic acid, only iodobenzene underwent irreversible anodic oxidation with an onset potential of E = 1.25 Vv s. ferrocene.B ym eans of computation we also confirmed that the oxidation potential of the iodobenzene is 200 mV lower than that of the ruthenium(II/ IV) manifold, [12] substantiating the iodine co-catalysis.N otably,other organic halides are known to undergo oxidation at considerably higher potentials, [18,12] reflecting the unique catalytic competence of iodine reagents (see above, Table 1). Thea mide 1a and electron-deficient iodoarenes showed significantly higher potentials for anodic oxidation than unsubstituted and electron-rich iodoarenes.Amixture of iodobenzene and amide 1a did not lead to significant changes in the voltammogram, which is in agreement with the control experiments summarized in Table 1. Cyclic voltammetry of the independently prepared ruthenacycle 10 in DCE provided support for its facile oxidation. [13] Based on our detailed mechanistic studies,w ep ropose ap lausible catalytic cycle for the ioda/ruthena-electrocatalyzed CÀHo xygenation (Scheme 8). Thec atalytic cycle is initiated by CÀHa ctivation on amide 1 by ar uthenium(II) carboxylate.M eanwhile,i odobenzene undergoes at wo-electron-transfer anodic oxidation to generate the hypervalent iodine(III) species.The iodine(III) reagent then mediates the oxidation of 12 by carboxylate transfer to the ruthena-(II)cycle,d elivering ruthenium(IV) intermediate 13,w hich then undergoes rapid oxidatively induced reductive elimination to furnish product 2 after hydrolysis.L astly,t he regeneration of the active catalyst takes place.The formation  respectively.C onversion determined by 1 HNMR analysis using CH 2 Br 2 as the internalstandard. i) Reaction profile of the anodic formation of CH 3 C 6 H 4 I(OCH 2 CF 3 ) 2 (11 a). ii)Reaction profile of the anodic synthesis/formationo fCH 3 C 6 H 4 I(OCOCF 3 ) 2 (11 b). b) Cyclic voltammetry (TFA, 0.1 m nBu 4 NPF 6 ,100 mVs À1 )using glassy carbon as the working electrode. Cyclic voltammograms of different reaction components and their mixtures as well as of different haloarenes.

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Communications of molecular hydrogen as the only stoichiometric by-product was confirmed by GC headspace analysis, [12] and bears great potential for paired electrochemical approaches. [19] In conclusion, we have devised an ovel electrochemical co-catalytic system for the CÀHo xygenation of synthetically useful amides and ketones by challenging weak O-coordination. Theversatile iodine(III)/ruthenium(II)-electrocatalyzed CÀHf unctionalization was enabled by orchestrating the catalytic generation of hypervalent iodine(III) reagents with sustainable electricity as ac ost-effective terminal oxidant, with the formation of molecular hydrogen as the sole byproduct. Detailed mechanistic studies by experiment, computation, and flow-NMR spectroscopy provided-in contrast to chemical oxidation-support for afast and reversible CÀH ruthenation. Theruthenium catalyst also allowed for electrochemical remote C À Ho xygenations in the absence of directing groups.