Nickela‐electrocatalyzed C−H Alkoxylation with Secondary Alcohols: Oxidation‐Induced Reductive Elimination at Nickel(III)

Abstract Nickela‐electrooxidative C−H alkoxylations with challenging secondary alcohols were accomplished in a fully dehydrogenative fashion, thereby avoiding stoichiometric chemical oxidants, with H2 as the only stoichiometric byproduct. The nickela‐electrocatalyzed oxygenation proved viable with various (hetero)arenes, including naturally occurring secondary alcohols, without racemization. Detailed mechanistic investigation, including DFT calculations and cyclovoltammetric studies of a well‐defined C−H activated nickel(III) intermediate, suggest an oxidation‐induced reductive elimination at nickel(III).

Transformations that form C À Ob onds [1] are of utmost importance in the synthesis of bioactive pharmaceuticals, [2] natural products, [3] and functional materials. [4] Classical approaches for the synthesis of aryl ethers,s uch as the palladium-catalyzed Buchwald-Hartwig cross-couplings [5] and copper-catalyzed Ullmann-Goldberg [6] or Chan-Evans-Lam reactions, [7] rely on prefunctionalized substrates,t he preparation and use of which result in undesired byproducts and solvent waste.I nc ontrast, dehydrogenative functionalizations of otherwise inert CÀHb onds constitute more sustainable strategies,which significantly reduce the footprint of organic syntheses. [8] Despite major advances in CÀH activation, C À Halkoxylations are less developed than typical hydroxylations, [9] acetoxylations, [10] and phenoxylations [11] because competing b-hydride elimination or overoxidation represent undesired side reactions.S pecifically,C ÀHa lkoxylations with sterically encumbered secondary alcohols continue to be difficult, which contrasts the wealth of viable methods for the use of primary alcohols. [12] In recent years,e lectrosynthesis [13] has gained significant attention through the use of waste-free and inexpensive electric current as redox equivalent, thereby avoiding stoichiometric amounts of toxic and costly chemical redox reagents.E lectrochemical CÀHa ctivations [14] have until recently largely required expensive 5d and 4d metals,s uch as palladium, [15] ruthenium, [16] rhodium, [17] and iridium. [18] In sharp contrast, major recent momentum was gained by the use of earth-abundant, less toxic 3d metals, [19] such as cobalt [20] and copper, [21] as reported by the groups of Ackermann, Lei, and Mei, among others.Inspite of the indisputable progress, such cost-effective nickel electrocatalysis has proven elusive until very recently,w hen we established nickela-electrocatalyzed CÀHa minations,w hich were however restricted to morpholine-type amines. [22] In contrast, we have now found that versatile nickel catalysts are uniquely effective for challenging CÀHelectro-alkoxylations with sterically encumbered secondary alcohols,w hich we report herein. It is noteworthy that complexes of cobalt, copper,a nd even precious palladium, iridium, ruthenium, and rhodium did not catalyze the difficult secondary CÀHa lkoxylations.I n addition, we disclose mechanistic support for an oxidationinduced reductive elimination nickel(III/IV) regime ( Figure 1). We began our studies by optimizing the reaction conditions for the envisioned nickela-electrocatalyzed CÀH oxygenation of amide 1a with the challenging secondary alcohol 2a in an undivided cell set-up (Table 1and Table S1-S7 in the Supporting Information). After considerable experimentation, the desired product 3aa was obtained with Ni(DME)Cl 2 as the catalyst and bulky carboxylate NaO 2 CAd as an additive,w hilst reticulated vitreous carbon (RVC) and nickel-foam electrodes were found to be beneficial (entries 1-4). C À Hacetoxylations were not observed. Theperformance of the catalysts was improved by adjusting the alcohol concentration (Table S4). Control experiments confirmed that the eletrooxidative CÀHt ransformation could not be realized in the absence of electricity,t he nickel complex, or the additive (entries 7-9). Other nickel compounds,s uch as Ni(COD) 2 ,Ni(acac) 2 ,orNi(OAc) 2 also furnished the desired product 3aa (entry 10, and Table S3). It is particularly noteworthy that the nickel catalysts featured proved uniquely effective for the challenging CÀHa ctivation with secondary alcohols,w hile other transition metals,i ncluding cobalt, copper, and even precious palladium, iridium, ruthenium, or rhodium, fell short under otherwise identical reaction conditions (entries 11-17 and Table S7). Indeed, while palladium, copper, and cobalt catalysts were highly effective for primary alcohols,n oo rv ery minor catalytic turnover was accomplished with the secondary alcohol 2a (Table S9).
Thee fficacyo ft he nickela-electrooxidation was considerably affected by the substitution pattern of the quinoline moiety (Scheme 1). Analysis by computation at the PEB0/ Def2TZVP level of theory [23] unraveled the key importance of increased electron-density at the quinolinyl nitrogen, while decreased electron density at the amide nitrogen was beneficial ( Figure S19 in the Supporting Information). These findings indicate the importance of increased sdonation at the sp 2 -hybridized quinolinyl nitrogen in concert with an anionic amide nitrogen.
With the optimized reaction conditions in hand, we probed the versatility of the nickela-electrocatalyzed CÀH alkoxylation with various secondary alcohols 2 (Scheme 2).
Not only benzylic alcohols 2b and 2c were well accepted, but also alicyclic, cyclic, and heterocyclic alcohols were successfully converted with moderate to excellent yields (3ab-3ap). Remarkably,t he naturally occurring alcohols menthol, cholesterol, and b-estradiol 2q-2s were identified as viable substrates,n otably without racemization at the stereogenic centers (Figures S1 and S2). 1N i(DME)Cl 2 NaOPiv 45 [b] 2N i(DME)Cl 2 NaO 2 CAd 55 [b] 3N i(DME)Cl 2 KOAc 24 [b] 4N i(DME)Cl 2 K 2 HPO 4 - [b]   Moreover,w ee valuated the robustness of the nickelaelectrocatalyzed C À Halkoxylation with avariety of functionalized benzamides 1 (Scheme 3). Thus,t he reactions proceeded efficiently with arenes 1 bearing valuable functional groups,s uch as halo,s ulfido,a nd cyano substituents.F or the meta-substituted substrates 1b and 1c,t he reaction occurred with high position selectivity owing to repulsive steric interactions.T he nickela-electrocatalysis was not limited to arenes,b ut the heteroarene 1o was also selectively transformed. It is noteworthy that strongly coordinating pyridine was fully tolerated to give bidentate amide-guided C À H functionalization (3pa). Likewise,t he gram-scale synthesis was realized without compromising the efficacyo ns cale (3ba).
In addition, we carried out electricity on/off experiments to probe ar adical-chain scenario (Scheme 4a). Ther eaction was halted without electrochemistry,h owever,t he C À H alkoxylation continued when switching the electric current back on, thereby ruling out ar adical-chain process.
Thec lear benefits of electricity in this case were not restricted to it being agreen and inexpensive oxidant. Indeed, the electrocatalytic reaction was characterized by significantly improved levels of performance as compared to the chemical oxidants AgOAc,C u(OAc) 2 ,m olecular oxygen, PhI(OAc) 2 ,orK 2 S 2 O 8 (Scheme 4b).
Given the unique performance of the nickela-electrocatalyzed CÀHa ctivation, as eries of experiments were conducted to gain insight into the reaction mechanism. Intermolecular competition experiments between secondary alcohol 2p and amine 2t,o rw ith primary alcohol 2u, highlighted the particular challenge of nickela-eletrooxidative secondary CÀHalkoxylations (Scheme 5a,b). In contrast to cobalta-electrocatalysis by aB IES mechanism, an intermolecular competition experiment showed electron-deficient arenes 1 to be inherently more reactive (Scheme 5c). This finding is indicative of aconcerted metalation-deprotonation (CMD) mechanism for the CÀHa ctivation. [24] Head-space gas-chromatographic analysis identified H 2 as the only stoichiometric byproduct ( Figure S14). Thee lectrocatalysis was inhibited by the typical radical scavengers TEMPO,BHT, and BQ,which is indicative of single-electron transfer (SET) steps (Scheme 5d). Am inor kinetic isotope effect of k H /k D % 1.4 as measured by independent experiments gave support Scheme 3. Electrooxidative CÀHalkoxylation of arenes.
for afacile CÀHscission ( Figure S13). H/D exchange was not found when using isotopically labeled tBuOD as the additive ( Figure S11). An irreversible nickelation [25] was further found by DFT calculations to generate the substrate-coordinated nickel(II) intermediate Ni II -II ( Figure S20). Thus,c ombined analysis by DFT and CV studies provided strong support for av iable nickel(II/III) oxidation (purple,F igure S22).
To rationalize the elementary process of CÀOformation, the well-defined nickel(III) complex Ni III -I was independently synthesized, and fully characterized, including by X-ray diffraction analysis (Scheme 6a). [26] Ni III -I was competent in acatalytic and stoichiometric setting,provided that electricity was applied (Scheme 6b,c). Cyclic voltammetric studies of Ni III -I showed facile oxidation at apotential of 0.50 Vvs. Fc 0/+ (red, Scheme 6e), thus suggesting the formation of af ormal nickel(IV) complex.
In good agreement with these results,D FT calculations indicate an on-innocent ligand phenomenon in the oxidation process to generate af ormal nickel(IV) species (Scheme 7). Theo xidation is thus best described as al igand-centered process.F inally,h igh-valent intermediate Ni IV -I will be coordinated by the alcohol 2,a long with subsequent deprotonation and reductive elimination to furnish the alkoxylated products 3 ( Figure S21). [26] As to the synthetic utility of this method, it is noteworthy that the 6-methylquinuoline was easily removed in atraceless fashion to provide efficient access to benzamide 4,b enzoic acid 5,o raromatic aldehyde 6 (Scheme S17-S19).
In summary,w eh ave developed ac arboxylate-enabled nickela-electrocatalyzed alkoxylations with challenging secondary alcohols.T he robust electrochemical CÀHa ctivation was accomplished with broad substrate scope through the use of traceless removable quinoline amides.T he most userfriendly nickel electrocatalyst ensured high levels of both chemoselectivity and position selectivity.T he C À Ho xygenation was more effective with electricity than with any other chemical oxidant. Detailed mechanistic studies through isolation experiments,c yclovoltammetry,a nd computation provided strong support for an oxidation-induced reductive elimination nickel(III/IV) manifold.

Conflict of interest
Theauthors declare no conflict of interest.
Scheme 7. Calculated electronic configuration of Ni IV -I ground triplet state.