Electroreductive room-temperature C–H activations with RuCl₃·nH₂O precatalyst via cathodic ruthenium(III/II) manifold

Abstract

We, herein, disclose a strategy to directly utilize user-friendly RuCl₃·nH₂O for ortho- as well as meta-C–H functionalizations at low temperatures. The key to success was the in situ formation of the active ruthenium catalyst through cathodic electron transfer, setting the stage for C–H activations under exceedingly mild reaction conditions. The robustness of our electrocatalysis process was highlighted by the late-stage diversification of compounds of relevance to chemical, agrochemical, and pharmaceutical industries, as well as simple amines as terminal reductants for the electroreduction. Detailed mechanistic studies by, among others, spectroelectrochemical analysis provided strong evidence for a cathodic reduction manifold.

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Introduction

Ruthenium-catalyzed C–H activation chemistry has evolved into an indispensable chemical toolbox for selectively functionalizing arene scaffolds.^1–10 For instance, site-selectivity can be precisely modulated^11–17 without exploiting elaborate auxiliaries, providing instant access to ortho-^18–27 or meta-decorated frameworks.^28–41 Our group indeed discovered that the addition of phosphine ligands can alter the site-selectivity in C–H benzylations from ortho- to unusual meta-selectivities.¹⁴ Precise selectivity control can also be achieved depending on the nature of the electrophilic substrates.^13,16 Among such transformations, C–H arylations hold a significant potential for the assembly of valuable biaryl scaffolds,^6,9,10 with carboxylate-assisted ruthenium(II/IV)-catalyzed C–H activations representing the most robust and efficient strategy.²³ In recent years, substantial efforts have been made to render reaction conditions milder. Notable advancements include the use of light irradiation, as disclosed by Ackermann and Greaney,^42–45 as well as the employment of arene ligand-free ruthenium precatalysts.^46,47

Despite the considerable progress,^48–52 the majority of existing approaches heavily depend on ruthenium(II) precatalysts, which require lengthy organometallic syntheses by experts with glovebox techniques. This reliance jeopardizes the resource efficiency and user-friendly nature of the overall processes. Importantly, when tracing back the synthesis routes, one can realize that ruthenium(II) complexes, such as [RuCl₂(p-cymene)]₂, [Ru(OAc)₂(p-cymene)], arene ligand-free complexes Ru1 and Ru2, originate from RuCl₃·nH₂O (Scheme 1A).^46,47,53 Therefore, the direct employment of RuCl₃·nH₂O as the catalyst offers a more sustainable and user-friendly strategy for executing C–H activation. In 2007, our group first disclosed the use of arene ligand-free RuCl₃·nH₂O for ortho-C–H arylation.²⁴ Subsequent studies also demonstrated that RuCl₃·nH₂O can be utilized for ortho-^54–62 as well as meta-C–H functionalizations.^63–65 Nevertheless, rather harsh conditions with reaction temperatures from 100–140 °C are generally required, representing a considerable limitation.

Scheme 1 (A) Ruthenium(II) complexes prepared from RuCl₃·nH₂O. (B) This study. Het: heterocycle.

To directly unlock the inherent reactivity of ruthenium catalysis using RuCl₃·nH₂O, we hypothesized whether, upon the electroreduction of a ruthenium(III) species, an active ruthenium(II) intermediate could be formed,^54,57,59 setting the stage for economically-attractive, yet user-friendly C–H activation. As a result of our studies, we, herein, disclose the direct use of RuCl₃·nH₂O for C–H activations at mild reaction temperatures, enabling ortho-C–H arylations and meta-C–H alkylations across a wide array of substrates, including challenging pharmaceutical, agrochemical, and naturally-occurring molecules (Scheme 1B). Thus, we harness electricity as a sustainable reductant, eliminating the need for potentially hazardous chemical redox agents.^66–69 A notable feature of our findings is that both a sacrificial anode or a simple amine could be employed as the terminal oxidant. Detailed spectroelectrochemical studies uncovered the key reduction of the ruthenium(III) precatalyst.

Results and discussion

Reaction optimization

To probe our original hypothesis, we performed the C–H arylation under electroreductive conditions using transformable oxazoline 1a and aryl bromide 2a as the model substrates in the presence of RuCl₃·nH₂O as the bench-stable and commercially available precatalyst (Table 1). We thus employed NaOAc for a base-assisted internal electrophilic substitution (BIES) C–H activation manifold^7,10 with K₂CO₃ as the stoichiometric base. We probed dipolar DMA as the solvent to ensure conductivity, along with a zinc plate as the sacrificial anode. Gratifyingly, we indeed obtained the desired arylation product 3 in 85% yield after electrolysis using a non-precious zinc plate anode and a nickel foam cathode (j = 2.5 mA cm⁻², 1.8 F mol⁻¹, entries 1 and 2). We were delighted to observe that the reaction proceeded at 35 °C, significantly lower than the temperatures required in previous studies using RuCl₃·nH₂O.^24,54–62N-Methyl-2-pyrrolidone (NMP) as the reaction medium led to a lower yield (entry 3). Other leaving groups of aryl halides, such as chloro and iodo groups, proved viable, with the bromo group being superior in the ruthenium electrocatalysis (entry 4). Thus far, chloroarenes gave inferior results, likely due to their higher bond dissociation energies (BDE).^24,62 A control experiment without electricity highlighted the indispensable role of the electroreduction (entry 5). Likewise, no product formation or a diminished yield was observed in the absence of either RuCl₃·nH₂O or NaOAc (entries 6 and 7). Particularly, the crucial presence of NaOAc suggests that carboxylate-assisted C–H activation is the operative working mode.²³ We also tested other bench-stable ruthenium(II) complexes, such as [RuCl₂(p-cymene)]₂ or [Ru(OAc)₂(PPh₃)₂], albeit with limited success (entry 8).

Table 1 Reaction optimization^a

Entry	Deviations from the above conditions	3 (%)^b
a Reaction conditions: 1a (0.50 mmol), 2a (1.5 equiv.), RuCl3·nH2O (10 mol%), NaOAc (30 mol%), K2CO3 (2.0 equiv.), DMA (3.0 mL), 24 h, 35 °C, CCE at 2.0 mA, Zn anode, Ni cathode, undivided cell. b Determined by ^1H-NMR analysis using dibromomethane as the internal standard. c Isolated yield. d Catalyst loading: 5.0 mol%. CCE: constant current electrolysis, DMA: N,N-dimethylacetamide, N.D.: not detected.
1	None	90 (85)^c
2	Room temperature	37
3	NMP instead of DMA	78
4	Aryl iodide or aryl chloride instead of 2a	60/73
5	No electricity but with electrodes	N.D.
6	No RuCl3·nH2O	N.D.
7	No NaOAc	23
8	[RuCl2(p-cymene)]2^d or [Ru(OAc)2(PPh3)2] instead of RuCl3·nH2O and no electricity	N.D.

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Electrocatalysis robustness

With the optimal conditions in hand, we next explored the viable (hetero)aryl bromide scope for the electro-enabled C–H arylation (Fig. 1A). Various para-substituted aryl bromides were well tolerated, regardless of the electronic nature of their substituents (3–10). We were particularly pleased to find that valuable electrophilic functional groups, such as ester (3), ketone (4), hydroxy (9), and chloro (10) groups, were fully tolerated by the electrocatalysis, without any significant signs of cross-electrophile couplings (CEC)^70–80 induced by the electricity. Furthermore, meta- and more challenging ortho-substituted aryl bromides gave the desired arylation products likewise (11–17). To our delight, the ruthena-electrocatalysis proved compatible with hetaryl bromides, such as dibenzofuran, 1,3-benzodioxoles, and NH-free indoles (18–22).

Fig. 1 (Hetero)aryl bromide and heterocycle scope. ^aReaction conditions: 1 (0.50 mmol), 2 (1.5–3.0 equiv.), RuCl₃·nH₂O (10 mol%), NaOAc (30 mol%), K₂CO₃ (2.0 equiv.), DMA (3.0 mL), 24 h, 35 °C, CCE at 2.0 mA, Zn anode, Ni cathode, undivided cell. Ar: 4-(CO₂Me)C₆H₄ for products 23–27.

Next, we turned our attention to evaluating heterocycle-attached arenes (Fig. 1B). The benzene-substituted oxazoline yielded the difunctionalization product 23 in excellent yield. The electrocatalysis proved tolerant of the fluoro-attached aryl oxazoline (24). Notably, the chloro group on the para-position of the aromatic ring remained intact (25), demonstrating the high electrocatalysis chemo-selectivity and its potential for further diversification. We were pleased to selectively obtain arylation products using pyridine and pyrazole-derived substrates (26 and 27).

We have confirmed, thus far, that our electrochemical C–H arylation efficiently proceeded under mild conditions to furnish various arylation products. Hence, we next explored the challenging late-stage diversification of complex molecules (Fig. 2). Thus, we employed commercially available pharmaceutical and agrochemical compounds bearing chloro leaving groups. For instance, fenofibrate and chlorpropham were successfully incorporated into the aryl oxazoline scaffolds, even when sensitive ester and carbamate functional groups were present (28 and 29). The drug haloperidol with a free OH-hydroxyl group was fully tolerated by the ruthenium electrocatalysis (30). To our delight, ezetimibe and δ-tocopherol furnished the target arylation products 31 and 32. Furthermore, glyburide was also tolerated, leading to the arylation product bearing a sulfonylurea fragment, one of the important building blocks in medicinal chemistry (33).⁸¹ We were also pleased that the azapeptide drug, atazanavir, underwent selective functionalization on the phenylpyridine scaffold (34).

Fig. 2 Electro-late-stage diversification. General reaction conditions: 1 (0.50 mmol), 2 (1.5–3.0 equiv.), RuCl₃·nH₂O (10 mol%), NaOAc (30 mol%), K₂CO₃ (2.0 equiv.), DMA (3.0 mL), 24 h, 35 °C, CCE at 2.0 mA, Zn anode, Ni cathode, undivided cell. ^a Reaction temperature: 50 °C. ^bRuCl₃·nH₂O: 20 mol%, NaOAc: 60 mol%, K₂CO₃: 3.0 equiv., 70 °C. Ar: m-xylyl for product 34. Bn: benzyl.

To replace the zinc anode, we evaluated N,N-diisopropylethylamine (DIPEA) as a terminal reductant with a stable anode material.⁸² Upon experimentation,⁸³ the desired products 3, 15, and 24 were selectively obtained without a sacrificial anode (Fig. 3). Detailed mass-spectrometry analysis confirmed the Hünig base (DIPEA) serving as the terminal reductant.

Fig. 3 Sacrificial anode-free electrochemical ruthenium-catalyzed ortho-C–H arylation. Reaction conditions: 1 (1.2 equiv.), 2 (0.50 mmol), RuCl₃·nH₂O (10 mol%), NaOAc (30 mol%), K₂CO₃ (2.0 equiv.), DIPEA (2.0 equiv.), DMA (3.0 mL), 24 h, 35 °C, CCE at 2.0 mA, platinum anode, GF cathode, undivided cell.

The ruthena-electrocatalysis was not limited to ortho-C–H arylations. Indeed, it also proved to be applicable to challenging meta-C–H alkylations, when employing secondary and tertiary alkyl (pseudo)halides (Fig. 4). By the judicious choice of additive and solvent, we accomplished the meta-C–H alkylations of arenes, thus giving the desired products 36 and 37. Inspired by our previous findings,⁸⁴ we also tested the pyridinium salt derived from aspartic acid and successfully isolated the corresponding meta-secondary alkylation product 38.

Fig. 4 Electrochemical ruthenium-catalyzed meta-C–H alkylation. Reaction conditions: 1 (0.50 mmol), 35 (2.0–3.0 equiv.), RuCl₃·nH₂O (10 mol%), (PhO)₂PO₂H (30 mol%), K₂CO₃ (2.0 equiv.), ⁿBu₄NPF₆ (50 mM), THF (3.0 mL), 50 °C, CCE at 1.0 mA, 4 h, and 13 h at 50 °C, Zn anode, Ni cathode, undivided cell. THF: tetrahydrofuran.

Mechanistic studies

Having validated the robustness of the new ruthenium electrocatalysis, we turned our attention to elucidating the modus operandi. First, we performed a control experiment wherein 10 mol% of electrons were supplied within the initial 40 minutes, and the current was switched off thereafter (Fig. 5A). Here, the arylation product 3 was obtained in 59% yield. This outcome suggests that electricity is primarily required to induce the formation of the key monocyclometalated ruthenium(II) intermediate (Fig. 5B, left). The involvement of such a species was verified by the experiment using a well-defined monocyclometalated complex Ru3, in which we obtained the desired arylation product 24 in 79% yield, further corroborating the electrochemical initiation being operative (Fig. 5B, right).

Fig. 5 (A) Electrolysis for 40 min. (B) Electrochemical generation of a monocyclometalated complex. (C) CV studies. (D-1) UV/vis absorption spectrum of the DMA solution containing substrate 1a (0.13 mM), RuCl₃·nH₂O (0.13 mM), and NaOPiv (0.13 mM). (D-2) Spectroelectrochemical analysis of the DMA solution containing substrate 1a (0.2 mM), RuCl₃·nH₂O (0.2 mM), NaOPiv (0.2 mM), and ⁿBu₄NPF₆ (0.1 M) at 35 °C under N₂. Measurements were performed at −0.40, −1.00, or −1.75 V. (D-3) Spectroelectrochemical analysis performed at −1.75 V (vs. Fc/Fc⁺) over 85 s.

To rationalize the electrochemical features of our electrocatalysis, we conducted detailed cyclic voltammetry (CV) studies using RuCl₃·nH₂O, substrate 1a, and NaOAc (Fig. 5C). Interestingly, the presence of substrate 1a resulted in a pronounced irreversible reduction event at −1.7 V, implying coordination of arene 1a to ruthenium. In all cases, oxidation events were observed at 0.7 V. To gain more insights, we selected specific voltage values from the cyclic voltammograms and sought to observe the potential-dependent consumption of the ruthenium(III) precatalyst by means of spectroelectrochemistry. Thus, we conducted potentiostatic analysis mode and focused on the absorption of the ruthenium(III) precatalyst at 400 nm (Fig. 5D-1). As depicted in Fig. 5D-2, whereas there was no significant change in the absorbance at 400 nm during the measurements at −0.40 and −1.00 V, spectroelectrochemical analysis at −1.75 V allowed us to detect a notable decrease in absorbance, which was also visible from the spectra with entire wavelengths (Fig. 5D-3). Overall, these observations are indicative of an electrochemical reduction of the ruthenium(III) precatalyst to afford a catalytically relevant ruthenium(II) complex. Also, electrochemical analysis by a rotating disk electrode was supportive of a ruthenium(III)/ruthenium(II) scenario.^83,85,86

DFT calculations

To rationalize the modus operandi of the electrocatalysis, detailed density functional theory (DFT) calculations were performed for the key oxidative addition step, considering both mono- and biscycloruthenated species Ru-I and Ru-IV, respectively, at the PBE0-D4/def2-TZVPP-SMD(DMA)//TPSS-D3(BJ)/def2-SVP level of theory (Fig. 6). The biscycloruthenated complex Ru-IV, generated via two C–H ruthenations, exhibits an energy barrier of 20.2 kcal mol⁻¹ for the oxidative addition with aryl bromide 2a, leading to the ruthenium(IV)-aryl species Ru-VI. Notably, the oxidative addition pathway involving the monocycloruthenated species is energetically disfavored with a considerably higher activation barrier of 25.5 kcal mol⁻¹. These results are consistent with earlier computational studies by Ackermann¹⁹ and very recent findings by Macgregor⁸⁷ for the oxidative addition occurring on the biscyclometalated ruthenium(II) intermediates.

Fig. 6 Computed relative Gibbs free energies on the oxidative addition step for both (a) monocycloruthenated and (b) biscycloruthenated species at the PBE0-D4/def2-TZVPP-SMD(DMA)//TPSS-D3(BJ)/def2-SVP level of theory.

Proposed mechanism

On the basis of our experimental and computational findings, we propose a catalytic cycle for the electro-induced C–H arylations as depicted in Fig. 7. The reaction commences upon cathodic ruthenium(III) reduction, along with carboxylate-assisted C–H activation to form complex Ru-I. Next, biscyclometalated intermediate Ru-IV is formed and undergoes oxidative addition with aryl bromide 2. Reductive elimination from the thus formed ruthenium complex Ru-IV releases the arylation product and regenerates the complex Ru-I.

Fig. 7 Proposed mechanism.

Conclusions

In conclusion, we have realized a low-temperature ruthenium-catalyzed C–H activation directly employing commercially-available RuCl₃·nH₂O as a resource-economical precatalyst. The reaction provided selective access to ortho- or meta-functionalized products from a wide array of substrates, including structurally-complex drug molecules and natural products. Detailed electroanalysis provided strong support for a ruthenium(III)/ruthenium(II) manifold enabled by cathodic reduction. A sacrificial anode could be avoided. Overall, our electrocatalysis strategy offers a user-friendly and general strategy to replace the established ruthenium(II) precatalysts in the field of C–H activation chemistry to enable catalysis under exceedingly mild conditions.

Data availability

The data supporting this article have been uploaded as part of the ESI.†

Author contributions

Conceptualization, L. A.; methodology, T. M.; investigation, T. M.; spectroelectrochemical analysis, T. v. M.; rotating disk electrode experiments, T. M. and Z. L.; DFT calculations, B. Y. and J. C. A. O.; writing – original draft, all authors; writing – review & editing, all authors; funding acquisition, L. A.; resources, L. A.; supervision, L. A.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors gratefully acknowledge support from the DZHK, the ERC Advanced Grant No. 101021358, the DFG (SPP2363, Gottfried Wilhelm Leibniz award to L. A.), the European Union's Horizon 2020 research and innovation program (Marie Skłodowska-Curie Grant Agreement No. 860762 to T. M.), the FCI (Kekulé-Fellowship no. 110091 to T. v. M.), and the CSC (scholarship to Z. L. and B. Y.). We thank Dr M. John (University of Göttingen) for assistance with NMR analysis and Dr H. Frauendorf (University of Göttingen) for HRMS.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5sc02780b

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