Optimization Studies for the Cobaltaelectro-Catalyzed C–H

activations were evaluated.^[55a] Here, particularly arenes with electron-deficient bidentate amide directing groups^[11b] were chosen as the model substrate to stabilize the cobalt intermediates^[99] and to avoid undesired direct anodic amide oxidation.^[270] Furthermore, alcoholic solvents were envisioned to serve as the ideal reaction medium for the metallaelectro-catalyzed C–H transformation, due to its protic nature and high conductivity.^[271] Inert electrode materials, such as platinum or graphite, were chosen as the anode and cathode material,^[272] respectively, to avoid electrode fouling under the

electrolysis conditions and in case of platinum, to facilitate the hydrogen evolution reaction (HER).^[273]

After initial successes for the cobaltaelectro-catalyzed C–H oxygenations with benzamide 34a and readily available ethanol (35a), it was found that the electrochemical conditions, inter alia electrolysis cell dimensions,^[274] electrode materials as well as the mode of electrolysis had a strong impact on the reaction outcome (Table 1).^[43] Thus, by the use of an undivided electrolysis cell (cf. Figure 77), constant potential electrolysis at 2.0 V vs.

Ag/Ag⁺ and two platinum electrodes, product 36aa was isolated in 18% yield and significant metal-deposition was observed on the cathode (entry 1). To avoid electrodeposition of the cobalt catalyst, a H-type divided cell was developed, based on previously reported designs.^[275] With the custom-made divided setup in hand (cf. Figure 78), the C–H alkoxylation of benzamide 34a was achieved in 51% yield (entry 2).

Table 1. Preliminary results for the cobaltaelectro-catalyzed C–H oxygenation.^[a]

Entry Mode of Electrolysis Anode Cathode T [°C] Yield [%]

[a] Reaction conditions: 34a (0.50 mmol), Co(OAc)2·4H2O (20 mol %), NaOPiv (2.00 equiv in each half-cell), EtOH (35a) (7.0 mL in each half-half-cell), T [°C], electrolysis, 16 h, graphite felt anode, Pt-plate cathode, divided cell. Isolated yields are given. [b] Undivided cell, EtOH (35a) (14 mL). [c] Electrolysis for 6 h. [d]

Reaction was performed by Dr. N. Sauermann.

Notably, decreasing the reaction temperature from 60 °C to 23 °C resulted in negligible differences in the catalytic efficacy (entry 3), while lowering the applied potential or the reaction time proved less efficient (entries 4 and 5). In contrast, by changing the anode

material from platinum to graphite felt allowed for significantly higher catalytic efficacy (entry 6). Likewise, the more user-friendly constant current electrolysis was found to generate aryl ether 36aa in comparable yields (entries 7 and 8). Additionally, several repetitions of entries 6 and 7 revealed that the constant current electrolysis was more robust in terms of reproducibility and was therefore favored for further optimization studies.

Encouraged by these preliminary findings, various reaction parameters were evaluated for the cobaltaelectro-catalyzed C–H oxygenation in a divided cell setup (Table 2). For the screening of different carboxylate additives, Dr. N. Sauermann observed that the countercation did not have a significant influence on the reaction outcome,^[269] whereas NaOPiv was found to outperform the sterically less demanding acetate salts (entry 2). In contrast, carbonate or trifluoroacetate bases led to a significant drop in reactivity (entries 3 and 4). The optimization of different cobalt(II) catalysts revealed that Co(OAc)2·4H2O was indeed the best catalyst for the electrocatalytic manifold (entries 5–7), while no conversion was observed when copper(II) salts were employed as the catalyst (entry 8).^[268b]

Furthermore, increasing the reaction temperature under the optimized reaction conditions or lowering the catalyst loading did not improve the product formation (entries 9 –11). The reversal of the polarity on the electrodes highlighted the essential role of the platinum cathode for the HER (entry 12). Additional control experiments verified that the cobalta-electrocatalysis was not viable in the absence of either electrical current, base, or cobalt catalyst (entries 13–15). Although the preliminary studies in undivided electrolysis cells did not lead to a satisfactory reaction outcome (cf. Table 1, entry 1), a more standardized undivided cell setup was later developed by a subsequent extensive cell design (cf. Figures 79–82).^[274] Notable contributions for the design and construction have been made by Dr.

N. Sauermann, Dr. C. Tian, Dr. L. Finger, M. Stangier and the mechanical workshop of the chemistry department at the University of Göttingen. Here, important features of the revised electrolysis cell included a fixed and reduced inter-electrode distance as well as a decreased cell volume. These key characteristics allowed for a reduction in cell resistance and according to Ohm’s law, a lower applied potential to ensure the desired constant current. When using the novel undivided cell for the cobaltaelectro-catalyzed C–H oxygenation, product 36aa was obtained in 70% yield under slightly modified reaction conditions (entry 16).

Table 2. Optimization studies for the cobaltaelectro-catalyzed C–H oxygenation.^[a]

[a] Reaction conditions: 34a (0.50 mmol), [TM] (20 mol %), additive (2.00 equiv in each half-cell), EtOH (35a) (7.0 mL in each half-cell), T, 8.0 mA, 6 h, graphite felt anode, Pt-plate cathode, divided cell. Isolated yields are given. [b] 40 °C. [c] 60 °C. [e] Co(OAc)2·4H2O (10 mol %). [f] Graphite felt cathode, Pt-plate anode. [g] Without current. [g] Undivided cell, 16 h, 4 mA.

The robustness of the protocol was further demonstrated conducting the electrolysis with the commercially available electrosynthesis kit ElectraSyn 2.0 from the IKA company (Table 3 and Figure 83). Here, a carbon electrode material other than graphite felt proved to be equally viable to promote the cobalta-electrocatalysis in a user-friendly undivided cell setup (entries 1 and 2). However, the use of more cost-efficient nickel cathodes resulted in a diminished reaction outcome (entry 3).

Table 3. Cobaltaelectro-catalyzed C–H oxygenation with IKA ElectraSyn 2.0.^[a]

Entry Anode Cathode Yield [%]

1 RVC Pt 68

2 GF Pt 69

3 RVC Ni 38

[a] Reaction conditions: 34a (0.50 mmol), Co(OAc)2·4H2O (20 mol %), NaOPiv (2.00 equiv), EtOH (35a) (5.0 mL), 25 °C, 4.0 mA, 16 h, undivided cell (10 mL). Isolated yields are given. Platinum-plated electrodes.

Ni = nickel foam electrode.

In spite of the success with the undivided electrolysis cells, the subsequent co-solvent optimization studies were completed with the more efficient divided cell setup (Table 4).

Table 4. Evaluation of the co-solvent.^[a]

Entry Solvent Ratio (Solvent/EtOH) Yield [%]

1 EtOH --- 75

2 MeCN 16:1 12

3 MeCN 1:1 19

4 DMSO 16:1 ---

5 DMSO 1:1 ---

6 CH2Cl2 1:1 ---

[a] Reaction conditions: 34a (0.50 mmol), Co(OAc)2·4H2O (20 mol %), NaOPiv (2.00 equiv in each half-cell), solvent (7.0 mL in each half-half-cell), 23 °C, 8.0 mA, 6 h, graphite felt anode, Pt-plate cathode, divided cell. Isolated yields are given.

The investigation of a suitable co-solvent to decrease the used equivalents of the alcohol coupling partner 35 proved to be challenging (entries 1–6).^[269] Thus, different mixtures of MeCN and 35a were found to be tolerated under the standard conditions, however, aryl

ether 36aa was isolated in significantly reduced yields (entries 2 and 3). Unfortunately, other co-solvents failed to serve as a reaction medium for the electrocatalysis (entries 4–6).

Next, different N-substituted benzamides 26, 34, 64, 162–167 were tested as the directing group to chelate the cobalt catalyst, and thus to guide the C–H activation event (Table 5).

Table 5. Studies on the directing group effect for the C–H oxygenation.^[a]

Entry Benzamide Product Yield

[%]

1 34a 36aa 75

2 26a 161aa 36

3 162a 163aa ---

4 164a 165aa ---

5 N

H H

O N

64a 166aa ---

6 167a 168aa ---

[a] Reaction conditions: Benzamide (0.50 mmol), Co(OAc)2·4H2O (20 mol %), NaOPiv (2.00 equiv in each half-cell), EtOH (35a) (7.0 mL in each half-cell), 23 °C, 8.0 mA, 6 h, graphite felt anode, Pt-plate cathode, divided cell. Isolated yields are given.

Here, substrate 34a bearing a Lewis-basic pyridine-N-oxide group was found to promote the cobaltaelectro-catalyzed C–H oxygenation in high yield (entry 1). In addition, the commonly employed 8-aminoquinoline directing group^[96a] enabled electrochemical C–H oxygenation in moderate yield (entry 2). Other structural motifs, including monodentate N-methylbenzamide (167a) failed to provide any alkoxylated products (entries 3–6), thus showcasing the unique features of the bidentate scaffold of 34a (entry 6).^[269]