Oxidative C–H Activation using Cobalt Salts

As mentioned before, the use of high valent cobalt catalysts in C–H activation greatly enhances the simplicity of the experimental setup and user-friendliness. However, the most simple setup would be the direct use of air-stable cobalt(II) salts as the (pre)catalyst. In 2005, Daugulis popularized the use of bidentate, monoanionic directing groups in the form of 8-aminoquinoline (Q) benzamides for palladium-catalyzed C–H activation.^[90] This concept was applied to include other metals and directing groups, such as TAM,^[91] PIP^[92] and PyO^[93] (Figure 1.3).

Figure 1.4 Common bidentate directing groups in catalyzed C–H activation.

However, it took nearly 10 years, before the 8-aminoquinoline directing group was applied to cobalt catalysis. Daugulis disclosed a cobalt-catalyzed C–H/N–H annulation of quinolinebenzamides 115 and alkynes 8 to generate isoquinolones 118 (Scheme 1.28a).^[94] It soon became apparent, that heterocycle formation by C–H/X–H annulation was one strength of oxidative cobalt-catalyzed C–H activation. Further heterocycle syntheses followed soon by the same group regarding tetrahydroisoquinolones 119,^[95]

cyclic phosphoramides 120^[96] and isocoumarines 121 from benzoic acids 116 (Scheme 1.28e, 1.28h, 1.28c).^[97] Important contributions were also disclosed by Ackermann, establishing the formation of isoindolones 122 (Scheme 1.28d),^[98] and furthermore the first use of molecular oxygen as a competent terminal oxidant for this reaction employing PyO substituted benzamide 117 (Scheme 1.28b).^[99] Besides alkenes 60 and alkynes 8, also allenes 124 were shown to be reactive by Volla and Maiti.^[100] Finally, the synthesis of sultam motifs 126 by cobalt catalysis was disclosed independently by Ribas and Sundararaju under identical conditions (Scheme 1.28g).^[101]

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Scheme 1.28 Heterocycle formation by C–H/X–H annulation.

All the above-mentioned C–H/X–H annulation protocols generally follow similar mechanistic pathways, which should be explained with the example of the cobalt catalyzed isoindolone synthesis (Scheme 1.29).^[98] The initial step of the mechanism is proposed to be the base-assisted C–H activation of the chelating substrate-catalyst complex to form five membered cobaltacycle 128. This intermediate is reactive towards unsaturated multiple bonds and can undergo migratory insertion. The resulting seven-membered intermediate 129 reacts by β-hydride elimination to yield the final product 122. Subsequently, the cobalt species 131 is reoxidized to regenerate the active species 127.

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Scheme 1.29. Proposed catalytic cycle for the cobalt-catalyzed isoindolone formation.^[98]

Furthermore, carbonylations have been reported as a method for heterocycle formation, for example by Daugulis in 2014.^[102]

Besides C–H/X–H annulations, C–C forming reactions have been reported. In 2016, Balaraman disclosed a cobalt-catalyzed oxidative alkynylation of benzamides 115 (Scheme 1.30a).^[103] Although the functional group tolerance on the benzamide moiety is generally good, the reaction suffers from a limited alkyne scope. In the same year, Lu and coworkers achieved a methylation under assistance of the PIP directing group in an elegant protocol using highly reactive dicumylperoxide 135 as the methylating reagent as well as the oxidant, avoiding the use of costly silver(I) salts (Scheme 1.30b).^[104] Although ortho-substituted benzamides 115 were used preferentially, other substitution patterns led to bis methylation. Further, Chatani reported on a cobalt-catalyzed allylation protocol using terminal alkenes 137 (Scheme 1.30c).^[105]

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Scheme 1.30. Cobalt-catalyzed C–H activation for the formation of C–C bonds.^[103-105]

Without a doubt, the formation of biaryls is one of the most important applications of C–H activation, due to the abundance of biaryls in biologically active motifs and the deficits regarding sustainability and atom economy associated with cross coupling chemistry.^[4] In oxidative cobalt-catalyzed C–H activation, biaryl formations have been established beginning with the dimerization of quinoline benzamides 115.^[106] This approach was elaborated by the use of different directing groups to achieve selective C–H/C–H cross-activation,^[107] while other methods used boronic acids 139 or activated heterocycles 52 or 53 (Scheme 1.31a).^[108] A noteworthy example for an oxidative cobalt-catalyzed C–H arylation was published by Song, employing indoles 23 and boronic acids 139. While arylations of this substrate have also been achieved using low valent cobalt catalysis,^{[49, 52]} (vide supra) this example remains one of the very rare oxidative-cobalt catalyzed transformations not dependent on a bidentate directing group (Scheme 1.31b).^[109]

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Scheme 1.31. Arylations using oxidative cobalt-catalyzed C–H activation.^[108-109]

Oxidative cobalt-catalyzed C–H activation is not limited to C–C forming reactions, as also several C–X formations have been disclosed. C–N forming transformations have been realized using 8-aminoquinoline as well as pyridine-N-oxide directing groups using (cyclic) secondary alkyl amines 146 as well as arylamines 144 (Scheme 1.32a).^[110] With regard to C–O bond forming reactions, both alkoxygenations and acyloxylations have been reported, by Song and recently by Chatani (Scheme 1.32b).^[111] Both reactions proceeded with good to excellent functional group tolerance and good yields. Furthermore, also alkenes were viable substrates in the presented alkoxylation protocol.^[111b] Moreover, an oxidative cobalt-catalyzed C–H halogenation was recently achieved by Chatani using molecular iodine 154 as the iodination reagent (Scheme 1.32c).^[112] While the reaction showed good functional group tolerance, the directing group had to be modified to exclude undesired side reactions. The mechanism of these transformations shall be discussed with the example of the cobalt-catalyzed C–H acyloxylation (Scheme 1.33).^[111a] After coordination of the cobalt catalyst to the deprotonated amide 115, oxidation from cobalt(II) to cobalt(III) followed by C–H bond cleavage generates the five-membered intermediate 158. This species can then undergo ligand exchange with the present acid to form intermediate 159.

From this complex, the product 152 can be released by reductive elimination, followed by reoxidation of the cobalt catalyst.

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Scheme 1.32. Oxidative cobalt-catalyzed C–X formations.^[109-112]

Scheme 1.33. Plausible mechanism for the cobalt-catalyzed C–H acyloxylation.^[111a]

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Finally, besides the oxidative C–H activation of C(sp²)–H bonds, a few reports have highlighted the ability of cobalt to activate C(sp³)–H bonds. An intramolecular cyclizytion to generate small ring lactams was reported by He in 2015 (Scheme 1.34a).^[113] Intermolecular transformations using either terminal alkynes^[114] or carbonmonooxide, (Scheme 1.34c)^[115] as coupling partners were disclosed recently likewise.

Scheme 1.34. Oxidative cobalt-catalyzed C(sp³⁾–H activation.^[113-115]