1.3 Organic Electrocatalysis
1.3.2 Cobaltaelectro-Catalyzed C–H Activation
While electrochemical cobalt-catalyzed cross-couplings,[245] reductive couplings with CO2[246] or outer-sphere transformations[247] had been reported earlier,[248]
cobaltaelectro-catalyzed C–H activations were unprecedented until the beginning of this thesis. Based on the pioneering work on C–O formations (cf. Chapter 3.1),[249] further cobaltaelectro-catalyzed C–H transformations have been investigated and shall be discussed in the following chapter.
At the beginning of 2018, Ackermann developed oxidative C–H/N–H annulations of benzamides 34 with terminal alkynes 53 as versatile coupling partners in a cobaltaelectro-catalyzed manifold (Scheme 41a).[250] The reaction proceeded at exceedingly mild reaction conditions and tolerated a broad range of functional groups, including halides, ethers and oxidatively labile heterocycles such as thiophene. Notably, the same group later expanded the electrooxidative alkyne annulation for the functionalization of benzamides 62 with internal alkynes 6 by means of an electroreductively removable benzhydrazide auxiliary (Scheme 41b).[251]
Scheme 41. Cobaltaelectro-catalyzed isoquinolone synthesis via C–H/N–H activation.
Thereafter, Lei reported a similar C–H/N–H activation of benzamides 26 with 8-aminoquinoline as the directing group (Scheme 41c). Key findings of their report included the use of gaseous acetylene (6c) or ethylene as the coupling partner. Also, kinetic studies were indicative of an overall rate-limiting anodic oxidation event. However, in direct
comparison with the previous reports of Ackermann, the activation of benzamides 26 required inherently higher reaction temperatures, additional conducting salts and a divided cell setup.
Later in 2018, Ackermann elegantly devised valuable cobaltaelectro-catalyzed C–H aminations of benzamides 34 under mild reaction conditions and the absence of chemical oxidants (Scheme 42).[252] Moreover, biomass-derived GVL was used as the reaction medium, thus enabling full resource economy. However, to overcome the low conductivity of the solvent, n-Bu4NPF6 was required as the conducting salt. Under the optimized reaction conditions, various aromatic or heteroaromatic amides 34 were aminated, using a broad range of secondary amines 149 as the coupling partner.
Scheme 42. Cobaltaelectro-catalyzed C–H amination with H2 as the sole byproduct.
In addition, in-depth mechanistic studies were performed. Here, headspace gas chromatography unambiguously confirmed the formation of hydrogen as the sole byproduct. Furthermore, kinetic reaction profiles were recorded by in-operando electro-IR-spectroscopic analysis and revealed a non-rate-limiting C–H activation step. The proposed working mode followed previously established cobaltaelectro-catalyzed C–O formations (vide infra). Concurrently, Lei reported a related cobaltaelectro-catalyzed C–H amination of benzamides 26. To enable high yields, higher reaction temperatures of 65 °C and the use of a divided cell setup were required.[253]
Based on these seminal reports, a plethora of dehydrogenative cobaltaelectro-catalyzed C–
C or C–Het formations with hydrogen as a valuable byproduct were subsequently disclosed (Scheme 43). Thus, Ackermann developed C–H acyloxylation of benzamides 34 with abundant carboxylic acids 46 (Scheme 43a).[254] Notably, biomass-derived GVL proved to be the optimal solvent for the electrocatalysis. Almost at the same time, Ackermann demonstrated the effective conversion of isocyanides 152 or gaseous carbon monoxide (153) for the synthesis of valuable heterocycles 154 (Scheme 43b) and 155 (Scheme 43c),
respectively.[255] Here, N-2-pyridylhydrazide proved to be the optimal directing group and allowed for ample substrate scope with high levels of functional group tolerance.
Concurrently, Lei reported a similar cobaltaelectro-catalyzed C–H/N–H carbonylation of quinolineamides 26 with a divided cell setup (Scheme 43d).[256] On the basis of the previously reported electrooxidative alkyne annulations, Lei recently devised the synthesis of pharmaceutically-relevant sultams 157 under anodic cobalt catalysis (Scheme 43e). [257]
The scalability of the approach was highlighted in a gram-scale electrocatalytic reaction with no loss of efficiency. The cobalta-electrocatalysis gained further momentum for the conversion of π-containing substrates. In this context, in 2020, Ackermann devised a C–H allylation of benzamides 26 with unactivated alkenes 158, delivering the corresponding allylated arenes 159 with high levels of chemo- and regiocontrol (Scheme 43f).[258] The robust cobalta-electrocatalysis proved likewise effective for regio- and chemoselective C–H/N–H annulation of hydrazides 62 with 1,3-diynes 70 (Scheme 43g).[259] Remarkably, unsymmetrical 1,3-diynes 70 were inserted with excellent levels of regiocontrol.
CO
Scheme 43. Recent advances in cobaltaelectro-catalyzed C–H activation.
2 O BJECTIVES
The development of novel concepts for selective metal-catalyzed C–C or C–Het bond forming processes is of key-importance to expand the toolbox of modern organic synthesis.
The several past decades have been witnessed major advances toward these goals by implementing step- and atom economical C–H activation manifolds. But in spite of the indisputable advances, most of the developed approaches fall short in fulfilling sustainable or green synthetic criteria and rely on harsh reaction conditions, generation of undesired waste, and the use of precious metal catalysts. Thus, the focus of this thesis is directed toward the exploration of novel resource economical C–H functionalizations, with a major center of attention on the previously underdeveloped merger of metal-catalyzed C–H activation and electrosynthesis.[9, 13a, 213a, 225, 240f]
In recent years, Earth-abundant and cost-effective cobalt complexes have emerged as viable catalyst for oxidative C–H activations.[23a, 44c, 55, 61] Despite major progress,[55a] these transformations largely suffer from the use of stoichiometric amounts of toxic metal-based oxidants, which contradicts the inherently green nature of the C–H activation strategy.
Within this thesis the first cobalt-catalyzed oxidative C–H/C–H or C–H/Het–H coupling should be explored, employing anodic oxidation to reactivate the catalyst and cathodic proton reduction to generate molecular H2, which would obviate the use of sacrificial oxidants (Scheme 44). The envisioned concept would be highly desirable for the environmentally-benign formation of C–O bonds or the synthesis of heterocycles via straightforward C–C/C–N formation.
Scheme 44. The merger of cobalt-catalyzed C–H activation and electrochemistry.
In previous studies on cobalt-catalyzed C–H activations, the catalysis was largely reported to proceed via a cobalt(II/III/I) catalytic manifold.[60] Likewise, cobaltaelectro-catalyzed
C–H activations were postulated to follow similar pathways, albeit detailed experimental or computational studies were lacking.[240c, 240e, 240f] For this purpose, comprehensive mechanistic insights would be highly desirable to not only elucidate the working-mode of the existing methodologies,[249-250, 260] but also to unravel novel reactivities (Scheme 45).
Co
Scheme 45. Mechanistic insights into cobaltaelectro-catalyzed C–H activation.
Electrochemical synthesis offers the possibility to directly utilize electrical power and to transform the harvested energy in value-added chemical products.[261] This concept represents an ideal scenario for a sustainable energy economy since unprofitable energy conversions from electricity to chemical charge carriers can be circumvented.[13a]
Furthermore, a major environmental drawback of metal-catalyzed C–H activation is reflected in the reaction media of the catalysis as commonly toxic halogenated organic solvents are used.[3a, 4e, 4i, 45, 262] Thus, in a proof-of-concept study, a cobaltaelectro-catalyzed C–H activation was intended to be powered by renewable energy sources and performed within a biomass-derived reaction medium to enable full resource economy (Scheme 46).
Scheme 46. Cobalta-electrocatalysis powered by renewable energy sources and performed in biomass-derived solvents.
Electroanalytical methods represent a powerful tool for the elucidation of short-lived redox-active reaction intermediates.[263] During the course of this thesis, a selection of these tools such as cyclic voltammetry or rotating disc electrode experiments should be utilized to examine the reaction mechanism of various organic electrocatalytic transformations (Scheme 47).
Scheme 47. Modern electroanalytical tools for reaction mechanism elucidation.
Efficient synthetic methods toward direct C–N formations are in strong demand.[11h] In this context, bioinspired manganese(V)oxo complexes have proven to be particularly powerful for various undirected C(sp3)–H functionalizations, such as C–H azidation reactions.[182d,
196a, 198] However, these methodologies unfortunately require the employment of sacrificial oxidants, such as iodosobenzene, to generate the high-valent oxo species, thus resulting in undesired waste-products and low chemoselectivity due to competing C–H oxygenation reactions.[24c, 264] Here, the exploration of an electrochemical method for direct manganese-catalyzed C–H functionalization of otherwise unactivitated C(sp3)–H bonds would be highly desirable and of prime importance for inter alia late-stage drug diversification (Scheme 48).
Scheme 48. Manganaelectro-catalyzed C–H azidation of unactivated C(sp3)–H bonds.