Recently, Lutz Ackermann's research group at the University of Göttingen (Georg-August-Universität Göttingen) in Germany reported the use of cobalt instead of precious metal catalysts, through hydrogen evolution reaction (HER) instead of chemical oxidation, high enantioselectivity to achieve the C-H activation of aryl groups. By using this cobalt-mediated electrocatalytic process, not only the construction of C-C, C-N and C-O can be achieved with high selectivity, but also the construction of key carbon chiral, axial chiral and phosphine chiral three-dimensional centers commonly found in drugs and pesticides. The results were published in Science at DOI: 10.1126/science.adg2866.
(Image source: Science)
Over the past few decades, organic electrocatalysis has been used as an environmentally friendly synthesis strategy to synthesize a range of molecules using renewable electrical energy. Among them, the electrooxidative C-H activation reaction can effectively realize the later modification of molecules through HER. Compared with traditional synthesis methods, it avoids the use of stoichiometric reagents to achieve multi-step functional group conversion (Fig. 1A）。 However, achieving complete selective control in electrocatalysis has had only limited success. Only recently has the enantioselective C-H activation process catalyzed by transition metals been realized in electrosynthesis. However, the methods that have been developed so far are limited to expensive 4D metal catalysts (Fig. 1B), and the conversion is achieved by the two-electron transfer process. However, the electrochemical synthesis process of enantioselective C-H activation through single-electron transfer using the first row of transition metals abundant on Earth has not been reported. Recently, Lutz Ackermann's research group at the University of Göttingen, Germany, developed electrooxidation, cobalt-catalyzed aryl C-H activation reactions, constructed C-C, C-N and C-O bonds with good chemoselectivity, regional selectivity and enantioselectivity, respectively, and realized the construction of key carbon stereocenters, axial chiral stereoscopic centers and phosphine chiral stereoscopic centers common in drugs and pesticides (Fig. 1C）。
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Firstly, the authors selected benzamide 1 and olefin 2 as template substrates for conditional screening (Fig. 2A) (Fig. 2B), found when using Co(OAc)2∙4H2O (20 mol%), CPA1((S)-BINOL phosphoric acid) (30 mol%), BmimPF6 (1-butyl-3-methylimidazolium hexafluorophosphate) (0.05 M), PivOH, 80 in DCE/t-AmOH (4:1). The oC reaction for 24 hours can obtain a product 3 (e.r. = 94: 6）（undivided cell, 0.20 mmol scale）。 Subsequently, the authors explored the range of substrates for this transformation (Fig. 2C）。 The experimental results show that a series of electron-absorbing groups (5, 6, 9, 13, 14, 15), electron-donor groups (4, 10, 11, 12) and oxidation-sensitive groups (8) are compatible, and the synthesis of target products 3-23 (28-74%) is achieved with good enantioselectivity. Next, the authors explored the reaction mechanism through controlled experiments (Fig. 2D）。 First, the authors achieved the stoichiometric synthesis of the C-H-activated complex Co(III)-C1 of ring metallization under constant current conditions, and the compound was separated and characterized. The stoichiometric conversion of the complex Co(III)-C1 shows that electricity is necessary for efficient and selective formation of products. In addition, high-resolution mass spectrometry (Fig. 2D) and UV/VIS spectroelectrochemical analysis (Fig. 2E) further supported the presence of diverse Co(III/IV/II), thus indicating the formation of cobalt-CPA1 intermediates. Therefore, the direct coordination of CPA1 in the cobalt center appears to be more reasonable than enantioselective induction by the extrasphere mechanism. KIE parallel experiments (kH/kD ≈ 1.0) showed that the cleavage of the C-H bond was not a rate-determining step in this reaction. Therefore, the authors explored the possibility of migration insertion as a rate-determining step using logarithmic plots of initial rates at different concentrations of maleimide. Since the authors did not find a significant correlation, the authors considered the insertion step to be relatively quick (Fig. 2F）。 In contrast, the authors monitored the formation of products at different currents to have a direct correlation. Therefore, electron transfer is considered to be a rate determinant of this conversion.
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Spirocyclization reaction based on electrooxidation and cobalt catalysis (Fig. 2), the author also explored non-activated olefins. The experimental results show that the carbonation process of olefins replaces spirocyclization, resulting in a complementary reaction mode. Moreover, the authors found that the use of salicyloxazoline ligands can effectively achieve enantioselective transformation (Fig. 3A）（Fig. 3B）。 In addition, the authors concluded that L-valinol-derived ligand L3 was the optimal through conditional screening, and a series of chiral dihydroisoquinolone 25-32 (74-94%) synthesis was achieved at room temperature with good yield, enantioselectivity and enantioselectivity (Fig. 3C）。 In order to evaluate the practicality of this method, the authors performed ten-gram-scale synthesis of the reaction, which also maintained good reaction efficiency and enantioselectivity. It is worth noting that despite the significant increase in the size of the reaction, the reaction can still be performed with a Faraday efficiency of 89% (Fig. 3D）。
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Next, in order to explore whether this asymmetric-induced reaction system can be applied to the construction of axial chiral products, the authors used benzamide 34 and 4-hydroxyalkynoate 35 to explore the synthesis of C-N axial chiral compound 36 (Fig. 4A）。 Using DFT calculations, the authors concluded that the rotational energy barrier of C-N in compound 36 was 48.3 kcal/mol, indicating that its half-life was t1/225°C and 3.2 × 1018 years (Fig. 4B）。 Under these electro-oxidative conditions (L5 as ligand and isopropanol as solvent), compound 36 can be obtained with a yield of 92% and an e.r. of 99.5:0.5, and its structure is verified by single crystal diffraction (Fig. 4C）。 Next, the authors examine the range of substrates for this transformation. The experimental results show that different substitutions of amide (36-38) and 4-hydroxyynoate (40-43) are compatible (87-95%). In addition, the conversion also maintained excellent reaction efficiency and enantioselectivity during large-scale synthesis (2.0 mmol) (80%, 99.5:0.5 e.r.) (Fig. 4D）。
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Finally, the authors apply this system to achieve the desymmetry of phosphonamide, so as to realize the construction of phosphine chiral center (Fig. 5）。 Experiments showed that the bidentate ligand L1 could effectively induce this enantioselective dehydrogenation of C-H etherification, and the synthesis of chiral phosphonamide 45-48 was achieved with good enantioselectivity (Fig. 5A）。 In addition to the C-O bond formation reaction, this symmetry process can also be cyclized with alkyne by C-H and N-H activation, resulting in 49-52 (Fig. 5B）。 In addition, the synthesis of a series of polycyclic phosphine chiral compounds 53-60 (42-70%) can also be achieved by the formation of C-C, C-N and C-O bonds by using the C-H and N-H activation tandem of alkyne, which can also be formed by C-C, C-N and C-O bonds (Fig. 5C）。 And the absolute configuration of products 48 and 53 was confirmed by single crystal diffraction (Fig. 5D）。 Notably, this HER-coupled electrocobalt oxide catalytic reaction can also be performed using commercially available solar photovoltaic cells, thus demonstrating the robustness of the method to current and voltage fluctuations (Fig. 5E）。
(Image source: Science)
Summary: Lutz Ackermann's group reports an electrooxidative, inexpensive cobalt-catalyzed enantioselective aryl C-H activation reaction. It uses HER instead of chemical oxidation, and achieves the synthesis of spironolactam, dihydroisoquinolinone and phosphomide with high enantioselectivity through dehydroC-H etherification and C-H, N-H CYCLIZATION. This enantioselective cobalt electrocatalytic process produces only hydrogen molecules as the only by-product through HER, which has a wide range of application potential.
Literature Details:
Tristan von Münchow, Suman Dana, Yang Xu, Binbin Yuan, Lutz Ackermann*. Enantioselective electrochemical cobalt-catalyzed aryl C–H activation reactions. Science, 2023, 379, 1036-1042. https://www.science.org/doi/10.1126/science.adg2866.