Scalable Rhodaelectro-Catalyzed Expedient Access to Seven-Membered Azepino[3,2,1- hi ]indoles via [5 + 2] C–H/N–H Annulation

Open AccessCCS ChemistryCOMMUNICATION28 Mar 2022Scalable Rhodaelectro-Catalyzed Expedient Access to Seven-Membered Azepino[3,2,1-hi]indoles via [5 + 2] C–H/N–H Annulation Yumeng Yuan†, Jinlan Zhu†, Zhongyuan Yang, Shao-Fei Ni, Qiufeng Huang and Lutz Ackermann Yumeng Yuan† Fujian Key Laboratory of Polymer Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, Fujian 350007 , Jinlan Zhu† Fujian Key Laboratory of Polymer Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, Fujian 350007 , Zhongyuan Yang Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou, Guangdong 515063 , Shao-Fei Ni *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University, Shantou, Guangdong 515063 , Qiufeng Huang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Fujian Key Laboratory of Polymer Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, College of Chemistry and Materials Science, Fujian Normal University, Fuzhou, Fujian 350007 and Lutz Ackermann *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Institut Für Organische Und Biomolekulare Chemie, Wöhler Research Institute for Sustainable Chemsitry, Georg-August-Universität Göttingen, 37077 Göttingen https://doi.org/10.31635/ccschem.022.202101654 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report the establishment of a rhodaelectro-catalyzed [5 + 2] N–H/C–H oxidative annulation of alkynes by 7-arylindoles, enabling the synthesis of seven-membered azepino[3,2,1-hi]indoles using electricity as the sole oxidant. The reaction could be scaled up to gram-scale by flow-electrocatalysis. Two key rhodium(III) intermediates were isolated and fully characterized. Cyclovoltammetric analysis, X-ray photoelectron spectroscopy studies, and density functional theory calculations are suggestive of a rhodium(III–IV–II–III) manifold. Download figure Download PowerPoint Introduction The synthesis of nitrogen-containing heterocycles, considered privileged scaffolds in medicinal and material chemistry, is of key relevance for molecular synthesis, crop protection, and drug discovery.1–5 Among various available methods, transition-metal-catalyzed C–H/N–H oxidative annulation is an ideal approach for the rapid construction of nitrogen-containing heterocycles.6–8 In this context, the past decades have witnessed the emergence of efficient synthesis of five-9–17 or six-membered18–26 nitrogen-containing heterocyclic compounds. In sharp contrast, transition-metal-catalyzed C–H/N–H oxidative annulations leading to seven-membered rings remain a challenge,27–29 and thus far, have been dominated by stoichiometric chemical oxidants such as hypervalent iodine(III) agents, as well as copper(II)30–32 and silver(I)33–38 salts for the regeneration of active sites, high-valent active catalysts. The merger of transition-metal catalysis and electrocatalysis has recently emerged as a powerful platform for unlocking new synthetic methodologies.39–46 Furthermore, oxidative C–H coupling reaction, proceeding under exogenous-oxidant-free conditions by metalla-electrocatalysis, has expedited with significant contributions by Xu and co-workers,47–49 Mei and co-workers,50–59 Lei and co-workers,60–67 Ackermann and co-workers,16,68–88 and others.89–94 Within our program on matalla-electrochemical C–H activation, herein, we present the first example of electrooxidative [5 + 2] C–H/N–H annulation for efficient synthesis of seven-membered azepino[3,2,1-hi]indoles. Salient features of our findings include (1) exogenous-oxidant-free C–H activations, (2) scalability through flow electrooxidation, (3) isolation of two key rhodium(III) intermediates, (4) X-ray photoelectron spectroscopy (XPS) studies, and (5) density functional theory (DFT) calculations providing key mechanistic insights. Download figure Download PowerPoint Results and Discussion We initially performed our research by exploring the reaction conditions of electrooxidative [5 + 2] C–H/N–H annulation using 7-phenyl-1H-indole-3-carbaldehyde ( 1a) and diphenylacetylene ( 2a) in a facile undivided cell set-up, equipped with a graphite felt (GF) anode and a platinum (Pt) cathode (Table 1). After considerable experimentation, we observed that the desired product 3aa was obtained using [Cp*RhCl2]2 (2.5 mol %) with Li2CO3 (2.0 equiv) as the optimal combination. Among various solvents, the desired product 3aa was obtained in 1,4-dioxane with 86% yield (entries 1–5). Replacing Li2CO3 with other additives, such as NaOPiv, K3PO4, nBu4NPF6, K2CO3, and Na2CO3, resulted in a sharp decrease in yield (entries 6–10). Increasing or decreasing the amount of Li2CO3 also reduced the yield (entries 11 and 12). Control experiments verified the crucial role of Li2CO3, rhodium catalysts, and electricity (entries 13–15). Three other typical transition metals were also explored, but no target products were obtained (entries 16–18). The present rhodium-catalyzed [5 + 2] C–H/N–H annulation can also precede with Ag2CO3 as the terminal oxidant instead of electricity, delivering a comparable yield (84%, entry 19). Table 1 | Optimization of the Rhodaelectro-Catalyzed [5 + 2] C–H/N–H Cyclization Reactiona Entry Catalyst Additive Solvent Yield (%)b 1 [Cp*RhCl2]2 Li2CO3 MeCN 21 2 [Cp*RhCl2]2 Li2CO3 t-AmOH 0 3 [Cp*RhCl2]2 Li2CO3 THF 0 4 [Cp*RhCl2]2 Li2CO3 DMF 0 5 [Cp*RhCl2]2 Li2CO3 1,4-Dioxane 86 6 [Cp*RhCl2]2 NaOPiv 1,4-Dioxane 45 7 [Cp*RhCl2]2 n-Bu4NPF6 1,4-Dioxane Trace 8 [Cp*RhCl2]2 K3PO4 1,4-Dioxane 30 9 [Cp*RhCl2]2 K2CO3 1,4-Dioxane 15 10 [Cp*RhCl2]2 Na2CO3 1,4-Dioxane 40 11 [Cp*RhCl2]2 Li2CO3 1,4-Dioxane 69c 12 [Cp*RhCl2]2 Li2CO3 1,4-Dioxane 73d 13 [Cp*RhCl2]2 — 1,4-Dioxane NR 14 — Li2CO3 1,4-Dioxane NR 15 [Cp*RhCl2]2 Li2CO3 1,4-Dioxane Tracee 16 Pd(OAc)2 Li2CO3 1,4-Dioxane NR 17 [Cp*IrCl2]2 Li2CO3 1,4-Dioxane NR 18 [Ru(p-cymene)2Cl2]2 Li2CO3 1,4-Dioxane NR 19 [Cp*RhCl2]2 Ag2CO3 t-AmOH 84e Note: THF, tetrahydrofuran; DMF, dimethylformamide; NR, no reaction. aReaction conditions: undivided cell, 1a (0.2 mmol), 2a (0.4 mmol), catalyst (2.5 mmol%), additive (2.0 equiv), solvent (4.0 mL), 100 °C, 5 h, constant current = 5 mA, GF anode, Pt cathode. bYields of isolated product 3aa. cLi2CO3 (1.0 equiv). dLi2CO3 (3.0 equiv). eNo electricity. Having determined the optimal reaction conditions, the scope of the electrooxidative rhodium-catalyzed C–H/N–H annulation reaction was first examined with a set of 7-phenyl-1H-indole-3-carbaldehyde ( 1) (Scheme 1). The reaction was highly sensitive relative to the substituents at the 3-position of the indole ring. A formyl group at the 3-position favored the reaction, delivering the desired product in an excellent yield ( 3aa), while other substitution patterns at C-3 proved less suitable, with a recovery of starting material 1. We also found that the position of substituents played a dominant role regarding the catalyst's efficiency: Substrates 1 with substituents at the heteroaromatic motif or the benzene moiety provided high to excellent yields of the desired products ( 3ac, 3ae, 3ag, and 3ai– 3ar). The electrocatalysis was, however, sluggish when the 6-position of the indole ring was replaced by a methyl group ( 3ad). Substituents at the 2-position of the indole ring or the benzene ring disabled the reaction ( 3ab and 3af), and the starting material was recovered unchanged. The electrochemical annulation was amenable to functional groups, such as F, CF3, Cl, OMe, NPh2, SiMe3, CO2Me, COMe, and CN. It is noteworthy that an electrolytic protocol generally provided superior performance to the conventional reoxidation strategy ([Cp*RhCl2]2/Ag2CO3) in terms of yields. Scheme 1 | Scope of the Rhodaelectro-catalyzed C–H/N–H annulation by indoles 1. aReaction condition: Undivided cell, 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (2.5 mmol%), Li2CO3 (2.0 equiv), 1,4-Dioxane/H2O = 3:1 (4.0 mL), 100 °C, 5 h, constant current = 5 mA, GF anode, Pt cathode. bReaction condition: 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (2.5 mmol %), Ag2CO3 (2.0 equiv), t-AmOH, 12 h, 100 °C. Download figure Download PowerPoint Next, we explored the scope of the rhodaelectro-catalyzed [5 + 2] C–H/N–H cyclization with decorated diphenylacetylenes 2 (Scheme 2). Ortho-, meta-, or para-substituted diphenylacetylenes bearing various functional groups such as methoxy, fluoro, bromo, and chloro were all compatible with the standard conditions, affording the corresponding products. When an asymmetrical internal alkyne was employed, the formation of two possible regioisomers was observed 3bm; 3bn; Supporting Information Figures S1–S3. The reaction of 4-octyne was unsuccessful and failed to generate the desired product 3bq with intact starting material 1a. Scheme 2 | Scope of the Rhodaelectro-catalyzed C–H/N–H annulation by diphenylacetylenes 2.aReaction condition: Undivided cell, 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (2.5 mmol%), Li2CO3 (2.0 equiv), 1,4-Dioxane/H2O = 3∶1 (4.0 mL), 100 °C, 5 h, constant current = 5 mA, GF anode, Pt cathode. bReaction condition: 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (2.5 mmol %), Ag2CO3 (2.0 equiv), t-AmOH, 12 h, 100 °C. Download figure Download PowerPoint Further, we conducted deuterium-labeling and competition experiments to shed light on the reaction mechanism. First, the H/D exchange experiment using D2O as the isotopically labeled solvent showed that deuterium incorporation was observed both in product 3aa and the recovered substrate 1a (Scheme 3a, Supporting Information Figure S5). These findings were suggestive of a reversible C–H cleavage. Intermolecular competition experiments using electron-rich and electron-poor 7-phenyl-1H-indole 1i and 1r indicated that electronic effects of the substituent on the 7-phenyl-1H-indole played an important role. In contrast, no significant electronic effect on the reaction efficiency was observed between electron-rich and electron-deficient alkynes 2f and 2l (Scheme 3b). Scheme 3 | (a and b) Summary of key mechanistic experiments involving rhodaelectro-catalyzed [5 + 2] N–H/C–H cyclization reaction. Download figure Download PowerPoint Due to the essential role of metallacyclic intermediates in the rhodium-catalyzed C–H activations, we conducted extensive experiments to isolate the crucial rhodium complexes. Notably, a tetrameric six-membered cyclometalated rhodium(III) complex 4a via NH-directed C–H activation was obtained in 91% yield upon treatment of 1a with [Cp*RhCl2]2 and Ag2CO3. We reasoned that the formyl group was beneficial in generating relative stable six-membered cyclometalated rhodium(III) intermediate 4a, enabled by weak coordination of the carbonyl oxygen to rhodium. Meanwhile, attempts to recrystallize or in situ high-resolution mass spectrometry (HRMS) analysis of intermediates of stoichiometric reaction of 7-phenyl-1H-indole with [Cp*RhCl2]2 have, thus far, met with limited success. Mixing 4a with 2 equiv of diphenylacetylene 2a in CH2Cl2 at room temperature for 0.1 h allowed for the isolation of the eight-membered cyclometalated rhodium(III) complex 5a in 87% yield. The connectivities of metallacycles 4a and 5a were verified unambiguously by X-ray crystallography (Scheme 4a). The electrooxidative [5 + 2] annulation in the presence of 4a and 5a as the catalyst in place of [Cp*RhCl2]2 under the standard conditions gave 3aa in 77% and 71% yield, respectively, indicating that 4a and 5a are both competent in the present catalytic cycle (Scheme 4b). Furthermore, the rhodium(III) complex 5a remained intact even when it is was heated at 130 °C for an extended period under N2 atmosphere ( Supporting Information Figure S4), which suggested that two-electron reductive elimination from 5a affording rhodium(I) complex may be slow, and kinetically and thermodynamically unfavorable. Cyclic voltammogram of 5a showed the first irreversible oxidation peak at Epa = 0.349 V (vs Fc/Fc+, 100 mV/s), assigned to the oxidation of rhodium(III) species to Rh(IV) (Figure 1; Supporting Information Figures S7–S9). Scheme 4 | (a and b) Preparation and electrolysis studies of Rh complexes. Download figure Download PowerPoint XPS was employed to investigate the rhodium valent state. For intermediate 5a, the peak of Rh 3d5/2 localized at 308.48 eV.95 After 650 cyclic voltammetry (CV) cycles across a potential range of 0–0.5 V versus Ag/AgNO3, this peak slightly shifted toward lower binding energy (308.13 eV), suggesting a decrease in rhodium valent state, most likely, Rh(II) species deriving from reduction elimination of Rh(IV) intermediate. After electrolysis under the standard reaction conditions (Table 1, entry 5), the peak of Rh 3d5/2 shifted toward higher binding energy (308.93 eV), similar to Cp*RhCO3 or [Cp*RhCl2]2, indicating that the low valent state rhodium(II) was reoxidized to Rh(III) (Figure 2; Supporting Information Figures S10 and S11). Figure 1 | CV studies. Full scan of 5a at 100 mV/s. Inset: Narrow scan of 5a in variable scan rates. Reaction condition: 5a (2.5 mM) and n-Bu4NPF6 (0.1 M), MeCN, r.t. Download figure Download PowerPoint Figure 2 | Rh 3d5/2 XPS spectra showing: (a) Cp*RhCO3 (green line); (b) [Cp*RhCl2]2 (blue line); (c) electrolysis of 5a at the current of 5 mA for 6 h (black line); (d) after 650 CV cycles across a potential range of 0 to 0.5 V of 5a (red line); (e) 5a (purple line). Download figure Download PowerPoint These findings provided strong support for an oxidation-induced reductive elimination within the rhodium(III/IV) regime.48,96,97 The oxidation-induced reductive elimination mechanism was further confirmed by DFT calculations (see Supporting Information for details). The transition state of the direct reductive elimination of rhodium(III) intermediate 5a was located as TS(A-B) (Figure 3), with a Gibbs free energy barrier of 32.4 Kcal/mol, unreasonable under the current experimental conditions. However, an oxidatively-induced reductive elimination mechanism, whose transition state was located as TS(A′-B′), required only an energy barrier of 6.7 Kcal/mol. Figure 3 | DFT calculated Gibbs free energy profile in Kcal/mol comparing the direct reductive elimination and oxidatively induced reductive elimination pathways at the ωB97X-D/6-311++G(d,p), LANL2DZ(Rh)+SMD(1,4-dioxane)//ωB97X-D/6-31G(d), LANL2DZ(Rh) level of theory. Download figure Download PowerPoint To demonstrate the practical application of the rhodaelectro-catalyzed [5 + 2] C–H/N–H cyclization, the gram-scale reaction was carried out within a simple flow-cell device, yielding 1.013 g of the desired product 3aa (Scheme 5a). A reduction reaction driven by Pd(OAc)2 transformation of 3aa into the deformylation product 4aa with a high yield of 82% (Scheme 5b). Scheme 5 | (a and b) Summary of gram-scale reaction and transformation of 3aa. Download figure Download PowerPoint Based on the detailed mechanistic studies, the catalytic cycle was proposed, as depicted in Scheme 6. First, the active rhodium(III) species I undergo N–H bond cleavage and subsequent C–H bond cleavage to give six-membered rhoda(III)cycle II. Then alkyne coordination and migratory insertion provide eight-membered rhoda(III)cycle IV. DFT calculations indicate that the migratory insertion process is fast, with a free energy barrier of 12.1 kcal/mol ( Supporting Information Figure S12). Subsequently, anodic oxidation-induced reductive elimination of IV by a rhodium (III–IV–II) manifold gives intermediate VI. Further anodic oxidation of VI regenerates the active rhodium(III) catalyst I and the final product 3aa. Molecular hydrogen was generated as a byproduct at the cathode. Scheme 6 | Proposed catalytic cycle of the rhodaelectro-catalyzed [5 + 2] N–H/C–H cyclization reaction. Download figure Download PowerPoint Conclusion We have developed a rhodaelectro-catalyzed oxidative annulation of 7-phenylindoles with alkynes using electricity as the sole oxidant in an undivided cell. A variety of highly functionalized seven-membered azepino[3,2,1-hi]indoles were obtained in good to excellent yield. Significantly, this electrolytic reaction could be conducted in flow with a gram scale. Two key rhodium intermediates, viz, a six-membered cyclometalated rhodium(III) complex via NH-directed C–H activation and an eight-membered metallacyclic rhodium(III) species via alkyne insertion, were isolated and fully characterized. Detailed mechanistic studies were carried out to shed light on the mechanism. Cyclovoltammetric analysis, XPS studies, and DFT calculations provided strong support for a rhodium(III–IV–II–III) manifold. Supporting Information Supporting Information is available and includes experimental details and characterization of all new compounds and details for DFT calculations. CCDC 2045896, 2110757, 2110456, and 2110326. Conflict of Interest There is no conflict of interest to report. Funding Information Financial supports from the National Natural Science Foundation of China (NSFC; grant no. 21872028), the Natural Science Foundation of Fujian Province (grant no. 2020J01149), and the Fujian Province University Fund for New Century Excellent Talents is greatly acknowledged. S.-F.N. acknowledges funding from the STU Scientific Research Foundation for Talents (no. NTF20022). Acknowledgments The authors thank Hao Zhang and Prof. Shengchang Xiang (Fujian Normal University) for obtaining crystal X-ray diffraction data. References 1. Dongbang S.; Confair D. N.; Ellman J. 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