Rhodium-Catalyzed Pyridine-Assisted C–H Arylation for the Synthesis of Planar Chiral Ferrocenes

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE1 Dec 2020Rhodium-Catalyzed Pyridine-Assisted C–H Arylation for the Synthesis of Planar Chiral Ferrocenes Chen-Xu Liu, Zhong-Jian Cai, Qiang Wang, Zhi-Jie Wu, Qing Gu and Shu-Li You Chen-Xu Liu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Zhong-Jian Cai State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Qiang Wang State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Zhi-Jie Wu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Qing Gu State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 and Shu-Li You *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 https://doi.org/10.31635/ccschem.020.202000157 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Planar chiral ferrocenes are widely applied in organic synthesis, materials science, and medicinal chemistry, but their synthesis is not trivial. Herein, a highly efficient synthesis of planar chiral ferrocene-based pyridine derivatives via Rh(I)-catalyzed direct coupling of pyridylferrocenes with aryl halides was developed. Good yields and excellent enantioselectivity (95–>99% ee) are obtained for a wide range of substrates. The compatibility of gram-scale synthesis and relatively low catalyst loading (down to 1 mol% based on [Rh]) enhance the practicality of the current method. The generated coupling products can be readily transformed into chiral ligands. Mechanistic studies suggest that the C–H bond cleavage of pyridylferrocene may be a reversible step and not the rate-determining step. Significant nonlinear effects indicate the existence of multiple metals or ligands in the active catalyst. Download figure Download PowerPoint Introduction Ferrocene derivatives have been intensively studied in the areas of organic synthesis, materials science, and medicinal chemistry because of their unique electronic and structural properties.1,2 Particularly, planar chiral ferrocenes have been widely utilized in organic synthesis serving as versatile ligands and catalysts.3–6 With the growing number of chiral pyridine-derived ligands/catalysts in asymmetric catalysis,7 efficient synthesis of planar chiral pyridine-derived ferrocenes is highly desirable. Transition metal-catalyzed C–H functionalization reactions have proved to be increasingly powerful methods to construct C–C or C–heteroatom bonds in modern organic synthesis.8–10 Significant progress on transition metal-catalyzed C–H functionalization reactions to introduce planar chirality into the ferrocene backbone has been made during the past decade.11–14 Nevertheless, the majority of them are based on intramolecular designs for the construction of planar chiral ferrocenes.15–24 For intermolecular designs, dialkylamino groups25–29 have been used as efficient directing groups, but others30–32 have been rarely reported. Pyridine is known to be a suitable directing group for C–H functionalization of ferrocenes as reported by Kasahara,33 Shibata,34 Butenschön,35 and You.36 However, generally, the reactions have challenges in controlling mono-functionalization selectivity and enantioselectivity. Of particular note, Shibata37 reported an Ir/chiral diene-catalyzed asymmetric C–H alkylation of ferrocenes with moderate yields and good enantioselectivity using an isoquinolin-2-yl directing group to appropriately suppress secondary alkylation reactions. When pyridine was used as the directing group, poor mono-/di-selectivity was obtained. Therefore, the C–H functionalization of ferrocenyl pyridines with high efficiency, mono-selectivity, and enantioselectivity remains challenging, likely as a result of a lack of proper chiral catalysts due to the strong coordination of pyridine groups. Meanwhile, Rh(I)-catalyzed C–H arylations have also rapidly progressed.38–58 Breakthroughs has been achieved by Glorius and co-workers,55 who discovered a rhodium(I) chiral monodentate phosphonite complex as an efficient catalyst for highly enantioselective C–H activation of tetrahydroquinolines and saturated aza-heterocycles. Inspired by these pioneering results, we recently found that enantioselective arylation of pyridylferrocene can be realized in the presence of Rh(I)/chiral monodentate phosphonite complex. This catalyst system delivers planar chiral ferrocenyl pyridines in high yields and excellent monoarylation selectivity and enantioselectivity. Here, we report the results of this study (Figure 1). Figure 1 | Pyridine-assisted enantioselective C–H arylation. (a) Previous works for asymmetric C–H bond functionalization of ferrocenes. (b) The challenges of pyridine as the directing group. (c) Our new strategy for pyridine-assisted C–H arylation for the synthesis of planar chiral ferrocenes. Download figure Download PowerPoint Experimental Methods General procedure for Rh(I)-catalyzed enantioselective C–H arylation: A standard 10 mL Schlenk tube was charged with LiOtBu (48.0 mg, 0.6 mmol), L7 (25.3 mg, 0.04 mmol), [Rh(C2H4)2Cl]2 (3.9 mg, 0.01 mmol), 1 (0.2 mmol, 1.0 equiv), and aryl bromide 2 (0.4 mmol, 2.0 equiv). Then, the flask was evacuated and backfilled with argon three times, which was followed by the addition of tetrahydrofuran (THF) (2.0 mL). The mixture was stirred at 80 °C. After the reaction was complete (monitored by thin layer chromatography [TLC]), the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (5.0 mL) and filtered through a pad of celite. The filtrate was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20∶1) to generate the corresponding product 3. More experimental details and characterization are available in the Supporting Information. Results and Discussion Reaction development Initially, we began our investigation with the reaction between 2-pyridylferrocene 1a and 4-methoxybromobenzene 2a (Table 1). The desired product 3aa was obtained in 50% NMR yield and >99% ee in the presence of 5 mol% [Rh(C2H4)2Cl]2, 20 mol% L1,59,60 and 3.0 equiv of LiOtBu (entry 1). Screening a variety of bases disclosed that LiOtBu was the optimal choice (see Supporting Information Table S1 for details). Then, solvent effects were examined, and THF was found to give better results, leading to 3aa with 76% NMR yield and >99% ee (entry 2). In addition, other solvents such as toluene, p-xylene, mesitylene, and 1,2-dichloroethane (DCE) also gave comparable results (25–48% NMR yields, 99% ee, entries 3–6). Unfortunately, neither N,N-dimethylformamide (DMF) nor CH3OH gave the desired product (entries 7 and 8). Other aryl-substituted 4,5-Bis[hydroxy(diphenyl)methyl]-2,2-dimethyl-1,3-dioxolane (TADDOL)-derived ligands such as 2-naphthyl, 3,5-(CF3)2-C6H3, and 3,5-(tBu)2-C6H3 significantly reduced the yield and enantioselectivity of the reaction (entries 9–11). Meanwhile, the substituents attached to the phosphorus atom in the ligand were also investigated. Likely due to steric hindrance, tBu-substituted ligand ( L5)-derived catalysts did not promote this reaction (entry 12). The reaction with 3,5-(CF3)2-C6H3-substituted ligand ( L6) gave similar results as those of ligand L1 (72% NMR yield, 99% ee, entry 13). Interestingly, with 3,5-(MeO)2-C6H3-substituted ligand L7, the corresponding product 3aa was obtained in 88% NMR yield and >99% ee (entry 14). The utilization of TADDOL-derived phosphoramidite L8 resulted in a slight decrease in yield but with excellent enantioselectivity (68% NMR yield, 99% ee, entry 15). Using diastereoisomers of the Feringa ligand ( L10 or L11)61,62 led to 3aa in modest yields but with opposite absolute configuration, and L11 gave better results (55% NMR yield, 99% ee; entries 17 and 18). Spiro phosphonite L1263,64 failed to give 3aa (entry 19). Thus, 3,5-(MeO)2-C6H3-substituted ligand L7 was the optimal choice. With 2.0 equivalents of 4-methoxybromobenzene 2a, 3aa was isolated in 93% yield (entry 22). Lowering the temperature to 60 °C did not afford better results (89% NMR yield, 99% ee, see Supporting Information Table S2 for details). Finally, the optimized conditions were identified as follows: [Rh(C2H4)2Cl]2 (5 mol%), L7 (20 mol%), and LiOtBu (3.0 equiv) in THF at 80 °C (entry 22). The exclusive mono-selectivity is likely due to the bulkiness of the chiral ligand and catalyst. Table 1 | Optimization of the Reaction Conditions Entrya Ligand Solvent Yield (%)d ee (%)e 1 L1 Dioxane 50 >99 2 L1 THF 76 >99 3 L1 Toluene 48 99 4 L1 p-Xylene 36 99 5 L1 Mesitylene 28 99 6 L1 DCE 25 99 7 L1 DMF – – 8 L1 CH3OH – – 9 L2 THF 23 98 10 L3 THF – – 11 L4 THF 42 86 12 L5 THF – – 13 L6 THF 72 99 14 L7 THF 88 >99 15 L8 THF 68 99 16 L9 THF 24 99 17 L10 THF 15 85 18 L11 THF 55 −99 19 L12 THF – – 21b L7 THF 92 >99 22c L7 THF 97 (93)f >99 aReaction conditions: 1a (0.1 mmol), 2a (1.1 equiv), [Rh(C2H4)2Cl]2 (5 mol%), ligand (0.02 mmol), LiOtBu (0.3 mmol) in solvent (1.0 mL) at 80 °C. b 2a (1.5 equiv). c 2a (2.0 equiv). dNMR yields using 1,3,5-trimethoxybenzene as an internal standard. eDetermined by HPLC analysis. fIsolated yield, 0.2 mmol scale. With the optimized conditions in hand, we next explored the substrate scope of this reaction (Table 2). First, the yield and ee were slightly decreased with 4-methoxyiodobenzene (73% yield, 95% ee). The substrate, 4-methoxychlorobenzene, was also compatible with the reaction conditions, and comparable results were obtained (84% yield, >99% ee). After that, a series of aryl bromides bearing either an electron-withdrawing group or electron-donating group were investigated. The coupling of 1a with electron-rich aryl bromides (–OMe, –SMe, –NMe2) afforded the arylated products in good yields with excellent enantioselectivity ( 3aa– 3ac, 86–93% yields, >99% ee). In contrast, aryl bromides containing electron-withdrawing groups (–Ph, CF3, –F, –Br, –COCH3) tended to give the desired arylated products in slightly lower yields with excellent enantioselectivity ( 3ae– 3ai, 52–90% yields, 99% to >99% ee). Bromobenzene is also compatible, resulting in the isolation of 3ad in 87% yield and >99% ee. Cyano group could also be tolerated, and product ( 3aj) was obtained with 59% yield and 97% ee. meta-Substituted aryl bromides proceeded smoothly to give the arylated products ( 3ak and 3al) in 85–95% yields with >99% ee. With 10 mol% [Rh(C2H4)2Cl]2, ortho-substituted substrates 3am could still give acceptable results (40% yield, 93% ee). 2-Bromonaphthalene was found to be a suitable substrate, and 3an was obtained in 90% yield with >99% ee. Substrates of multisubstituted aryl bromides also gave excellent results ( 3ao– 3ap, 97% yields, >99% ee). A wide array of hetero-aryl bromides including benzothiophene, benzofuran, N-Ts indole, thiophene, and furan motifs were all tolerated ( 3aq– 3aw, 47–86% yields, 98 to >99% ee), as well as strongly coordinating coupling partners such as 2-methyl-6-bromoquinoline ( 3ax, 90% yield, >99% ee) and 2,6-dimethyl-4-bromopyridine ( 3ay, 80% yield, >99% ee). Notably, the absolute configuration of product 3ax was determined by X-ray crystallographic diffraction as Sp (see the Supporting Information for details). Interestingly, cyclic alkenyl bromide is also compatible giving product 3az in 40% yield and 95% ee in dioxane. Table 2 | Scope of Rh-Catalyzed C−H Atroposelective Arylation with Aryl, Heteroaryl, and Alkenyl Bromidesa aGeneral conditions: 1a (0.2 mmol), 2 (2.0 equiv), [Rh(C2H4)2Cl]2 (5 mol%), L7 (0.04 mmol), LiOtBu (0.6 mmol) in THF (2.0 mL) at 80 °C, 12 h. Yield of isolated product. Determined by HPLC analysis. b4-Methoxyiodobenzene was used instead of 4-methoxybromobenzene 2a. c4-Methoxychlorobenzene was used instead of 4-methoxybromobenzene 2a. d[Rh(C2H4)2Cl]2 (10 mol%) and L7 (0.08 mmol) were used. eDioxane was used instead of THF as the solvent. Then the directing groups were examined (Table 3). The reaction occurred smoothly using 2-, 3-, or 4-methyl pyridine as the directing group ( 3ba– 3da, 91–96% yields, 97 to >99% ee). Unfortunately, the reaction of 5-methyl pyridine was sluggish, which was likely due to weak coordination with rhodium ( 3ea). In addition, 4-fluoro pyridine and isoquinoline were well tolerated ( 3fa–3ga, 92–97% yields, 99 to >99% ee). Meanwhile, introducing a substituent on the other Cp ring was also well tolerated. Ferrocenes possessing a methoxymethyl (MOM) or iPr group gave their corresponding arylation products 3ha or 3ia in 88% yield and >99% ee and 90% yield and >99% ee, respectively. The reaction displays excellent functional group tolerance that is reflected by the fact that sensitive functional groups, such as 2-propenyl and benzoyl, can be present on the Cp ring ( 3ja and 3ka, 82–91% yields, >99% ee). Table 3 | Scope of Rh-Catalyzed C−H Arylation of Ferrocene Derivativesa aGeneral conditions: 1 (0.2 mmol), 2a (2.0 equiv), [Rh(C2H4)2Cl]2 (5 mol%), L7 (0.04 mmol), LiOtBu (0.6 mmol) in THF (2.0 mL) at 80 °C, 12 h. Yield of isolated product. Determined by HPLC analysis. Synthetic applications To further demonstrate the potential utility of this reaction, gram-scale reactions were carried out. Pleasingly, when the catalyst loading was reduced to 1.0 mol% based on [Rh], the arylative product 3ae was obtained in 71% yield and 98% ee. In addition, the reaction of 2h gave 3ah in 63% yield and 98% ee. Such unprecedented low catalyst loading in the enantioselective Rh(I)-catalyzed arylation reaction greatly improves its synthetic practicality (Scheme 1a). Scheme 1 | Gram-scale reactions, transformations of 3ae and an asymmetric allylic alkylation reaction. (a) Gram-scale reactions. (b) Transformations of 3ae. (c) Application of 4a in Pd-catalyzed asymmetric allylic alkylation reaction. Download figure Download PowerPoint As further demonstration of the utility of this method, various straightforward transformations of the coupling product 3ae were carried out to prepare planar chiral ligands, which are difficult to access using other methods. As illustrated in Scheme 1b, 3ae was converted to an array of planar chiral ferrocene ligands through ortho-lithiation and subsequent reactions with electrophiles ( 4a–4d). Chiral bidentate P,N-ligand 4a was found to be an efficient ligand in a palladium-catalyzed allylic alkylation reaction (96% yield, 80% ee, Scheme 1c). Mechanistic studies To gain insights into the reaction mechanism, preliminary experiments were carried out. Notably, a nonlinear effect was detected,65 suggesting that more than one ligand is involved in the active catalyst (Figure 2a). In addition, the result that the kinetic isotope effect of 2-pyridylferrocene is only 1.23 (kH/kD) suggests that C–H cleavage of 2-pyridylferrocene is not the rate-determining step (Figure 2b). Next, the H/D exchange experiments of 2-pyridylferrocene were carried out under standard conditions. It was found that 2-pyridylferrocene 1a was deuterated with 9% deuteration, and 1a-[D] was obtained with only 21% deuteration after 12 h (Figure 2c). In addition, the deuteration reaction did not occur in the absence of Rh catalyst. Meanwhile, 37% deuteration was observed for the recovered starting material 1a when the C–H arylation reaction was performed in the presence of 15 equivalents of CD3OD (Figure 2d). These results further indicate that the C–H cleavage of 2-pyridylferrocene is reversible and may be not the rate-determining step. The competitive experiment between 4-methoxybromobenzene 2a and 4-cyanobromobenzene 2j revealed that electron-deficient substrates are more reactive than electron-rich substrates (Figure 2e). Then, 31P NMR analyses of the stoichiometric reaction were carried out (see the Supporting Information for details) and indicated that preformed rhodium complexes do not interact with substrate 2a, while new signals readily appear at 60 °C in the presence of 1a. Figure 2 | Mechanistic studies. (a) Nonlinear effect experiment. (b) KIE intermolecular parallel experiment. (c) H/D exchange experiment of 1a. (d) H/D exchange experiment of 1a and 2a. (e) Competitive experiment between 4-methoxybromobenzene 2a and 4-cyanobromobenzene 2j. (f) Plausible reaction pathways. Download figure Download PowerPoint On the basis of the aforementioned studies and the precedent reports,57 a plausible catalytic cycle was proposed for this enantioselective C–H arylation. As illustrated in Figure 2f, [Rh(C2H4)2Cl]2 and chiral ligands first coordinate to the N atom of 1a, which leads to the formation of complex A. A reversible cyclometalation through a tbutoxide-assisted deprotonation delivers intermediate B. Then, the oxidative addition of aryl bromide to intermediate B affords the C species. Finally, the reductive elimination of C affords planar chiral product 3aa. Meanwhile, the released Rh(I) coordinates with another molecule of the substrate, generating A species for the next catalytic cycle. Another process involves oxidative addition of complex A into aryl bromides ahead of C–H activation, and then the base-assisted metalation affording the same intermediate C cannot be completely ruled out at the current stage. Additional investigation is necessary to fully elucidate the details of the reaction mechanism. Conclusions In summary, we have developed a highly efficient synthesis of planar chiral ferrocenes by enantioselective Rh(I)-catalyzed direct C–H arylation of ferrocenyl pyridines with readily available aryl halides under mild reaction conditions. These processes take place with excellent levels of monoarylation selectivity and enantioselectivity and high catalytic efficiency. The low catalyst loading greatly improves the practicality of the reaction. The new protocol provides concise access to a variety of enantiopure ferrocenyl pyridines, which offer an excellent platform for designing chiral ligands or catalysts. Nonlinear effect experiments, H/D scrambling experiments, competitive experiments, and NMR studies have been carried out to give insights into the mechanism. Supporting Information Supporting Information is available. Conflict of Interest The authors declare no competing interest. Acknowledgments We thank the National Key R&D Program of China (2016YFA0202900), NSFC (21821002, 91856201), and the CAS (XDB20000000, QYZDY-SSW-SLH012) Science and Technology Commission of Shanghai Municipality (18JC1411302) for generous financial support. S.-L.Y. acknowledges the support from the Tencent Foundation through the XPLORER PRIZE. This paper is dedicated to Professor Xue-Long Hou on the occasion of his 65th birthday. References 1. Štěpnička P.Ferrocenes; Wiley-VCH: Weinheim, 2008. Google Scholar 2. 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Google Scholar Previous Information Chinese thank the National Key R&D Program of China (2016YFA0202900), NSFC (21821002, 91856201), and the CAS (XDB20000000, QYZDY-SSW-SLH012) Science and Technology Commission of Shanghai Municipality (18JC1411302) for generous financial support. S.-L.Y. acknowledges the support from the Tencent Foundation through the XPLORER PRIZE. This paper is dedicated to Professor Xue-Long Hou on the occasion of his 65th birthday.

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