Modular Synthesis of Diarylalkanes by Nickel-Catalyzed 1,1-Diarylation of Unactivated Terminal Alkenes

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Jan 2021Modular Synthesis of Diarylalkanes by Nickel-Catalyzed 1,1-Diarylation of Unactivated Terminal Alkenes Zheqi Li, Dong Wu, Chao Ding and Guoyin Yin Zheqi Li The Institute for Advanced Studies, Wuhan University, Wuhan 430072, Hubei Province , Dong Wu The Institute for Advanced Studies, Wuhan University, Wuhan 430072, Hubei Province , Chao Ding The Institute for Advanced Studies, Wuhan University, Wuhan 430072, Hubei Province and Guoyin Yin *Corresponding author: E-mail Address: [email protected] The Institute for Advanced Studies, Wuhan University, Wuhan 430072, Hubei Province https://doi.org/10.31635/ccschem.020.202000183 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail A nickel-catalyzed 1,1-diarylation of electronically unbiased alkenes has been developed, providing straightforward access to diarylalkanes from readily available materials. Importantly, both the efficiency and the regioselectivity of this transformation are ensured by reaction conditions, rather than the coordinating group of substrates. We also demonstrate that under balloon pressure, ethylene and propylene can also be utilized as substrates. Preliminary mechanistic experiments suggest that this transformation involves a Ni(0)/Ni(II) catalytic cycle rather than a Ni(I)/Ni(III) cycle. Download figure Download PowerPoint Introduction Fragment-based drug discovery has been recognized as an important strategy to identify lead compounds in the pharmaceutical industry.1,2 Diarylalkanes, as an important pharmacophore, are frequently found in drugs and other biologically active molecules,3–5 thus the synthesis of diarylalkane frameworks has aroused great interest in the chemistry community.6,7 A two-component cross-coupling of benzylic electrophiles with aryl partners is the most commonly employed strategy (Figure 1a, left part).8–11 The cross-coupling of transient nucleophiles from styrenes or alkenylarenes and silanes constitutes a significant advance of this strategy.12–15 A landmark of this two-component cross-coupling strategy is the development of direct benzylic C–H arylations. The reactions under oxidative conditions were demonstrated by Stahl16 and Liu17 independently, and reactions under redox-neutral conditions were reported by the Doyle18 and Lu19 groups. From a retrosynthetic viewpoint, a single three-component assembly method undoubtedly is the most efficient strategy to access diarylalkanes (Figure 1a, right part). With this concept in mind, Yu and co-workers20 reported a sequential diarylation of primary sp3C–H bonds, which constitutes the ideal route to these types of compounds. However, the application of directing groups largely limited its substrate scope. Moreover, the 1,1-diarylation of terminal olefins has been developed, and extensive efforts have also been devoted to palladium catalysis (Figure 1b).21 In 2008, Le Bras and co-workers22 demonstrated the first report, wherein only 2-alkylfurans could be used as the aryl coupling partners with benzoquinone (BQ) as the oxidant. Soon thereafter, the Sigman group23 disclosed Pd-catalyzed, aerobic oxidative intermolecular diarylations by using aryl stannanes as the aryl partners. Significant progress has been made by the same group, and a redox-neutral variant utilizing aryldiazonium salts and arylboronic acids as the coupling partners was developed; this allows one to introduce two distinct aryl groups.24 However, the olefin scope is still limited. Olefins without directing groups and without bearing steric hindrance at allylic positions still cannot be used in the reaction, which seriously restricts the application of this strategy. Figure 1 | Background and reaction design. Download figure Download PowerPoint Recently, the construction of 1,1-diarylalkanes by nickel-catalyzed migratory cross-couplings, which involved a key intermediate benzyl–nickel species (Figure 1c, intermediate II), was achieved by our own group.25,26 We speculated that if the benzyl–nickel intermediate could also be generated by olefin insertion into an aryl–nickel species and followed by a 1,2-nickel migration (Figure 1c, right part), the same product could be expected from more readily available starting materials. It is noteworthy that achieving the desired regioselectivity for the intermolecular migratory insertion of unactivated olefins into the Ar–M bonds is still a challenging task in the presence of halides.27 Guided by this idea, we herein describe a coordinating-group-free, nickel-catalyzed 1,1-diarylation of electronically unbiased terminal alkenes, which provides a modular protocol to the synthesis of 1,1-diarylalkanes (Figure 1d).28–32 Abundant and inexpensive aryl bromides and aryl boronic acids are used as the coupling partners in this redox-neutral reaction. Experimental Methods Experimental Methods is available in Supporting information. Results and Discussion We embarked on this three-component reaction by choosing terminal alkene 1a, 4-methylbromobenzene ( 2a), and phenyl boronic acid ( 3a) as model substrates. We selected Ni(cod)2, a nickel(0) precatalyst, to examine the impact of bases in dioxane (Table 1, entries 1–4). It was found that only potassium and sodium methoxide salts could produce the diarylation products 4a and 5a. We chose NaOMe as the optimal base to continue the studies. We followed that study with solvent surveying (Table 1, entries 5–8), which proved that cyclopentyl methyl ether (CPME) was the best choice, with 41% yield and 11/1 regioisomeric ratio (rr) (Table 1, entry 8). Catalyst examination (Table 1, entries 9–11) indicated that Ni(NO3)2·6H2O, a cheap and air-stable Ni(II) salt, was able to improve the yield to 55% (Table 1, entry 11). An analysis of the reaction found that a large quantity of starting materials was still left under these conditions. Therefore, parameters that could promote the consumption of starting materials, such as prolonging the reaction time and increasing the reaction temperature, were further investigated. To our delight, when the reaction temperature was elevated to 100 °C, most of the alkene was consumed and the diarylation product was isolated in 75% yield with 14/1 rr (Table 1, entry 11). Notably, the products from Suzuki–Miyaura cross-coupling and Heck reaction constitute the major by-products (please see Supporting Information for more details). In addition, ancillary ligands, such as PyrBox and bipyridine frameworks, negatively affected both yield and regioselectivity. Table 1 | Reaction Developmenta Entry Nickel Source Base Solvent Yield of 4a (%) rr ( 4a/ 5a) 1 Ni(cod)2 KOMe Dioxane 16 9/1 2 Ni(cod)2 LiOMe Dioxane trace – 3 Ni(cod)2 NaOMe Dioxane 22 8/1 4 Ni(cod)2 LiOtBu Dioxane 0 – 5 Ni(cod)2 NaOMe DME Trace – 6 Ni(cod)2 NaOMe Toluene 21 7/1 7 Ni(cod)2 NaOMe MTBE 26 10/1 8 Ni(cod)2 NaOMe CPME 41 11/1 9 NiBr2·DME NaOMe CPME 29 12/1 10 Ni(acac)2 NaOMe CPME 31 12/1 11 Ni(NO3)2·6H2O NaOMe CPME 55 11/1 12b Ni(NO3)2·6H2O NaOMe CPME 83(75)c 14/1 aGeneral conditions: Ni catalyst (5 mol %), 1a (0.2 mmol, 1.0 equiv), 2a (0.5 mmol), 3a (0.5 mmol), Base (0.6 mmol), in CPME (1 mL), stirred at 80 °C for 15 h. GC yields against naphthalene. Ratios of 4a/ 5a are determined by GC. bReaction performed in 2.5 mL CPME at 100 °C for 15 h. cThe number in parentheses is yield average over two runs. Having identified the optimal reaction conditions, we next investigated the generality of this Ni-catalyzed 1,1-diarylation reaction. As illustrated in the top of Table 2, we first chose the terminal olefin 1a to investigate a variety of aryl coupling partners. Aryl electrophiles bearing diverse substituents were examined in this reaction. All could successfully transform to the corresponding 1,1-diarylalkanes in moderate to good yields with good regioselectivity. Interestingly, both unprotected aniline and indole were well tolerated in this transformation, albeit with a lower regioselectivity. Furthermore, the 1,1-diarylalkanes could also be produced from a number of aryl boronic acids in these conditions. Importantly, the regioselectivity was not affected by the electronic density of either aryl coupling partner in this nickel-catalyzed 1,1-difunctionalization reaction. Notably, aryl chloride was able to survive in this system, which opens avenues for further downstream cross-couplings. In addition, this 1,1-diarylation reaction was compatible with a wide range of flexible functional groups including esters, ethers, ketones, and amines, as well as functionalized pyridine. Table 2 | Reaction Scopea aStandard conditions: Ni(NO3)2·6H2O (5 mol %), 1a (0.2 mmol, 1.0 equiv), 2a (0.5 mmol, 2.5 equiv), 3a (0.5 mmol, 2.5 equiv), NaOMe (0.6 mmol, 3 equiv) in CPME (2.5 mL), stirred at 100 °C for 15–24 h. Yield average over two runs. Ratios in parentheses are the regioisomeric ratios, which are determined by GCMS. bThese reactions performed in 2.5 mL benzotrifluoride at 120 °C for 48 h. To further assess the generality of these catalytic conditions, we next investigated the scope of potential alkene substrates. As shown in the bottom of Table 2, a series of unactivated terminal alkenes were examined, and alkenes either bearing a coordinating atom or not were able to produce the corresponding 1,1-diarylation products in an efficient and selective manner. To further explore the potential scope of this 1,1-diarylation, gaseous ethylene and propylene were tested in this reaction.24,33 As shown in Figure 2a, the desired products could be obtained from a set of aryl coupling partners with only balloon pressure. Figure 2 | Reactions of light olefins and mechanistic studies. Download figure Download PowerPoint Based on literature precedent,34,35 there are two possible pathways to rationalize this nickel-catalyzed 1,1-diarylation reaction (Figure 2b, please see the Supporting Information for more details): (1) an Ar–i(II) species ( I) was generated from a Ni(0) species and an aryl bromide via oxidative addition. Then an olefin migratory insertion into the carbon–nickel bond and a subsequent 1,2-nickel migration led to the formation of a π–benzyl nickel(II) intermediate ( II). The Ni(II) intermediate underwent transmetallation with an aryl boronic acid to produce a new Ni(II) intermediate ( III), which produced the desired product ( 4) by reductive elimination. (2) Another possible pathway is that the reaction was initiated by an Ar–Ni(I) species ( IV), which was generated from the aryl boronic acid and the nickel precatalyst. Subsequent olefin migratory insertion and nickel migration resulted in the formation of a π–benzyl nickel(I) intermediate ( V).36 The intermediate V reacted with an aryl halide to afford a Ni(III) intermediate IV, which delivered the 1,1-diarylation product ( 4) by reductive elimination. In order to differentiate the aforementioned two pathways, several experiments were designed and conducted. First, vinylarene 6 was examined under the standard conditions and could also undergo diarylation, but only 1,2-products ( 7a and 7b) were isolated in good yields in these reactions (Figure 2c), consistent with Brown's reaction.37 The regioselectivity observed in these reactions is consistent with the reaction being initiated by the aryl electrophile part, which supports path A but not path B. Second, when allylbenzene was used, either electron-rich or -deficient aryl bromide afforded a mixture of 1,1- and 1,3-products ( 9 and 10; Figure 2d). If path B operated in these reactions, a single isomer should be obtained. Therefore, these results also agree with path A and rule out path B. Additionally, the ratios of the 1,1- and 1,3-products ( 9/ 10) observed in these reactions indicate that the more electron-rich aryl group favors the formation of the π–benzyl nickel(II) species. Conclusion In summary, we have developed the first nickel-catalyzed 1,1-regioselective diarylation of unactivated alpha-alkenes. Accordingly, a series of substituted 1,1-diarylalkane compounds have been prepared efficiently from readily accessible terminal alkenes, aryl boronic acids, and aryl halides. Moreover, light olefins, such as ethylene and propylene, can also undergo the diarylation under balloon pressure and afford the 1,1-products. The reaction conditions are simple and do not require any external ligands. In addition, this reaction displays good compatibility with a broad range of functional groups. Importantly, the regioselectivity and the efficiency of this reaction are not governed by the substrates. We believe this development will greatly promote alkene transformations and medicinal chemistry. Supporting Information Supporting Information is available. Conflict of Interest The authors declare no competing interests. Acknowledgments The authors thank Profs. 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