Nitromethane-Enabled Fluorination of Styrenes and Arenes

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Dec 2020Nitromethane-Enabled Fluorination of Styrenes and Arenes Weijin Wang, Tongyu Huo, Xinyi Zhao, Qixue Qin, Yujie Liang, Song Song, Guosheng Liu and Ning Jiao Weijin Wang State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Tongyu Huo State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Xinyi Zhao State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Qixue Qin State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Yujie Liang State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 , Song Song *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, Jiangsu , Guosheng Liu State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032 and Ning Jiao *Corresponding author(s): E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191 https://doi.org/10.31635/ccschem.020.202000172 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The electrophilic fluorination of unsaturated compounds provides a reliable approach to the generation of organofluorides, which are used widely in agrochemicals, pharmaceuticals, and other materials. Numerous active electrophilic fluorine reagents, such as the fluorine molecule (F2) or xenon difluoride (XeF2), have been applied in fluorination. However, these reagents suffer from their hazardous, toxic, corrosive, and poor selective properties, and the relatively weak electrophilicity of Selectfluor or N-fluorobenzenesulfonimide (NFSI) usually limits their broad applications. Herein, we disclose nitromethane (MeNO2) as an efficient activator of Selectfluor and NFSI, as well as a stabilizer of carbocations. Therefore, the fluoro-azidation, fluoroamination, fluoroesterification of styrenes, and C–H fluorination of (hetero)arenes were well realized just by the facilitation of MeNO2. The mild reaction conditions and practicability made our current method a versatile protocol for accessing organofluorides. Download figure Download PowerPoint Introduction Fluorine atom is found commonly in agrochemicals, pharmaceuticals, and materials due to its unique properties.1–4 Nucleophilic5–9 and electrophilic10–14 fluorinations provide the general approaches to organofluorides.15–18 Arenes and alkenes are common nucleophiles, and their electrophilic fluorination has been considered as a reliable strategy for the generation of organofluorides. Compared with the reactive and corrosive F2,19 trifluoromethyl hypofluorite (CF3OF), hypofluorous acid (HOF), cesium fluoroxysulfate (CsSO4F), and xenon difluoride (XeF2),20 reagents bearing N–F bonds,21–25 including Selectfluor23–24 and NFSI,25 are relatively stable and operable readily (Figure 1a). However, their relatively weak electrophilicity usually limits their extended applications. Thus, strategies such as transition-metal catalysis,26–29 hypervalent iodine reagents,30–32 and phase-transfer catalysis33–35 have been employed widely to achieve fluorination with Selectfluor or NFSI (Figure 1b). Recently, Ritter and co-workers36–39 and Sanford's group40–43 generated elegantly, transition-metal-catalyzed fluorinated arenes with unreactive N–F reagents. Liu44–49 and Zhang,50 independently, obtained the significant fluoroamination of styrenes with NFSI via fluoropalladation and copper-catalyzed radical strategy. Li and co-workers51 reported the fluoroazidation of olefins with Selectfluor and trimethylsilyl azide (TMSN3) in the presence of excess trifluoroacetic acid (TFA). Despite these advances, most of these fluorination systems, typically, could only enable one type of reaction, and lack universality with other organic reactions. Therefore, it is highly desirable to develop a new activation method to achieve fluorinations as diverse as possible. Figure 1 | Overview of this work. (a) The properties of electrophilic fluorine reagents. (b) The strategies applied in the activation of N-fluorobenzenesulfonimide (NFSI) or Selectfluor. (c) This work: MeNO2-enabled fluorination with Selectfluor or NFSI. Download figure Download PowerPoint Lewis bases have been widely used to activate chlorinating, brominating, and iodinating reagents,52–55 which suggested that a Lewis base might be able to activate the electrophilic fluorinating reagents. However, most of them are incompatible with the strong oxidizing "F+, " as they usually contain low-valent state with P or S center. Inspired by the oxygen-centered Lewis base dimethyl sulfoxide (DMSO), which showed unique performance in the elements incorporation reactions,56–60 we speculated that the oxygen-centered Lewis bases, likely, would activate the electrophilic fluorinating reagents, which has rarely been reported previously. Nitro alkanes are typical oxygen-centered Lewis bases commonly used as solvents because of their good solubility and strong polarity. Besides, they show high performance in polyene halocyclization reactions reported by Snyder,61,62 Yamamoto,63 and Ishihara.64 The key attribute of these halocyclizations is that nitro alkanes could stabilize the generated carbocations because of their high dielectric constant.65 Based on the above-mentioned significant discovery and our continuous research on MeNO2,66 we disclose a new approach of the application of MeNO2 in fluorination as the activator of Selectfluor or NFSI and the stabilizer of carbocations (Figure 1c). Therefore, the fluoroazidation, fluoroamination, fluoroesterification of styrenes, and C–H bond fluorination of (hetero)arenes, which previously, unfeasible to achieve by Selectfluor or NFSI without an activator, were executed efficiently by our current simple MeNO2 promotion protocol. Results and Discussion Initial optimization of the reaction conditions β-Fluoroamine is a key structural motif in many candidate drugs.3 The fluoroazidation of olefins provides an accessible approach to β-fluoroamine. Thus, we tested the fluoroazidation of 1a in the presence of Selectfluor (1.2 equiv) and NaN3 (2.4 equiv) at 60 °C for 12 h (Table 1). Indeed, the Selectfluor was not active enough for fluoroazidation of 1a in toluene, DMSO, tetrahydrofuran (THF), dichloroethane (DCE), acetone, acetonitrile (MeCN), or methanol (MeOH) solvents (entries 1–7). The addition of Lewis bases, including Ph3P=S, DMSO, and thiourea, also failed to deliver the product (entries 8–10). Then, we tested the MeNO2 as an additive, using MeCN as a solvent, which afforded only trace product 2a (entry 11). Delightedly, the reaction in MeNO2 without an additive afforded a 56% yield of 2a (entry 12). Inscrutably, the reaction did not work in EtNO2, nPrNO2, or PhNO2, possibly, due to the poor solubility of Selectfluor in these solvents (entries 13–15). Brønsted acid or Lewis acid additives failed to facilitate this transformation (entries 16–18). While basic additives such as KH2PO4, Na3PO4, and Na2CO3 were favorable for the conversion (entries 19–22), achieving an 82% yield of 2a using 0.4 equiv of Na2CO3 as the additive (entry 22). The role of the basic additives here might be attributable to its prevention of the decomposition of the substrates.67,68 On the other hand, decreasing the amount of the Na2CO3 additive showed a negative effect on the reaction outcome (entry 23). Other F+ reagents, such as NFSI or PyF•BF4, performed poorly (entries 24 and 25). Compound 2a was detected only in trace amounts when NaN3 was substituted with TMSN3 in the fluoroazidation reaction, probably because of the low nucleophility of TMSN3 (entry 26). Table 1 | Optimization of Reaction Conditions for the Fluoroazidation of 1aa aThe solution of 1a (0.50 mmol), Selectfluor (0.60 mmol), NaN3 (1.2 mmol), and additive (0.20 mmol) in solvent (2.0 mL) was stirred at 60 °C for 12 h under air. bIsolated yields. cNa2CO3 (0.10 mmol) was used. dNFSI was used instead of Selectfluor. eN-Fluoropyridinium tetrafluoroboric acid was used instead of Selectfluor. fTMSN3 was used instead of NaN3. MeNO2-Enabled fluoroazidation of styrenes Under the optimized conditions, the fluoroazidation of various styrenes was investigated (Table 2). The substituents at para-, meta-, or ortho-position of the phenyl group showed little influence on the yields. The halo, ester, amide, or ketone groups were tolerated well in the present system. Moreover, the gram-scale fluoroazidation of styrene 1a resulted in a 72% yield, which showed the potential application of this protocol in such reactions. Table 2 | Substrate Scope of Fluoroazidationa aThe solution of 1 (0.50 mmol), Selectfluor (0.60 mmol), NaN3 (1.2 mmol), and Na2CO3 (0.20 mmol) in MeNO2 (2.0 mL) was stirred at 60 °C for 12 h under air. Isolated yields. bPerformed at 10 mmol scale. cPerformed at 80 °C for 2 h. dThe number in the parenthesis is the diastereomeric ratio. MeNO2-Enabled fluoroamination of styrenes The fluoroamination of olefins was achieved with various impressive strategies,69–78 when tested fluoroamination of styrenes with our present MeNO2 system (Table 3). After extensive exploration of the reaction conditions, 3i was obtained in 95% yield in the presence of NFSI and NaOH/MeNO2 (see Supporting Information Table S2). This reaction did not work with other solvents except MeNO2, which demonstrated the dominating role of MeNO2. Terminal styrenes were converted into their corresponding products 3a–f in moderate yields. The fluoroamination of cyclic olefins underwent smoothly to afford cyclic vicinal amino organofluorides in good yields, although with moderate stereoselectivities. Table 3 | Substrate Scope of Fluoroaminationa aThe solution of 1 (0.50 mmol), NFSI (0.70 mmol), and NaOH (0.20 mmol) in MeNO2 (2.0 mL) was stirred at 60 °C for 12 h under air. Isolated yields. bPerformed with NFSI (2.0 mmol) at 80 °C for 24 h. c10 mmol scale reaction. dPerformed with NFSI (1.0 mmol). Furthermore, the fluorinated products 2a and 3a were demonstrated as useful building blocks in organic synthesis and were converted to a ketone, triazole, aniline, sulfamide, fluorinated diarylethane, and vicinal dibromide under simple, one-step conditions in 43–88% yields (see Supporting Information Figure S1). MeNO2-Enabled fluorofunctionalization of styrenes We were curious to investigate if this system was also suitable for other nucleophiles. Despite the significant progress achieved in this field with other methods,79–82 the fluorofunctionalization of 1a with H2O, n-pentanol, p-toluenesulfonamide (TsNH2), and L-menthol as the nucleophile underwent smoothly to afford the corresponding products in good yields (Table 4). It is noteworthy that intermolecular fluoroesterification is, typically, very challenging. In fact, previous reports always involved carrying out such reactions in strong electrophilic fluorinating reagents as AcOF83 or special carboxylic acids as TCA and TFA.45 Favorably, our method provided a general approach to fluoroesterification of styrenes with a broad scope of carboxylic acids, including phenylpropionic acid, flurbiprofen, and isoxepac, as nucleophiles. Table 4 | MeNO2-Enabled Fluorofunctionalization of Styrenesa aThe solution of 1a (0.50 mmol), Selectfluor (0.70 mmol), nucleophile (1.5 mmol), and 4 Å MS (10 mg) in MeNO2 (2.0 mL) was stirred at 80 °C for 12 h under air. Isolated yields. bWithout 4 Å MS. MeNO2-Enabled fluorination of arenes Nondirected C–H bond fluorination of (hetero)arenes has made considerable progress recently.84–86 Despite the significance, a practical method for aromatic fluorination is still necessary. We speculated that MeNO2 could also promote aromatic fluorination (Table 5). To our delight, fluorination of 1-phenylpyrazole 5a proceeded smoothly under optimized conditions in MeNO2 (see Supporting Information Table S3). Pyrazole 5b, indole 5c, and indazole 5e–f were converted smoothly into the desired products. Surprisingly, late-stage fluorination of pharmaceuticals 5g–k was also achieved with success in this system. Notably, many functional groups, including ester, amide, trifluoromethyl, halo, sulfamide, ether, even aldehyde, were all tolerated well. Table 5 | Substrate Scope of C–H Fluorination of Arenesa aThe solution of 5 (0.50 mmol), Selectfluor (1.0 mmol), and Na2CO3 (0.20 mmol) in MeNO2 (2.0 mL) was stirred at 80 °C for 24 h under air. Isolated yields. bPerformed at 25 °C. c2-Indolinone derivative product was obtained using tropisetron as the substrate. Mechanistic Studies We determined the roles of MeNO2 by treating NFSI with different amounts of MeNO2, followed by fluorine-19 nuclear magnetic resonance (19F-NMR). We observed that the NFSI signal shifted to a higher field as the amount of MeNO2 increased (see Supplementary Figure S2), which indicated that the electron density of the fluorine atom increased due to the effect of MeNO2. In contrast, such changes were not significantly observed when NFSI was treated with other solvents. Other typical Lewis bases such as Ph3P=O,87 thiourea,88,89 and DMSO56–57 also affected the 19F-NMR chemical shift of NFSI (Figure 2), but none of them showed changes as significant as MeNO2 at the same molar ratio. In additon, when the MeNO2 was monitored by 1H NMR and 13C NMR, following the addition of Na2CO3, there was no detectable methyleneazinate intermediate (see Supporting Information Figure S4). These results indicated that MeNO2 acted as an efficient Lewis base to activate NFSI. Figure 2 | Fluorine-19 nuclear magnetic resonance (19F-NMR) study of N-fluorobenzenesulfonimide (NFSI). Download figure Download PowerPoint Further, the addition of 2,6-di-tert-butyl-4-methylphenol (BHT) or p-dinitrobenzene to the standard reaction conditions showed little influence on the transformation of 1i (eq 1), suggesting that a radical or single-electron-transfer (SET) process was unlikely in this transformation. The radical clock experiment of olefin 790 gave the difunctionalization product 8 rather than the ring-opening product 9 (eq 2), which also ruled out the possibility of a radical pathway. ((eq 1)) ((eq 2)) Based on previous reports on MeNO2-stablized carbocations,91 we proposed the mechanism of the transformation of heteroarenes and styrenes (Figure 3). The reaction was initiated through an electrophilic addition process with MeNO2-activated Selectfluor/NFSI A to give the MeNO2-stablized cationic intermediate B. Then species B was attacked by a nucleophile (e.g., NaN3, H2O, TsNH2 or ROH) to afford the desired fluorofunctionalizated product ( 2, 3, or 4). Figure 3 | Proposed mechanism for fluorofunctionalization of styrenes. Download figure Download PowerPoint Experimental Methods Experimental Methods are available in the Supporting Information. Conclusion We have demonstrated that MeNO2 is a key promoter of fluorination reactions. The mechanistic studies revealed a cationic process in which MeNO2 played multiple roles as an efficient Lewis base to activate electrophilic fluorinating reagents, an excellent stabilizer of the carbocation, and the solvent. The fluoroazidation, fluoroamination, fluorohydroxylation, and fluoroesterification of styrenes, as well as the C–H fluorination of various (hetero)arenes, were achieved efficiently for the synthesis of organofluorides under mild reaction conditions. This novel fluorination method might offer new opportunities for the development of fluorination reactions. Supporting Information Supporting Information is available and includes experimental procedures and compound characterization data. Conflict of Interest There is no conflict of interest to report. Acknowledgments The authors wish to acknowledge Yachong Wang in this group for reproducing the results of 2 m, 3 g, and 3 f. 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A.; J. of the of on and Chem. Soc. Google Scholar Information Chinese authors wish to acknowledge Yachong Wang in this group for reproducing the results of 2 m, 3 g, and 3 f. This research was made possible as a result of a generous grant from the National Natural Science Foundation of China (nos. 21871011, 21602005, 21632001, and 21772002), the Drug Innovation Major Project (2018ZX09711-001), and the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (grant no. KF-GN-201906).